Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.

A multisite comparison using electronic health records and natural language processing to identify the association between suicidality and hospital readmission amongst patients with eating disorders.

OBJECTIVES: To describe and compare the association between suicidality and subsequent readmission for patients hospitalized for eating disorder treatment, within 2 years of discharge, at two large academic medical centers in two different countries. METHODS: Over an 8-year study window from January 2009 to March 2017, we identified all inpatient eating disorder admissions at Weill Cornell Medicine, New York, USA (WCM) and South London and Maudsley Foundation NHS Trust, London, UK (SLaM). To establish each patient's-suicidality profile, we applied two natural language processing (NLP) algorithms, independently developed at the two institutions, and detected suicidality in clinical notes documented in the first week of admission. We calculated the odds ratios (OR) for any subsequent readmission within 2 years postdischarge and determined whether this was to another eating disorder unit, other psychiatric unit, a general medical hospital admission or emergency room attendance. RESULTS: We identified 1126 and 420 eating disorder inpatient admissions at WCM and SLaM, respectively. In the WCM cohort, evidence of above average suicidality during the first week of admission was significantly associated with an increased risk of noneating disorder-related psychiatric readmission (OR 3.48 95% CI = 2.03-5.99, p-value < .001), but a similar pattern was not observed in the SLaM cohort (OR 1.34, 95% CI = 0.75-2.37, p = .32), there was no significant increase in risk of admission. In both cohorts, personality disorder increased the risk of any psychiatric readmission within 2 years. DISCUSSION: Patterns of increased risk of psychiatric readmission from above average suicidality detected via NLP during inpatient eating disorder admissions differed in our two patient cohorts. However, comorbid diagnoses such as personality disorder increased the risk of any psychiatric readmission across both cohorts. PUBLIC SIGNIFICANCE: Suicidality amongst is eating disorders is an extremely common presentation and it is important we further our understanding of identifying those most at risk. This research also provides a novel study design, comparing two NLP algorithms on electronic health record data based in the United States and United Kingdom on eating disorder inpatients. Studies researching both UK and US mental health patients are sparse therefore this study provides novel data.

A systematic review and meta-analysis of cell-free DNA testing for detection of fetal sex chromosome aneuploidy.

OBJECTIVES: The aim was to determine the accuracy of cell-free DNA testing (cfDNA) for detecting sex chromosome aneuploidies (SCA) in singleton pregnancies. METHODS: A systematic review and meta-analysis was performed to assess cfDNA accuracy for prenatal detection of 45,X, 47,XXY, 47,XXX and 47,XYY. Inclusion was restricted to studies published between January 2010 and December 2021 reporting both cfDNA and confirmatory diagnostic test results. RESULTS: For 45,X, the sensitivity was 98.8% (95%CI 94.6%-100%), specificity 99.4% (95%CI 98.7%-99.9%) and positive predictive value (PPV) 14.5% (95%CI 7.0%-43.8%). For 47,XXY, the sensitivity was 100% (95%CI 99.6%-100%), specificity 100% (95%CI 99.9%-100%) and PPV 97.7% (95%CI 78.6%-100%). For 47,XXX, the sensitivity was 100% (95%CI 96.9%-100%), specificity 99.9% (95%CI 99.7%-100%) and PPV 61.6% (95%CI 37.6%-95.4%). For 47,XYY, the sensitivity was 100% (95%CI 91.3%-100%), specificity 100% (95% CI 100%-100%) and PPV 100% (95%CI 76.5%-100%). All four SCAs had estimated negative predictive values (NPV) exceeding 99.99%, though false negatives were reported. CONCLUSIONS: This analysis suggests that cfDNA is a reliable screening test for SCA, though both false negatives and false positives were reported. These estimates of test performance are derived from pregnancies at high pretest risk for aneuploidy, limiting the generalisability to average risk pregnancies.

The impact of open versus closed weighing on rate of weight gain and length of stay among inpatients with anorexia nervosa.

Anorexia nervosa (AN) is a serious illness associated with significant morbidity and mortality. Few data exist to guide practice regarding sharing daily weight information (open weighing) or withholding it (closed weighing) from patients. We investigated the effect of open versus closed weighing on weight-related outcomes among inpatients with AN. Data were collected during a 4-month period when 43 patients were not told their daily weight, and a consecutive 4-month period when 41 patients were told their weights during rounds. There was no significant difference in mean overall weight change (3.6 ± 2.7 kg vs. 3.5 ± 2.5 kg), hospital duration (14.3 ± 10.0 vs. 14.2 ± 7.6 days), or rate of weight gain (0.26 ± 0.11 vs. 0.25 ± 0.13 kg) between groups. It is possible that one weighing procedure may not be preferable with respect to certain clinical outcomes for inpatients with AN, suggesting there may be multiple ways to navigate the discussion of weight progress in weight restoration programs.

In Utero Fetal Therapy: Stem Cells, Cell Transplantation, Gene Therapy, and CRISPR-Cas9.

In utero fetal therapy offers the opportunity to prevent and treat diseases with a cellular or genetic basis. Components of successful fetal treatment include isolation of a replacement cell population, in utero stem cell transplantation, cell engraftment with fetal immune tolerance, and ongoing cell function. Fetal gene therapy with CRISPR-Cas9 represents an exciting potential therapy for genetic diseases not amenable to gene supplementation via adenoviral vector transduction. These fetal therapies have unique ethical and safety considerations. Clinical trials for in utero cell therapy are underway, as additional discoveries in stem cell biology and gene therapy move closer to clinical translation.

Blasts from the past: is morphology useful in PGT-A tested and untested frozen embryo transfers?

RESEARCH QUESTION: Day of cryopreservation, inner cell mass (ICM) grade, trophectoderm grade and blastocyst expansion grade have been associated with differences in live birth rate in frozen embryo transfer (FET) cycles. This study sought to examine the likelihood of live birth and whether the morphological grade of the blastocyst is more or equally useful in FET cycles among preimplantation genetic testing for aneuploidies (PGT-A) tested and untested blastocysts. DESIGN: This was a retrospective cohort study of 6271 vitrified-warmed, autologous, single-embryo transfer cycles among patients undergoing IVF from July 2013 to December 2017 at a single, university-affiliated infertility practice. The primary outcome was live birth, calculated by generalized estimating equations. RESULTS: Among PGT-A tested embryos, inferior ICM grade was associated with a lower chance of live birth (ICM grade B versus A: adjusted risk ratio [aRR] 0.91, 95% confidence interval [CI] 0.84-0.99). Among untested blastocysts there was a lower live birth rate in blastocysts cryopreserved on day 6 versus day 5 (aRR 0.87, 95% CI 0.78-0.96), and those with inferior pre-vitrification trophectoderm grade (trophectoderm grade B versus A: aRR 0.86, 95% CI 0.79-0.94). Blastocysts with a higher pre-vitrification expansion grade (pre-vitrification expansion grade 5 versus 4: aRR 1.1, 95% CI 1.01-1.2) were associated, but ICM grade was not associated (ICM grade B versus A: aRR 0.93, 95% CI 0.86-1.02), with chance of live birth. CONCLUSIONS: Among PGT-A untested blastocysts, assessing embryo quality by day of cryopreservation, trophectoderm grade and expansion grade may help to identify embryos with the highest likelihood of live birth. Identifying euploid embryos by PGT-A appears to homogenize the cohort, making blastocyst morphological grade and day of cryopreservation less important.

Adoption of enhanced recovery after laparotomy in gynecologic oncology.

INTRODUCTION: Enhanced recovery after surgery (ERAS) pathways combine a comprehensive set of peri-operative practices that have been demonstrated to hasten patient post-operative recovery. We aimed to evaluate the adoption of ERAS components and assess attitudes towards ERAS among gynecologic oncologists. METHODS: We developed and administered a cross-sectional survey of attending, fellow, and resident physicians who were members of the Society of Gynecologic Oncology in January 2018. The χ2 test was used to compare adherence to individual components of ERAS. RESULTS: There was a 23% survey response rate and we analyzed 289 responses: 79% were attending physicians, 57% were from academic institutions, and 64% were from institutions with an established ERAS pathway. Respondents from ERAS institutions were significantly more likely to adhere to recommendations regarding pre-operative fasting for liquids (ERAS 51%, non-ERAS 28%; p<0.001), carbohydrate loading (63% vs 16%; p<0.001), intra-operative fluid management (78% vs 32%; p<0.001), and extended duration of deep vein thrombosis prophylaxis for malignancy (69% vs 55%; p=0.003). We found no difference in the use of mechanical bowel preparation, use of peritoneal drainage, or use of nasogastric tubes between ERAS and non-ERAS institutions. Nearly all respondents (92%) felt that ERAS pathways were safe. DISCUSSION: Practicing at an institution with an ERAS pathway increased adoption of many ERAS elements; however, adherence to certain guidelines remains highly variable. Use of bowel preparation, nasogastric tubes, and peritoneal drainage catheters remain common. Future work should identify barriers to the implementation of ERAS and its components.

Neuropathy target esterase activity predicts retinopathy among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. PNPLA6 encodes Neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a clinical meta-analysis of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6 -associated clinical diagnoses unambiguously reclassified 10 variants as likely pathogenic and 36 variants as pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship and the generation of a preclinical animal model pave the way for therapeutic trials, using NTE as a biomarker.

Use of Stimulants in Patients with Comorbid Anorexia Nervosa and Attention-Deficit/Hyperactivity Disorder in a Structured Inpatient Setting.

OBJECTIVE: Clinicians may be concerned about using psychostimulant medications in patients in whom weight gain is desired because of their potential side effects of appetite suppression and weight loss. This report depicts the successful treatment of 2 adolescent patients with anorexia nervosa (AN) and attention-deficit/hyperactivity disorder (ADHD) in an inpatient eating disorders unit. METHOD: A report of 2 clinical cases (ages 19 and 20 years) was used to describe the management of comorbid AN and ADHD. Tolerance to stimulants, meal completion, and ability to restore weight were assessed over the course of hospitalization. RESULTS: Behaviorally focused refeeding combined with psychostimulants notably improved symptoms of AN and comorbid ADHD without adverse effects. CONCLUSION: Psychostimulant medications may be used successfully in patients with AN and ADHD in the context of structured behavioral treatment designed for weight restoration.

Inviting eating disorder patients to discuss the academic literature: a model program for psychoeducation.

BACKGROUND: Psychoeducation initiatives in which patients read primary scientific literature have not yet been studied as a treatment intervention for eating disorders. In this paper, we discuss and evaluate the acceptability of a novel psychoeducational journal club for individuals with anorexia and bulimia nervosa in inpatient and partial hospitalization program settings. Primary literature about eating disorders is presented and discussed with patients. By presenting scientifically-supported information, our "Psychoeducational Research Group" is designed to help patients restructure disordered thoughts and encourage adherence to evidence-based treatment. METHODS: Using a Likert scale questionnaire (0 = not at all; 5 = very much), participants provided ratings for how much they liked the group and felt that it helped them across several domains. RESULTS: Average scores from 33 participants (26 inpatient, 7 partial hospital patients) indicated they would recommend this group to others receiving eating disorder treatment (4.8 ± 0.6). Scores also suggested patients' likeability (4.6 ± 0.8), benefit regarding challenging eating disorder thoughts (4.1 ± 1.1), improved motivation for eating behavior change (4.0 ± 1.0) and completion of prescribed nutritional plan (3.6 ± 1.0), and usefulness in working towards treatment goals (4.2 ± 0.9) associated with group participation. CONCLUSIONS: Preliminary findings support the acceptability of this psychoeducational group and that it may serve as a useful adjunct to larger evidence-based programming across eating disorder treatment settings.

Reactive Astrocytes Promote ALS-like Degeneration and Intracellular Protein Aggregation in Human Motor Neurons by Disrupting Autophagy through TGF-ß1.

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron disease. Astrocytic factors are known to contribute to motor neuron degeneration and death in ALS. However, the role of astrocyte in promoting motor neuron protein aggregation, a disease hallmark of ALS, remains largely unclear. Here, using culture models of human motor neurons and primary astrocytes of different genotypes (wild-type or SOD1 mutant) and reactive states (non-reactive or reactive), we show that reactive astrocytes, regardless of their genotypes, reduce motor neuron health and lead to moderate neuronal loss. After prolonged co-cultures of up to 2 months, motor neurons show increased axonal and cytoplasmic protein inclusions characteristic of ALS. Reactive astrocytes induce protein aggregation in part by releasing transforming growth factor ß1 (TGF-ß1), which disrupts motor neuron autophagy through the mTOR pathway. These results reveal the important contribution of reactive astrocytes in promoting aspects of ALS pathology independent of genetic influences.

Complications of pre-operative anorexia nervosa in bariatric surgery.

It is important to recognise that patients who seek weight loss surgery may have a history of restrictive eating or anorexia nervosa. The following case report describes a woman with a history of anorexia nervosa who underwent Roux-en-Y gastric bypass surgery. Her eating disorder symptoms subsequently reappeared and were largely resistant to treatment. To the best of our knowledge, this is the first case report of a bariatric surgery patient with a prior history of anorexia nervosa. Further research is required to determine how best to select patients for weight loss surgery.

In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes.

Direct lineage conversion of adult cells is a promising approach for regenerative medicine. A major challenge of lineage conversion is to generate specific cell subtypes. The pancreatic islets contain three major hormone-secreting endocrine subtypes: insulin(+) ß-cells, glucagon(+) α-cells, and somatostatin(+) δ-cells. We previously reported that a combination of three transcription factors, Ngn3, Mafa, and Pdx1, directly reprograms pancreatic acinar cells to ß-cells. We now show that acinar cells can be converted to δ-like and α-like cells by Ngn3 and Ngn3+Mafa respectively. Thus, three major islet endocrine subtypes can be derived by acinar reprogramming. Ngn3 promotes establishment of a generic endocrine state in acinar cells, and also promotes δ-specification in the absence of other factors. δ-specification is in turn suppressed by Mafa and Pdx1 during α- and ß-cell induction. These studies identify a set of defined factors whose combinatorial actions reprogram acinar cells to distinct islet endocrine subtypes in vivo. DOI: http://dx.doi.org/10.7554/eLife.01846.001.