Two 5-year studies of bictegravir/emtricitabine/tenofovir alafenamide in people with HIV: a plain-language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain-language summary of an article that reported on two studies of the medication bictegravir/emtricitabine/tenofovir alafenamide (shortened to B/F/TAF). B/F/TAF is a single pill containing three different drugs used to treat human immunodeficiency virus (known as HIV). The drugs work together to lower the levels of HIV (called viral load) in the body and make the virus undetectable in the blood. Researchers measured whether B/F/TAF was safe and effective when taken over 5 years in over 400 people in 10 countries who had never taken HIV medication before. WHAT WERE THE RESULTS?: After 5 years, almost all (99%) of the people who took B/F/TAF had an undetectable viral load. This does not mean that they were cured, but that the levels of HIV were so low that the tests used by researchers could not detect the virus in the blood. CD4 is a type of immune system cell. HIV causes CD4 cell numbers to decrease. On average, the number of CD4 cells increased by more than 300 cells per microliter (cells/µL) of blood over 5 years. This means that the immune system was improving. HIV is able to change its genes to escape the effects of the drugs. This is known as HIV resistance to treatment. Nine people had a viral load high enough to suggest that the drugs might not be working, but no resistance to B/F/TAF was seen. Some people (less than one in three) experienced medical problems thought to be linked to B/F/TAF treatment, known as side effects. The most common side effects were headache, diarrhea, nausea, tiredness (fatigue), dizziness, and difficulty falling or staying asleep (insomnia). On average, people's body weight increased by 3 kg in the first year of taking B/F/TAF. This might be because their general health improved after starting HIV treatment. Weight gained after that time was similar to the level of weight gain expected in the general population. Very few people (less than 1 in 100) stopped taking B/F/TAF because of side effects thought to have been caused by B/F/TAF. WHAT DO THE RESULTS MEAN?: B/F/TAF was effective at treating HIV in people who had never taken HIV medication before. Most (70%) people were still taking B/F/TAF after 5 years.Clinical Trial Registration: NCT02607930 (Study 1489); NCT02607956 (Study 1490) (ClinicalTrials.gov).

Association of serum vitamin D with diagnosis and growth of abdominal aortic aneurysm.

Objective: We examined the associations between 25-hydroxy vitamin D (25(OH)D3) concentration and the diagnosis and growth of abdominal aortic aneurysm (AAA). Methods: AAA cases and healthy controls were recruited from vascular centers or the community. A subset of participants with AAA were monitored by repeat ultrasound examination to assess AAA growth. Serum 25(OH)D3 concentration was measured using a validated mass spectrometry method and categorized into guideline-recommended cut-points after deseasonalization. The associations between deseasonalized 25(OH)D3 concentration and AAA diagnosis and growth were examined using logistic regression and linear mixed effects modeling. Results: A total of 4673 participants consisting of 873 (455 controls and 418 cases) from Queensland and 3800 (3588 controls and 212 cases) from Western Australia were recruited. For every 1 standard deviation increase in 25(OH)D3 concentration, odds of AAA diagnosis was significantly reduced in both Queensland (adjusted odds ratio: 0.81; 95% confidence interval [CI]: 0.69-0.95; P = .009) and Western Australia (adjusted odds ratio: 0.80; 95% CI: 0.68-0.94; P = .005) cohorts. A subset of 310 eligible participants with small AAA from both regions were followed for a median of 4.2 (interquartile range: 2.0-5.8) years. Compared with vitamin D sufficient participants (50 to ˂75 nmol/L), annual mean AAA growth was significantly greater in those with higher vitamin D (≥75 nmol/L) (adjusted mean difference: 0.1 mm/y, 95% CI: 0.1-0.2; P < .001). Conclusions: High 25(OH)D3 concentration was paradoxically associated with a lower likelihood of AAA diagnosis and faster AAA growth. Further research is needed to resolve these conflicting findings.

Implementation of Flexible Days Off Improves Surgical Resident Attendance of Personal Health Appointments, Perceived Wellbeing, and Sense of Control.

OBJECTIVE: Surgical resident schedules are demanding. Despite ACGME requirements that residents be able to attend personal appointments, many residents put off essential health tasks due to work hours. We designed a method for surgical residents to request a "flex" or personal day utilizing an online system for requesting and tracking. DESIGN: Residents were given 5 days to use during 1 academic year. A float rotation was implemented to cover scheduled absences. We conducted an anonymous REDCap survey pre and postimplementation regarding resident ability to attend personal appointments and wellbeing. The results of these surveys were compared using descriptive statistics, t-test, and chi-square testing. SETTING: Single large academic training institution. PARTICIPANTS: Sixty general surgery residents. RESULTS: Over 9 months, we scheduled 195 flex days and 91% of residents had used the program. The most common uses were travel, time with family/friends, and attending personal health appointments Postimplementation, of residents who needed an appointment, an increased percentage attended a physician (92% vs. 71%, p 0.02), dental (94% vs. 65%, p < 0.01) or mental health (96% vs. 64%, p < 0.01) appointment. A decreased percentage delayed a necessary appointment due to work hours (45% vs. 19.5%, p 0.01), 94% reported improved schedule control, and 100% believed the program was important for wellbeing. When comparing Mayo Wellbeing Index scores pre and postimplementation there was a decrease in the number of trainees reporting high distress (18.8% vs. 29.3%, p 0.03). Postimplementation, our program noted an 80% decrease in the number of duty hours violations (16 vs. 3 violations) and a 12% increase in compliance with the ACGME survey for ability to attend personal appointments. CONCLUSION: "Flex" days offer surgical residents improved schedule control and the ability to schedule essential personal appointments. They are feasible, even within large training programs, with significant uptake in our sample.

Lipid and glucose profiles in pregnant women with HIV on tenofovir-based antiretroviral therapy.

OBJECTIVE: Tenofovir alafenamide (TAF)-based antiretroviral therapy (ART) regimens have been associated with adverse changes in lipid and glucose profiles compared with tenofovir disoproxil fumarate (TDF)-based ART, but data in pregnancy is limited. We evaluated metabolic markers in pregnant women with HIV after starting TAF- vs TDF-based ART. METHODS: We analyzed data within the IMPAACT 2010/VESTED trial, which demonstrated better pregnancy outcomes in pregnant women randomized to initiate TAF/Emtricitabine/Dolutegravir (TAF/FTC+DTG; n=217) or TDF/FTC+DTG (n=215). We measured non-fasting plasma concentrations of glucose, total-cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), lipoprotein (a), and triglycerides from samples collected eight weeks after enrollment. We employed linear regression models to estimate by-arm mean differences. RESULTS: 219 participants enrolled in the DTG arms in Zimbabwe and Uganda: 109 in the TAF/FTC+DTG and 110 in the TDF/FTC+DTG arms. At study entry, mean gestational age was 22.6 weeks, median HIV-1 RNA was 711 copies/mL, and mean age was 25.8 years. By eight weeks, mean total cholesterol was 12 mg/dL higher in women randomized to TAF/FTC+DTG versus TDF/FTC+DTG (95% CI 3.8, 21.1). Pregnant women in the TAF/FTC+DTG arm had higher mean LDL-C (7.1 mg/dL, 95% CI 0.2, 14.0), triglycerides (12.3 mg/dL, 95% CI 1.8, 22.7), lipoprotein (a) (7.3 mg/dL, 95% CI 1.1, 13.6), and lower mean HDL-C (2.8 mg/dL, 95% CI 0.1, 5.6) compared to the TDF/FTC+DTG arm. CONCLUSION: Pregnant women randomized to start TAF/FTC+DTG had higher lipids than those randomized to TDF/FTC+DTG within eight weeks of ART initiation. However, lipid levels were within normal reference ranges.

A Dose-Finding, Biomarker Validation, and Effectiveness Study of Transcranial Magnetic Stimulation for Adolescents With Depression.

OBJECTIVE: Research and clinical application of transcranial magnetic stimulation (TMS) for adolescents with major depressive disorder (MDD) has advanced slowly. Significant gaps persist in our understanding of optimized, age-specific protocols and dosing strategies. This study aimed to compare the clinical effects of 1 Hz versus 10 Hz TMS regimens and examine a biomarker-informed treatment approach with glutamatergic intracortical facilitation (ICF). METHOD: Participants with moderate-to-severe symptoms of MDD were randomized to 30 sessions of left prefrontal 1 Hz or 10 Hz TMS, stratified by baseline ICF measures. The primary clinical outcome measure was the Children's Depression Rating Scale, Revised (CDRS-R). The CDRS-R and ICF biomarker were collected weekly. RESULTS: Forty-one participants received either 1 Hz (n = 22) or 10 Hz (n = 19) TMS treatments. CDRS-R scores improved compared to baseline in both 1 Hz and 10 Hz groups. For participants with low ICF at baseline, the overall least squares means of CDRS-R scores over the 6-week trial showed that depressive symptom severity was lower for the group treated with 1 Hz TMS than for those who received 10 Hz TMS. There were no significant changes in weekly ICF measurements across the 6 weeks of TMS treatment. CONCLUSION: Low ICF may reflect optimal glutamatergic N-methyl-d-aspartate (NMDA) receptor activity that facilitates the therapeutic effect of 1 Hz TMS through long-term depression-like mechanisms on synaptic plasticity. The stability of ICF suggests that it is a tonic, trait-like measure of NMDA receptor-mediated neurotransmission, with potential utility to inform parameter selection for therapeutic TMS in adolescents with MDD.

Factors Associated With Improvement Following In-office Steroid Injections for Vocal Fold Scar.

OBJECTIVE: This study aims to evaluate the clinical outcomes of patients receiving in-office vocal fold steroid injections (VFSI), highlighting relatively new measures around vocal pitch. METHODS: Patients with a diagnosis of vocal fold scar who received in-office VFSI from 2013 to 2024 were evaluated. Pre- and post-steroid Voice Handicap Index (VHI-10) scores, stroboscopic vibratory parameters, acoustic measures of cepstral peak prominence (CPP), and fundamental frequency coefficient of variation (F0CoV) during sustained phonation were analyzed using Wilcoxon signed-rank tests and McNemar's tests. RESULTS: Twenty-two patients had follow-up data 1-3 months after steroid injection. The median decrease in VHI-10 after one injection was 4 points (p = 0.02). We found no difference in CPP and F0CoV measures at follow-up. Forty-five percent of patients improved in mucosal wave and amplitude of at least one vocal fold. Earlier presentation from vocal injury was associated with improvement in mucosal wave and amplitude of the left vocal fold (p = 0.03). We found no difference in sex, tobacco smoking history, singing status, secondary diagnosis, and baseline VHI-10 score between patients who improved in vibratory parameters and those who did not. CONCLUSION: This single-center study is one of the largest exploring patient outcomes following in-office VFSI. Though patients reported modest improvement in voice use after VFSI, this may not be as impactful as previously believed. Improvement in videostroboscopy is expected in about half of the patients, with recency from vocal injury a likely predictor of success. These partially negative results provide insight into counseling patients regarding benefits from in-office VFSI. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

PULSE Ambassadors program: empowering departments to transform STEM education for inclusion and student success.

The Partnership for Undergraduate Life Sciences Education (PULSE) is a non-profit educational organization committed to promoting the transformation of undergraduate STEM education by supporting departments in removing barriers to access, equity, and inclusion and in adopting evidence-based teaching and learning practices. The PULSE Ambassadors Campus Workshop program enables faculty and staff members of host departments to 1) develop communication, shared leadership, and inclusion skills for effective team learning; 2) implement facilitative leadership skills (e.g., empathic listening and collaboration); 3) create a shared vision and departmental action plan; and 4) integrate diversity, equity, and inclusion practices in the department and curriculum. From the first workshop in 2014, teams of trained Ambassadors conducted workshops at 58 institutions, including associate, bachelor, master, and doctoral institutions. In their workshop requests, departments cited several motivations: desire to revise and align their curriculum with Vision and Change recommendations, need for assistance with ongoing curricular reform, and wish for external assistance with planning processes and communication. Formative assessments during and immediately following workshops indicated that key outcomes were met. Post-workshop interviews of four departments confirm progress achieved on action items and development of individual department members as agents of change. The PULSE Ambassadors program continues to engage departments to improve undergraduate STEM education and prepare departments for the challenges and uncertainties of the changing higher education landscape.

Assessment of lesion insertion tool in pelvis PET/MR data with applications to attenuation correction method development.

BACKGROUND: In modern positron emission tomography (PET) with multi-modality imaging (e.g., PET/CT and PET/MR), the attenuation correction (AC) is the single largest correction factor for image reconstruction. One way to assess AC methods and other reconstruction parameters is to utilize software-based simulation tools, such as a lesion insertion tool. Extensive validation of these simulation tools is required to ensure results of the study are clinically meaningful. PURPOSE: To evaluate different PET AC methods using a synthetic lesion insertion tool that simulates lesions in a patient cohort that has both PET/MR and PET/CT images. To further demonstrate how lesion insertion tool may be used to extend knowledge of PET reconstruction parameters, including but not limited to AC. METHODS: Lesion quantitation is compared using conventional Dixon-based MR-based AC (MRAC) to that of using CT-based AC (CTAC, a "ground truth"). First, the pre-existing lesions were simulated in a similar environment; a total of 71 lesions were identified in 18 pelvic PET/MR patient images acquired with a time-of-flight simultaneous PET/MR scanner, and matched lesions were inserted contralaterally on the same axial slice. Second, synthetic lesions were inserted into four anatomic target locations in a cohort of four patients who didn't have any observed clinical lesions in the pelvis. RESULTS: The matched lesion insertions resulted in unity between the lesion error ratios (mean SUVs), demonstrating that the inserted lesions successfully simulated the original lesions. In the second study, the inserted lesions had distinct characteristics by target locations and demonstrated negative max-SUV%diff trends for bone-dominant sites across the patient cohort. CONCLUSIONS: The current work demonstrates that the applied lesion insertion tool can simulate uptake in pelvic lesions and their expected SUV values, and that the lesion insertion tool can be extended to evaluate further PET reconstruction corrections and algorithms and their impact on quantitation accuracy and precision.

Omission of 5-Fluorouracil Bolus From Multidrug Regimens for Advanced Gastrointestinal Cancers: A Multicenter Cohort Study.

BACKGROUND: 5-Fluorouracil (5-FU) is a major component of gastrointestinal cancer treatments. In multidrug regimens such as FOLFOX, FOLFIRI, and FOLFIRINOX, 5-FU is commonly administered as a bolus followed by an infusion. However, the pharmacologic rationale for incorporating the 5-FU bolus in these regimens is unclear, and there are other effective regimens for gastrointestinal cancers that do not include the bolus. The purpose of this study was to determine whether omission of the 5-FU bolus was associated with a difference in survival and toxicity. METHODS: A real-world database from Flatiron Health was queried for patients with advanced colorectal, gastroesophageal, and pancreatic cancers who received first-line FOLFOX, FOLFIRI, and FOLFIRINOX regimens. Cox proportional hazards and Kaplan-Meier analyses were performed to compare survival outcomes between patients who received the 5-FU bolus and those who did not. Inverse probability of treatment weighted (IPTW) analysis was performed to adjust for treatment selection bias. RESULTS: This study included 11,765 patients with advanced colorectal (n=8,670), gastroesophageal (n=1,481), and pancreatic (n=1,614) cancers. Among all first-line 5-FU multidrug regimens, 10,148 (86.3%) patients received a 5-FU bolus and 1,617 (13.7%) did not. After IPTW analysis, we found that omitting the bolus was not associated with a decrease in overall survival (hazard ratio, 0.99; 95% CI, 0.91-1.07; P=.74). However, omitting the bolus was associated with reductions in neutropenia (10.7% vs 22.7%; P<.01), thrombocytopenia (11.2% vs 16.1%; P<.01), and use of granulocyte colony-stimulating factors after treatment (19.6% vs 29.1%; P<.01). CONCLUSIONS: After adjusting for baseline clinical factors, we found that omission of the 5-FU bolus from FOLFOX, FOLFIRI, and FOLFIRINOX regimens was not associated with decreased survival, but resulted in decreased toxicity and possible health care savings.

Development of the coreHEM mental health patient-reported outcome measure - A novel mental health outlook measure for people with haemophilia.

INTRODUCTION: Currently, no quality-of-life instrument exists that captures the full experience of the mental health outlook (MHO), a coreHEM core outcome, in people with haemophilia, including the potential transformational experience of receiving gene therapy. AIM: To describe the methods used to develop a content validated patient-reported outcome measure (PROM) that measures MHO for people with haemophilia. METHODS: A conceptual framework, developed from a literature/evidence review, was used to create an interview guide and draft a questionnaire. Males aged 15 or older with severe/moderate haemophilia were eligible to participate in concept elicitation or cognitive debriefing interviews. The conceptual framework was refined based on a thematic analysis of concept elicitation interviews and PROM items were developed from the conceptual framework. Cognitive debriefing sessions that prioritised relevance and understanding of the PROM were held in two rounds; items were updated iteratively. RESULTS: A conceptual framework with five domains (stigma, anxiety, depression, life interference and identity) was constructed from over 300 identified MHO concepts. Fifty-three participants took part in interviews. After 32 concept elicitation interviews, the framework was updated by including eight new sub-concepts and eliminating two. Updates to the questionnaire included items added or removed and improved wording. The final coreHEM MHO PROM has 26 questions in two sections (general mental health associated with haemophilia, and a gene therapy section). CONCLUSIONS: The instrument is content-validated and can be used as an exploratory outcome. MHO scores can be measured and compared to give more insight into patient quality of life.

Hyaluronic acid and urology: a systematic review and meta-analysis.

INTRODUCTION: The use of hyaluronic acid as a nonsurgical treatment for various conditions within urology has been of great interest in recent literature. OBJECTIVES: In this study, we aimed to provide an updated review and analysis of the current state of hyaluronic acid use in urology, characterize its adverse effects, and briefly discuss future directions of research for hyaluronic acid in urology. METHODS: PubMed searches were run utilizing multiple terms, including "hyaluronic acid," "penile," "augmentation," "Peyronie disease," "premature ejaculation," and "cosmetic urology," among other related iterations. Relevant data extracted included International Index of Erectile Function score, intravaginal ejaculatory latency, glans circumference, penile girth, and plaque size. We also included studies which reported on complications of hyaluronic acid injections. Aggregated analysis was performed on studies with complete pre and post injection data at time closest to 6 months postinjection. RESULTS: A total of 33 studies met our inclusion criteria. Studies had marked heterogeneity in design, but most reported positive results. A total of 16 studies were included in our analysis. Intravaginal ejaculatory latency, penile girth, glans circumference, and International Index of Erectile Function were all increased on a fixed-effects model. Reduction in plaque size was not significant (P = .069). Complications were rare. CONCLUSION: Literature on hyaluronic acid for urologic issues demonstrates promising results; however, the quality of studies was variable. Our analysis of these studies largely corroborates these findings; however, the results are limited by the data available. Hyaluronic acid may be promising, but we highly implore standardization of study regimens in randomized controlled trials.

Do 3-dimensional Spinopelvic Characteristics Normalize After THA? A Prospective, Comparative Study Using Motion Capture Analysis.

BACKGROUND: Spinopelvic stiffness (primarily in the sagittal plane) has been identified as a factor associated with inferior patient-reported outcomes (PROs) and increased dislocation risk after THA. Incorporating preoperative spinopelvic characteristics into surgical planning has been suggested to determine a patient-specific cup orientation that minimizes dislocation risk. Sagittal plane radiographic analysis of static postures indicates that patients exhibit a degree of normalization in their spinopelvic characteristics after THA. It is not yet known whether normalization is also evident during dynamic movement patterns, nor whether it occurs in the coronal and axial planes as well. QUESTIONS/PURPOSES: (1) Does motion capture analysis of sagittal spinopelvic motion provide evidence of normalization after THA? (2) Do changes in coronal and axial plane motion accompany those in the sagittal plane? METHODS: Between April 2019 and February 2020, 25 patients agreed to undergo motion capture movement analysis before THA for the treatment of hip osteoarthritis (OA). Of those, 20 underwent the same assessment between 8 and 31 months after THA. Five patients were excluded because of revision surgery (n = 1), contralateral hip OA (n = 1), and technical issues with a force plate during post-THA assessment (n = 3), leaving a cohort total of 15 (median age [IQR] 65 years [10]; seven male and eight female patients). A convenience sample of nine asymptomatic volunteers, who were free of hip and spinal pathology, was also assessed (median age 51 years [34]; four male and five female patients). Although the patients in the control group were younger than those in the patient group, this set a high bar for our threshold of spinopelvic normalization, reducing the possibility of false positive results. Three-dimensional motion capture was performed to measure spinal, pelvic, and hip motion while participants completed three tasks: seated bend and reach, seated trunk rotation, and gait on a level surface. ROM during each task was assessed and compared between pre- and post-THA conditions and between patients and controls. Statistical parametric mapping (SPM) was used to assess the timing of differences in motion during gait, and spatiotemporal gait parameters were also measured. RESULTS: After THA, patients demonstrated improvements in sagittal spinal (median [IQR] 32° [18°] versus 41° [14°]; difference of medians 9°; p = 0.004), pelvis (25° [21°] versus 30° [8°]; difference of medians 5°; p = 0.02), and hip ROM (21° [18°] versus 27° [10°]; difference of medians 6°; p = 0.02) during seated bend and reach as well in sagittal hip ROM during gait (30° [11°] versus 44° [7°]; difference of medians 14°; p < 0.001) compared with their pre-THA results, and they showed a high degree of normalization overall. These sagittal plane changes were accompanied by post-THA increases in coronal hip ROM (12° [9°] versus 18° [8°]; difference of medians 6°; p = 0.01) during seated trunk rotation, by both coronal (6° [4°] versus 9° [3°]; difference of medians 3°; p = 0.01) and axial (10° [8°] versus 16° [7°]; difference of medians 6°; p = 0.003) spinal ROM, as well as coronal (8° [3°] versus 13° [4°]; difference of medians 5°; p < 0.001) and axial hip ROM (21° [11°] versus 34° [24°]; difference of medians 13°; p = 0.01) during gait compared with before THA. The SPM analysis showed these improvements occurred during the late swing and early stance phases of gait. CONCLUSION: When restricted preoperatively, spinopelvic characteristics during daily tasks show normalization after THA, concurring with previous radiographic findings in the sagittal plane. Thus, spinopelvic characteristics change dynamically, and incorporating them into surgical planning would require predictive models on post-THA improvements to be of use. LEVEL OF EVIDENCE: Level II, prognostic study.

Sward type alters enteric methane emissions, nitrogen output and the relative abundance of the rumen microbial ecosystem in sheep.

Observed improvements in animal and sward performance, coupled with a desire for more sustainable pasture-based feeding systems has triggered a surge in the implementation of more botanically diverse pastures. However, thus far, there has been limited research investigating the effects of botanically diverse sward types on enteric methane (CH4) or nitrogen (N) excretion, alongside the ruminal microbiota and fermentation profile, in sheep. Hence, this study investigates the effect of sward type on CH4 production and N excretion, in addition to assessing the rumen microbiome, volatile fatty acid (VFA) proportions, and ammonia nitrogen (NH3-N) concentration in sheep. A 5×5 Latin square design experiment was implemented to investigate five dietary treatments; perennial ryegrass (Lolium perenne L.;PRG) only or PRG plus white clover (Trifolium repens L.;PRG+WC), red clover (Trifolium pratense L.;PRG+RC), chicory (Chicorium intybus L.;PRG+Chic) or plantain (Plantago lanceolata L.;PRG+Plan). Diets were mixed at a ratio of 75% PRG and 25% of the respective companion forage and 100% PRG for the PRG treatment, on a dry matter basis. Twenty castrated male sheep were housed in metabolism crates across five feeding periods. Methane measurements were acquired utilizing portable accumulation chambers. Rumen fluid was harvested using a transoesophageal sampling device. Microbial rumen DNA was extracted and subjected to 16S rRNA amplicon sequencing and fermentation analysis. Data were analysed using PROC MIXED in SAS. Results show that animals consuming PRG+WC ranked lower for CH4 production (g/d) than sheep offered PRG, PRG+Chic or PRG+Plan (P<0.01) while the addition of any companion forage ranked CH4 yield (g/kg DMI) lower (P<0.001) than PRG. There was a moderate positive correlation between DMI and CH4 (g/d; r=0.51). Ruminal NH3-N was lowest in animals consuming the PRG diet (P<0.01). There was a greater abundance of Methanobrevibacter and reduced abundance of Methanosphaera (P<0.001) in sheep offered PRG, compared with any binary sward. On average, herb diets (PRG+Chic or PRG+Plan) reduced urinary nitrogen concentration of sheep by 34% in comparison to legume diets (PRG+WC or PRG+RC) and 13% relative to the PRG diet (P<0.001). Sheep offered PRG+Chic had a greater dietary nitrogen use efficiency than PRG+RC (P<0.05). This study demonstrates the potential for sward type to influence rumen function and the microbial community, along with CH4 and N output from sheep.

Next-generation precision medicine for suicidality prevention.

Suicidality remains a clear and present danger in society in general, and for mental health patients in particular. Lack of widespread use of objective and/or quantitative information has hampered treatment and prevention efforts. Suicidality is a spectrum of severity from vague thoughts that life is not worth living, to ideation, plans, attempts, and completion. Blood biomarkers that track suicidality risk provide a window into the biology of suicidality, as well as could help with assessment and treatment. Previous studies by us were positive. Here we describe new studies we conducted transdiagnostically in psychiatric patients, starting with the whole genome, to expand the identification, prioritization, validation and testing of blood gene expression biomarkers for suicidality, using a multiple independent cohorts design. We found new as well as previously known biomarkers that were predictive of high suicidality states, and of future psychiatric hospitalizations related to them, using cross-sectional and longitudinal approaches. The overall top increased in expression biomarker was SLC6A4, the serotonin transporter. The top decreased biomarker was TINF2, a gene whose mutations result in very short telomeres. The top biological pathways were related to apoptosis. The top upstream regulator was prednisolone. Taken together, our data supports the possibility that biologically, suicidality is an extreme stress-driven form of active aging/death. Consistent with that, the top subtypes of suicidality identified by us just based on clinical measures had high stress and high anxiety. Top therapeutic matches overall were lithium, clozapine and ketamine, with lithium stronger in females and clozapine stronger in males. Drug repurposing bioinformatic analyses identified the potential of renin-angiotensin system modulators and of cyclooxygenase inhibitors. Additionally, we show how patient reports for doctors would look based on blood biomarkers testing, personalized by gender. We also integrated with the blood biomarker testing social determinants and psychological measures (CFI-S, suicidal ideation), showing synergy. Lastly, we compared that to machine learning approaches, to optimize predictive ability and identify key features. We propose that our findings and comprehensive approach can have transformative clinical utility.

Twice-Yearly Depemokimab in Severe Asthma with an Eosinophilic Phenotype.

BACKGROUND: Depemokimab is an ultra-long-acting biologic therapy with enhanced binding affinity for interleukin-5 that may enable effective 6-month dosing intervals. METHODS: In these phase 3A, randomized, placebo-controlled replicate trials, we evaluated the efficacy and safety of depemokimab in patients with severe asthma and an eosinophilic phenotype characterized by a high eosinophil count (≥300 cells per microliter in the previous 12 months or ≥150 cells per microliter at screening) and a history of exacerbations despite the receipt of medium- or high-dose inhaled glucocorticoids. Patients were randomly assigned in a 2:1 ratio to receive either depemokimab (at a dose of 100 mg subcutaneously) or placebo at weeks 0 and 26, plus standard care. The primary end point was the annualized rate of exacerbations at 52 weeks. Secondary end points, which were analyzed in a hierarchical manner to adjust for multiplicity, included the change from baseline in the score on the St. George's Respiratory Questionnaire (SGRQ), the forced expiratory volume in 1 second, and asthma symptom reports at 52 weeks. RESULTS: Across the two trials, 792 patients underwent randomization and 762 were included in the full analysis; 502 were assigned to receive depemokimab and 260 to receive placebo. The annualized rate of exacerbations was 0.46 (95% confidence interval [CI]), 0.36 to 0.58) with depemokimab and 1.11 (95% CI, 0.86 to 1.43) with placebo (rate ratio, 0.42; 95% CI, 0.30 to 0.59; P<0.001) in SWIFT-1 and 0.56 (95% CI, 0.44 to 0.70) with depemokimab and 1.08 (95% CI, 0.83 to 1.41) with placebo (rate ratio, 0.52; 95% CI, 0.36 to 0.73; P<0.001) in SWIFT-2. No significant between-group difference in the change from baseline in the SGRQ score was observed in either trial, so no statistical inference was drawn on subsequent secondary end points. The proportion of patients with any adverse event was similar in the two groups in both trials. CONCLUSIONS: Depemokimab reduced the annualized rate of exacerbations among patients with severe asthma with an eosinophilic phenotype. (Funded by GSK; SWIFT-1 and SWIFT-2 ClinicalTrials.gov numbers, NCT04719832 and NCT04718103.).

Markers of Maternal Bone and Renal Toxicity Through 50 Weeks Postpartum: IMPAACT 2010 (VESTED) Trial.

BACKGROUND: Safety data from randomized trials of antiretrovirals in pregnancy are scarce. We evaluated maternal bone and renal data from the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 2010 trial, which compared the safety and efficacy of 3 antiretroviral therapy regimens started in pregnancy: dolutegravir + emtricitabine/tenofovir alafenamide (DTG + FTC/TAF), dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG + FTC/TDF), and efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). METHODS: A subset of participants underwent dual-energy X-ray absorptiometry scans at postpartum week 50 only. Maternal bone mineral density (BMD) Z-scores were compared between arms. Maternal creatinine was measured at enrolment and periodically through week 50 postpartum, and by-arm differences in average weekly change in estimated creatinine clearance were compared. RESULTS: Six hundred forty-three participants were randomized to DTG + FTC/TAF (N = 217) or DTG + FTC/TDF (N = 215) or EFV/FTC/TDF (N = 211). Median age = 27 years (IQR 23, 32), median CD4 count = 466 cells/mm3 (IQR 308, 624); 564 (88%) women enrolled in Africa and 479 (74%) breastfed. Week 50 postpartum dual-energy X-ray absorptiometry results from 154 women were included in the analysis. Hip and spine BMD was on average higher in women in the DTG + FTC/TAF and lower in the DTG + FTC/TDF and EFV/FTC/TDF arms, but no significant differences in BMD Z-scores were observed between treatment groups. The weekly rate of change in estimated creatinine clearance differed among treatment groups during the antepartum period, but not over the full study follow-up. CONCLUSIONS: Markers of bone and renal toxicity did not differ significantly through week 50 postpartum among women randomized to start DTG + FTC/TAF or DTG + FTC/TDF or EFV/FTC/TDF in pregnancy.

Impact of Adjuvant Chemotherapy on Resected Intraductal Papillary Mucinous Neoplasm-Derived Pancreatic Cancer: Results From an International Multicenter Study.

PURPOSE: The benefit of adjuvant therapy for intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) remains unclear because of severely limited evidence. Although biologically distinct entities, adjuvant therapy practices for IPMN-derived PDAC are largely founded on pancreatic intraepithelial neoplasia-derived PDAC. We aimed to evaluate the role of adjuvant chemotherapy in IPMN-derived PDAC. METHODS: This international multicenter retrospective cohort study (2005-2018) was conceived at the Verona Evidence-Based Medicine meeting. Cox regressions were performed to identify risk-adjusted hazard ratios (HR) associated with overall survival (OS). Kaplan-Meier curves and log-rank tests were employed for survival analysis. Logistic regression was performed to identify factors motivating adjuvant chemotherapy administration. A decision tree was proposed and categorized patients into overtreated, undertreated, and optimally treated cohorts. RESULTS: In 1,031 patients from 16 centers, nodal disease (HR, 2.88, P < .001) and elevated (≥37 to <200 µ/mL, HR, 1.44, P = .006) or markedly elevated (≥200 µ/mL, HR, 2.53, P < .001) carbohydrate antigen 19-9 (CA19-9) were associated with worse OS. Node-positive patients with elevated CA19-9 had an associated 34.4-month improvement in median OS (P = .047) after adjuvant chemotherapy while those with positive nodes and markedly elevated CA19-9 had an associated 12.6-month survival benefit (P < .001). Node-negative patients, regardless of CA19-9, did not have an associated benefit from adjuvant chemotherapy (all P > .05). Based on this model, we observed undertreatment in 18.1% and overtreatment in 61.2% of patients. Factors associated with chemotherapy administration included younger age, R1-margin, poorer differentiation, and nodal disease. CONCLUSION: Almost half of patients with resected IPMN-derived PDAC may be overtreated or undertreated. In patients with node-negative disease or normal CA19-9, adjuvant chemotherapy is not associated with a survival benefit, whereas those with node-positive disease and elevated CA19-9 have an associated benefit from adjuvant chemotherapy. A decision tree was proposed. Randomized controlled trials are needed for validation.

Extrapolative Validity Evidence of the Anastomosis Objective Structured Assessment of Technical Skill (A-OSATS) for Robotic Ileocolic Anastomosis.

OBJECTIVE: To collect validity evidence for the use of the Anastomosis Objective Structured Assessment of Technical Skills (A-OSATS) instrument, which has been developed to evaluate performance of a minimally invasive side-to-side bowel anastomosis with hand-sewn common enterotomy. DESIGN: Residents performed a robotic ileocolic anastomosis simulation on an ex vivo porcine model. Faculty scored each resident with the A-OSATS and performed a provocative leak test on the completed anastomoses. Residents were reassessed on the sewing sub-score 1 month later. Data were compared with parametric and nonparametric analysis. SETTING: Single academic general surgery residency PARTICIPANTS: PGY-4 and -5 general surgery residents (n = 17) RESULTS: PGY-5s performed better than PGY-4s in repeat A-OSATS sewing sub-score (mean 55/55 ± 0 vs 43 ± 4.9, p < 0.001) and time to complete (minutes, mean 14.5 ± 4.9 vs 21.2 ± 3.9, p = 0.01). There was a strong correlation between A-OSATS score and time (r = -0.67, p = 0.005). For the initial assessment, there was no significant difference in mean A-OSATS score between anastomoses that leaked and those that did not leak (137.3 ± 14.5 vs 150.1 ± 11.2, p = 0.098), but on repeat assessment, intact anastomoses had a higher mean A-OSATS sewing sub-score than those that leaked (52.2 ± 4.7 vs 39 ± 3.5, p = 0.007). There was no significant difference between initial A-OSATS score and repeat score (p = 0.14). CONCLUSIONS: We provide extrapolative validity evidence for the A-OSATS instrument by comparing A-OSATS score to time to sew, provocative leak test, and discrimination between PGY-4s and PGY-5s. Generalizability validity evidence is provided by test-retest reliability. Further refinement is needed for the A-OSATS tool to be used for high-stakes entrustment decisions in resident-performed robotic ileocolic anastomoses.

Association of prenatal vitamin E levels with child asthma and wheeze.

BACKGROUND: We investigated the individual and interaction effects of maternal plasma 𝛂- and ϒ-tocopherol levels (vitamin E isomers) on child asthma and wheeze at age 8-9. METHODS: Mother-child dyads were enrolled between 2006 and 2011 into the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) prenatal cohort. Maternal second-trimester samples were analyzed for tocopherol and lipid concentrations. We assessed child asthma/wheeze using the International Study of Asthma and Allergies in Childhood (ISAAC) and other self-reported Ent wheeze. In multivariable logistic regression analyses, we assessed associations between vitamin E isomers and child asthma/wheeze outcomes (n = 847 mother-child dyads) and tested for prespecified interaction terms. RESULTS: Median cholesterol-corrected tocopherol levels (interquartile range (IQR)) were 5.0 (4.3-5.7) and 0.8 (0.7-0.9) (umol/mmol) for 𝛂- and ϒ-tocopherol, respectively. Associations between 𝛂-tocopherol and asthma outcome variables were inverse but not statistically significant. In contrast, for ϒ-tocopherol, associations were in the positive direction, but also nonsignificant. Interactions analysis between tocopherols did not reach statistical significance for any outcome. Among children of women with a history of asthma, the likelihood of ever asthma in the child appears to be decreasing with increasing maternal 𝛂-tocopherol levels, whereas this trend was not observed among those without a history of asthma (p-interaction = .05). CONCLUSION: We observed no associations for prenatal 𝛂- or ϒ-tocopherol concentrations with child asthma/wheeze. We detected some evidence of effect modification by maternal asthma history in associations between 𝛂-tocopherol and child asthma.

Chameleonic Cages: Encapsulation of Anionic, Neutral, and Cationic Guest Species within [Fe4L4]8+ Tetrahedral Cages Synthesised from the tris(4-aminophenyl)phosphate pro-Ligand.

An adaptable Fe(II) tetrahedral cage, [Fe4L4][BF4]8 (L = tris(4-(((E)-pyridin-2-ylmethylene)amino)phenyl) phosphate), has been synthesised via self-assembly. By modulating the orientation of its pendant P=O groups, the cage was found to be capable of encapsulating anionic, neutral, and cationic guests, which was confirmed in the solid state via single-crystal X-ray diffraction (SCXRD) and in solution by high-resolution mass spectroscopy (HR-MS), as well as by NMR (1H, 19F, 31P) studies where possible.