Adding immunotherapy to first-line treatment of advanced and metastatic endometrial cancer.

BACKGROUND: Immunotherapy has transformed the endometrial cancer treatment landscape, particularly for those exhibiting mismatch repair deficiency [MMRd/microsatellite instability-hypermutated (MSI-H)]. A growing body of evidence supports the integration of immunotherapy with chemotherapy as a first-line treatment strategy. Recently, findings from ongoing trials such as RUBY (NCT03981796), NRG-GY018 (NCT03914612), AtTEnd (NCT03603184), and DUO-E (NCT04269200) have been disclosed. MATERIALS AND METHODS: This paper constitutes a review and meta-analysis of phase III trials investigating the role of immunotherapy in the first-line setting for advanced or recurrent endometrial cancer. RESULTS: The pooled data from 2320 patients across these trials substantiate the adoption of chemotherapy alongside immunotherapy, revealing a significant improvement in progression-free survival compared to chemotherapy alone [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.62-0.79] across all patient groups. Progression-free survival benefits are more pronounced in MMRd/MSI-H tumors (n = 563; HR 0.33, 95% CI 0.23-0.43). This benefit, albeit less robust, persists in the MMR-proficient/microsatellite stable group (n = 1757; HR 0.74, 95% CI 0.60-0.91). Pooled data further indicate that chemotherapy plus immunotherapy enhances overall survival compared to chemotherapy alone in all patients (HR 0.75, 95% CI 0.63-0.89). However, overall survival data maturity remains low. CONCLUSIONS: The incorporation of immunotherapy into the initial treatment for advanced and metastatic endometrial cancer brings about a substantial improvement in oncologic outcomes, especially within the MMRd/MSI-H subset. This specific subgroup is currently a focal point of investigation for evaluating the potential of chemotherapy-free regimens. Ongoing exploratory analyses aim to identify non-responding patients eligible for inclusion in clinical trials.

Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial.

BACKGROUND: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. PATIENTS AND METHODS: RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1 : 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint. RESULTS: A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death [hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54-0.89, P = 0.0020] in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17-0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60-1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis. CONCLUSIONS: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile.

Niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer: final overall survival results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

BACKGROUND: The phase III PRIMA/ENGOT-OV26/GOG-3012 trial met its primary endpoint. Niraparib first-line maintenance significantly prolonged progression-free survival (PFS) among patients with newly diagnosed advanced ovarian cancer that responded to first-line platinum-based chemotherapy, regardless of homologous recombination deficiency (HRD) status. Final overall survival (OS) results are reported. PATIENTS AND METHODS: Patients were randomized 2:1 to niraparib or placebo, stratified by response to first-line treatment, receipt of neoadjuvant chemotherapy, and tumor HRD status. After reaching 60% target maturity, OS was evaluated via a stratified log-rank test using randomization stratification factors and summarized using Kaplan-Meier methodology. OS testing was hierarchical [overall population first, then the homologous recombination-deficient (HRd) population]. Other secondary outcomes and long-term safety were assessed; an updated, ad hoc analysis of investigator-assessed PFS was also conducted (cut-off date, 8 April 2024). RESULTS: The median follow-up was 73.9 months. In the overall population, the OS hazard ratio was 1.01 [95% confidence interval (CI) 0.84-1.23; P = 0.8834] for niraparib (n = 487) versus placebo (n = 246). In the HRd (n = 373) and homologous recombination-proficient (n = 249) populations, the OS hazard ratios were 0.95 (95% CI 0.70-1.29) and 0.93 (95% CI 0.69-1.26), respectively. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 11.7% and 15.8% of niraparib patients and 37.8% and 48.4% of placebo patients in the overall and HRd populations, respectively. The 5-year PFS rate numerically favored niraparib in the overall (niraparib, 22%; placebo, 12%) and HRd populations (niraparib, 35%; placebo, 16%). Myelodysplastic syndromes/acute myeloid leukemia incidence was <2.5% (niraparib, 2.3%; placebo, 1.6%). No new safety signals were observed. CONCLUSIONS: In patients with newly diagnosed advanced ovarian cancer at high risk of recurrence, there was no difference in OS between treatment arms. In the HRd population, patients alive at 5 years were two times as likely to be progression free with niraparib treatment than placebo. Long-term safety remained consistent with the established niraparib safety profile.

Direct Evidence of Klein and Anti-Klein Tunneling of Graphitic Electrons in a Corbino Geometry.

Transport measurement of electron optics in monolayer graphene p-n junction devices has been traditionally studied with negative refraction and chiral transmission experiments in Hall bar magnetic focusing setups. We show direct signatures of Klein (monolayer) and anti-Klein (bilayer) tunneling with a circular "edgeless" Corbino geometry made out of gated graphene p-n junctions. Noticeable in particular is the appearance of angular sweet spots (Brewster angles) in the magnetoconductance data of bilayer graphene, which minimizes head-on transmission, contrary to conventional Fresnel optics or monolayer graphene which show instead a sharpened collimation of transmission paths. The local maxima on the bilayer magnetoconductance plots migrate to higher fields with increasing doping density. These experimental results are in good agreement with detailed numerical simulations and analytical predictions.

NSGO-OV-UMB1/ENGOT-OV30: A phase II study of durvalumab in combination with the anti-CD73 monoclonal antibody Oleclumab in patients with relapsed ovarian cancer.

OBJECTIVES: In patients with epithelial ovarian cancer (EOC), the clinical efficacy of monotherapy with immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 is modest. To enhance response rates to these immunotherapeutic agents and broaden the indications for their use, new approaches involving combinational therapy are needed. The immune regulator CD73 is a potential target, as it promotes tumor escape by producing immunosuppressive extracellular adenosine in the tumor microenvironment. Here, we present the results from the NSGO-OV-UMB1/ENGOT-OV-30 trial evaluating the activity of combining the anti-CD73 antibody oleclumab with the anti-PD-L1 checkpoint inhibitor durvalumab in patients with recurrent EOC. METHODS: In this phase II open-label non-randomized study, patients with CD73-positive relapsed EOC were intravenously administered oleclumab (3000 mg, Q2W) and durvalumab (1500 mg, Q4W). The primary endpoint was disease control rate (DCR) at 16 weeks. The expression of PD-L1 and CD8 was assessed by immunohistochemistry of archival tumors. RESULTS: This trial included 25 patients with a median age of 66 years (47-77 years). Twenty-two patients were evaluable for treatment activity analysis. The DCR was 27%, the median progression-free survival was 2.7 months (95% CI: 2.2-4.2) and the median overall survival was 8.4 months (95% CI: 5.0-13.4). Infiltration of CD8+ cells and PD-L1 expression on tumor cells were observed in partially overlapping sets of 74% of the tumor samples. Neither CD8- nor PD-L1-positivity were significantly associated with better DCR. CONCLUSIONS: Combined treatment with oleclumab and durvalumab was safe and demonstrated limited anti-tumor activity in patients with recurrent EOC.

Global inequality remotely sensed.

Economic inequality is notoriously difficult to quantify as reliable data on household incomes are missing for most of the world. Here, we show that a proxy for inequality based on remotely sensed nighttime light data may help fill this gap. Individual households cannot be remotely sensed. However, as households tend to segregate into richer and poorer neighborhoods, the correlation between light emission and economic thriving shown in earlier studies suggests that spatial variance of remotely sensed light per person might carry a signal of economic inequality. To test this hypothesis, we quantified Gini coefficients of the spatial variation in average nighttime light emitted per person. We found a significant relationship between the resulting light-based inequality indicator and existing estimates of net income inequality. This correlation between light-based Gini coefficients and traditional estimates exists not only across countries, but also on a smaller spatial scale comparing the 50 states within the United States. The remotely sensed character makes it possible to produce high-resolution global maps of estimated inequality. The inequality proxy is entirely independent from traditional estimates as it is based on observed light emission rather than self-reported household incomes. Both are imperfect estimates of true inequality. However, their independent nature implies that the light-based proxy could be used to constrain uncertainty in traditional estimates. More importantly, the light-based Gini maps may provide an estimate of inequality where previously no data were available at all.

Treatment of renal artery aneurysm by ex-situ repair and autotransplantation: a nationwide cohort study.

Introduction Renal artery aneurysm (RAA) is a rare vascular disease with a mortality rate of up to 80% upon rupture. This study aims to investigate the safety and efficacy of ex-situ repair and autotransplantation for endovascularly untreatable RAA. Methods A retrospective nationwide cohort study was conducted in RAA patients undergoing ex-situ repair and autotransplantation in the Netherlands. Surgical techniques, postoperative complications, and graft outcomes were assessed. Results Ex-situ repair was performed in 9 patients with 11 RAAs. Eight RAAs were located at the first bifurcation, one on the main trunk, one on the first branch, and one on the second branch. Nephrectomy was performed via laparoscopy (n=7), robotic-assisted laparoscopy (n=1) and laparotomy (n=1). Postoperative complications were recorded in four patients, including bowel obstruction, delirium, pneumonia and hydronephrosis due to double-J dislocation. Median estimated glomerular filtration rate (eGFR) was 83 ml/min/1.73m2 pretransplant and 88 ml/min/1.73m2 posttransplant. By an average follow-up of 3 years, two patients had died due to lung adenocarcinoma and stroke, while all autotransplanted kidneys had good patency and remained functional. Conclusions Ex-situ repair and autotransplantation are safe and feasible for endovascularly untreatable RAA cases. Larger cohorts with longer follow-up periods are necessary to further evaluate the role of this surgical approach.

INOVATYON/ ENGOT-ov5 study: Randomized phase III international study comparing trabectedin/pegylated liposomal doxorubicin (PLD) followed by platinum at progression vs carboplatin/PLD in patients with recurrent ovarian cancer progressing within 6-12 months after last platinum line.

BACKGROUND: This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC). METHODS: Patients with OC (up to two previous platinum-based lines), with a TFIp of 6-12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75). RESULTS: The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94-1.35; p = 0.197). Grade 3-5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP). CONCLUSIONS: This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6-12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01379989.

Endothelial c-Myc knockout enhances diet-induced liver inflammation and fibrosis.

Endothelial cells play an essential role in inflammation through synthesis and secretion of chemoattractant cytokines and expression of adhesion molecules required for inflammatory cell attachment and infiltration. The mechanisms by which endothelial cells control the pro-inflammatory response depend on the type of inflammatory stimuli, endothelial cell origin, and tissue involved. In the present study, we investigated the role of the transcription factor c-Myc in inflammation using a conditional knockout mouse model in which Myc is specifically deleted in the endothelium. At a systemic level, circulating monocytes, the chemokine CCL7, and the extracellular-matrix protein osteopontin were significantly increased in endothelial c-Myc knockout (EC-Myc KO) mice, whereas the cytokine TNFSF11 was downregulated. Using an experimental model of steatohepatitis, we investigated the involvement of endothelial c-Myc in diet-induced inflammation. EC-Myc KO animals displayed enhanced pro-inflammatory response, characterized by increased expression of pro-inflammatory cytokines and leukocyte infiltration, and worsened liver fibrosis. Transcriptome analysis identified enhanced expression of genes associated with inflammation, fibrosis, and hepatocellular carcinoma in EC-Myc KO mice relative to control (CT) animals after short-exposure to high-fat diet. Analysis of a single-cell RNA-sequencing dataset of human cirrhotic livers indicated downregulation of MYC in endothelial cells relative to healthy controls. In summary, our results suggest a protective role of endothelial c-Myc in diet-induced liver inflammation and fibrosis. Targeting c-Myc and its downstream pathways in the endothelium may constitute a potential strategy for the treatment of inflammatory disease.

Transcatheter closure of ventricular septal defects: preliminary results in children weighing 10 kg or less.

INTRODUCTION: Ventricular septal defect is one of the commonest heart defect in children and closure of this defect with devices has seen a rapid progression over a period of time. The availability of new and safer devices has made the transcatheter closure of ventricular septal defect a suitable option even in young children. AIM: The study was done to evaluate the feasibility and complications of device closure of ventricular septal defect in children weighing 10 kg or less with different types of devices. METHODS: The present study was undertaken in a newly established dedicated Paediatric Cardiac Unit at a Tertiary Care Hospital. Relevant data were obtained retrospectively from the case files and the catheterisation records and data were analysed for first 50 patients with ventricular septal defect weighing 10 kg or less between March 2018 and March 2021. RESULTS: Among these 50 patients selected, device closure was successfully done in 45 (90%) cases while 5 (10%) attempts were unsuccessful for various reasons. The mean weight in this study was 7.46 ± 1.89 kg (2.3-10 kg), 21 (42%) cases were females while 29 (58%) were males; mean age was 19.4 ± 11.88 months (4-48 months). Right heart catheterisation study showed 21 (42%) patients with normal pulmonary artery pressures (no pulmonary artery hypertension). Among 29 patients with pulmonary arterial hypertension, 13 patients (22%) were having mild pulmonary arterial hypertension, 4 (8%) were with moderate pulmonary arterial hypertension, and 12 (24%) were with severe pulmonary arterial hypertension. Mean Qp/Qs was 2.73 ± 0.72 (2.5-4.5) and mean pulmonary vascular resistance was 1.5 ± 1.04 (0.6-4.6 WU). Amplatzer Duct Occluder (ADOI) was used in 15 (30%) cases, 27 (52%) cases were closed with Amplatzer Duct Occluder (ADOII), and the 3 (6%) cases closure was done with Amplatzer muscular ventricular septal defect occluder. CONCLUSIONS: Transcatheter closure of ventricular septal defect in children 10 kg or less is feasible and safe alternative to surgical ventricular septal defect closure. The immediate and short-term outcomes have proven this method to be safe and valid.

Relationship Between Mental Health Disorders and Readmissions Following Total Joint Arthroplasty: A Systematic Review and Meta-Analysis.

BACKGROUND: There is limited evidence exploring the relationship between mental health disorders and the readmissions following total joint arthroplasty (TJA). Therefore, we conducted a meta-analysis to evaluate the relationship between mental health disorders and the risk of readmission following TJA. METHODS: We searched PubMed, Cochrane, and Google Scholar from their inception till April 19, 2022. Studies exploring the association of mental health disorders and readmission risk following TJA were selected. The outcomes were divided into 30-day readmission, 90-day readmission, and readmission after 90 days. We also performed subgroup analyses based on the type of arthroplasty: total hip arthroplasty (THA) and total knee arthroplasty (TKA). A total of 12 studies were selected, of which 11 were included in quantitative analysis. A total of 1,345,893 patients were evaluated, of which 73,953 patients suffered from mental health disorders. RESULTS: The risk of 30-day readmission (odds ratio = 1.43, 95% CI 1.14-1.80, P = .002, I2 = 87%) and 90-day readmission (OR = 1.35, 95% CI 1.22-1.49, P < .00001, I2 = 89%) was significantly associated with mental health disorders. On subgroup analyses, 30-day readmission was significantly associated with THA (OR = 1.29, 95% CI 1.04-1.60, P = .02), but not with TKA (OR = 1.44, 95% CI 0.51-4.06, P = .50). Similarly, 90-day readmission was significantly associated with both THA (OR = 1.21, 95% CI 1.14-1.29, P < .00001) and TKA (OR = 1.33, 95% CI 1.17-1.51, P < .0001). CONCLUSION: Mental health disorders are significantly associated with increased 30-day and 90-day readmissions. Increasing awareness regarding mental health disorders and readmission in arthroplasty will help in efficient preoperative risk stratification and better postoperative management in these patients.

Refining the metabolisable energy value of field beans for turkeys.

1. This study examined the feeding value of ten UK grown field bean (Vicia faba L. var. minor) cultivar samples from the same harvest year on nitrogen corrected apparent metabolisable energy (AMEn) and nutrient retention coefficients when fed to young female turkeys.2. A balancer feed (BF) was formulated to contain 12.39 MJ/kg ME and 269 g/kg crude protein. Ten nutritionally complete, mash diets were prepared by mixing 200 g/kg of each ground field bean cultivar with 800 g/kg of the BF, totalling eleven diets. Diets were fed to female BUT Premium turkeys from 40 to 50 d of age. Each diet was fed to eight raised floor pens, housing two birds, following randomisation. The AMEn was determined by the total collection technique over the last 4 d of the study. Relationships were examined between AMEn, chemical composition and quality variables of the field bean samples.3. The overall determined AMEn value of the beans ranged from 7.72 MJ/kg DM to 9.87 MJ/kg DM, giving an average AMEn of 8.80 MJ/kg DM (P < 0.05). The soluble non-starch polysaccharide (NSP) content of the beans negatively correlated with their determined AMEn (r = -0.730; P < 0.05). Bean flour lightness-darkness degree (L*) correlated positively with the AMEn (r = -0.643; P < 0.05)4. A positive correlation was observed between the degree of yellowness-blueness of bean flour and condensed tannins content (r = 0.696; P < 0.05). Step-wise regression indicated that soluble NSP + L* of field beans provided explanatory variables suitable for estimating the AMEn value for turkeys (r2 = 0.737; P < 0.05).

State of gaseous air pollutants and resulting health effects in Karachi, Pakistan.

Karachi, Pakistan, is a priority site for air pollution research due to high emissions of air pollutants from vehicular traffic, industrial activities, and biomass burning, as well as rapid growth in population. The objectives of this study were to investigate the levels of gaseous pollutants (NO, NO2, O3, HNO3, and SO2) in Karachi, to determine temporal and seasonal variations, to compare Karachi's air quality with other urban centers, to identify relationships with meteorological conditions, to identify source characterization, and to perform a backward-in-time trajectory analysis and a health impact assessment. Daily samples of gaseous pollutants were collected for six consecutive weeks in each of the four seasons for a year. Daily maximum concentrations of NO (90 parts per billion by volume (ppbv)), NO2 (28.1 ppbv), O3 (57.8 ppbv), and SO2 (331 ppbv) were recorded in fall, while HNO3 (9129 parts per trillion by volume (pptv)) was recorded in spring. Seasonal average concentrations were high in winter for NO (9.47 ± 7.82 ppbv), NO2 (4.84 ± 3.35 ppbv), and O3 (8.92 ± 7.65 ppbv), while HNO3 (629 ± 1316 pptv) and SO2 (20.2 ± 39.4 ppbv) were high in spring and fall, respectively. The observed SO2 seasonal average concentration in fall (20.2 ± 39.4) was 5 times higher than that in summer (3.97 ± 2.77) with the fall 24-h average (120 ppbv) exceeding the WHO daily guideline (7.64 ppbv) by a factor of about 15.7. A health impact assessment estimated an increase of 1200 and 569 deaths due to short-term exposure to SO2 in fall and spring, respectively. Chronic daily intake estimated risk per 1000 was 0.99, 0.47, 0.45, and 0.26 for SO2 in fall, NO in winter, O3 in winter, and NO2 in spring, respectively. This study confirms the effect of poor urban air quality on public health and demonstrated the influence of photochemical reactions as well as unfavorable meteorological conditions on the formation of secondary pollutants.

European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer.

BACKGROUND: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. DESIGN: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. CONCLUSION: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer.

Item-level analysis of mental health symptom trajectories during the COVID-19 pandemic in the UK: Associations with age, sex and pre-existing psychiatric conditions.

BACKGROUND: There is widespread concern regarding how the COVID-19 pandemic has affected mental health. Emerging meta-analyses suggest that the impact on anxiety/depression may have been transient, but much of the included literature has major methodological limitations. Addressing this topic rigorously requires longitudinal data of sufficient scope and scale, controlling for contextual variables, with baseline data immediately pre-pandemic. AIMS: To analyse self-report of symptom frequency from two largely UK-based longitudinal cohorts: Cohort 1 (N = 10,475, two time-points: winter pre-pandemic to UK first winter resurgence), and Cohort 2 (N = 10,391, two time-points, peak first wave to UK first winter resurgence). METHOD: Multinomial logistic regression applied at the item level identified sub-populations with greater probability of change in mental health symptoms. Permutation analyses characterised changes in symptom frequency distributions. Cross group differences in symptom stability were evaluated via entropy of response transitions. RESULTS: Anxiety was the most affected aspect of mental health. The profiles of change in mood symptoms was less favourable for females and older adults. Those with pre-existing psychiatric diagnoses showed substantially higher probability of very frequent symptoms pre-pandemic and elevated risk of transitioning to the highest levels of symptoms during the pandemic. Elevated mental health symptoms were evident across intra-COVID timepoints in Cohort 2. CONCLUSIONS: These findings suggest that mental health has been negatively affected by the pandemic, including in a sustained fashion beyond the first UK lockdown into the first winter resurgence. Women, and older adults, were more affected relative to their own baselines. Those with diagnoses of psychiatric conditions were more likely to experience transition to the highest levels of symptom frequency.

Graphene transistor based on tunable Dirac fermion optics.

We present a quantum switch based on analogous Dirac fermion optics (DFO), in which the angle dependence of Klein tunneling is explicitly utilized to build tunable collimators and reflectors for the quantum wave function of Dirac fermions. We employ a dual-source design with a single flat reflector, which minimizes diffusive edge scattering and suppresses the background incoherent transmission. Our gate-tunable collimator-reflector device design enables the quantitative measurement of the net DFO contribution in the switching device operation. We obtain a full set of transmission coefficients between multiple leads of the device, separating the classical contribution from the coherent transport contribution. The DFO behavior demonstrated in this work requires no explicit energy gap. We demonstrate its robustness against thermal fluctuations up to 230 K and large bias current density up to 102 A/m, over a wide range of carrier densities. The characterizable and tunable optical components (collimator-reflector) coupled with the conjugated source electrodes developed in this work provide essential building blocks toward more advanced DFO circuits such as quantum interferometers. The capability of building optical circuit analogies at a microscopic scale with highly tunable electron wavelength paves a path toward highly integrated and electrically tunable electron-optical components and circuits.

Palmar Creases and Their Implication on Carpal Tunnel Surgery.

BACKGROUND: A thorough knowledge of normal and variant anatomy of the wrist and hand is fundamental to avoiding complications during carpal tunnel release. The purpose of this study was to document variations of the surface anatomy of the hand to identify a safe zone in which the initial carpal tunnel incision could be placed. The safe zone was identified as the distance between the radial side of hook of hamate and the ulnar edge of the origin of the motor branch of the median nerve (MBMN). METHODS: Kaplan's cardinal line and other superficial markers were used to estimate the size of the safe zone, in accordance to prior published anatomical studies. The presence of a longitudinal palmar crease (thenar, median, or ulnar creases) within the safe zone was recorded. RESULTS: Of the 150 participants (75 male, 75 female) examined, the average safe zone widths were 10.85 (right) and 10.28 (left) mm. In all the hands examined, 86.33% of the safe zones (259 of 300) contained a longitudinal palmar crease. In the White population (n = 50), the average safe zone widths were 11.49 (right) and 10.01 (left) mm; in the African American population (n = 50), the average safe zone widths were 12.27 (right) and 12.01 (left) mm; and in the Asian population (n = 50), the average safe zone widths were 8.79 (right) and 8.82 (left) mm. On overage, males had a larger safe zone width than females by 4.55 mm. CONCLUSIONS: Although there seems to be variability between race and sex with regard to safe zone width, finding 86.33% of longitudinal palmar creases within the safe zone suggests that, for most patients, the initial carpal tunnel surgery incision may be hidden within the palmar crease while minimizing the risk of motor branch of the median nerve injury. Overall, the safe zone width is on average up to 10.5 mm measured from the hook of the hamate along Kaplan's cardinal line.

Feeding guanidinoacetic acid to broiler chickens can compensate for low dietary metabolisable energy formulation.

1. This study compared the responses of broilers to diets supplemented with the same level of guanidinoacetic acid (GAA) but formulated to have different N-corrected apparent metabolisable energy (AMEn) contents. The study involved 1280, one-day-old Ross 308 broilers, in 64 pens comprising 32 pens of males and 32 pens females, (20 birds in each) aged from 0 to 42 d.2. Commercial AME levels of 12.55 MJ/kg, 12.97 MJ/kg and 13.18 MJ/kg in the starter, grower and finisher diets, respectively, were set for the positive control (PC) feed. Four dietary treatments were prepared: PC (as above); negative control 1 (NC; PC - 0.21 MJ ME /kg); NC1 + 0.06% GAA; NC2 (PC - 0.42 MJ ME/kg + 0.06% GAA). Each diet was provided in 16 pens (eight male and eight female), following randomisation.3. Overall, birds fed NC1 had lower feed intakes (FI) compared to birds fed the PC and NC2+ GAA, lower weight gain (WG) compared to all the other diets and lower final body weight than birds fed the GAA diets (P < 0.05). There was a diet x sex interaction (P = 0.039), whereby feeding NC+GAA to female birds improved feed efficiency compared to being fed NC2 and NC1+ GAA, but not in males. Birds fed diets with GAA had a higher poultry efficiency factor (P < 0.001) than those fed NC1.4. There were no effects of treatment or sex on litter moisture, footpad score, white striping, wooden breast, AMEn, dry matter and fat retention (P > 0.05). However, the diet NC1+ GAA had 11.2% higher nitrogen retention coefficient compared to the NC1 diet (P = 0.038).5. Overall, the results implied that lower performance induced by a reduction of dietary AMEn in the range of 0.21 to 0.42 MJ/kg was more than compensated by supplementing 600 g/t GAA to the feed.

Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase III trial☆.

BACKGROUND: This study evaluated maintenance treatment with niraparib, a potent inhibitor of poly(ADP-ribose) polymerase 1/2, in patients with platinum-sensitive recurrent ovarian cancer. PATIENTS AND METHODS: In this phase III, double-blind, placebo-controlled study conducted at 30 centers in China, adults with platinum-sensitive recurrent ovarian cancer who had responded to their most recent platinum-containing chemotherapy were randomized 2 : 1 to receive oral niraparib (300 mg/day) or matched placebo until disease progression or unacceptable toxicity (NCT03705156). Following a protocol amendment, patients with a bodyweight <77 kg or a platelet count <150 × 103/µl received 200 mg/day, and all other patients 300 mg/day, as an individualized starting dose (ISD). Randomization was carried out by an interactive web response system and stratified by BRCA mutation, time to recurrence following penultimate chemotherapy, and response to most recent chemotherapy. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review. RESULTS: Between 26 September 2017 and 2 February 2019, 265 patients were randomized to receive niraparib (n = 177) or placebo (n = 88); 249 patients received an ISD (300 mg, n = 14; 200 mg, n = 235) as per protocol. In the intention-to-treat population, median PFS was significantly longer for patients receiving niraparib versus placebo: 18.3 [95% confidence interval (CI), 10.9-not evaluable] versus 5.4 (95% CI, 3.7-5.7) months [hazard ratio (HR) = 0.32; 95% CI, 0.23-0.45; P < 0.0001], and a similar PFS benefit was observed in patients receiving an ISD, regardless of BRCA mutation status. Grade ≥3 treatment-emergent adverse events occurred in 50.8% and 19.3% of patients who received niraparib and placebo, respectively; the most common events were neutrophil count decreased (20.3% versus 8.0%) and anemia (14.7% versus 2.3%). CONCLUSIONS: Niraparib maintenance treatment reduced the risk of disease progression or death by 68% and prolonged PFS compared to placebo in patients with platinum-sensitive recurrent ovarian cancer. Individualized niraparib dosing is effective and safe and should be considered standard practice in this setting.

Clinical, histopathologic and molecular features of idiopathic and diabetic nodular mesangial sclerosis in humans.

BACKGROUND: Idiopathic nodular mesangial sclerosis, also called idiopathic nodular glomerulosclerosis (ING), is a rare clinical entity with an unclear pathogenesis. The hallmark of this disease is the presence of nodular mesangial sclerosis on histology without clinical evidence of diabetes mellitus or other predisposing diagnoses. To achieve insights into its pathogenesis, we queried the clinical, histopathologic and transcriptomic features of ING and nodular diabetic nephropathy (DN). METHODS: All renal biopsy reports accessioned at Indiana University Health from 2001 to 2016 were reviewed to identify 48 ING cases. Clinical and histopathologic features were compared between individuals with ING and DN (n = 751). Glomeruli of ING (n = 5), DN (n = 18) and reference (REF) nephrectomy (n = 9) samples were isolated by laser microdissection and RNA was sequenced. Immunohistochemistry of proline-rich 36 (PRR36) protein was performed. RESULTS: ING subjects were frequently hypertensive (95.8%) with a smoking history (66.7%). ING subjects were older, had lower proteinuria and had less hyaline arteriolosclerosis than DN subjects. Butanoate metabolism was an enriched pathway in ING samples compared with either REF or DN samples. The top differentially expressed gene, PRR36, had increased expression in glomeruli 248-fold [false discovery rate (FDR) P = 5.93 × 10-6] compared with the REF and increased 109-fold (FDR P = 1.85 × 10-6) compared with DN samples. Immunohistochemistry revealed a reduced proportion of cells with perinuclear reaction in ING samples as compared to DN. CONCLUSIONS: Despite similar clinical and histopathologic characteristics in ING and DN, the uncovered transcriptomic signature suggests that ING has distinct molecular features from nodular DN. Further study is warranted to understand these relationships.