The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance.

The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, Mbd1(-/-) mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance.

Building, benchmarking, and exploring perturbative maps of transcriptional and morphological data.

The continued scaling of genetic perturbation technologies combined with high-dimensional assays such as cellular microscopy and RNA-sequencing has enabled genome-scale reverse-genetics experiments that go beyond single-endpoint measurements of growth or lethality. Datasets emerging from these experiments can be combined to construct perturbative "maps of biology", in which readouts from various manipulations (e.g., CRISPR-Cas9 knockout, CRISPRi knockdown, compound treatment) are placed in unified, relatable embedding spaces allowing for the generation of genome-scale sets of pairwise comparisons. These maps of biology capture known biological relationships and uncover new associations which can be used for downstream discovery tasks. Construction of these maps involves many technical choices in both experimental and computational protocols, motivating the design of benchmark procedures to evaluate map quality in a systematic, unbiased manner. Here, we (1) establish a standardized terminology for the steps involved in perturbative map building, (2) introduce key classes of benchmarks to assess the quality of such maps, (3) construct 18 maps from four genome-scale datasets employing different cell types, perturbation technologies, and data readout modalities, (4) generate benchmark metrics for the constructed maps and investigate the reasons for performance variations, and (5) demonstrate utility of these maps to discover new biology by suggesting roles for two largely uncharacterized genes.

Current and future perspectives of liquid biopsies in genomics-driven oncology.

Precision oncology seeks to leverage molecular information about cancer to improve patient outcomes. Tissue biopsy samples are widely used to characterize tumours but are limited by constraints on sampling frequency and their incomplete representation of the entire tumour bulk. Now, attention is turning to minimally invasive liquid biopsies, which enable analysis of tumour components (including circulating tumour cells and circulating tumour DNA) in bodily fluids such as blood. The potential of liquid biopsies is highlighted by studies that show they can track the evolutionary dynamics and heterogeneity of tumours and can detect very early emergence of therapy resistance, residual disease and recurrence. However, the analytical validity and clinical utility of liquid biopsies must be rigorously demonstrated before this potential can be realized.

Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development.

The thymus is responsible for generating a diverse yet self-tolerant pool of T cells1. Although the thymic medulla consists mostly of developing and mature AIRE+ epithelial cells, recent evidence has suggested that there is far greater heterogeneity among medullary thymic epithelial cells than was previously thought2. Here we describe in detail an epithelial subset that is remarkably similar to peripheral tuft cells that are found at mucosal barriers3. Similar to the periphery, thymic tuft cells express the canonical taste transduction pathway and IL-25. However, they are unique in their spatial association with cornified aggregates, ability to present antigens and expression of a broad diversity of taste receptors. Some thymic tuft cells pass through an Aire-expressing stage and depend on a known AIRE-binding partner, HIPK2, for their development. Notably, the taste chemosensory protein TRPM5 is required for their thymic function through which they support the development and polarization of thymic invariant natural killer T cells and act to establish a medullary microenvironment that is enriched in the type 2 cytokine, IL-4. These findings indicate that there is a compartmentalized medullary environment in which differentiation of a minor and highly specialized epithelial subset has a non-redundant role in shaping thymic function.

Epidemiology and prevalence of somatic symptom disorder at the primary care level in Muscat, Oman: A cross-sectional study.

OBJECTIVES: Somatic symptom disorder (SSD) is a diagnostic classification to describe the occurrence of physical symptoms without organic cause. This study aimed to identify prevalence rates and associated characteristics of SSD among adults in primary care settings. METHODS: This cross-sectional study took place between July 2020 and March 2021 and included a random selection of 3383 Omani adults attending 12 primary healthcare centres in Muscat Governorate. Screening was conducted using an Arabic version of the Somatic Symptom Scale-8 (SSS-8). RESULTS: A total of 2000 adults participated in the study (response rate: 67.3%), of which most were female (71.7%) and under 50 years old (86.2%). Based on their SSS-8 scores, 602 participants (17.8%) had SSD, resulting in an overall prevalence estimate of 30.1% (95% confidence interval: 28.13-32.15). Significant associations were observed between SSD and age (p = 0.002), gender (p < 0.001), marital status (p = 0.030) and chronic comorbidities (p = 0.001). In addition, adjusted odds ratio estimates revealed SSD to be significantly associated with gender (p < 0.001), education level (p < 0.001) and chronic comorbidities (p = 0.001). CONCLUSION: The estimated prevalence of SSD in primary care settings is high compared to reports from elsewhere in the Gulf region. There is an urgent need to enhance the diagnosis of SSD at the primary care level in order to reduce healthcare service overutilisation and patient dissatisfaction. Moreover, healthcare practitioners should be aware of the effect of age, gender, educational status and chronic comorbidities on somatic symptoms.

The Syringe External Fixator: Short- and Medium-Term Functional Outcomes From This Inexpensive and Customizable Treatment for Comminuted Intra-Articular Fractures of the Hand.

PURPOSE: Comminuted intra-articular fractures and fracture dislocations of the metacarpophalangeal (MCP) and interphalangeal joints are challenging. Dynamic external fixation, permitting early joint motion while still minimizing forces across the healing joint, can result in acceptable postoperative active range of motion (AROM). However, some fractures are not initially stable enough for early dynamic motion; further, many available dynamic external fixation systems are costly and cumbersome. We reviewed our experience using an external fixator made from a 1-mL syringe and K-wires and report outcomes using it as a static fixator, dynamic fixator, or configured as a static fixator and then converted to a dynamic fixator in the clinic. METHODS: Patients with intra-articular fractures and fracture dislocations of the MCP and proximal interphalangeal (PIP) joints treated between 2014 and 2020 using syringe external fixators were retrospectively reviewed. We reviewed demographics, mechanisms, treatment types and durations, and postoperative AROM, as well as complications including infection, pin loosening, nonunion, hardware failure, and need for further surgery. Patients were analyzed by the level of joint injury (MCP versus PIP) and by treatment pattern. RESULTS: After excluding 23 patients with 25 joint injuries who were lost to follow-up or had inadequate outcome data, 27 patients with 29 joint injuries were reviewed. The average follow-up was 171 days after surgery. The postoperative AROM at the MCP level averaged 55° for static fixation and 30° for static-to-dynamic fixation. The postoperative AROM at the PIP level averaged 64° for static fixation, 66° for static-to-dynamic fixation, and 80° for dynamic fixation. Three pin site infections and 2 loose pins were reported. CONCLUSIONS: The syringe external fixator is an inexpensive, effective, and customizable treatment for intra-articular MCP and interphalangeal fractures and fracture dislocations, and results in acceptable postoperative AROM outcomes and complication rates. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Correction: The population genetics of human disease: The case of recessive, lethal mutations.

[This corrects the article DOI: 10.1371/journal.pgen.1006915.].

Assessing the Relationship Between Bone Density and Loss of Reduction in Nonsurgical Distal Radius Fracture Treatment.

PURPOSE: Whether low bone mineral density affects loss of reduction for distal radius fractures (DRFs) managed without surgery is unknown. Our purpose was to understand how bone mineral density, based on second metacarpal cortical percentage (2MCP) measurement, affects DRF healing after nonsurgical treatment. METHODS: We retrospectively reviewed 304 patients from 2 health systems with DRFs treated without surgery. The AO classification, 2MCP (<50% indicating osteoporosis), and fracture stability based on Lafontaine criteria were determined from prereduction radiographs. Radial inclination, radial height, volar tilt, ulnar variance, and intra-articular stepoff were measured on initial and 6-week final follow-up radiographs and compared. Bivariate analysis was used to evaluate the association between Lafontaine criteria or 2MCP and changes in radiographic parameters. Radiographic parameters with significant associations in bivariate analysis were evaluated in multivariable models adjusted for age, sex, initial radiographic parameters, reduction status, and AO fracture type. RESULTS: Across all patients, after 6 weeks of nonsurgical treatment, ulnar variance (shortening of the radius) increased by an average of 1.4 mm. Bivariate analysis showed that lower 2MCP and unstable fractures per Lafontaine criteria were each significantly associated with an increase in ulnar variance (P < .05). In adjusted multivariable models, having both 2MCP less than 50% and an unstable fracture together was associated with an additional 1.2-mm increase in ulnar variance (P < .05). CONCLUSIONS: A 2MCP in the osteoporosis range and unstable fractures by Lafontaine criteria were each associated with a significant increase in ulnar variance after nonsurgical treatment for DRFs. Patients with unstable fractures and 2MCP less than 50% are likely to have an additional increase of greater than 1 mm in ulnar variance at the end of nonsurgical fracture treatment than patients with similar injuries, but without these features. Using initial radiographs to identify patients with low bone mineral density that may be at risk for more substantial loss of reduction can assist with decision making for managing DRFs. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

Early Outcomes of Endoscopic Versus Open Carpal Tunnel Release.

PURPOSE: To compare the short-term outcomes of endoscopic carpal tunnel release (ECTR) and open carpal tunnel release (OCTR), including patient-reported outcomes, pain and satisfaction scores, return to work, and postoperative prescription pain medication use. METHODS: We included all patients over 18 years of age undergoing carpal tunnel release at a single hand center between January 2018 and December 2019. The carpal tunnel release method was driven by variations in surgeon practice. Data from patient-reported outcomes measurement information system (PROMIS) questionnaires and brief Michigan hand outcomes questionnaires and data on patient-reported pain levels, satisfaction with care, return to work, and postoperative prescription pain medication use were collected at preoperative visits and the first follow-up visit between postoperative days 7 and 14. RESULTS: We included 678 (586 ECTR and 92 OCTR) patients. The median age was 58 years, and 75% of the patients were women. At early follow up, patients who underwent OCTR reported significantly lower postoperative PROMIS upper-extremity scores than those who underwent ECTR (median, 32 vs 36 points, respectively) but similar postoperative PROMIS pain interference, global physical health, global mental health, and brief Michigan hand outcomes questionnaire scores. The postoperative pain and satisfaction scores were similar between the 2 groups. In multivariable models, patients who underwent OCTR had 62% lower odds of returning to work and 30% greater odds of remaining on a postoperative pain prescription at the first follow-up visit. CONCLUSIONS: This study found no evidence suggesting the definitive superiority of 1 surgical technique with regard to clinical outcomes in the early postoperative period. However, OCTR was associated with lower postoperative PROMIS upper-extremity scores of unclear clinical significance, higher odds of remaining on pain medication, and lower odds of returning to work by the first postoperative visit. Endoscopic carpal tunnel release may be preferred in patients who need to return to work within the first 2 weeks after the procedure. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Genetic ancestry analysis on >93,000 individuals undergoing expanded carrier screening reveals limitations of ethnicity-based medical guidelines.

PURPOSE: Carrier status associates strongly with genetic ancestry, yet current carrier screening guidelines recommend testing for a limited set of conditions based on a patient's self-reported ethnicity. Ethnicity, which can reflect both genetic ancestry and cultural factors (e.g., religion), may be imperfectly known or communicated by patients. We sought to quantitatively assess the efficacy and equity with which ethnicity-based carrier screening captures recessive disease risk. METHODS: For 93,419 individuals undergoing a 96-gene expanded carrier screen (ECS), correspondence was assessed among carrier status, self-reported ethnicity, and a dual-component genetic ancestry (e.g., 75% African/25% European) calculated from sequencing data. RESULTS: Self-reported ethnicity was an imperfect indicator of genetic ancestry, with 9% of individuals having >50% genetic ancestry from a lineage inconsistent with self-reported ethnicity. Limitations of self-reported ethnicity led to missed carriers in at-risk populations: for 10 ECS conditions, patients with intermediate genetic ancestry backgrounds-who did not self-report the associated ethnicity-had significantly elevated carrier risk. Finally, for 7 of the 16 conditions included in current screening guidelines, most carriers were not from the population the guideline aimed to serve. CONCLUSION: Substantial and disproportionate risk for recessive disease is not detected when carrier screening is based on ethnicity, leading to inequitable reproductive care.

The population genetics of human disease: The case of recessive, lethal mutations.

Do the frequencies of disease mutations in human populations reflect a simple balance between mutation and purifying selection? What other factors shape the prevalence of disease mutations? To begin to answer these questions, we focused on one of the simplest cases: recessive mutations that alone cause lethal diseases or complete sterility. To this end, we generated a hand-curated set of 417 Mendelian mutations in 32 genes reported to cause a recessive, lethal Mendelian disease. We then considered analytic models of mutation-selection balance in infinite and finite populations of constant sizes and simulations of purifying selection in a more realistic demographic setting, and tested how well these models fit allele frequencies estimated from 33,370 individuals of European ancestry. In doing so, we distinguished between CpG transitions, which occur at a substantially elevated rate, and three other mutation types. Intriguingly, the observed frequency for CpG transitions is slightly higher than expectation but close, whereas the frequencies observed for the three other mutation types are an order of magnitude higher than expected, with a bigger deviation from expectation seen for less mutable types. This discrepancy is even larger when subtle fitness effects in heterozygotes or lethal compound heterozygotes are taken into account. In principle, higher than expected frequencies of disease mutations could be due to widespread errors in reporting causal variants, compensation by other mutations, or balancing selection. It is unclear why these factors would have a greater impact on disease mutations that occur at lower rates, however. We argue instead that the unexpectedly high frequency of disease mutations and the relationship to the mutation rate likely reflect an ascertainment bias: of all the mutations that cause recessive lethal diseases, those that by chance have reached higher frequencies are more likely to have been identified and thus to have been included in this study. Beyond the specific application, this study highlights the parameters likely to be important in shaping the frequencies of Mendelian disease alleles.

Outcomes of the Medial Femoral Trochlea Osteochondral Free Flap for Proximal Scaphoid Reconstruction.

PURPOSE: To describe the radiographic, functional, and patient-reported outcomes (PROs) of medial femoral trochlea (MFT) osteochondral free flap reconstruction of the proximal scaphoid at approximately 2 years follow-up. METHODS: Eleven patients who underwent MFT reconstruction of the proximal scaphoid returned for clinical examination, radiographs, and completion of PROs questionnaires. For another 10 patients who were unable to return, data were gathered remotely or from the medical record. RESULTS: Mean radiographic follow-up was 2.0 years and mean examination follow-up ranged from 2.6 to 2.8 years. Mean follow-up for several PROs ranged from 2.8 to 2.9 years. On average, carpal collapse did not progress, and radiolunate angle was significantly improved by 9.5°. Wrist flexion (41.6°; -6%) and extension (43.8°; -7%) were only slightly changed, and dominance-corrected postoperative pinch and grip strength were 77% and 72% of the uninjured side, respectively. Mean postoperative Disabilities of the Arm, Shoulder, and Hand (DASH) score was 10.7. In patients with both pre- and postoperative scores available, DASH significantly improved by 15 points. Knee donor-site morbidity was measured on the Knee Injury and Osteoarthritis Outcome Score (KOOS)-Sports and Recreation and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scales. The Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health, Physical Function, Pain Intensity, Pain Interference, and Pain Behavior scores reflected good postoperative patient health and function and low pain levels. Higher body mass index (BMI) was found to be predictive of inferior lower extremity and global PROs. CONCLUSIONS: An MFT reconstruction of proximal scaphoid nonunion has the potential to restore normal functional radiocarpal anatomy, improve function, and relieve pain without causing wrist stiffness or weakness. Donor-site morbidity has been further delineated in this study. Caution is warranted when considering this procedure in patients with elevated BMI because they may be at increased risk for donor-site morbidity. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Machine learning enables detection of early-stage colorectal cancer by whole-genome sequencing of plasma cell-free DNA.

BACKGROUND: Blood-based methods using cell-free DNA (cfDNA) are under development as an alternative to existing screening tests. However, early-stage detection of cancer using tumor-derived cfDNA has proven challenging because of the small proportion of cfDNA derived from tumor tissue in early-stage disease. A machine learning approach to discover signatures in cfDNA, potentially reflective of both tumor and non-tumor contributions, may represent a promising direction for the early detection of cancer. METHODS: Whole-genome sequencing was performed on cfDNA extracted from plasma samples (N = 546 colorectal cancer and 271 non-cancer controls). Reads aligning to protein-coding gene bodies were extracted, and read counts were normalized. cfDNA tumor fraction was estimated using IchorCNA. Machine learning models were trained using k-fold cross-validation and confounder-based cross-validations to assess generalization performance. RESULTS: In a colorectal cancer cohort heavily weighted towards early-stage cancer (80% stage I/II), we achieved a mean AUC of 0.92 (95% CI 0.91-0.93) with a mean sensitivity of 85% (95% CI 83-86%) at 85% specificity. Sensitivity generally increased with tumor stage and increasing tumor fraction. Stratification by age, sequencing batch, and institution demonstrated the impact of these confounders and provided a more accurate assessment of generalization performance. CONCLUSIONS: A machine learning approach using cfDNA achieved high sensitivity and specificity in a large, predominantly early-stage, colorectal cancer cohort. The possibility of systematic technical and institution-specific biases warrants similar confounder analyses in other studies. Prospective validation of this machine learning method and evaluation of a multi-analyte approach are underway.

Reconstruction of digit planer injuries using component transfer of double second toes: A case report.

The purpose of this report is to show that customized component second-toe transfers may improve functional and aesthetic outcomes following bone, soft tissue, and joint destruction of traumatically injured digits. A 22-year-old male sustained a planer injury resulting in loss of the distal volar soft tissues of the middle, ring, and small fingers, along with variable destruction of middle phalanges and distal interphalangeal joints. Simultaneous vascularized second-toe transfers were performed with customized joint and pulp reconstruction of middle and small fingers. The ring finger was salvaged using non-vascularized autologous bone graft and acellular dermal matrix. The patient had an uncomplicated postoperative course. Five-year strength, sensory and patient reported outcomes represent overall satisfactory results. Strength testing revealed the injured hand to perform within 90% strength of the uninjured side. Sensory outcomes showed present but diminished sensory perception in each of the injured digits. The patient's upper extremity function, physical health, quality of life, and foot health were overall acceptable, and he returned to using his hand for typing, writing, weight-lifting, and woodworking.

Systematic design and comparison of expanded carrier screening panels.

PurposeThe recent growth in pan-ethnic expanded carrier screening (ECS) has raised questions about how such panels might be designed and evaluated systematically. Design principles for ECS panels might improve clinical detection of at-risk couples and facilitate objective discussions of panel choice.MethodsGuided by medical-society statements, we propose a method for the design of ECS panels that aims to maximize the aggregate and per-disease sensitivity and specificity across a range of Mendelian disorders considered serious by a systematic classification scheme. We evaluated this method retrospectively using results from 474,644 de-identified carrier screens. We then constructed several idealized panels to highlight strengths and limitations of different ECS methodologies.ResultsBased on modeled fetal risks for "severe" and "profound" diseases, a commercially available ECS panel (Counsyl) is expected to detect 183 affected conceptuses per 100,000 US births. A screen's sensitivity is greatly impacted by two factors: (i) the methodology used (e.g., full-exon sequencing finds more affected conceptuses than targeted genotyping) and (ii) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome).ConclusionThe described approaches enable principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.

Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification.

BACKGROUND: By identifying pathogenic variants across hundreds of genes, expanded carrier screening (ECS) enables prospective parents to assess the risk of transmitting an autosomal recessive or X-linked condition. Detection of at-risk couples depends on the number of conditions tested, the prevalence of the respective diseases, and the screen's analytical sensitivity for identifying disease-causing variants. Disease-level analytical sensitivity is often <100% in ECS tests because copy number variants (CNVs) are typically not interrogated because of their technical complexity. METHODS: We present an analytical validation and preliminary clinical characterization of a 235-gene sequencing-based ECS with full coverage across coding regions, targeted assessment of pathogenic noncoding variants, panel-wide CNV calling, and specialized assays for technically challenging genes. Next-generation sequencing, customized bioinformatics, and expert manual call review were used to identify single-nucleotide variants, short insertions and deletions, and CNVs for all genes except FMR1 and those whose low disease incidence or high technical complexity precluded novel variant identification or interpretation. RESULTS: Screening of 36859 patients' blood or saliva samples revealed the substantial impact on fetal disease-risk detection attributable to novel CNVs (9.19% of risk) and technically challenging conditions (20.2% of risk), such as congenital adrenal hyperplasia. Of the 7498 couples screened, 335 were identified as at risk for an affected pregnancy, underscoring the clinical importance of the test. Validation of our ECS demonstrated >99% analytical sensitivity and >99% analytical specificity. CONCLUSIONS: Validated high-fidelity identification of different variant types-especially for diseases with complicated molecular genetics-maximizes at-risk couple detection.

Clinical Utility of Expanded Carrier Screening: Reproductive Behaviors of At-Risk Couples.

Expanded carrier screening (ECS) analyzes dozens or hundreds of recessive genes to determine reproductive risk. Data on the clinical utility of screening conditions beyond professional guidelines are scarce. Individuals underwent ECS for up to 110 genes. Five-hundred thirty-seven at-risk couples (ARC), those in which both partners carry the same recessive disease, were invited to participate in a retrospective IRB-approved survey of their reproductive decision making after receiving ECS results. Sixty-four eligible ARC completed the survey. Of 45 respondents screened preconceptionally, 62% (n = 28) planned IVF with PGD or prenatal diagnosis (PNDx) in future pregnancies. Twenty-nine percent (n = 13) were not planning to alter reproductive decisions. The remaining 9% (n = 4) of responses were unclear. Of 19 pregnant respondents, 42% (n = 8) elected PNDx, 11% (n = 2) planned amniocentesis but miscarried, and 47% (n = 9) considered the condition insufficiently severe to warrant invasive testing. Of the 8 pregnancies that underwent PNDx, 5 were unaffected and 3 were affected. Two of 3 affected pregnancies were terminated. Disease severity was found to have significant association (p = 0.000145) with changes in decision making, whereas guideline status of diseases, controlled for severity, was not (p = 0.284). Most ARC altered reproductive planning, demonstrating the clinical utility of ECS. Severity of conditions factored into decision making.

Smith-Lemli-Opitz syndrome carrier frequency and estimates of in utero mortality rates.

OBJECTIVE: To tabulate individual allele frequencies and total carrier frequency for Smith-Lemli-Opitz syndrome (SLOS) and compare expected versus observed birth incidences. METHODS: A total of 262 399 individuals with no known indication or increased probability of SLOS carrier status, primarily US based, were screened for SLOS mutations as part of an expanded carrier screening panel. Results were retrospectively analyzed to estimate carrier frequencies in multiple ethnic groups. SLOS birth incidences obtained from existing literature were then compared with these data to estimate the effect of SLOS on fetal survival. RESULTS: Smith-Lemli-Opitz syndrome carrier frequency is highest in Ashkenazi Jews (1 in 43) and Northern Europeans (1 in 54). Comparing predicted birth incidence with that observed in published literature suggests that approximately 42% to 88% of affected conceptuses experience prenatal demise. CONCLUSION: Smith-Lemli-Opitz syndrome is relatively frequent in certain populations and, because of its impact on prenatal and postnatal morbidity and mortality, merits consideration for routine screening. © 2017 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

Noninvasive prenatal screening at low fetal fraction: comparing whole-genome sequencing and single-nucleotide polymorphism methods.

OBJECTIVE: Performance of noninvasive prenatal screening (NIPS) methodologies when applied to low fetal fraction samples is not well established. The single-nucleotide polymorphism (SNP) method fails samples below a predetermined fetal fraction threshold, whereas some laboratories employing the whole-genome sequencing (WGS) method report aneuploidy calls for all samples. Here, the performance of the two methods was compared to determine which approach actually detects more fetal aneuploidies. METHODS: Computational models were parameterized with up-to-date published data and used to compare the performance of the two methods at calling common fetal trisomies (T21, T18, T13) at low fetal fractions. Furthermore, clinical experience data were reviewed to determine aneuploidy detection rates based on compliance with recent invasive screening recommendations. RESULTS: The SNP method's performance is dependent on the origin of the trisomy, and is lowest for the most common trisomies (maternal M1 nondisjunction). Consequently, the SNP method cannot maintain acceptable performance at fetal fractions below ~3%. In contrast, the WGS method maintains high specificity independent of fetal fraction and has >80% sensitivity for trisomies in low fetal fraction samples. CONCLUSION: The WGS method will detect more aneuploidies below the fetal fraction threshold at which many labs issue a no-call result, avoiding unnecessary invasive procedures. © 2017 Counsyl Inc. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

Pharmacologic Treatment of Insomnia Disorder: An Evidence Report for a Clinical Practice Guideline by the American College of Physicians.

BACKGROUND: Pharmacologic interventions are often prescribed for insomnia disorder. PURPOSE: To assess the benefits, harms, and comparative effectiveness of pharmacologic treatments for adults with insomnia disorder. DATA SOURCES: Several electronic databases (2004-September 2015), reference lists, and U.S. Food and Drug Administration (FDA) documents. STUDY SELECTION: 35 randomized, controlled trials of at least 4 weeks' duration that evaluated pharmacotherapies available in the United States and that reported global or sleep outcomes; 11 long-term observational studies that reported harm information; FDA review data for nonbenzodiazepine hypnotics and orexin receptor antagonists; and product labels for all agents. DATA EXTRACTION: Data extraction by single investigator confirmed by a second reviewer; dual-investigator assessment of risk of bias; consensus determination of strength of evidence. DATA SYNTHESIS: Eszopiclone, zolpidem, and suvorexant improved short-term global and sleep outcomes compared with placebo, although absolute effect sizes were small (low- to moderate-strength evidence). Evidence for benzodiazepine hypnotics, melatonin agonists, and antidepressants, and for most pharmacologic interventions in older adults, was insufficient or low strength. Evidence was also insufficient to compare efficacy within or across pharmacotherapy classes or versus behavioral therapy. Harms evidence reported in trials was judged insufficient or low strength; observational studies suggested that use of hypnotics for insomnia was associated with increased risk for dementia, fractures, and major injury. The FDA documents reported that most pharmacotherapies had risks for cognitive and behavioral changes, including driving impairment, and other adverse effects, and they advised dose reduction in women and in older adults. LIMITATIONS: Most trials were small and short term and enrolled individuals meeting stringent criteria. Minimum important differences in outcomes were often not established or reported. Data were scant for many treatments. CONCLUSION: Eszopiclone, zolpidem, and suvorexant may improve short-term global and sleep outcomes for adults with insomnia disorder, but the comparative effectiveness and long-term efficacy of pharmacotherapies for insomnia are not known. Pharmacotherapies for insomnia may cause cognitive and behavioral changes and may be associated with infrequent but serious harms. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. ( PROSPERO: CRD42014009908).