Using social media for patient care, research, and professional development: A North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition position paper.

The advent of social media has changed numerous aspects of modern life, with users developing and maintaining personal and professional relationships, following and sharing breaking news and importantly, searching for and disseminating health information and medical research. In the present paper, we reviewed available literature to outline the potential uses, pitfalls and impacts of social media for providers, scientists and institutions involved in digestive health in the domains of patient care, research and professional development. We recommend that these groups become more active participants on social media platforms to combat misinformation, advocate for patients, and curate and disseminate valuable research and educational materials. We also recommend that societies such as NASPGHAN assist its members in accessing training on effective social media use and the creation and maintenance of public-facing profiles and that academic institutions incorporate substantive social media contributions into academic promotion processes.

Returning Individual Research Results from Digital Phenotyping in Psychiatry.

Psychiatry is rapidly adopting digital phenotyping and artificial intelligence/machine learning tools to study mental illness based on tracking participants' locations, online activity, phone and text message usage, heart rate, sleep, physical activity, and more. Existing ethical frameworks for return of individual research results (IRRs) are inadequate to guide researchers for when, if, and how to return this unprecedented number of potentially sensitive results about each participant's real-world behavior. To address this gap, we convened an interdisciplinary expert working group, supported by a National Institute of Mental Health grant. Building on established guidelines and the emerging norm of returning results in participant-centered research, we present a novel framework specific to the ethical, legal, and social implications of returning IRRs in digital phenotyping research. Our framework offers researchers, clinicians, and Institutional Review Boards (IRBs) urgently needed guidance, and the principles developed here in the context of psychiatry will be readily adaptable to other therapeutic areas.

Are dietitian recommendations followed? A descriptive study of paediatric hospitalised and ambulatory patients.

BACKGROUND: The primary objective of this cross-sectional retrospective study was to describe the implementation of dietitian prescribed nutrition recommendations in malnourished paediatric patients in the hospital and ambulatory settings. We also aimed to investigate other characteristics that could be associated with differences in implementation. METHODS: Data were collected from 186 hospitalised and 565 ambulatory patients between February 2020 and January 2021. Data included age, hospital or ambulatory specialty departments, primary diagnosis, malnutrition status, hospital length of stay (LOS), and medical nutrition therapy recommendations. Implementation by the medical team in the hospital setting and adherence by the family in the outpatient setting were categorised as "Full", "Partial" or "None". "Partial" and "None" were combined for analysis. RESULTS: Dietitian prescribed recommendations were implemented in 79.6% of hospitalised patients. In the ambulatory population, 46.4% of patients were adherent with nutrition recommendations. Within the hospital, there was a significant difference in implementation of nutrition recommendations based on age (p = 0.047), hospital department (p = 0.002) and LOS (p = 0.04), whereas, in the ambulatory population, there were no significant differences in the rate of adherence among any of the studied characteristics. CONCLUSIONS: Dietitian recommendations are frequently implemented in the hospital, whereas adherence to such recommendations is poor in the outpatient population. Interventions to improve adherence to nutrition recommendations in the ambulatory setting are needed.

Phenotypic and genomic characterizations of Klebsiella pneumoniae ssp. pneumoniae and Rahnella inusitata strains reveal no clear association between genetic content and ropy phenotype.

Ropy defect of pasteurized fluid milk is a type of spoilage which manifests itself by an increased viscosity, slimy body, and string-like flow during pouring. This defect has, among other causes, been attributed to the growth, proliferation and exopolysaccharide production by coliform bacteria, which are most commonly introduced in milk as post-pasteurization contaminants. As we identified both Klebsiella pneumoniae ssp. pneumoniae and Rahnella inusitata that were linked to a ropy defect, the goal of this study was to characterize 3 K. pneumoniae ssp. pneumoniae strains and 2 R. inusitata for (1) their ability to grow and cause ropy defect in milk at 6°C and 21°C and to (2) probe the genetic basis for observed ropy phenotype. Although all K. pneumoniae ssp. pneumoniae and R. inusitata strains showed net growth of >4 log10 over 48 h in UHT milk at 21°C, only R. inusitata strains displayed growth during 28-d incubation period at 6°C (>6 log10). Two out of 3 K. pneumoniae ssp. pneumoniae strains were capable of causing the ropy defect in milk at 21°C, as supported by an increase in the viscosity of milk and string-like flow during pouring; these 2 strains were originally isolated from raw milk. Only one R. inusitata strains was able to cause the ropy defect in milk; this strain was able to cause the defect at both 6°C and 21°C, and was originally isolated from a pasteurized milk. These findings suggest that the potential of K. pneumoniae ssp. pneumoniae and R. inusitata to cause ropy defect in milk is a strain-dependent characteristic. Comparative genomics provided no definitive answer on genetic basis for the ropy phenotype. However, for K. pneumoniae ssp. pneumoniae, genes rffG, rffH, rfbD, and rfbC involved in biosynthesis and secretion of enterobacterial common antigen (ECA) could only be found in the 2 strains that produced ropy defect, and for R. inusitata a set of 2 glycosyltransferase- and flippase genes involved in nucleotide sugar biosynthesis and export could only be identified in the ropy strain. Although these results provide some initial information for potential markers for strains that can cause ropy milk, the relationship between genetic content and ropiness in milk remains poorly understood and merits further investigation.

Troubleshooting high laboratory pasteurization counts in organic raw milk requires characterization of dominant thermoduric bacteria, which includes nonsporeformers as well as sporeformers.

Laboratory pasteurization count (LPC) enumerates thermoduric bacteria and is one parameter used to assess raw milk quality. No regulatory limit has presently been set for LPC, but LPC data are used by some dairy processors and cooperatives to designate raw milk quality premiums paid to farmers and may also be used for troubleshooting bacterial contamination issues. Although it is occasionally used as a proxy for levels of bacterial spores in raw milk, limited knowledge is available on the types of organisms that are enumerated by LPC in contemporary raw milk supplies. Although historical studies have reported that thermoduric bacteria quantified by LPC may predominantly represent gram-positive cocci, updated knowledge on microbial populations enumerated by LPC in contemporary organic raw milk supplies is needed. To address this gap, organic raw milk samples from across the United States (n = 94) were assessed using LPC, and bacterial isolates were characterized. LPC ranged from below detection (<0.70 log cfu/mL) to 4.07 log cfu/mL, with a geometric mean of 1.48 log cfu/mL. Among 380 isolates characterized by 16S rDNA sequencing, 52.6%, 44.5%, and 2.4% were identified as gram-positive sporeformers, gram-positive nonsporeformers, and gram-negatives, respectively; 0.5% could not be categorized into those groups because they could only be assigned a higher level of taxonomy. Isolates identified as gram-positive sporeformers were predominantly Bacillus (168/200), and gram-positive nonsporeformers were predominantly Brachybacterium (56/169) and Kocuria (47/169). To elucidate if the LPC level can be an indicator of the type of thermoduric (e.g., sporeforming bacteria) present in raw milk, we evaluated the proportion of sporeformers in raw milk samples with LPC of ≤100 cfu/mL, 100 to 200 cfu/mL, and ≥200 cfu/mL (51%, 67%, and 35%), showing a trend for sporeformers to represent a smaller proportion of the total thermoduric population when LPC increases, although overall linear regression showed no significant association between the proportion of sporeformers and the LPC concentration. Hence, LPC level alone provides no insight into the makeup of the thermoduric population in raw milk, and further characterization is needed to elucidate the bacterial drivers of elevated LPC in raw milk. We therefore further characterized the isolates from this study using MALDI-TOF mass spectrometry (MALDI-TOF MS), a rapid microbial identification tool that is more readily available to dairy producers than 16S rDNA PCR and sequencing. Although our data indicated agreement between 16S rDNA sequencing and MALDI-TOF MS for 66.6% of isolates at the genus level, 24.2% and 9.2% could not be reliably identified or were mischaracterized using MALDI-TOF MS, respectively. This suggests that further optimization of this method is needed to allow for accurate characterization of thermoduric organisms commonly found in raw milk. Ultimately, our study provides a contemporary perspective on thermoduric bacteria selected by the LPC method and establishes that the LPC alone is not sufficient for identifying the bacterial drivers of LPC levels. Further development of rapid characterization methods that are accessible to producers, cooperatives, and processors will support milk quality troubleshooting efforts and ultimately improve outcomes for dairy industry community members.

Longitudinal associations between interpersonal relationship functioning and posttraumatic stress disorder (PTSD) in recently traumatized individuals: differential findings by assessment method.

BACKGROUND: The role of interpersonal relationship functioning in trauma recovery is well-established. However, much of this research has been done with cross-sectional samples, often years after trauma exposure, using self-report methodology only, and is focused on intimate relationship adjustment. METHODS: The current study investigated the longitudinal associations between interpersonal (intimate and non-intimate) relationship functioning and clinician- and self-reported posttraumatic stress disorder (PTSD) symptoms in 151 recently (within the past 6 months) traumatized individuals. Participants were assessed at four time points over 1 year. RESULTS: Approximately 53% of the sample was diagnosed with PTSD at initial assessment, with declining rates of diagnostic status over time to 16%. Latent difference score (LDS) modeling revealed nonlinear declines in both clinician-assessed and self-reported PTSD symptom severity, with faster declines in earlier periods. Likewise, LDS models revealed nonlinear declines in negative (conflict) aspects of interpersonal relationship functioning, but linear declines in positive (support, depth) aspects. The relationship between PTSD and relationship functioning differed for clinician- and self-reported PTSD. Bivariate LDS modeling revealed significant cross-lagged effects from relationship conflict to clinician-assessed PTSD, and significant cross-lagged effects from self-reported PTSD to relationship conflict over time. CONCLUSIONS: These results highlight that the variability in prior results may be related to the method of assessing PTSD symptomatology and different relational constructs. Implications for theory and early intervention are discussed.

Fetal akinesia deformation sequence syndrome associated with recessive TTN variants.

Arthrogryposis multiplex congenita (AMC) [also known as multiple joints contracture or Fetal Akinesia Deformation Sequence (FADS)] is etiologically a heterogeneous condition with an estimated incidence of approximately 1 in 3000 live births and much higher incidence when prenatally diagnosed cases are included. The condition can be acquired or secondary to fetal exposures and can also be caused by a variety of single-gene disorders affecting the brain, spinal cord, peripheral nerves, neuromuscular junction, muscle, and a variety of disorders affecting the connective tissues (Niles et al., Prenatal Diagnosis, 2019; 39:720-731). The introduction of next-generation gene sequencing uncovered many genes and causative variants of AMC but also identified genes that cause both dominant and recessive inherited conditions with the variability of clinical manifestations depending on the genes and variants. Molecular diagnosis in these cases is not only important for prognostication but also for the determination of recurrence risk and for providing reproductive options including preimplantation and prenatal diagnosis. TTN, the largest known gene in the human genome, has been known to be associated with autosomal dominant dilated cardiomyopathy. However, homozygote and compound heterozygote pathogenic variants with recessive inheritance have rarely been reported. We report the effect of recessive variants located within the fetal IC and/or N2BA isoforms in association with severe FADS in three families. All parents were healthy obligate carriers and none of them had cardiac or skeletal muscle abnormalities. This report solidifies FADS as an alternative phenotypic presentation associated with homozygote/compound heterozygous pathogenic variants in the TTN.

A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature.

AMOTL1 encodes angiomotin-like protein 1, an actin-binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricular anomalies, and gastrointestinal manifestations in individuals with variants in AMOTL1 affecting amino acids 157-161, a functionally undefined but highly conserved region. Three individuals with AMOTL1 variants outside this region are also described who had variable presentations with orofacial clefting and multi-organ disease. Our case cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157-161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.

Warmer and more acidic conditions enhance performance of an endemic low-shore gastropod.

Changing ocean temperatures are predicted to challenge marine organisms, especially when combined with other factors, such as ocean acidification. Acclimation, as a form of phenotypic plasticity, can moderate the consequences of changing environments for biota. Our understanding of how altered temperature and acidification together influence species' acclimation responses is, however, limited compared with that of responses to single stressors. This study investigated how temperature and acidification affect the thermal tolerance and righting speed of the girdled dogwhelk, Trochia cingulata. Whelks were acclimated for 2 weeks to combinations of three temperatures (11°C: cold, 13°C: moderate and 15°C: warm) and two pH regimes (8.0: moderate and 7.5: acidic). We measured the temperature sensitivity of the righting response by generating thermal performance curves from individual data collected at seven test temperatures and determined critical thermal minima (CTmin) and maxima (CTmax). We found that T. cingulata has a broad basal thermal tolerance range (∼38°C) and after acclimation to the warm temperature regime, both the optimal temperature for maximum righting speed and CTmax increased. Contrary to predictions, acidification did not narrow this population's thermal tolerance but increased CTmax. These plastic responses are likely driven by the predictable exposure to temperature extremes measured in the field which originate from the local tidal cycle and the periodic acidification associated with ocean upwelling in the region. This acclimation ability suggests that T. cingulata has at least some capacity to buffer the thermal changes and increased acidification predicted to occur with climate change.

Tezepelumab reduces exacerbations across all seasons in patients with severe, uncontrolled asthma (NAVIGATOR).

BACKGROUND: Asthma exacerbation frequencies vary throughout the year owing to seasonal triggers. Tezepelumab is a human monoclonal antibody that targets thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab significantly reduced the annualized asthma exacerbation rate (AAER) vs placebo in patients with severe, uncontrolled asthma. OBJECTIVE: To evaluate the effect of tezepelumab on asthma exacerbations across all seasons in NAVIGATOR patients (post hoc). METHODS: NAVIGATOR was a multicenter, randomized, double-blind, placebo-controlled study. Patients (12-80 years old) were randomized 1:1 to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. AAER over 52 weeks was assessed by season. Data from patients in the Southern Hemisphere were transformed to align with Northern Hemisphere seasons. RESULTS: Tezepelumab reduced the AAER vs placebo by 63% (95% confidence interval [CI], 52-72) in winter, 46% (95% CI, 26-61) in spring, 62% (95% CI, 48-73) in summer, and 54% (95% CI, 41-64) in fall. In matched climates, during the spring allergy season (March 1 to June 15) and ragweed allergy season (September), tezepelumab reduced the AAER vs placebo in patients with seasonal allergy by 59% (95% CI, 29-77) and 70% (95% CI, 33-87), respectively. In patients with perennial allergy and in those with seasonal allergy, tezepelumab reduced the AAER vs placebo across all seasons. CONCLUSION: Tezepelumab reduced exacerbations across all seasons vs placebo in patients with severe, uncontrolled asthma, including patients with seasonal and perennial allergies. These data further support the efficacy of tezepelumab in a broad population of patients with severe, uncontrolled asthma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03347279 (https://clinicaltrials.gov/ct2/show/NCT03347279).

Epistemic Rights and Responsibilities of Digital Simulacra for Biomedicine.

Big data and AI have enabled digital simulation for prediction of future health states or behaviors of specific individuals, populations or humans in general. "Digital simulacra" use multimodal datasets to develop computational models that are virtual representations of people or groups, generating predictions of how systems evolve and react to interventions over time. These include digital twins and virtual patients for in silico clinical trials, both of which seek to transform research and health care by speeding innovation and bridging the epistemic gap between population-based research findings and their application to the individual. Nevertheless, digital simulacra mark a major milestone on a trajectory to embrace the epistemic culture of data science and a potential abandonment of medical epistemological concepts of causality and representation. In doing so, "data first" approaches potentially shift moral attention from actual patients and principles, such as equity, to simulated patients and patient data.

Low-cost, on-farm intervention to reduce spores in bulk tank raw milk benefits producers, processors, and consumers.

Bacterial spores, which are found in raw milk, can survive harsh processing conditions encountered in dairy manufacturing, including pasteurization and drying. Low-spore raw milk is desirable for dairy industry stakeholders, especially those who want to extend the shelf life of their product, expand their distribution channels, or reduce product spoilage. A recent previous study showed that an on-farm intervention that included washing towels with chlorine bleach and drying them completely, as well as training milking parlor employees to focus on teat end cleaning, significantly reduced spore levels in bulk tank raw milk. As a follow up to that previous study, here we calculate the costs associated with that previously described intervention as ranging from $9.49 to $13.35 per cow per year, depending on farm size. A Monte Carlo model was used to predict the shelf life of high temperature, short time fluid milk processed from raw milk before and after this low-cost intervention was applied, based on experimental data collected in a previous study. The model predicted that 18.24% of half-gallon containers of fluid milk processed from raw milk receiving no spore intervention would exceed the pasteurized milk ordinance limit of 20,000 cfu/mL by 17 d after pasteurization, while only 16.99% of containers processed from raw milk receiving the spore intervention would reach this level 17 d after pasteurization (a reduction of 1.25 percentage points and a 6.85% reduction). Finally, a survey of consumer milk use was conducted to determine how many consumers regularly consume fluid milk near or past the date printed on the package (i.e., code date), which revealed that over 50% of fluid milk consumers surveyed continue to consume fluid milk after this date, indicating that a considerable proportion of consumers are exposed to fluid milk that is likely to have high levels spore-forming bacterial growth and possibly associated quality defects (e.g., flavor or odor defects). This further highlights the importance of reducing spore levels in raw milk to extend pasteurized fluid milk shelf life and thereby reducing the risk of adverse consumer experiences. Processors who are interested in extending fluid milk shelf life by controlling the levels of spores in the raw milk supply should consider incentivizing low-spore raw milk through premium payments to producers.

Oral famotidine versus placebo in non-hospitalised patients with COVID-19: a randomised, double-blind, data-intense, phase 2 clinical trial.

OBJECTIVE: We assessed whether famotidine improved inflammation and symptomatic recovery in outpatients with mild to moderate COVID-19. DESIGN: Randomised, double-blind, placebo-controlled, fully remote, phase 2 clinical trial (NCT04724720) enrolling symptomatic unvaccinated adult outpatients with confirmed COVID-19 between January 2021 and April 2021 from two US centres. Patients self-administered 80 mg famotidine (n=28) or placebo (n=27) orally three times a day for 14 consecutive days. Endpoints were time to (primary) or rate of (secondary) symptom resolution, and resolution of inflammation (exploratory). RESULTS: Of 55 patients in the intention-to-treat group (median age 35 years (IQR: 20); 35 women (64%); 18 African American (33%); 14 Hispanic (26%)), 52 (95%) completed the trial, submitting 1358 electronic symptom surveys. Time to symptom resolution was not statistically improved (p=0.4). Rate of symptom resolution was improved for patients taking famotidine (p<0.0001). Estimated 50% reduction of overall baseline symptom scores were achieved at 8.2 days (95% CI: 7 to 9.8 days) for famotidine and 11.4 days (95% CI: 10.3 to 12.6 days) for placebo treated patients. Differences were independent of patient sex, race or ethnicity. Five self-limiting adverse events occurred (famotidine, n=2 (40%); placebo, n=3 (60%)). On day 7, fewer patients on famotidine had detectable interferon alpha plasma levels (p=0.04). Plasma immunoglobulin type G levels to SARS-CoV-2 nucleocapsid core protein were similar between both arms. CONCLUSIONS: Famotidine was safe and well tolerated in outpatients with mild to moderate COVID-19. Famotidine led to earlier resolution of symptoms and inflammation without reducing anti-SARS-CoV-2 immunity. Additional randomised trials are required.

Effectiveness of cognitive behavioral conjoint therapy for posttraumatic stress disorder (PTSD) in a U.S. Veterans Affairs PTSD clinic.

Cognitive behavioral conjoint therapy (CBCT) for posttraumatic stress disorder (PTSD) is a 15-session conjoint treatment for PTSD designed to improve PTSD symptoms and enhance intimate relationship functioning. Numerous studies of CBCT for PTSD document improvements in patient PTSD and comorbid symptoms, partner mental health, and relationship adjustment. However, little is known about its effectiveness in real-world clinical settings. Using an intention-to-treat sample of couples who participated in CBCT for PTSD in an outpatient U.S. Veterans Affairs (VA) PTSD clinic (N = 113), trajectories of session-by-session reports of veterans' PTSD symptoms and both partners' relationship happiness were examined. Across sessions, there were significant reductions in veteran-rated PTSD symptoms, d = -0.69, and significant increases in veteran- and partner-rated relationship happiness, ds = 0.36 and 0.35, respectively. Partner ratings of veterans' PTSD symptoms increased before significantly decreasing, d = -0.24. Secondary outcomes of veteran and partner relationship satisfaction, ds = 0.30 and 0.42, respectively; veteran and partner depressive symptoms, ds = -0.75 and -0.29, respectively; and partner accommodation of PTSD symptoms, d = -0.44, also significantly improved from pre- to posttreatment. The findings suggest that CBCT for PTSD was effective for decreasing PTSD and comorbid symptoms in veterans, as well as for improving relationship functioning and partners' mental health, among a sample of real-world couples seeking treatment in a VA PTSD specialty clinic.

An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids.

PURPOSE: In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu). METHODS: Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics. RESULTS: All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production. CONCLUSION: Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.

Heterozygous NOTCH1 deletion associated with variable congenital heart defects.

Pathogenic heterozygous variants in the NOTCH1 gene are known to be associated with both left and right-sided congenital cardiac anomalies with strikingly incomplete penetrance and variable phenotypic expressivity. De novo NOTCH1 whole gene deletion has been reported rarely in the literature and its association with cardiac defects is less well established. Here, we report four cases of NOTCH1 gene deletion from two families associated with a spectrum of congenital heart defects from bicuspid aortic valve to complex cardiac anomalies. This is the first description of a familial NOTCH1 deletion, showing apparently high penetrance, which may be unique to this mechanism of disease. Immunohistochemical staining of cardiac tissue demonstrated reduced levels of NOTCH1 expression in both the left and right ventricular outflow tracts. These cases suggest that haploinsufficiency caused by NOTCH1 gene deletion is associated with both mild and severe cardiac defects, similar to those caused by pathogenic variants in the gene, but with apparently higher, if not complete, penetrance.

Reexamining the optimal nuchal translucency cutoff for diagnostic testing in the cell-free DNA and microarray era: results from the Victorian Perinatal Record Linkage study.

BACKGROUND: The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recently recommended offering genetic counseling and diagnostic testing for enlarged nuchal translucency at ≥3.0 mm, regardless of previous negative screening with noninvasive prenatal testing. OBJECTIVE: This study aimed to perform a population-based, individual record linkage study to determine the optimal definition of an enlarged nuchal translucency for the detection of atypical chromosome abnormalities. STUDY DESIGN: This was a retrospective study of women resident in Victoria, Australia, undergoing combined first-trimester screening during the 24-month period from January 2015 to December 2016. Linkages between statewide results for combined first-trimester screening, prenatal diagnostic procedures, and postnatal cytogenetic results from products of conception and infants up to 12 months of age were used to ascertain the frequency and type of chromosome abnormality by gestation and nuchal translucency measurement. An atypical chromosome abnormality was defined as any major chromosome abnormality other than whole chromosome aneuploidy involving chromosomes 21, 18, 13, X, and Y. RESULTS: Of the 81,244 singleton pregnancies undergoing combined first-trimester screening, 491 (0.60%) had a nuchal translucency of ≥3.5 mm, 534 (0.66%) had a nuchal translucency of 3.0 to 3.4 mm, and 80,219 (98.74%) had a nuchal translucency of < 3.0 mm. When grouped by nuchal translucency multiples of the median (MoM), 192 (0.24%) had a nuchal translucency of ≥3.0 MoM, 513 (0.63%) had a nuchal translucency of 1.9 to 2.9 MoM, and 80,539 (99.13%) had a nuchal translucency of <1.9 MoM. A total of 1779 pregnancies underwent prenatal or postnatal diagnostic testing, of which 89.60% were performed by whole-genome single-nucleotide polymorphism chromosomal microarray. The frequency of total major chromosome abnormalities was significantly higher in the group with a nuchal translucency of ≥3.5 mm (147 of 491, 29.94%) than the group with a nuchal translucency of 3.0 to 3.4 mm (21 of 534, 3.93%) or a nuchal translucency of <3.0 mm (71 of 80,219, 0.09%) (P<.001). There were 93 atypical chromosome abnormalities in the total screened cohort. The frequency of an atypical chromosome abnormality was 4.07% (95% confidence interval, 2.51-6.22), 0.37% (95% confidence interval, 0.05-1.35), and 0.09% (95% confidence interval, 0.07-0.11) in the groups with a nuchal translucency of ≥3.5 mm, 3.0 to 3.4 mm, and <3.0 mm, respectively. The frequency of atypical chromosome abnormalities was 4.69% (95% confidence interval, 2.17-8.71), 2.53% (95% confidence interval, 1.36-4.29), and 0.09% (95% confidence interval, 0.07-0.11) in the groups with a nuchal translucency of ≥3.0 MoM, 1.9 to 2.9 MoM, and <1.9 MoM, respectively. When defining thresholds for offering diagnosis with chromosomal microarray at 11 to 13 weeks, both a nuchal translucency threshold of 1.9 MoM and a fixed threshold of 3.0 mm captured 22 of 93 fetuses (23.7%) with an atypical chromosome abnormality. Of these, 50.0% had a coexisting fetal abnormality on ultrasound. However, the gestation-specific threshold of 1.9 MoM had a better specificity than 3.0 mm. The positive predictive value of an enlarged nuchal translucency for any atypical chromosome abnormality was 1 in 47 for nuchal translucency of >3.0 mm and 1 in 32 for nuchal translucency of >1.9 MoM. Our nuchal translucency threshold of 1.9 MoM captured 0.87% of fetuses, thus approximating the 99th centile. CONCLUSION: A gestational age-adjusted nuchal translucency threshold of 1.9 MoM or 99th centile is superior to the fixed cutoff of 3.0 mm for the identification of atypical chromosome abnormalities. The risk of an atypical chromosome abnormality in a fetus with an enlarged nuchal translucency is more than tripled in the presence of an additional ultrasound abnormality.

Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction.

BACKGROUND: Beta-blockers and inhibitors of the renin-angiotensin-aldosterone system improve survival and reduce morbidity in people with heart failure with reduced left ventricular ejection fraction (LVEF); a review of the evidence is required to determine whether these treatments are beneficial for people with heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: To assess the effects of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor neprilysin inhibitors, and mineralocorticoid receptor antagonists in people with HFpEF. SEARCH METHODS: We updated searches of CENTRAL, MEDLINE, Embase, and one clinical trial register on 14 May 2020 to identify eligible studies, with no language or date restrictions. We checked references from trial reports and review articles for additional studies.  SELECTION CRITERIA: We included randomised controlled trials with a parallel group design, enrolling adults with HFpEF, defined by LVEF greater than 40%. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 41 randomised controlled trials (231 reports), totalling 23,492 participants across all comparisons. The risk of bias was frequently unclear and only five studies had a low risk of bias in all domains. Beta-blockers (BBs) We included 10 studies (3087 participants) investigating BBs. Five studies used a placebo comparator and in five the comparator was usual care. The mean age of participants ranged from 30 years to 81 years. A possible reduction in cardiovascular mortality was observed (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.62 to 0.99; number needed to treat for an additional benefit (NNTB) 25; 1046 participants; three studies), however, the certainty of evidence was low. There may be little to no effect on all-cause mortality (RR 0.82, 95% CI 0.67 to 1.00; 1105 participants; four studies; low-certainty evidence). The effects on heart failure hospitalisation, hyperkalaemia, and quality of life remain uncertain. Mineralocorticoid receptor antagonists (MRAs) We included 13 studies (4459 participants) investigating MRA. Eight studies used a placebo comparator and in five the comparator was usual care. The mean age of participants ranged from 54.5 to 80 years. Pooled analysis indicated that MRA treatment probably reduces heart failure hospitalisation (RR 0.82, 95% CI 0.69 to 0.98; NNTB = 41; 3714 participants; three studies; moderate-certainty evidence). However, MRA treatment probably has little or no effect on all-cause mortality (RR 0.91, 95% CI 0.78 to 1.06; 4207 participants; five studies; moderate-certainty evidence) and cardiovascular mortality (RR 0.90, 95% CI 0.74 to 1.11; 4070 participants; three studies; moderate-certainty evidence). MRA treatment may have little or no effect on quality of life measures (mean difference (MD) 0.84, 95% CI -2.30 to 3.98; 511 participants; three studies; low-certainty evidence). MRA treatment was associated with a higher risk of hyperkalaemia (RR 2.11, 95% CI 1.77 to 2.51; number needed to treat for an additional harmful outcome (NNTH) = 11; 4291 participants; six studies; high-certainty evidence). Angiotensin-converting enzyme inhibitors (ACEIs) We included eight studies (2061 participants) investigating ACEIs. Three studies used a placebo comparator and in five the comparator was usual care. The mean age of participants ranged from 70 to 82 years. Pooled analyses with moderate-certainty evidence suggest that ACEI treatment likely has little or no effect on cardiovascular mortality (RR 0.93, 95% CI 0.61 to 1.42; 945 participants; two studies), all-cause mortality (RR 1.04, 95% CI 0.75 to 1.45; 1187 participants; five studies) and heart failure hospitalisation (RR 0.86, 95% CI 0.64 to 1.15; 1019 participants; three studies), and may result in little or no effect on the quality of life (MD -0.09, 95% CI -3.66 to 3.48; 154 participants; two studies; low-certainty evidence). The effects on hyperkalaemia remain uncertain. Angiotensin receptor blockers (ARBs) Eight studies (8755 participants) investigating ARBs were included. Five studies used a placebo comparator and in three the comparator was usual care. The mean age of participants ranged from 61 to 75 years. Pooled analyses with high certainty of evidence suggest that ARB treatment has little or no effect on cardiovascular mortality (RR 1.02, 95% 0.90 to 1.14; 7254 participants; three studies), all-cause mortality (RR 1.01, 95% CI 0.92 to 1.11; 7964 participants; four studies), heart failure hospitalisation (RR 0.92, 95% CI 0.83 to 1.02; 7254 participants; three studies), and quality of life (MD 0.41, 95% CI -0.86 to 1.67; 3117 participants; three studies). ARB was associated with a higher risk of hyperkalaemia (RR 1.88, 95% CI 1.07 to 3.33; 7148 participants; two studies; high-certainty evidence). Angiotensin receptor neprilysin inhibitors (ARNIs) Three studies (7702 participants) investigating ARNIs were included. Two studies used ARBs as the comparator and one used standardised medical therapy, based on participants' established treatments at enrolment. The mean age of participants ranged from 71 to 73 years. Results suggest that ARNIs may have little or no effect on cardiovascular mortality (RR 0.96, 95% CI 0.79 to 1.15; 4796 participants; one study; moderate-certainty evidence), all-cause mortality (RR 0.97, 95% CI 0.84 to 1.11; 7663 participants; three studies; high-certainty evidence), or quality of life (high-certainty evidence). However, ARNI treatment may result in a slight reduction in heart failure hospitalisation, compared to usual care (RR 0.89, 95% CI 0.80 to 1.00; 7362 participants; two studies; moderate-certainty evidence). ARNI treatment was associated with a reduced risk of hyperkalaemia compared with valsartan (RR 0.88, 95% CI 0.77 to 1.01; 5054 participants; two studies; moderate-certainty evidence). AUTHORS' CONCLUSIONS: There is evidence that MRA and ARNI treatment in HFpEF probably reduces heart failure hospitalisation but probably has little or no effect on cardiovascular mortality and quality of life. BB treatment may reduce the risk of cardiovascular mortality, however, further trials are needed. The current evidence for BBs, ACEIs, and ARBs is limited and does not support their use in HFpEF in the absence of an alternative indication. Although MRAs and ARNIs are probably effective at reducing the risk of heart failure hospitalisation, the treatment effect sizes are modest. There is a need for improved approaches to patient stratification to identify the subgroup of patients who are most likely to benefit from MRAs and ARNIs, as well as for an improved understanding of disease biology, and for new therapeutic approaches.

Suicidal Ideation in a Veterans Affairs Residential Posttraumatic Stress Disorder Treatment Setting: The Roles of Thwarted Belongingness and Perceived Burdensomeness.

Suicide is a significant public health concern, and, specifically, the veteran population has exhibited a 22% higher risk of death by suicide than the general population (Department of Veterans Affairs, 2017). The interpersonal psychological theory of suicide (IPTS; Joiner, 2005) appears to be the most widely researched theory to examine factors associated with suicidal ideation. The IPTS applies to veteran suicidal ideation in that veterans may feel they are burdensome to others or that they do not belong following their transition from active duty. The current study sought to (a) identify the prevalence and correlates of the IPTS constructs perceived burdensomeness and thwarted belongingness; (b) examine the main and interactive effects of these constructs on suicidal ideation; and (c) examine their indirect effects in the associations between posttraumatic stress disorder (PTSD) symptomatology, depressive symptomatology, and substance use with suicidal ideation in a sample of veterans in PTSD residential treatment (N = 125). Regression results demonstrated that perceived burdensomeness was significantly associated with suicidal ideation, ß = .50, p < .001; however, thwarted belongingness and the interaction of the two were not. In the models of indirect effects, perceived burdensomeness emerged as the only significant indirect effect in the association between PTSD symptomatology and suicidal ideation, ß = .01 (SE = .00), 95% CI [.0050, .0149], as well as between depressive symptomatology and suicidal ideation, ß = .02 (SE = .01), 95% CI [.0109, .0311]. Study limitations and future directions are also discussed.

Residential Cognitive Processing Therapy Decreases Suicidality by Reducing Perceived Burdensomeness in Veterans with Posttraumatic Stress Disorder.

The interpersonal theory of suicide (Joiner, 2005) may help explain high suicide rates among veterans with posttraumatic stress disorder (PTSD). It suggests that suicidal ideation results from believing that one is a burden on others (i.e., perceived burdensomeness) and does not belong among family, friends, or other social groups (i.e., thwarted belongingness). Evidence-based PTSD treatments, including cognitive processing therapy (CPT), decrease suicidal ideation, potentially through changes in these two theory constructs. The current study examined whether (a) changes in PTSD severity and suicidal ideation and (b) changes in negative cognitions about self and suicidal ideation were indirectly associated through changes in perceived burdensomeness and thwarted belongingness across PTSD treatment. Participants (N = 107) were veterans in a residential treatment program who were diagnosed with full or subthreshold PTSD and received CPT. Changes in PTSD symptom severity and negative cognitions about self predicted changes in suicidal ideation, B = 0.18, p < .001 and B = 0.50, p < .001, respectively. Changes in PTSD symptom severity and negative cognitions about self were indirectly associated with suicidal ideation through changes in perceived burdensomeness, B = 0.16, 95% CI [0.07, 0.25]; B = 0.27, 95% CI [0.05, 0.50], but not thwarted belongingness, B = -0.002; 95% CI [-0.06, 0.06]; B = 0.06, 95% CI [-0.12, 0.21] in separate models. These findings suggest that residential CPT may be uniquely equipped to decrease suicidality by restructuring negative beliefs, including perceptions of being a burden on others, and/or by alleviating the objective burden of PTSD.