Condensin-mediated restriction of retrotransposable elements facilitates brain development in Drosophila melanogaster.

Neural stem and progenitor cell (NSPC) maintenance is essential for ensuring that organisms are born with proper brain volumes and head sizes. Microcephaly is a disorder in which babies are born with significantly smaller head sizes and cortical volumes. Mutations in subunits of the DNA organizing complex condensin have been identified in microcephaly patients. However, the molecular mechanisms by which condensin insufficiency causes microcephaly remain elusive. We previously identified conserved roles for condensins in repression of retrotransposable elements (RTEs). Here, we show that condensin subunit knockdown in NSPCs of the Drosophila larval central brain increases RTE expression and mobility which causes cell death, and significantly decreases adult head sizes and brain volumes. These findings suggest that unrestricted RTE expression and activity may lead to improper brain development in condensin insufficient organisms, and lay the foundation for future exploration of causative roles for RTEs in other microcephaly models.

Short-term removal of exercise impairs glycemic control in older adults: A randomized trial.

Postprandial glycemia (PPG) predicts cardiovascular disease, and short-term physical inactivity increases PPG in young, active adults. Whether this occurs in older, active adults who may be more prone to bouts of inactivity is unknown. This study determined if postprandial interstitial glucose (PPIG) was impaired in active older adults following the removal of exercise for 3 days (NOEX) compared to active young adults. In this randomized, crossover study, 11 older (69.1 ± 1.9 years) and 9 young (32.8 ± 1.8 years) habitually active (≥90 min/week of exercise) adults completed 3-days of NOEX and 3-days of normal habitual exercise (EX), separated by ≥1 week. Diet was standardized across phases. Glycemic control (3-day average) was assessed via continuous glucose monitoring during both phases. Significant main effects of age and phase were detected (p < 0.05), but no interaction was found for steps/day (p > 0.05) (old EX: 6283 ± 607, old NOEX: 2380 ± 382 and young EX: 8798 ± 623, young NOEX: 4075 ± 516 steps/day). Significant main effects of age (p = 0.002) and time (p < 0.001) existed for 1-h PPIG, but no effect of phase or interactions was found (p > 0.05). Significant main effects (p < 0.05) of age (old: 114 ± 1 mg/dl, young: 106 ± 1 mg/dl), phase (NOEX: 112 ± 1 mg/dl, EX: 108 ± 1 mg/dl), and time (0 min: 100 ± 2, 30 min: 118 ± 2, 60 min: 116 ± 2, 90 min: 111 ± 2, 120 min: 108 ± 2 mg/dl) in 2-h PPIG were detected, but no interaction was found (p > 0.05). However, only significant main effects of phase (NOEX: 14 ± 1 and EX:12 ± 1, p > 0.05) were found for 24-h blood glucose standard deviation. Older adults appear to have impaired glycemic control compared to young adults and exercise removal impairs glycemic control in both populations. Yet, the impairment in glycemic control with exercise removal is not different between old and young adults.

Development of donor specific antibodies after SARS-CoV-2 vaccination in kidney and heart transplant recipients.

This study examined the development of new or changes in donor specific antibodies (DSA) mean-fluorescence intensity (MFI) after SARS-CoV-2 vaccination in 100 kidney and 50 heart transplant recipients. The study was performed when the Center for Disease Control and Prevention (CDC) recommended two doses of Pfizer/BioNTech [BNT162b2] and Moderna [mRNA-1273 SARS-CoV-2] vaccine or 1 dose Johnson & Johnson/Janssen [Ad26.COV2·S] vaccines for full vaccination in transplant recipients. A novel assay bead-based platform for detecting antibodies against 4 domains of the SARS-CoV-2 spike protein to determine vaccine response (SA) and one nucleocapsid protein (NC) to determine prior SARS-CoV-2 infection was utilized. These assays were performed on the multiplex, bead-based platform utilized to assay DSA levels. 61/150 patients (40.7%) had successful vaccination. 18 patients had confirmed SARS-CoV-2 infection based on positive NC assay or previous Covid-19 oropharyngeal swab. 138 patients had no DSA prior to vaccination but 3 heart recipients developed new DSA's. Among 12 patients with known DSA prior to vaccination, 4 developed new DSA's or increased MFI. All 7 patients with new or increased DSA had stable graft function without rejection and had no changes in immunosuppression. All 8 patients with stable post vaccine DSA had stable graft function and immunosuppression was not changed. The presence of DSA before vaccination was associated with subsequent development of increased MFI or new DSA's (p = 0.001). There was no association between pre-vaccine DSA and positive vaccine response (NS). There was no association with successful vaccination or prior SARS-CoV-2 infection and DSA changes (NS).

How accurate are the longer-term projections of overall survival for cancer immunotherapy for standard versus more flexible parametric extrapolation methods?

AIMS: To assess the accuracy of standard parametric survival models, spline models, and mixture cure models (MCMs) fitted to overall survival (OS) data available at the time of submission in the NICE HTA process compared with data subsequently made available. METHODS: Standard parametric distributions, spline models, and MCMs were fitted to OS data presented in single technology appraisals (TAs) for immune-checkpoint inhibitors (ICIs) in cancer. For each TA, the estimated survival from the fitted models was compared with Kaplan-Meier (KM) data that were made available following the HTA submission using differences between point estimates and restricted area under the curve (AUC) at both the midpoint and the end of additional follow-up. Differences in interval AUC values (calculated for each 6-month period) were also assessed. RESULTS: Standard parametric survival models and spline models were more likely to underestimate longer-term survival, irrespective of the measure used to assess model accuracy. MCMs were more likely to overestimate survival; however, this was improved in some cases by applying an additional hazard of mortality for "statistically cured" patients. LIMITATIONS: The accuracy of the models was assessed based on much shorter OS data than the period for which extrapolation is needed, which may impact conclusions regarding the most accurate models. The most recent TAs for ICIs have not been captured. CONCLUSIONS: There are no definitive findings that unquestionably support the use of one specific extrapolation technique. Rather, each has the potential to provide accurate or inaccurate extrapolation to longer-term data in certain circumstances, but the added flexibility of more complex models can be justified for treatments, like ICIs, that have extended survival for patients across disease areas. The use of mortality adjustments for "statistically cured" patients allows decision-makers to explore more conservative scenarios in the face of high decision uncertainty.

Timely intervention and control of a novel coronavirus (COVID-19) outbreak at a large skilled nursing facility-San Francisco, California, 2020.

OBJECTIVE: To describe epidemiologic and genomic characteristics of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in a large skilled-nursing facility (SNF), and the strategies that controlled transmission. DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted during March 22-May 4, 2020, among all staff and residents at a 780-bed SNF in San Francisco, California. METHODS: Contact tracing and symptom screening guided targeted testing of staff and residents; respiratory specimens were also collected through serial point prevalence surveys (PPSs) in units with confirmed cases. Cases were confirmed by real-time reverse transcription-polymerase chain reaction testing for SARS-CoV-2, and whole-genome sequencing (WGS) was used to characterize viral isolate lineages and relatedness. Infection prevention and control (IPC) interventions included restricting from work any staff who had close contact with a confirmed case; restricting movement between units; implementing surgical face masking facility-wide; and the use of recommended PPE (ie, isolation gown, gloves, N95 respirator and eye protection) for clinical interactions in units with confirmed cases. RESULTS: Of 725 staff and residents tested through targeted testing and serial PPSs, 21 (3%) were SARS-CoV-2 positive: 16 (76%) staff and 5 (24%) residents. Fifteen cases (71%) were linked to a single unit. Targeted testing identified 17 cases (81%), and PPSs identified 4 cases (19%). Most cases (71%) were identified before IPC interventions could be implemented. WGS was performed on SARS-CoV-2 isolates from 4 staff and 4 residents: 5 were of Santa Clara County lineage and the 3 others were distinct lineages. CONCLUSIONS: Early implementation of targeted testing, serial PPSs, and multimodal IPC interventions limited SARS-CoV-2 transmission within the SNF.

Ambulatory abdominoplasty tailored to patients with an appropriate body mass index.

BACKGROUND: The office-based surgery setting potentially offers advantages to both the patient and the plastic surgeon, but some patients may not be considered good candidates for abdominoplasty or combined abdominoplasty/lipoplasty performed in the ambulatory setting. OBJECTIVE: We conducted a retrospective case review of 22 patients who underwent ambulatory abdominoplasty to correct diastasis recti during a 1-year period to evaluate the utility of body mass index (BMI) in patient selection for office-based abdominoplasty procedures using a tumescent technique. METHODS: Patients selected for ambulatory abdominoplasty in an office-based setting had BMIs ranging from 22 to 34, with an average BMI of 27, and were American Society of Anesthesiologists (ASA) class I or II. Patients with a BMI that placed them in a "morbidly obese" category (BMI of 35 or above) received general anesthesia with an overnight hospital stay. In borderline cases involving obese patients, a qualified anesthesia provider was consulted to determine whether ambulatory surgery was appropriate, based on the patient's airway and an overall evaluation of the patient's history and physical examination. Patients who underwent ambulatory abdominoplasty received a tumescent anesthetic solution of 50 mL 1% lidocaine with 1 mg epinephrine per liter of normal saline, up to 35 mg/kg body weight. Lipoplasty of the lateral and epigastric regions was routinely performed at the end of all abdominoplasties. The length of surgery was 3 hours to 5.5 hours, depending on the number of regions undergoing lipoplasty. RESULTS: There were no reportable surgical or anesthetic complications in any of our patients. Patients reported a high level of satisfaction with the results. CONCLUSIONS: BMI evaluation, and in some cases additional risk assessment by a qualified anesthesia provider, can be helpful in determining proper candidates for ambulatory abdominoplasty and combined abdominoplasty/lipoplasty procedures.

Hysterical paralysis: a report of three cases and a review of the literature.

STUDY DESIGN: Three cases of hysterical paralysis are reported and the literature is reviewed. OBJECTIVE: To report and discuss three cases of psychogenic paraplegia in order to increase the awareness and assist in the diagnosis and treatment of this uncommon disorder. SUMMARY OF BACKGROUND DATA: Hysterical paralysis, a form of conversion disorder, is an uncommon psychogenic, nonorganic loss of motor function precipitated by a traumatic event. The prevalence of conversion disorder in the general population reportedly is between 5 and 22 per 100,000 persons. The pursuit of a diagnosis for the hysterical paraplegic patient necessarily consumes valuable resources and time. If early recognition can be facilitated, these resources may be conserved. METHODS: The medical records for three healthy young women who presented to the authors' service reporting complete loss of lower extremity function were reviewed retrospectively along with the related laboratory, electrodiagnostic, and imaging studies. Two of the women were involved in motor vehicle accidents. One had a history of a previous hysterical seizure. Inconsistencies in physical examination and studies were noted. RESULTS: All three patients had normal laboratory, electrodiagnostic, and imaging studies. Discrepancies included complete loss of motor control and sensation in the lower extremities in the face of normal deep tendon reflexes as well as incontinence of bowel and bladder despite intact rectal tone. The patients spontaneously recovered and ambulated out of the hospital without assistance after their normal test results and physical examination inconsistencies were presented to them. CONCLUSIONS: Hysterical paraplegia is a type of conversion disorder. It is a diagnosis of exclusion that typically presents as mono-, hemi-, para-, or quadriplegia. The pursuit of a diagnosis for the hysterical paraplegic patient necessarily consumes valuable resources and time. The typical patient is a female from a low socioeconomic background with limited education. The DSM-IV-TR criteria must be met to fulfill the diagnosis of conversion disorder. Electrodiagnostic and imaging studies can aid in the diagnosis. Treatment revolves around explaining the normal diagnostic results to the patients and guiding them to appropriate psychiatric and physiotherapy. Rapid recovery should be expected, but can take up to 6 months.