text:
Original article

Identification and molecular characterisation of Lausanne Institutional Biobank participants with familial hypercholesterolaemia – a proof-of-concept study

DOI: https://doi.org/10.4414/smw.2016.14326
Publication Date: 06.08.2016
Swiss Med Wkly. 2016;146:w14326

Fabienne Maurera, Sylvain Pradervandb,c, Isabelle Guilleretb, David Nanchend, Ali Maghraouib, Laurence Chapatteb, Karolina Bojkowskac, Zahurul Alam Bhuiyana, Nathalie Jacquemontb, Keith Harshmanc, Vincent Moosera,b,e

a Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland
b Service of Clinical Research Support, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland
c Genomic Technologies Facility, Centre for Integrative Genomics, University of Lausanne, Switzerland
d Department of Ambulatory Care and Community Medicine, University of Lausanne, Switzerland
e Service of Biomedicine, Department of Laboratories, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland

AIMS: We aimed to identify familial hypercholesterolaemia mutation carriers among participants to the Lausanne Institutional Biobank (BIL). Our experimental workflow was designed as a proof-of-concept demonstration of the resources and services provided by our integrated institutional clinical research support platform.

METHODS: Familial hypercholesterolaemia was used as a model of a relatively common yet often underdiagnosed and inadequately treated Mendelian disease. Clinical and laboratory information was extracted from electronic hospital records. Patients were selected using elevated plasma cholesterol levels (total cholesterol ≥7.5 mM or low-density lipoprotein cholesterol ≥5 mM), premature coronary artery disease status and age (18–60 yr) as main inclusion criteria. LDLR, APOB and PCSK9 were analysed by high-throughput DNA sequencing. The most relevant mutations were confirmed by Sanger sequencing.

RESULTS: Of 23 737 patients contacted by the BIL, 17 760 individuals consented to participate and 13 094 wished to be recontacted if there were findings requiring clinical action. Plasma cholesterol records were available for 5111 participants, of whom 94 were selected for genetic screening. Twenty-five of the tested patients presented with premature coronary artery disease while 69 had no such diagnosis. Seven heterozygous carriers of eight rare coding missense variants were identified. Three mutations were pathogenic (APOB p.R3527Q) or likely pathogenic (LDLR p.C27W, LDLR p.P526S) for hypercholesterolaemia, while the others were either benign or of unknown significance. One patient was a double heterozygote for variants APOB p.R3527Q and LDLR p.P526S.

CONCLUSION: This work illustrates how clinical and translational research can benefit from a dedicated platform integrating both a hospital-based biobank and a data support team.

Key words: familial hypercholesterolaemia; Lausanne Institutional Biobank; genomic medicine

Introduction and background

The PSRC, a centralised support hub for translational research and genomic medicine

In 2013, the Centre Hospitalier Universitaire Vaudois (CHUV) and the University of Lausanne (UNIL) launched the Lausanne Institutional Biobank (BIL), a repository of biological samples and hospital records collected from CHUV patients. This facility is dedicated to research and, ultimately, genomic medicine [1]. In 2015, in partnership with competence centres based in Lausanne, in particular VITAL-IT, the high performance computing centre of the Swiss Institute of Bioinformatics (SIB), the Genomic Technologies Facility (GTF) of UNIL and the information security ISC-GE laboratory of EPFL, the Institutions further established an integrated in-house clinical research support platform, the PSRC. The platform combines expertise covering medical, scientific, regulatory, bioinformatic and technical specialties. Its mission is to provide in-house support to clinical research, with a primary focus on clinical monitoring, clinical trials, regulatory affairs, pre-analytics, information technology (IT) and bioinformatics. It is further responsible for collecting general consent forms signed by CHUV patients, providing assistance in the recruitment of clinical trial and research study participants, informing about clinical research activities conducted within the Institution, supervising the collection, storage and management of biological samples for the BIL, providing support to other institutional biobanks, and providing local researchers with secured access to coded medical data and information.

Familial hypercholesterolaemia as a model disease

Familial hypercholsterolaemia (FH) was selected as a generic model of genetic disease that matched our needs for a proof-of-concept study. FH is relatively common, autosomal dominant and of limited genetic complexity [2]. Depending on ethnicity, its frequency ranges from 1:500 to 1:200 heterozygous and around 1:1000000 homozygous affected carriers in the general population [3, 4]. In most cases, a single pathogenic variant is involved, primarily affecting one of three genes: LDLR (60–80% of the cases), APOB (1–5%), and PCSK9 (up to 3%). De novo mutations and mutations in other genes have been described, yet remain rare. Oligogenic or polygenic forms have been observed too. Although the number of implicated genes is limited, the diversity of the underlying variants is broad, with over 1500 variants documented for LDLR [5]. Disease penetrance is high (90–100%), but expressivity varies depending on the nature of the mutation [6].

The clinical significance of FH is well established. Male carriers are at ≈50% risk of experiencing a major cardiovascular insult before the age of 55 and females at ≈30% before that of 60 [3]. These percentages are up to twenty-fold higher than in subjects not carrying a mutation and add on to classical risk factors for cardiovascular disease, typically obesity, hypertension, diabetes, smoking and sedentariness [3, 7]. FH is clinically actionable: well-tolerated statins and other lipid-lowering compounds allow for first-line preventive and therapeutic management, altogether contributing to an up to two-fold reduction in cardiovascular risk [8, 9]. However, although effective, these regimens are often insufficient to achieve recommended low-density lipoprotein cholesterol (LDL-C) goals in affected subjects. Owing to their marked potency at further reducing plasma LDL-C in patients receiving maximally tolerated statin therapy, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors recently emerged as a promising novel class of biological agents capable of minimising residual cardiovascular risk [9–12].

Whereas genetic testing is essential to confirm the clinical diagnosis of FH, it is neither routinely performed nor reimbursed by the Swiss healthcare system. In the absence of any dedicated screening programme, the percentage of undiagnosed FH carriers likely exceeds 80% in this country [8]. In practice, diagnosis essentially rests on the calculation of clinical risk scores pertaining to criteria of personal or familial history of premature cardiovascular disease, elevated levels of blood cholesterol – in particular LDL-C – and lipid (cholesterol) deposits around tendons [6, 8]. Assessing those scores in a multicentre, Switzerland-based cohort of 4478 participants, Nanchen et al. recently estimated that up to 50% of those hospitalised for premature acute coronary syndrome (ACS), defined as ACS affecting males before the age of 55 and females before the age of 60, presented with a possible, probable or definite risk for FH [13]. While those results still need genetic confirmation, unpublished analyses of longitudinal CoLaus [14] data further indicate that >60% of adults with a clinical diagnosis of possible FH are inappropriately treated over 5 years of follow-up (Nanchen et al. personal communication 2015). Taken together, these observations highlight the patent need for improved clinical management and guidelines for FH in Switzerland.

LDLR or APOB mutations are detected in approximately 60% of patients with a definite risk for FH and in 20 to 30% of those with a possible risk [15]. Accordingly, the likelihood of carrying pathogenic mutations in FH genes strongly correlates with LDL-C levels. Circulating concentrations of total and LDL cholesterol in heterozygous FH patients typically range from 9–14 mM and 5–10 mM, respectively, reaching up to 17–26 mM and >15.5 mM in homozygous patients [6]. Interestingly, using extreme values of total cholesterol as sole stratification criterion for genetic testing is sufficient to enrich for LDLR mutation carrier detection [16]. Since blood values of (mainly total) cholesterol are routinely monitored at the CHUV, we reasoned that the number of BIL participants with documented cholesterol measurements would be high, and that these data would be easily retrievable from the corresponding hospital records.

For the reasons listed above, FH was an optimal model to test the procedures and support provided by the PSRC.

Materials and methods

Clinical and laboratory data extraction

All data and biological samples relate to BIL participants who signed the general consent for clinical research (for additional details, see [1]). Data extraction and crossing through clinical and/or personal information were performed by authorised personnel of the Institution, following secured procedures validated by the Institution. The following categories of information were extracted and the results were provided to the researchers in the form of independent lists of coded or anonymised data, depending on the nature of each item:

‒ general information: date of birth, gender, body weight, height, date(s) of hospital stay(s);

‒ laboratory values spanning years 2004 to 2014, each with the corresponding date of measurement: LDL-C and TC for 5111 participants; triglycerides (TG), creatinine, glycaemia, thyroid stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4) for the set of 94 selected patients;

‒ prescriptions of statin(s) and/or other lipid-lowering therapies at time of hospitalisation and/or during hospital stay: name, type, dose, date of prescription;

‒ International Classification of Diseases (ICD10) diagnostic codes for any of the following: CAD or ACS, diabetes, stroke, peripheral arterial disease, acquired immunodeficiency syndrome (AIDS), nephrotic syndrome, renal failure, dialysis, alcohol dependence, hyperglycaemia, hypothyroidism.

Patients positive for human immunodeficiency virus (HIV), nephrotic syndrome, renal failure or a prescription for dialysis, or for whom the quality of genomic DNA did not comply with high throughput DNA sequencing requirements were excluded from further analyses.

Purification of genomic DNA

Genomic DNA was extracted by LGC Genomics, Hoddesdon (UK), starting from frozen buffy coat collected from EDTA-blood samples. Procedures complied with good laboratory practice (GLP). DNA quantities and qualities were verified at the Genomic Technologies Facility (GTF) of UNIL, using the Nanodrop (Thermo Scientific) and Fragment Analyzer (Advanced Analytical) systems.

High-throughput DNA sequencing

The ADH MASTR v2 kit (Multiplicom), an amplicon-based gene panel targeting all exons, 5’UTRs and 300 to 500 base-pair promoter regions of LDLR, PCSK9 and APOE, together with exon 26 of APOB was used for high throughput DNA sequencing (supplementary table 2). An additional 12 common single nucleotide polymorphisms (SNPs) are included in the assay, allowing for polygenic risk score calculation for FH [34]. Library preparation and 250 nucleotide paired-end sequencing on the Illumina MiSeq system were performed at the GTF, closely following the recommendations of the supplier. Ten samples were tested in a pilot phase and 84 were multiplexed in a second, larger assay.

Approximately 2×20 mio sequencing reads were produced in each run. Illumina software was used for base-calling and demultiplexing on the MiSeq instrument. Given its link with Alzheimer’s disease, APOE was masked from downstream analyses, while in absence of control patients, polygenic risk scores were not assessed.

The variant calling workflow consisted of a set of standard open source tools [35]. The main steps were: (1) trimming of low-quality bases and sequencing adapters at read ends using FastqMcf; (2) sequencing read mapping onto the human reference genome (hg19) using BWA-MEM [36]; (3) local realignment around small insertions/deletions using GATK; (4) base quality score recalibration using GATK; (5) removal of polymerase chain reaction (PCR) primers using a custom Perl script; (6) variant calling using the GATK unified genotyper tool; and (7) removal of low-quality variants. At the end of the process, variant call format (VCF) files were imported into Annovar (wannovar.usc.edu) to annotate variants. The most relevant annotations for variant assessment include those of ClinVar ( http://www.ncbi.nlm.nih.gov/clinvar ), OMIM ( http://www.omim.org /), LOVD ( http://www.lovd.nl ), HGMD public ( http://www.hgmd.cf.ac.uk ), ExAC (exac.broadinstitute.org), dbSNP ( http://www.ncbi.nlm.nih.gov/SNP ), 1000 genomes ( http://www.1000genomes.org ) and EVS (evs.gs.washington.edu) databases and servers. The full list of annotation databases is available at annovar.openbioinformatics.org/en/latest/user-guide/download/.

Confirmatory Sanger sequencing

Genomic fragments covering LDLR and APOB variants were amplified by touch-down PCR using specific primers (Microsynth). For APOB p.R3527Q: 5’-GAGTCATCTACCAAAGGAGATG-3’ and 5’-TGCTCCCAGAG-GGAATATATGC-3’; for LDLR p.C27W: 5’-GACTGTTCCTGATCGGATGAC-3’ and 5’-TCTCCTGGGACTCATCAGAGC-3’; for LDLR p.P526S: 5’-CAGAGGCTGAGGCTGCAGTGG-3’ and 5’-GTGAGACATTGTCACTATCTCC-3’; and for LDLR p.V736I: 5’-CTGTGGACTGGATCCACAGC-3’ and 5’-CACTAACCAGTTCCTGAAGC-3’. PCR conditions consisted of 3 min denaturation at 94°C, 46 cycles of 1 min denaturation at 94°C, 1 min annealing at progressively lower temperatures (i.e. starting from 1 cycle at 68°C, followed by 2 cycles at 66°C, 3 cycles at 64°C, 4 cycles at 62°C, 5 cycles at 60°C, 6 cycles at 58°C and 25 cycles at 56°C), and 1 min elongation at 72°C, followed by a final extension of 10 min at 72°C. Bi-directional sequencing of the PCR-amplified genomic fragments was performed on an ABI 3500 sequencer (PE Biosystems) using standard methods.

Sample identity coding

Data storage management and confidentiality were provided by the PSRC information technology unit in close collaboration with the CHUV information systems department. In agreement with US Food and Drug Administration (FDA) [37], European Union (EU) [38] and Organization for Economic Collaboration and Development (OECD) [39] recommendations for privacy and security of genomic data, a double encoding procedure was used, where a coded identifier, different from the permanent patient identifier of the hospital, was assigned to each BIL participant, unique 2D-barcodes were assigned to each biological sample, and distinct unique identifiers were used for genetic data.

The protocol of the present study was submitted to the Research Ethics Committee of the Canton of Vaud (CER-VD, Lausanne, Switzerland) in June 2015 and granted authorisation on 21 August 2015. Protocol number: 273/15.

Figure 1
Selection scheme of 94 BIL participants for FH genetic testing and analysis workflow.
*As of April 26, 2015.
BIL = Lausanne Institutional Biobank; CAD = coronary artery disease; LDL-C = low-density lipoprotein cholesterol; PSRC = an integrated in-house clinical research support platform; TC = total cholesterol

Data extraction

At time of data extraction (26 April 2015), 23 737 CHUV patients had been contacted by the BIL and PSRC. Of the 17 760 (74.8%) consenting participants, 13 094 (73.7%) wished to be recontacted if there were findings requiring clinical action. For 5111 of the latter, a minimum of one plasma total cholesterol (TC) value could be extracted from electronic hospital records, spanning the years 2004 to 2014 (fig. 1). Among the 5111 patients, 2291 had also been tested at least once for LDL-C.

Figure 2
Mean amplicon coverage. Each bar corresponds to one of the 84 samples tested in the second sequencing run. Samples are ranked from the lowest to the highest fold-coverage value. Fold-coverage values of the first 10 samples ranged from 44 978 to 53 336 (data not shown).
Figure 3
Number of variants identified in each of the 94 patients for APOB, LDLR, and PCSK9. Each bar corresponds to a single sample.
Figure 4
Number of SNVs and indels identified in each of the 94 patients for APOB, LDLR, and PCSK9. Each bar corresponds to a single sample.
SNV = single nucleotide variant; indel = short insertion and/or deletion

Selection of a priority set of 94 patients

Given the 1:500 to 1:200 prevalence of FH in Switzerland, a sample of 5111 unselected patients was expected to include 10 to 25 FH mutation carriers. To enrich for those individuals in our selection procedure, we relied on criteria of elevated TC and/or LDL-C as well as young age (18–55 yr in males, 18–60 yr in females) and presence of premature coronary artery disease (CAD) at the time of cholesterol testing. Our initial intention was to select subjects presenting at least once with TC >8.5 mM, a cut-off suggested as clinically useful for the detection of FH by genetic testing [16]. Since only 41 such patients were retrieved, while up to 94 samples could be sequenced in parallel, we relaxed our inclusion criteria, ultimately prioritising subjects presenting either with (1) early CAD, and TC ≥7.5 mM or LDL-C ≥5 mM at least once, or (2) no CAD, but TC >7.7 mM or LDL-C ≥5 mM at least once, irrespective of treatment (fig. 1). A concentration of LDL-C ≥5 mM matches the minimum criterion for possible FH, as defined by the Dutch Lipid Clinic network [6]. Here, all patients presenting with at least one such value were selected. While treatment status was not considered for selection, retrospective inspection indicated that all subjects with at least one value of plasma LDL-C ≥4 mM when under statin(s) or lipid-lowering therapy were included.

Genetic testing

Genetic testing was performed by high throughput DNA sequencing of LDLR, APOB, and PCSK9 (see Methods). Resulting mean amplicon coverage was far above the usual requirements for germline sequencing, exceeding 4000-fold in almost all samples (fig. 2). Moreover, coverage uniformity was close to complete, with 100% of the targeted bases covered 30-fold or higher in 87 samples and >99.9% in the others. Overall, these results demonstrate excellent sequencing quality.

On average, 25 ± 3 (mean ± standard deviation) variants were detected in each patient (minimum 17, maximum 34; fig. 3). The vast majority were single nucleotide variants (SNVs) and the number of short insertions or deletions (indels) did not exceed three in any sample (fig. 4). Of the 84 distinct variants identified in total, 43 affected LDLR, 5 APOB and 36 PCSK9 (see appendix, supplementary table 1). According to the ExAC browser (http://exac.broadinstitute.org, version of July 2015), 23 SNVs were rare [i.e. occurring at global minor allele frequencies (MAF) <1% in the general population], while the others were common polymorphisms. Among the rare SNVs, eight coded for missense amino acids and five for synonymous variants, one was in a 3’UTR and nine were intronic (table 1).

None of the intronic variants was predicted to affect messenger RNA (mRNA) splicing (data not shown). Therefore, to identify likely causative mutations for FH, we restricted our investigations to low-frequency (MAF <1% in ExAC) missense coding variants. All of these heterozygous variants were documented in ExAC, indicating that none was novel.

We excluded two known SNVs from the list of candidates because of lack of evidence for a causal link with FH in the literature and/or databases relevant to FH (namely ClinVar [17], UCL [18], LOVD [5] and HGMD public [19]). The first one, PCSK9 p.A443T (rs28362263; genomic coordinates: chr1:55523855 G>A), is associated with reduced plasma LDL-C [20]. The second one, APOB p.Q3432E (rs1042023; genomic coordinates: chr2:21229446 G>C), was detected in four carriers and considered of low interest because of a lack of cosegregation with hypercholesterolaemia [21–24] and a classification as “likely benign for FH” in ClinVar.

Assessments of the remaining six missense coding variants were based on allele frequencies, predicted and/or experimentally demonstrated functional impact (focusing on predictive CADD scores of nonfunctionality [25] and on an extensive functional study of LDLR mutations [26]), and clinical relevance. Three variants were considered as pathogenic (APOB p.R3527Q) or likely pathogenic (LDLR p.C27W and LDLR p.P526S) for hypercholesterolaemia, whereas the others were of either uncertain or unknown significance (table 2). The most significant variants were verified by Sanger sequencing (fig. 5). Although the number of pathogenic mutation carriers was small, thus preventing further statistical demonstration, we note that LDL-C and TC plasma levels of patients 65 and 82 were among the highest values documented for the set of 94 high-cholesterol subjects, a trend expected to FH (fig. 6). In contrast, mean cholesterol levels of patients 39, 50 and 73, who carried potentially less damaging variants, were lower than the clinically relevant thresholds of 4.9 mM for LDL-C and 7.5 mM for TC.

Table 1: Types of genetic variants identified in the set of 94 selected patients.
Variants, all5453686
1. MAF(ExAC) ≤1%312  823
- SNVs312  823
- Coding3  6  413
- Non-synonymous2  5  1  8
- Nonsense   0  0  0
- Frameshift   0  0  0
- Upstream   0  0  0
- 3’UTR   0  1  1
- Intronic   6  3  9
- Indels   0  0  0
2. MAF(ExAC) = 1–2%   2  0  2
- Intronic   1  0  1
- ncRNA   1  0  1
MAF(ExAC): minor allele frequency as reported in the ExAC database; SNV = single nucleotide variant; UTR = untranslated region
Table 2: Details of the primary rare, missense, coding variants. Data are presented for five variant carriers, two females, three males. All of these patients were aged 18-60 yr at time of top cholesterol testing and presented with plasma triglyceride levels ≤2.2 mM.
 Patient 39Patient 50Patient 65Patient 73Patient 82
Variant(s)LDLR p.R595QLDLR p.G269DLDLR p.C27WLDLR p.V736I(1) APOB p.R3527Q

(2) LDLR p.P526S
Genomic coordinates19:11227613 G>A19:11217352 G>A19:11210912 C>T19:11233915 G>A(1) 2:21229160 C>T

(2) 19:11224428 C>T
dbSNP IDrs201102492rs143992984NA rs547268730(1) rs5742904;

(2) NA
MAF (ExAC)4.942×10–50.00021.65×10–52.475×10–5(1) 0.0002

(2) 1.66×10-5
CADD score [25]22.8 (high); see also [26]11.28 (moderate)16.97 (high)6.505 (low)(1) 19.81 (high)

(2) 20.1 (high)
LOVD/HGMD annotation and assertionFH, probably pathogenicFH, Rome alleleFH, San Francisco

NA(1) ApoB deficiency; cosegregates with ADH; is the most frequent mutation for FH/ADH

(2) FH, Cincinatti allele, reduced LDLR activity
CLINVAR assertionNot assertedUncertain significance for FHNot referencedNot referenced(1) Pathogenic, likely pathogenic for FH (see OMIM #107730 [40]; to be reported (ACMG, [31])

(2) Not asserted
Functional testing and clinical assertion by Thormaehlen et al. [26]Not disruptive; found in a patient with MI and in an unaffected control; pathogenic for MINot disruptive (see also [41]); found in a patient with MI; pathogenic for MINot testedNot tested(1) NA

(2) Disruptive; found in a patient with high LDL-C; pathogenic for high LDL-C
Confirmation by Sanger (fig. 5)NANAYESYES(1) YES

(2) YES
DiagnosticNo CADNo CADPremature CADPremature CADPremature CAD
ACMG: American college of medical genetics; HGMD: human gene mutation database; LLT: lipid-lowering therapy; NA: not applicable; LOVD: Leiden open (source) variation database.

The major finding of this work consists of the identification of seven carriers of rare, missense heterozygous coding variants in FH genes among 94 high-cholesterol participants in the BIL. Given the proof-of-concept nature of our study, these results are remarkable as they were obtained by applying a relatively crude analytical workflow, where laboratory and clinical data extracted from electronic hospital records of 5111 consenting participants were used to enrich for mutation carriers within a small test set of 94 selected individuals, and high-throughput DNA sequencing allowed for targeted genetic screening of the major FH genes.

Figure 5
Confirmatory Sanger sequencing. The most clinically relevant variants of patients 82 (panels A, B), 65 (panel C) and 73 (panel D) were confirmed by bidirectional Sanger sequencing. Each panel shows chromatograms of the forward (top) and reverse (bottom) sequencing reactions, together with the corresponding reference sequences on the (+) and (–) strands (hg19). The variants are boxed in grey on the chromatograms; the corresponding positions on the reference sequence are highlighted in red; the stretch of reference sequence shown in the respective chromatograms is in bold letters. APOB is coded by the (-) strand, LDLR is coded by the (+) strand.
fullscreen fullscreen
Figure 6
Cholesterol levels measured in carriers vs non carriers of rare, missense APOB and LDLR variants. Average LDL-C (panel A) and TC (panel B) levels were computed for each of the high-cholesterol patients tested by sequencing, irrespective of treatment. At least one value of LDL-C was available for 65 of the 94 subjects [n = 2 ± 4 data points per patient (mean ± SD)], while TC was measured at least once in all of them [n = 5 ± 6 data points per patient (mean ± SD)]. Data are presented as means ± standard error of the mean and are ranked from the lowest to the highest mean value. Data points referring to the carriers of pathogenic (patient #82) or likely pathogenic (patient #65) variants for FH are highlighted in red, while those referring to carriers of rare variants of unknown significance are highlighted in dark grey (patients #39, 73, and 50). The clinical thresholds of high LDL-C (4.9 mM) and TC (7.5 mM) are indicated by the green lines.
FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol

Given the prevalence of FH, an estimated 10 to 20 carriers of pathogenic mutations were expected. In reality, eight rare LDLR and/or APOB missense variants were identified, a number slightly below our predictions. Although presumably not reaching top performance in terms of sensitivity, our results compare well with the approximately 2% pathogenic mutation carriers identified by Norsworthy et al. upon testing a population of 193 hypercholesterolaemic primary care patients and applying selection criteria similar to ours [27]. Moreover, Futema et al. clearly demonstrated that using elevated cholesterol as the sole inclusion criterion for genetic testing was particularly efficient when considering extreme laboratory values (i.e. above 9 to 10 mM for TC), while specificity dropped quickly at lower levels, typically reaching less than 5% when applying relaxed thresholds of 7.5 to 7.7 mM TC, as was done here [16]. More recently, these observations were confirmed in the large study of Khera et al. who identified <2% FH mutation carriers in a cohort of 20 485 multiethnic participants presenting plasma LDL-C >4.9 mM [7]. Interestingly, this study also showed that, for a given LDL-C level in plasma, carriers of FH-causing mutations were at a much higher risk than noncarriers, providing strong support for the concept of adding genetic information when predicting CAD risk in suspected FH patients.

There are several explanations for suboptimal detection sensitivity. For the sake of simplicity, patient stratification and selection were performed regardless of treatment type and status, and no correction for age, gender or treatment was applied. Therefore, a number of mutation carriers may have escaped prioritisation, in particular those for whom cholesterol was monitored only in the presence of lipid-lowering treatment, reaching nominal values below 7.5 mM for TC and 4 mM for LDL-C. To improve detection efficiency, these data could be corrected for the type and intensity of therapy used [7, 28], but such a task was beyond our basic aims. A second limitation relates to the identification of (large) structural variants (SVs), which are not detected by amplicon-based sequencing. Also, while preliminary investigations did not point at copy number variants (CNVs) in our dataset (data not shown), we lacked proper positive controls to verify the reliability of those results. Further, one should keep in mind that a few genes other than LDLR, APOB, and PCSK9 are known to contribute to rare forms of FH [29, 30], but were not tested. And last, a few of the hypercholesterolaemic patients may be affected by oligo- or polygenic forms of FH, which we did not investigate.

Three of the rare APOB and LDLR variants comply with “pathogenic” or “likely pathogenic” clinical classifications [31]. Essentially based on existing variant annotations and published data, these assertions warrant further assessment and clinical validation by a panel of expert reviewers. Tentative scoring of the rare variant carriers using the data in table 2 and the criteria of the Dutch Lipid Clinic network [6] tend to suggest that patients 65 and 82, who carry the most damaging mutations, suffered stronger clinical manifestations than subjects 39, 50 and 73 (data not shown). In the absence of more comprehensive information, complementary clinical investigations will be necessary to confirm risk scoring and diagnosis. Nonetheless, our results provide important insights into information feedback to research study participants, a process formally supported by the general consent of the BIL [1]. Of note, the design of an appropriate feedback procedure will be the task of a dedicated working group, whose conclusions and recommendations will be the topic of a separate report.

Linking data derived from electronic hospital records to biological samples stored in biobanks such as the BIL enables cost- and time-effective research. According to comparisons with more traditional approaches, the total time and study cost necessary to recruit a cohort of a few hundred participants, phenotype each subject, collect biological specimens and proceed to genotyping can be reduced by up to 8- and 15-fold, respectively [32]. In a large biobank like the BIL, storage of biological specimens is often restricted to a small array of samples, typically DNA and plasma. However, the principle of the general consent [1] makes it possible to recontact consenting participants, thereby enabling subsequent enrichment with additional specimens and/or clinical data. These benefits may be amplified further by pooling analyses across collaborative networks, leading to an increase in sample sizes and minimisation of biases [33]. Networks will be instrumental in investigating rare diseases and/or rare variants, screening for specific variant carriers in larger pools of samples, crossing or replicating results with information gained in independent cohorts, or accessing complementary information or samples from other repositories. As recognised earlier, strong support structures will be necessary to streamline efficient and effective communication and management among the research teams and networks involved [32].

At the local level, the present study illustrates the capabilities of the PSRC and its partners to provide efficient assistance and support to research centered on genomic medicine, in particular for the recruitment of consenting patients, the secured management of high-quality biological samples and medical data, and the generation and analysis of genetic profiles. To address similar needs, and also to ascertain research quality and interconnectedness across biobanks at the national level, the Swiss National Science Foundation, the Swiss Academy of Medical Sciences (SAMS) and a dedicated Project Group recently launched the Swiss Biobanking Platform (SBP; http://www.swissbiobanking.ch/). The mission of the SBP will be to develop a reliable customer-oriented network across Swiss biobanks, with harmonised processes for general information and consent, pre-analytical sample processing and storage, laboratory informatics management systems, data storage and confidentiality, annotation of samples and data, traceability, access and distribution of samples and data to researchers, support to investigators and biobank sustainability.

Supplementary tables http://www.smw.ch/fileadmin/smw/pdf/SMW-14326-Appendix.pdf

Acknowledgements: We thank Drs Grégoire Würzner, Cindy Roth and Christine Currat for helpful discussions and insights during the preparation and realization of the project, and Fady Fares, Didier Foretay, Farid Ahmad and Sébastien Rocher for technical assistance.

Disclosure statement:The FH-BIL project was supported by Foundation SOLIS, Switzerland; administrators: Kostenbaum and associates, 10 Cours de Rive, CP 3397, 1211 Geneva 3, Switzerland.

Correspondence: Fabienne Maurer, PhD, Service of medical genetics, CHUV, Rue du Bugnon 27, CH-1005 Lausanne, fabienne.maurer[at]chuv.ch

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  8 Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478–90a.

  9 Reiner Z. Management of patients with familial hypercholesterolaemia. Nat Rev Cardiol. 2015;12(10):565–75.

10 Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500–9.

11 Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489–99.

12 Ballantyne CM, Neutel J, Cropp A, Duggan W, Wang EQ, Plowchalk D, et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am J Cardiol. 2015;115(9):1212–21.

13 Nanchen D, Gencer B, Auer R, Raber L, Stefanini GG, Klingenberg R, et al. Prevalence and management of familial hypercholesterolaemia in patients with acute coronary syndromes. Eur Heart J. 2015;36(36):2438–45.

14 Firmann M, Mayor V, Vidal PM, Bochud M, Pecoud A, Hayoz D, et al. The CoLaus study: a population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome. BMC Cardiovasc Disord. 2008;8:6.

15 Damgaard D, Larsen ML, Nissen PH, Jensen JM, Jensen HK, Soerensen VR, et al. The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population. Atherosclerosis. 2005;180(1):155–60.

16 Futema M, Kumari M, Boustred C, Kivimaki M, Humphries SE. Would raising the total cholesterol diagnostic cut-off from 7.5 mmol/L to 9.3 mmol/L improve detection rate of patients with monogenic familial hypercholesterolaemia? Atherosclerosis. 2015;239(2):295–8.

17 Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42(Database issue):D980–5.

18 Leigh SE, Foster AH, Whittall RA, Hubbart CS, Humphries SE. Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. Ann Hum Genet. 2008;72(Pt 4):485–98.

19 Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014;133(1):1–9.

20 Kotowski IK, Pertsemlidis A, Luke A, Cooper RS, Vega GL, Cohen JC, et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet. 2006;78(3):410–22.

21 Gaffney D, Hoffs MS, Cameron IM, Stewart G, O’Reilly DS, Packard CJ. Influence of polymorphism Q3405E and mutation A3371V in the apolipoprotein B gene on LDL receptor binding. Atherosclerosis. 1998;137(1):167–74.

22 Pullinger CR, Love JA, Liu W, Hennessy LK, Ghassemzadeh M, Newcomb KC, et al. The apolipoprotein B Q3405E polymorphism has no effect on its low-density-lipoprotein receptor binding affinity. Hum Genet. 1996;98(6):678–80.

23 Ludwig EH, Hopkins PN, Allen A, Wu LL, Williams RR, Anderson JL, et al. Association of genetic variations in apolipoprotein B with hypercholesterolemia, coronary artery disease, and receptor binding of low density lipoproteins. J Lipid Res. 1997;38(7):1361–73.

24 Leren TP, Bakken KS, Hoel V, Hjermann I, Berg K. Screening for mutations of the apolipoprotein B gene causing hypocholesterolemia. Hum Genet. 1998;102(1):44–9.

25 Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310–5.

26 Thormaehlen AS, Schuberth C, Won HH, Blattmann P, Joggerst-Thomalla B, Theiss S, et al. Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction. PLoS Genet. 2015;11(2):e1004855.

27 Norsworthy PJ, Vandrovcova J, Thomas ER, Campbell A, Kerr SM, Biggs J, et al. Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing: a population-based study. BMC Med Genet. 2014;15:70.

28 Fouchier SW, Hutten BA, and Defesche JC. Current novel-gene-finding strategy for autosomal-dominant hypercholesterolaemia needs refinement. J Med Genet. 2015;52(2):80–4.

29 Hegele RA, Ban MR, Cao H, McIntyre AD, Robinson JF, Wang J. Targeted next-generation sequencing in monogenic dyslipidemias. Curr Opin Lipidol. 2015;26(2):103–13.

30 Stitziel NO, Peloso GM, Abifadel M, Cefalu AB, Fouchier S, Motazacker MM, et al. Exome sequencing in suspected monogenic dyslipidemias. Circ Cardiovasc Genet. 2015;8(2):343–50.

31 Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.

32 Bowton E, Field JR, Wang S, Schildcrout JS, Van Driest SL, Delaney JT, et al. Biobanks and electronic medical records: enabling cost-effective research. Sci Transl Med. 2014;6(234):234cm3.

33 Ioannidis JP, Trikalinos TA, Khoury MJ. Implications of small effect sizes of individual genetic variants on the design and interpretation of genetic association studies of complex diseases. Am J Epidemiol. 2006;164(7):609–14.

34 Talmud PJ, Shah S, Whittall R, Futema M, Howard P, Cooper JA, et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet. 2013;381(9874):1293–301.

35 DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43(5):491–8.

36 Li H and Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754–60.

37 FDA. E15 definitions for genomic biomarkers, pharmacogenomics, pharmacogenetics, genomic data and sample coding categories. 2008.

38 EU. Proposal for a regulation of the European Parliament and of the Council on the protection of individuals with regard to the processing of personal data and on the free movement of such data; General data protection regulation. 2015.

39 OECD. OECD guidelines on human biobanks and genetic research databases recommendations for data privacy and security. 2009.

40 Online Mendelian Inheritance in Man, OMIM®. 2011, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University: Baltimore, MD.

41 Etxebarria A, Palacios L, Stef M, Tejedor D, Uribe KB, Oleaga A, et al. Functional characterization of splicing and ligand-binding domain variants in the LDL receptor. Hum Mutat. 2012;33(1):232–43.

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Scott Schultz of WAXX 104.5 and WAYY joins Hello Wisconsin to talk about Wisconsin losing dairy farms and the latest in Ag news. [Read More]
They have a record number of entries this year with 3,667 dairy products entered into the World Championship Cheese Contest. [Read More]
Boys basketball action as North hosts River Falls, Durand takes on Fall Creek and Immanuel faces Boyceville. [Read More]
Two members of the Eau Claire City Council want to give people another option to travel beyond western Wisconsin. [Read More]
A new program aims to help people with addictions get the help they need, before they enter the judicial system. [Read More]
Both vehicles involved in a Buffalo County battery investigation are located and in possession of the sheriff's office. [Read More]
Tracy Cadogan was arrested by state patrol last Friday after a traffic stop found more than 25 grams of marijuana in her vehicle, according to... [Read More]
Those with two-year degrees in human services or a related field can earn a Bachelor of Science degree in social work in four to five... [Read More]
A Wisconsin man has been found guilty of second degree reckless homicide in August was granted a new trial that began Monday. [Read More]
Gov. Tony Evers has selected a brigadier general in the U.S. Air Force reserves to take over as commander of the Wisconsin National Guard. [Read More]
The Lake Hallie Police Department is asking for the public's help in identifying the people in the photo regarding a theft/fraud investigation. [Read More]
The Chippewa-Eau Claire Beekeepers Club holding Beekeeping 101 class at Beaver Creek Reserve. [Read More]
A UW-Stout assistant professor of History, Le'Trice D. Donaldson, has published a book about African American soldiers. [Read More]
Congratulations to Sam Davey School Secretary Jean Derfus for being honored with the Golden Apple! [Read More]
The La Crosse Police Department is asking for help from the public in locating James Zaragoza for a welfare check. [Read More]
The man accused of defrauding 83 farmers is scheduled to reach a plea deal in the case in April 20. [Read More]
Polk County Sheriff's Department says that alcohol is believed to be a contributing factor in a Polk County fatal crash that happened Sunday, Feb. 23... [Read More]
The Stanley Police Department says one adult male and a pet cat were found dead inside a home after a fire. [Read More]
The University of Wisconsin- Eau Claire Chancellor James Schmidt says Vice Chancellor Albert Colom will be stepping down effective immediately. [Read More]
This year's event features raffles for great prizes including 50/50 cash raffles and attendance prize drawings will take place throughout evening. [Read More]
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14.245.050 Sign Permit – Historic District.
This section is included in your selections.

For signs within the Historic District, no permit for the erection of a sign shall be issued pursuant to this chapter until the permit applicant has complied with the permit and approval requirements of Chapter 14.225 SMC.


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About Us

The Malaysian Sikh Youth Organisation (Sikh Naujawan Sabha Malaysia) is a voluntary organisation which was officially formed in 1967. What began as a small regional organisation, has today transcended into a body with national concerns and links. SNSM is focussed on missionary activities and the Sikh community through the spread of the Guru’s Way. Over the years, SNSM has successfully become the bloodline of Malaysian Sikh youth.

Sikh Naujawan Sabha Malaysia (SNSM) organises various religious, social and cultural programmes throughout Malaysia. It is also in tune with various other organisations directly or indirectly involved within the Sikh World. Regular activities of SNSM include :-

  • Welfare projects.
  • Educational programmes.
  • Operating a Sikh reference bookshop.
  • Setting up youth prayer sessions in the country.
  • Continuous missionary activities all over the nation.
  • Organisation of youth leadership and training camps.
  • Representation of Sikh youth at governmental and other national forums.
  • Publication of quarterly publication “The Sikh”, monthly newsletters, monthly e-newsletters and other pamphlets or articles for distribution.
  • Programmes for spiritual, mental, social, physical and emotional development of youth and children.
  • Annual religious seminar (every December) to provide for Sikh youths in Malaysia and overseas to be together.


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Posts Tagged ‘socialism’

Something of a debate is afoot: Are nuclear families a good idea? Do they work in 21st Century America?

David Brooks, in a provocatively-titled Atlantic Magazine piece, argues that “The Nuclear Family Was a Mistake“. He recognizes the utility of the extended family, which predates the nuclear variety, but points out that “while extended families have strengths, they can also be exhausting and stifling.” Conversely, he observes, “family, once a dense cluster of many siblings and extended kin, fragmented into ever smaller and more fragile forms. The initial result of that fragmentation, the nuclear family, didn’t seem so bad. But then, because the nuclear family is so brittle, the fragmentation continued. In many sectors of society, nuclear families fragmented into single-parent families, single-parent families into chaotic families or no families.”

Brooks goes on to argue in favor of “forged families” — meaning people who voluntarily adopt the roles of extended family even though they are not biologically related. Brooks’ piece, while a worthy read, raises more questions than answers. For one, it not typically left to conservatives to fret over the state of American families? What would prompt a liberal journalist, however obliquely, to critique the adverse impacts individualism has had on society?

And why now?

While I was mulling this question over, I decided to revisit aspects of history I am not old enough to personally recall but studied in college. I watched the Amazon Prime documentary “She’s Beautiful When She’s Angry“.

While there is great value in the first-person recollections of the women who helped raise the nation’s consciousness in the 1960s and 1970s, I am struck by a question only a post-baby boomer would likely ask: In an era dominated by Greatest Generation Americans, how did a movement of this kind achieve critical mass — particularly in an era dominated by an FCC-mandated fairness doctrine and devoid of social media? This, of course, begs another question: Are we correct to attribute the second-wave women’s liberation movement to entirely organic (spontaneous) causes? The documentary acknowledges, for example, that J. Edgar Hoover planted informants in women’s consciousness-raising groups. What is less clear is at what stage government involvement occurred. That matters because the “when” and the “why” may very well be informed by a history we have yet to fully account for. (To that end, the documentary scarcely touches upon Gloria Steinem’s pivotal role in the feminist movement or her self-admitted associations with a CIA front group.)

It is said that history is written by the victors. In this case, the victors consist of self-described student radicals, most of whom are well into their Golden Years. But there’s another history this documentary doesn’t touch upon; namely, that of the post-World War II period, the Cold War and the Vietnam era. It’s a glaring omission that that circumscribes this documentary to the anecdotal recollections of long-ago activists. (Although in fairness, this may have been the producer’s intent.)

It cannot be stressed enough that the Cold War, which also encompassed the Vietnam war, was not merely an arms race or a tale of two competing ideologies. The stakes were far higher: freedom vs. tyranny; mutually-assured destruction vs. prosperity; patriotism vs. sedition. However it is remembered, it was also a time of, by and for policymakers — men! — of the era. When President Nixon vetoed a bill in 1971 that would have granted the pro-family policies the women’s liberation movement championed, his explanation reflects Cold War chauvinism as much as it reflects upon stereotypical gender-role expectations of the time. Similarly, the contrasting roles of Soviet and American women, for as genuine as they may have been, appear to have been propagandist ploys as much as anything.

If this kind of bravado occurred in the open, what kind of behind-the-scenes social engineering efforts went into assuring American cooperation on the home front?

In the documentary, a leader of the 1960s women’s movement relates — still with an apparent sense of awe — that women’s consciousness groups arose “spontaneously” around the country. For a country that was still decades removed from social media, is this not curious? Is there any research to suggest that the timeline of government efforts to monitor, if not influence, activist groups occurred well after such movements caught on? Has anyone within the journalism sphere, for that matter, pursued Freedom Of Information Act requests to explore whether the timing of this intrusion into the women’s movement took place well after-the-fact as opposed to serving as a more direct, if not lesser-appreciated, influence?

In my own way of thinking, having come of age during the 1980s at the height of the crack epidemic, yuppie culture, latchkey kid debates, urban gang proliferation and the nuclear arms race, my sense is that early second-wave activists who credit themselves with continuing where Suffrage left off seem to miss the fact that, far from being non-beneficiaries of women’s liberation, men — and more specifically the federal government— were working to advance one overarching goal: Proving that the United States, and by extension Capitalism, was superior to that of the U.S.S.R. (Communism).

While political leaders of the era may have continued to pay lip-service to the traditional roles of women, it had become something of an encumbrance. The Soviets actively worked to project cosmopolitan values, in which female labor was a man’s equal (or so the propaganda maintained). Soviet women’s children were supported by collectivist programs even as American women and children were not. Machismo undoubtedly shaped American foreign policy — which dovetailed with some aspects of the women’s liberation movement even as other aspects, such as universal childcare, flounder to this very day. The thinking may very well have been — if not explicitly, tacitly — that while less robust Soviet citizens might require Marxist concessions to secure their cooperation, Capitalists are a tougher, more independent, patriotic and industrious lot. This would explain why aspects of the women’s liberation movement, such as labor force participation, succeeded in changing expectations and norms, whereas efforts to confront domestic inequality and to alleviate burdens that continue to fall disproportionately upon women largely failed.

The support garnered in 2016 and 2020 by a self-professed democratic socialist, presidential candidate and Vermont Sen. Bernie Sanders, reveals not just a desperation to unseat the current president, but a declining belief in the merits of Capitalism. College-age women today still envision for themselves what women of the 1960s and beyond sought: liberation. To a Millennial generation disproportionately raised by single and/or overworked parents, equality may not look like the gender-defined domestic roles one’s grandmother or great grandmother shouldered, a lifetime of student loan debt servitude or the seductive, if not disingenuous, women-can-have-it-all messaging of the 1970s, ’80s and ’90s (loving marriage, fulfilling career and quality, if not quantity, time with the kids). If hindsight is 20/20, women’s liberation, particularly in less affluent households, became a woman’s obligation as family breadwinner — not merely by choice but by economic necessity — contrasted to a man’s license to walk away. The result is that women are often left to juggle responsibilities they have been tasked with for hundreds, if not thousands of years, on the one hand, and the added obligation to demonstrate their worth to kin and country, alike, in a monetized manner, on the other.

Is this the “choice” our liberation-minded trailblazers promised?

With the exception of the affluent, who can readily hire the help they need to strike a better work-life balance, middle class and working class women have been sold a bill of goods about “having it all” when, in reality, something was bound give: the career; the marriage; non-work friendships; waning influence over the values of one’s own over-scheduled children; and, in the end, support for the nuclear family — if not Capitalism itself.

Conservatives have long decried the unraveling of the nuclear family, and in some ways their worst fears have been realized over the past 60-some years: By the 1980s, self-medicating yuppies and their latchkey adolescents were fueling a demand for recreational drugs; gangs overtook the inner cities to deal to users — while disproportionately maiming and killing each other in the ensuing turf wars; addicts dropped out of the workforce and/or began to commit crimes in support of their addictions, contributing to a still-proliferating homelessness crisis; violent crime rates hit new highs in the 1980s and 1990s, divorce rates climbed and, in a mea culpa that is just now beginning to make the rounds, Brooks’ assertion that the nuclear family was a mistake. Is this chain of superficially-unrelated events purely a fluke? Or is it possible that Hoover’s FBI was involved not merely in an effort to suppress the women’s movement of the 1960s and ’70s, as is commonly believed, but to exploit aspects of the movement as a means to gain the upper hand in the Cold War?

The fact is, the U.S. was left with a sky-high bill for the cost of rebuilding Europe after WWII, and subsequently for its commitment to NATO. To this we add the Cold War and an even costlier nuclear arms buildup — which was joined by fears of ballooning deficits. In the span of only a few decades, the United States went from an isolationist foreign policy to one of unprecedented global responsibility, which demanded two things: rapid economic growth and an increase in the tax base (meaning more working-age adults in the labor market, both male and female, by which to bankroll our national security interests). Fast forward to the 21st Century, and women and children are still lacking in access to affordable childcare, healthcare and other quality (or equality) of life indicators one might expect to find in a First World country.

Against this backdrop, is it any surprise that the Millennial generation is inclined to believe that the only way to achieve a work-life balance is to renounce the Capitalist system their mothers and grandmothers worked so hard to participate in? Similarly, might falling marriage and birthrates among Millennials, first noted among Generation-X, who were themselves less financially secure than their parents, explain why politicians increasingly condemn efforts to distinguish between legal and illegal immigration? Do our leaders genuinely believe unsecured borders pose no terrorism risk or that limits to immigration carry xenophobic overtones — or is it the case, rather, that our deficit-riddled federal government would rather rely on climate-endangering “pyramid scheme migration” than to implement family-supportive policies similar to those applied by our socialist counterparts to forestall precipitous demographic declines?

If these observations are in any way prescient, they illustrate one of the most ironic, if not tragic, developments in the entirety of our Great Experiment: whereas the Soviet Union disbanded into a quasi-Capitalist Russian state, Americans are increasingly inclined to romanticize the greener grass on the other side of the socialist fence. To bring this full circle, we must ask a fundamental question: How historically certain are we that the women’s liberation movement of the 1960s and ’70s was entirely grassroots in nature? Is it possible the U.S. government’s effort to win the Cold War were so all-encompassing that it motivated policymakers — who were still largely answerable to traditional values-driven voters — to disavow their role in social engineering efforts that may have been perceived as too radical to endorse outright? Could this explain, in turn, why Steinem — who at the face of it might have been expected to be at odds with a male-dominated, hierarchical government — later said of her relationship to the CIA, “In my experience The Agency was completely different from its image; it was liberal, nonviolent and honorable.”?

To reflect upon Steinem’s own words, perhaps aspects of the radicalism-driven image of civil rights we hold today are completely different from the Cold War-combating cooperation that existed in those days, in defiance of its own apparent contradictions.

While it may not be inaccurate to assert, as some do, that the entire point of the women’s liberation movement was to destroy the nuclear family in order to make Americans increasingly dependent upon government for their welfare, there is no getting around the fact that Cold War posturing backed us into ideological corners from which we are only now beginning to emerge. The question is, what will that emergence look like? Will it take the long-overdue form of a more family-friendly version of Capitalism — or a wholesale exodus to a Socialist future in which economic growth, even more so than our European counterparts, is stifled by the impossible burden of our own over-exuberant corrections, thanks to social benefits we cannot afford to keep?

We now have seen two, if not three, generations of Americans faced with untenable choices: one in which they attain the education, career and financial stability necessary to support a family but are severely delayed if not denied the opportunity by virtue of a prolonged pursuit; the other in which life stages such as marriage and family are realized within traditional time frames, but all too often without the requisite skills and economic mobility to adequately sustain those choices. Our political leaders on the Right and Left, alike, have done so little for so long to address real-world domestic concerns — to include a wholesale failure to shore up the entitlements retiring baby boomers will deplete!  — that their inaction is so ubiquitous that is, paradoxically, rarely questioned. Nonetheless, our leaders should make no mistake: The price their inaction or ineptitude may ultimately extract is public faith in the Great Experiment itself.

A government who’s elected representatives spend their time appearing on Right vs. Left-wing media to point fingers at one another is a government that is actively deflecting from its own public policy failures. As American citizens, do we still believe, as our idealistic counterparts of the 1960s did, in the power of activism and reform? Or will we find ourselves swept up in an ever-more contentious sociopolitical climate — with or without the current president to blame! — in which we are urged to question virtually everything, including our own immutable characteristics, even as we allow an ever-expansive federal government to continue serve every cause but our own?

Much like the 1960s, we are at a crossroads: Do we bog down in the weeds of Conservative/Liberal, Male/Female, Divorced/Married, Black/White, They/Them, Majority/Minority, Child/Childless distinctions — or identify the challenges we largely share in common so as to achieve some semblance of change even if such efforts do not pass the ideological/identity purity tests the less patient among us demand? Alternatively, do we plunge down the rabbit-hole to a post-nuclear family oblivion, once again unappreciative that our passions have been exploited, our energies redirected and our problems unchanged?

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What Raindrops Tell us About the Emergent World Order

President H.W. Bush, borrowing a phrase from an earlier era, popularized the term “New World Order” (NWO) in the early 1990s. But while the New World Order has legitimate roots, it has come to be associated with little more than paranoid conspiracy.

Given what we’ve witnessed in recent times, however, is it wise to continue to dismiss the notion out-of-hand?

Read Full Post »

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Requirement of Contract Mortgage Processing

Contracts are really there for a lot of many have seen the effective performance of set lower contracts additionally to aid in solving disagreements. Therefore, on the market of mortgaging this isn’t the most effective. Consequently, numerous lenders and lenders have develop anything mortgage processing, as a means of making certain the mortgage processing is transported by helping cover their needed and spend some time periods. The goal of this is often to lessen across the back log of applications, the mortgage loan provider might be handling in the after a while.

With contract mortgage processing, business between all concerned parties is definite to function easily since the put lower time period will there be to discover that no extra or unnecessary prices is incurred with the processing within the home loan applications. Because of this, most financiers delegate for mortgage processing companies. Because, their primary aim should be to make certain the minimization across the expenses within the mortgage processing and maximizing across the profit making in the industry. Additionally, they would like to help deal with the financial recession which has really impacted most financiers, by threatening lots of their operations.

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Forgiveness and Mercy

“Relax for a moment and be still. Imagine that you are a child and remember one way that you believed you were victimized. It could be someone yelling at you, lying to you, putting you down, hitting, incesting, or molesting you.

Can you see the person abusing you? Are they roaring like a tiger? Watch their lips as they talk to you. See their hand or body as it comes down on you, for example. Look at their face. Look deeply into their eyes. Don’t move away. Really look at them. Can you really know that they want to hurt you? Can you really know that they are not inflicting more abuse upon themselves in that moment? Sit in stillness with this.

Then ask yourself the following question: ‘If I had to choose one or the other for all eternity, would I rather be the abuser or the abused? Which position is the more merciful?'”

~ Byron Katie


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Return Policy

If you are not completely satisfied with your purchase, is pleased to offer the highest standard of customer service. We’ll gladly accept returns for products within 10 days from delivery date.

General Policy

• Item(s) must be returned in original condition and in original packaging including all original tags, any paperwork, manuals or accessories. Returned item(s) must be unopened, unused, not tried on, unaltered, and undamaged.

• Returning an item for any reason, please fill out our return form, found in the Customer Service section of our website, and submit it to us. We will review it and give you an authorized return number within 1-2 business days. It may take 3 to 10 business days from the date the package is received to be inspected.

• Customers are responsible for the additional costs associated with return.

• If returned items are not in the same condition as they were when sent, we will refuse or send the package back to you with shipping charge.

• Returned merchandise will receive a minimum 30% restocking fee, depending on the condition of the item(s).

• If the original order qualified for free shipping and promotional shipping, original shipping costs will be deducted.

• Original shipping fees will be refunded only if the item was shipped incorrectly or damaged. Otherwise the cost of the return shipping will be deducted from your refund. We suggest shipping all returns using a traceable delivery method as we are unable to refund or replace without proof of delivery.

• Any claims for damaged, defected, wrong, or missing items must be submitted within 14 days from delivery date. It must be accompanied by a photo displaying the evidence of the claim. All of these claims can range from 1 to 8 business days to be resolved after claim is submitted.

• Return Credit will be issued after the inspection of returned item(s) is completed and always be issued to the same card to which they were originally charged.

Refused Package / Undeliverable as Addressed (Return To Sender)

• If you wish to have your order reshipped, there will be an additional payment needed for the cost of shipping.

• Unwilling or unable to pay for shipping, package will be treated as a regular return. A 10% restocking fee will be applied and shipping cost are not refundable.

Ineligible Items for return

• Clearance items, Special Sale items, Promotional items, Special Order items.

• ALL Fashion Jewelries and Cosmetics are Final Sale.

• Any product that is opened, used, tried on, altered, and damaged by customers, missing pieces, and missing packaging materials.


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Tag Archives: coils

Stand-alone Inductance Meter

Some of you may have seen my arduino-based inductance meter in this post: https://soldernerd.com/2014/12/14/arduino-based-inductance-meter/. The guys at dangerousprototypes.com picked it up (http://dangerousprototypes.com/2014/12/16/arduino-based-inductance-meter/) and this blog got more visitors than I could ever have imagined. Thanks, dangerousprototypes.

The arduino-based meter works well and made a great proof-of-concept. But for everyday use you’re probabely not looking for an arduino solution but rather something that looks and feels more like a multimeter. That’s why I’m following up with this stand-alone version.

So this version is battery powered and comes complete with a 3D-printed case. It uses a mid-range PIC microcontroller, a PIC16F1936. Not that there’s much special about this model, I just happened to have some left from previous projects. I also thought about using a Atmel Atmega328, the same chip that is on the Arduino UNO.

Using an entirely different chip means I’ll have to write the software from scratch. But I felt that the Atmega328 was just too much of an overkill just to measure a frequency and control an LCD. They are quite a bit more expensive than the PIC, CHF 3.70 compared to CHF 1.90 @10pieces at Farnell where I get just about all my chips.

Talking of the LCD: The one I’m using here comes with a I2C interface. It’s blue with a white backlight and 2×16 characters and really tiny. I bought 2 of them years ago because they were small and relatively cheap (around 15CHF) and don’t require so many precious I/O pins of your microcontroller. Somehow I never used them but here their small size makes them a good choice. I/O pins aren’t a constraint here obviously as most of the 28 pins are unused.

I’m not yet familiar with the details of how they are controlled. I had a look at the data sheet and it looks like you send them just about the same commands like with the standard Hitachi compatible ones, just over I2C. But I expect to spend an evening or two figuring out the details.

The case was designed using FreeCAD. As the name suggest, it’s a free (and open-source) CAD design tool. This was only the second time I was using it but I found it quite easy to learn.

I printed the case at the Zürich fab lab (zurich.fablab.ch) on one of their Ultimakers. Was my first 3D-printing project, thank you very much for your support, everyone.

As always, I’ll put all the files online as a zip. So you can download all the Eagles plus PDFs as well as the FreeCAD models. Here it is: InductanceMeter. I haven’t written any software yet but I’ll but that online, too, as soon as it’s finished.

The software is ready now. Klick here for the next post: https://soldernerd.com/2015/01/23/stand-alone-incuctance-meter-finished/.

Arduino-based Inductance Meter

Incuctance meter in action. It displays the resonance frequency together with the inductance

I’ve just finished a little Arduino project. It’s a shield for the Arduino Uno that lets you measure inductance. This is a functionality that I found missing in just about any digital multi meter. Yes, there are specialized LCR meters that let you measure inductance but they typically won’t measure voltages or currents. So I had to build my inductance meter myself.

Close-up of the circuit with the display removed

The basic design is really simple. It a colpitts oscillator (http://en.wikipedia.org/wiki/Colpitts_oscillator) with the coil missing. You use the test leads to connect it to a coil which will make it resonate. The Arduino then measures the frequency at which the oscillator is resonating and calculates the inductance. The capacitors are part of the shield so the capacity is known.

With the test leads open, the oscillator can’t resonate. The current calibration/zero-offset is displayed in stead

There is 1uH of inductance included on the schield which is placed in series with the coil to be measured. This serves two purposes: The oscillator can resonate when you short-circuit the test leads. When you then press the push button on the shield, the software will use the current measurement as new calibration. It also puts an upper limit on the resonance frequency. This ensures that the software the rest of the circuit can keep up with the oscillator.

Pressing this blue button zeroes the meter

As can be seen from the schematic, the oscillator uses two 1nF capacitors in series. Together with the 1uH inductance, this limits the frequency to about 7.1MHz. In practice, it oscillates at around 5.4MHz when the test leads are short-circuited.

The Arduino shield from below

The oscillator output is followed by a comparator turning the sine wave of the oscillator into a square wave. I’ve used an inexpensive but fast Microchip MCP6561R. It has a maximum propagation delay of 80ns which allows it to keep up at the maximum frequency.

Viewed from straight above

But of course, 5.4MHz is way too fast for the Arduino to keep up. The Arduino runs at 16MHz and will need at least a few dozend instructions to process each pulse from the shield. My solution was to add a 74HC590 8-bit binary counter dividing the frequency by 256. That gives a theoretical maximum frequency of 7.2MHz / 256 = 27.7kHz. That’s something the Arduino can deal with.

The entire shield with the display removed

For obvious reasons, there is also a display included on the shield. And then there’s that pushbutton which is debounced in hardware by running it through an RC low-pass filter and a Schmitt-triggered buffer. The button is used to zero the meter, i.e. the current measurement is used as the new zero-offset.

Even very small inductance values can be measured

All related files can be downloaded as a .zip file: LMeterShield. This includes the Arduino source code (aka sketch) as well as the Eagle files and PDFs of both the layout and the schematic.

Now there’s also a stand-alone version: https://soldernerd.com/2015/01/14/stand-alone-inductance-meter/


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a more INTELLIGENT approach to equipment finance

The Customer:

A global communications and news organisation.

The Challenge:

Financing a $12 million technology initiative to accommodate the shift from analog to digital technology for local affiliates of the Customer with a staggered delivery schedule spanning six months all during the global financial crisis.

Going beyond finance:

Somerset prides itself on never having backed out on a commitment it has made on a transaction throughout its 30 plus year history. This facet of our makeup has endured through many economic cycles including periods where credit markets have limited the access to outside funding. Our commitment to our clients was never more apparent than during the great recession of 2008-2009. To address the needs of our client on this transaction Somerset used a mix of our internal resources and those of closest banking partner, who had ceased funding business for many of their business partners, to complete the financing of this critical project for our customer.
The vendors providing the equipment and services were paid on time without delay and our client was able to complete their conversion prior to their target completion date.

  • $12MM conversion from analog to digital

  • Creative capital needed during the financial crisis

  • 6 month project timeline

  • Vendors paid on time and project was completed prior to the target completion date

  • Can this aviation services company get more ROI out of the end of lease assets?
    Read More
  • Can this US-based support center lease IT assets for their operations in Asia through a US lender?
    Read More
  • Can this R&D company get equipment in-service 6 months before budgeted funds become available?
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  • Can this ROV services company acquire revenue producing equipment without straining cash resources?
    Read More
  • Can an IT company develop a cost effective way to stay on the cutting edge of technology?
    Read More
  • Can this surgery department acquire the newest technology despite resistant attitudes of administrators?
    Read More
  • Can this manufacturer upgrade to automated guided vehicles while preserving capital?
    Read More
  • Can an energy services company finance equipment while maintaining mid-term flexibility?
    Read More
  • Can this global news organisation shift from analog to digital in the middle of the financial crisis?
    Read More

Across a wide variety of industries, equipment classes, brands and across the globe...

Energy & Power

Healthcare & Pharma

Higher Education

Metals Manufacturing

Automotive Manufacturing

Food & Beverage Manufacturing

Wholesale & Distribution

Our team is ready to help you take a different, more intelligent approach to your equipment finance


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Our Notes

Posts about research, open source and technologies.

10 Non-Technical Skills Every Developer Needs

What does it take to excel as a software developer? While knowledge of languages and frameworks is extremely important, outstanding developers aren't great at what they do because of technical proficiency alone. Check out the top ten qualities and skills every developer should hone if they want to take their performance to the next level.

1. A Client-Focused Approach

In order to deliver high-quality software, a developer's primary focus should be to help customers meet their goals. Empathizing with clients allows developers to better understand their needs, which enables developers to build more effective solutions. In addition, great developers recognize that customer feedback is extremely useful, and they look forward to implementing it and improving the product. A savvy developer also has a good sense of business value and prioritizes what is valuable to the client over what may be new or interesting to them as an engineer.

2. A Passion for Software Development

There's a reason one of our core values at sophilabs is "Love your craft." We think when developers love what they do, they are better able to produce quality work and stick with tough problems until they solve them. A developer who is truly dedicated to their craft even spends time working on programming puzzles outside of their job because of the pure joy it gives them to create something new and sharpen their skills with consistent practice.

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Spiritually Stuck? (No Such Thing)

June 30, 2019

People write to me, that they feel like they are spiritually stuck and are making no spiritual progress.

I previously wrote about ambition – spiritual ambition.
The problem is being overambitious, especially in the context of spirituality. It is very understandable that we want to get to where we have a vision about being, but that final touchdown will never manifest. There will be and there are a multitude of mundane or spiritual touchdowns, and we might rest there a bit on our voyage and harvest the fruits of our journey, but one thing we know is that: This Universe is ever creative, in movement, never in the Status Quo, it does not have a start and an ending. It’s a never-ending creative manifestation and we are part of that.

We never run out of spiritual fuel.

We miss a great point, we leave a lot out, if we think that spiritual progress or growth only takes place in predefined spiritual surroundings. What are we missing when we talk about our spiritual life?

We are clearly missing out on the fact of being incarnate. We are clearly suffering from belief that the Matrix of Spiritual is all a matter of spiritual practices like meditation, ESP, Yoga and what have we. Worst of all, we are suffering from the illusion of Earthly life, practical life, Karma Yoga, learning by doing and the list is long. If we think that spirituality doesn’t tie in with the practical life each of us is living, we will get stranded and miserable and feel there is no progress.

That is a crucial turning point.

Also, the reason why the historical Jesus only took ‘40 days in the desert’. He needed to detach, meditate, push the envelope before once again returning to his Dharma. His life calling. His mundane and celestial destiny. Ever think of the deeper meaning of being born into this world with this task as a Carpenter? A very practical skill. Hint, hint.

Jesus mentioned here, since the practice of working spiritually with oneself and then returning to the mundane life: in order to embed the insights into that life in the Mundane, to heighten its frequencies and to improve whatever we need to improve is of utmost importance.

It is very similar to this tale from the Tao:

In the tiny village, there lived a Sage, a Mystic, a Seer.
The villagers were very curious to know how it was to be so enlightened. So, they asked the Sage: What is it like to be that spiritual, that knowing, that enlightened. The Sage answered: Before I got enlightened, as you call it, I chopped wood and carried water. After I got enlightened, as you call it (an enlightened being would never refer to himself as enlightened or even awake), I carry water and chop wood, but now I know why I´m doing it.

The key to this answer lies in the understanding of, allow me to call it: Heaven and Earth.

If we are into spiritual self-empowerment, we prefer the Heavens. And that is alright since the picture of the 40 days in the desert applies to that. It all goes on in the spiritual realm in us; some would say the higher chakras. Hopefully we take those insights into our Earthly life and manifest them into that. It is often called: Manifesting Heaven on Earth.

So far so good.

But it is a contradiction in terms to even divide it into: Heaven and Earth. It’s dualism and what we want is Unity within ourselves. A strong coherence between the highest (heaven) and lowest (earth), until we can dissolve that division and see it as: One.

When we experience that, we can understand, fully understand, what the Sage is talking about. Carry water, chop wood and not seeing mundane tasks as an unwelcome break from our spiritual quest. If we do that, we will wind up in the predicament I started out with. We will wind up being a bit fluffier than seeds of dandelions giving in to the weakest of breezes. We’ll go flying without a sense of direction and much worse: Without being in charge of our own destiny, controlled only by the mood swings of the King of the Winds. So, we leave that responsibly to randomness. Not cool.

Being in a situation where we feel we are spiritually flatlining and nothing happens is a very big but understandable mistake.

What happened is that it doesn’t work anymore for us. Out of fuel. Critical mass.

If we go to the gym and train for a marathon – we reach a wall where we think nothing happens. We can’t see progress. Every runner knows that. There seems to be several ways of going about that:

Either we take a break and stop training for a while.

Or: we carry on without expectations of progress and at some given point we pick up steam again and we actually realize – that the pause did us good.

Or: We can start swimming or engage in training that doesn’t involve running, and find out: Cool, that is a great solution. I am still active and I need to keep training so my muscles are satisfied.

The solution to this is to leave the predefined spiritual. Let it rest.

The solution to this is, and it is not especially a solution people are keen to be let in on, since it is not fancy, nor complicated: Go into the practical life. Leave the high flying a bit and make a touchdown and find spirituality in the everyday life. Let the mundane fuel it.

What’s more spiritual: Meditating or cleaning the windows?
What’s more spiritual: Praying or playing with the kids.
What’s more spiritual: Surfing on Aya or going to the supermarket.

The answer to these silly questions are: There is no difference.

The only difference is whether you are in on the curve of learning, and that difference is but a mere illusion, since its all spirituality.

In this life we have, we need to conquer these misunderstandings, the touch of specialness, the idea that spiritual development is apart from daily life. Our finest job in the year to come and for millennium hereafter is to dissolve this illusion of how spiritual evolution works or nothing will change. Not within us, not without us, not on the so called outside of us.

If we perceive our daily life as ‘unspiritual’ I think it should be very clear to us, what to do next!
It makes no sense in perceiving spiritual practices and a spirituality as being apart from daily life especially since the idea is: To have a fully integrated spiritual life, whatever that means to you. And that of course will get our hands a bit dirty but isnt that also what makes spirituality such a challenge?

Whatever happened to ‘We Are Everything’? Did it vaporize in the scent of the ‘unspiritual everyday’ life?

EVERYTHING is spirituality – Embodiment – it is the new spiritual path for many now.

© 2019 Soren Dreier

Soren Dreier: Readings – Healings – Guidance


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On 1 March 2015 we released a new version of Sortd in anticipation of our presence at Launch Festival on 2 March 2015.

Features and Fixes

The biggest  and most important improvement by far is the improved speed with which new email is delivered to Sortd. You should see email arriving within seconds or at worst a few minutes after it appears in Gmail which is much quicker than then 5-7 minute delay that would sometimes occur previously.

We have added the ability to hide Sortd using the Sortd tab without activating Sortd so that you can run Sortd in one account and not another without having the Sortd sidebar displayed in the inactive (non-Sortd) accounts Gmail interface.

Creating Tasks from email inside the Gmail interface should now be faster and more reliable. Merging tasks in some cases caused the task to disappear, but this should hopefully be fixed now as well.

Various other Bugs, Stability and Reliability Improvements (though there are still many more to go) have been made.

Experimental Features

These features are currently very experimental and could change significantly or be dropped altogether and as such are marked Beta (although the whole product is still in Beta, these features are significantly more so). Please send us your thoughts and comments as we would love to hear what you think.

In anticipation of launching our iPhone and Android applications (tease) we have included a feature which allows you to Import email from Sortd sub-labels. This means that you can use your favourite Mobile Email App, and add the Sortd List label (Sortd sub-label in Gmail)  to the email and Sortd will import it into your list.

Sortd does this in the background with no additional input from you, but as it is done on a periodic basis one can force an import by selecting the Import button. Import only works with Sortd sub-labels and not with Gmail labels in general (even if you create a label and list with the same name). Currently Sortd will only import 20 items into a list in any given import iteration and will only import into a Sortd list if there are less than 100 active tasks in the list. This is to prevent the lists from becoming overwhelmingly large (and to prevent filters being defined in Gmail that swamp the lists). Once Sortd has imported the email into a list it will remove the list label from the email, although the main Sortd label will remain. Personal opinion: Lists really should contain tasks that can be considered active work otherwise they just become swamped and then you may as well have left them in your inbox. Obviously we all have exceptions to this rule ;-)

Date View

Date View lets you view your tasks ordered by date using the headings Today, Tomorrow, Soon and Later

Unfortunately dates are one of those things that are quite complicated in that people use them for different reasons (you will see we changed "Due Date" to just say “Date” as some people prefer the date to represent a Start Date, and we don’t want both as it makes Sortd too complicated - its supposed to be a really simple product).

The idea of Soon and Later becomes an issue in that those terms mean different things to different people, and what date do you set when someone drags a task/email into Soon/Later. Currently we set Soon as 3 days time, and Later as 14 days time, although changing the actual date to be anywhere between 3 and 14 days will leave it in Soon and anything after 14 days will leave it in Later.

Additionally because Date View is real time based, tasks that where scheduled for “Tomorrow”, roll forward to “Today” which means that the Today list can get large if one does not get through the tasks. Hopefully the ease with which someone can just drag the task to the Tomorrow, Soon or Later lists will alleviate this problem to some extent. In the future we may have an option to make the time static, i.e. tasks/emails won’t roll forward based on real time but stay in their relative time columns until moved by the user.

The Today list will also show overdue tasks in red.

All tasks are ordered by date and one cannot actually drag a task up and down within a Date (virtual) list like one can in a normal context (real) list.

Creating a task in a Date (virtual) list will cause a selection box to be displayed allowing one to select the context list the task/email should be added to. It will be added to the top of that list.

Known Issues

We are aware of many, many issues, too many to list here but in particular we are aware that the Show/Hide Completed toggle is getting out of sync and will be fixed in the next release.


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Snooze lets you to postpone emails that aren't relevant now and have them re-appear in your Inbox later.

From your Inbox, click on the Snooze icon and choose an option.

Sortd Snooze Feature

You can also use Snooze from the controls at the top of the email preview.

Here's what each option does:

- Later today: 3 hours from the Snooze time

- Tomorrow: At 7am the following day

- Next Week: On Monday at 7am

- In a month: 30 days from today at 7am

- Some day: In 3 months time

Where do my emails go when I Snooze them?

All emails that you Snooze are moved to folder that Sortd creates.  Look out for the Snoozed folder in your folder list...


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Sacré-Coeur Real Estate

Why live in Sacré-Coeur?

Côte-Nord is a vast, wild and lush region in Quebec, extending from Tadoussac to Blanc-Sablon and from the north shore of the St. Lawrence River northward to where the boreal forest gives way to the taiga. It’s a region boasting pristine wilderness and 25 proud municipalities that are home to slightly more than 1% of the province's population.

Sacré-Coeur Area Map

Côte-Nord Properties by Neighbourhood

Sacré-Coeur Properties For Sale

View All Latest Homes

Real Estate News & Trends


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Standard Interactive Audio

Music Producer, Mix Engineer

2 Reviews
Standard Interactive Audio on SoundBetter

I was the main engineer at Studio I-95 in West Haven, CT for 3 years where I produced tracks, mixed songs, mastered songs, and done remixes for hundreds of people. I now work independently at home in Stone Mountain, GA. I produce, mix, and master all genres and I also write songs.

Tell me about your project and how I can help, through the 'Contact' button above.

2 Reviews

Endorse Standard Interactive Audio
  1. Review by Rich Kim

    Standard Interactive helped my song rise up to its full potential. Working with Mike means more than working with just a producer--he is an adept musician as well. This company will sincerely consider and incorporate your ideas, but also offer the knowledge needed in order to bring the best out of your project so that it can stand against today's top professionally made productions.

  2. Review by Adrian Kudziński

    I am satisfied. Mike keeps his word, he is trying to do his best, appreciates the customer and he is honest. Thanks.

Classic Funky Pop

I was the Producer in this production

Terms Of Service

For instrumentals and mixing I allow 2 free revisions with up to 5 tasks per revision (take sounds out, add more sounds, extend/cut a part of the song, raise/lower volume of vocal, etc.).

GenresSounds Like
  • Justin Bieber
  • Bruno Mars
  • Kendrick Lamar
Gear Highlights
  • ASUS Multimedia Laptop
  • Blue Dragonfly Microphone
  • Focusrite 18i20 Interface
  • PRS Paul Allendar SE Guitar
More Photos
More Samples


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Our First Plug!

  This is very exciting. We’ve been asked to spread the news about a new book. Our first plug!  And we are very pleased to say that the book in question is rather lovely; it’s  a lavishly-illustrated, information-packed hardback book printed on high quality silk paper with colour digital photographs, comprehensive descriptions, technical details, originalContinue reading “Our First Plug!”


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Faith: Giving Up Lent for Lent

SFGN File Photo

If you happened to go out and about last Wednesday, you may have noticed quite a few people who looked like they had recently lost a fight with a chimney sweep… That’s right, it was just Ash Wednesday, which means here we are, back in the season of Lent.

For those of us who grew up Catholic, you’ll remember it as a ritual your parents and grandparents forced you to participate in. You’d be made to go to church more often than usual, have the priest schmear ashes on your forehead, give up meat on Fridays, and most notably “give up” something. And every year when it comes around I find myself asking the same question: “Does this have any real meaning in 2019 in South Florida, or has this been relegated to the realm of mindless ritual and unnecessary pius pageantry?”

The conclusion I’ve come to is that the answer is very closely related to the “spiritual, but not religious” phenom that has taken over the world.

When one says that they are “spiritual, but not religious,” to me, that means “I am still seeking the answers to the great mysteries of life, and hope to commune on a deeper level with my fellow man and the universe around me, but I find that religious tradition limits my ability to do so, or teaches things that I have found to be untrue or even harmful.” And even as a Catholic priest, when someone tells me that they are “spiritual, but not religious,” I find myself at a loss of any compelling reason for them to be anything else.

Why? Because spirituality must be at the core of everything we do in every aspect of our life. We must be seekers of meaning and truth and sowers of love and compassion… “Because I said so,” or “This is simply how things are done” is not an adequate justification to do anything anymore.

If our observation of Lent is nothing more than the fulfillment of childhood indoctrination and habituation, then it is valueless.

But it doesn’t need to be that way.

There is still a rich spiritual bounty to be had, but we need to do a little bit of work to unlearn some things, and to find the meaning that has been there all along but was lost.

Matthew 3:12 delivers an all too familiar line: “His winnowing fork is in his hand, and he will clear his threshing floor, gathering his wheat into the barn and burning up the chaff with unquenchable fire."

That verse is more often than not used to drive home the point that some of us are headed to Heaven, and others off to hell. But there is perhaps a better understanding of this allegory… What if we put ourselves into the place of the farmer with his “winnowing fork” and let that field, wheat, chaff, and all be the totality of our life? We can take this season of Lent to be an invitation to analyze our life, our decisions, our behaviors, our habits, and even our relationships, asking ourselves, “What do I have that is of tremendous value (the wheat),” and “What is hurting us or holding us back (the chaff (weeds)?”

Imagine if instead of giving up meat and chocolate, which does no real good for anybody, we gave up all our bad habits and hurtful behaviors for Lent. What an amazing world we would live in, and how much healthier we’d all be.

Fr. Rich Vitale is the associate pastor of Community Outreach of Holy Angels National Catholic Church, and the interim director of Operations of Impulse Group South Florida. He lives in Wilton Manors with his husband Sean, and his Cat, Miss Kitty.


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The Baron in the Trees

Author(s): Italo Calvino

A gorgeous new edition of a playful, romantic fable by one of the twentieth century's master storytellers.From the age of twelve, the Baron Cosimo Piovasco di Rondo makes his home among ash, elm, magnolia, plum and almond. He walks through paths made from the twisted branches of olive, makes his bed in a holly oak, bathes in a fountain constructed from poplar bark. An aerial library holds the books with which he educates himself in philosophy and mathematics. Suspended among the leaves, the Baron adventures with bandits and pirates, conducts a passionate love affair, and watches the Age of Enlightenment pass by beneath him. Published here in a beautiful new edition and translation, The Baron in the Treesis a delight and an enchantment.

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Product Information

General Fields

  • : 9781784874216
  • : penguin random house
  • : Arrow
  • : November 2018
  • : books

Special Fields

  • : 288
  • : Italo Calvino


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Frequency converter is used in the relatively big extraction ventilation systems with a number of suction points. It adjusts the central fan’s speed according to signals sent by USS coordination device. Frequency converter can also be used as an airflow regulation device for manual adjustments to the system.

Usually used with

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