Calibration-free reaction yield quantification by HPLC with a machine-learning model of extinction coefficients.

Reaction optimization and characterization depend on reliable measures of reaction yield, often measured by high-performance liquid chromatography (HPLC). Peak areas in HPLC chromatograms are correlated to analyte concentrations by way of calibration standards, typically pure samples of known concentration. Preparing the pure material required for calibration runs can be tedious for low-yielding reactions and technically challenging at small reaction scales. Herein, we present a method to quantify the yield of reactions by HPLC without needing to isolate the product(s) by combining a machine learning model for molar extinction coefficient estimation, and both UV-vis absorption and mass spectra. We demonstrate the method for a variety of reactions important in medicinal and process chemistry, including amide couplings, palladium catalyzed cross-couplings, nucleophilic aromatic substitutions, aminations, and heterocycle syntheses. The reactions were all performed using an automated synthesis and isolation platform. Calibration-free methods such as the presented approach are necessary for such automated platforms to be able to discover, characterize, and optimize reactions automatically.

From hit to vial: Precision discovery and development of an imidazopyrimidine TLR7/8 agonist adjuvant formulation.

Vaccination can help prevent infection and can also be used to treat cancer, allergy, and potentially even drug overdose. Adjuvants enhance vaccine responses, but currently, the path to their advancement and development is incremental. We used a phenotypic small-molecule screen using THP-1 cells to identify nuclear factor-κB (NF-κB)-activating molecules followed by counterscreening lead target libraries with a quantitative tumor necrosis factor immunoassay using primary human peripheral blood mononuclear cells. Screening on primary cells identified an imidazopyrimidine, dubbed PVP-037. Moreover, while PVP-037 did not overtly activate THP-1 cells, it demonstrated broad innate immune activation, including NF-κB and cytokine induction from primary human leukocytes in vitro as well as enhancement of influenza and SARS-CoV-2 antigen-specific humoral responses in mice. Several de novo synthesis structural enhancements iteratively improved PVP-037's in vitro efficacy, potency, species-specific activity, and in vivo adjuvanticity. Overall, we identified imidazopyrimidine Toll-like receptor-7/8 adjuvants that act in synergy with oil-in-water emulsion to enhance immune responses.

Consideration of T-cell profile in the examination of statin efficacy in inflammatory diseases, neurodegeneration, and neurocognitive performance.

Statins are a cornerstone in the medical management of cardiovascular disease, yet their efficacy varies greatly between individuals. In this commentary, we outline evidence for the role of CD4+CD28null T-cell expansion as a critical moderator of the effects of statins in preventing cardiovascular events via the reduction of pathological inflammation. Given this relationship, we argue that T-cell profiles should be considered as a patient characteristic in clinical and pre-clinical studies examining statin efficacy in other age- and inflammation-related pathologies. We discuss the implications this may have for studies of statin use in numerous disease processes - notably, dementia and neurocognitive dysfunction - and the potential for T-cell profiles to be used as a prognosticator for statin efficacy in rheumatoid arthritis, Alzheimer's disease, and multiple sclerosis.

Incidence of and risk factors for paediatric perioperative anaphylaxis in the USA.

BACKGROUND: Perioperative anaphylaxis is a serious and often life-threatening immediate hypersensitivity reaction. There are few published data on paediatric perioperative anaphylaxis (pPOA). We evaluated the incidence of and risk factors involved in the occurrence of pPOA within a large US national database. METHODS: Deidentified data from the US Nationwide Inpatient Sample from 2005 to 2014 were used to identify pPOA cases and to conduct a retrospective multivariate analysis of preselected independent variables. RESULTS: Among 3,601,180 surgeries and procedures in children aged 0-18 yr, 297 pPOA cases were identified for an incidence of one in 12,125 surgeries and procedures. Compared with controls, pPOA cases had an increased median length of stay (6 vs 2 days; P<0.001) and median hospital cost ($54 719 vs $5109; P<0.0001). The age groups between 6 and 12 yr (odds ratio [OR] 7.1; 95% confidence interval [CI] 3.9-12.9; P<0.001) and 13 and 17 yr (OR 8.5; 95% CI 4.7-15.2; P<0.001) were associated with increased odds of pPOA. Transplant (OR 46.3; 95% CI 20.8-102.9; P<0.001), cardiac (OR 16.4; 95% CI 7.5-35.9; P<0.001), and vascular (OR 15.2; 95% CI 7.5-30.7; P<0.001) procedures posed the highest risk for pPOA. Chronic pulmonary disease, coagulopathy, and fluid and electrolyte disorders were also associated with pPOA (OR 2.2; 95% CI 1.5-3.3; P<0.001). CONCLUSIONS: The incidence of pPOA was one in 12,125 cases. Risk factors included age, procedure type, and comorbidities.

Emotional preparedness for human body donor dissection in premedical education: A pilot program evaluation.

Dissection of bodies provided by donors continues to be utilized as a critical part of medical education. It also represents a rite of passage that socializes students to prepare them for the stress that comes with working in a clinical environment as a medical professional. Just as proper guidance in acquiring technical skills is critical in anatomy education, there is an important need for proper emotional guidance throughout the human dissection process. A pilot curriculum was developed by an interdisciplinary faculty team to emotionally prepare students for their first visit to the anatomy laboratory. Students were first-year foundation premedical students who had expressed an interest in visiting the laboratory. Pre- and post-visit surveys were conducted to explore students' emotional responses to a first visit to the anatomy laboratory and their utilization of coping strategies. The survey findings show an overwhelming favorable feeling in anticipation of the human gross anatomy laboratory visit. About 20% of the students experienced anxiety at the anticipation of the laboratory visit, but only 5.3% experienced anxiety during the visit. The decrease in the number of students experiencing anxiety may be attributed to the interventions introduced before and during the visit. Talking with a close friend was the main coping strategy utilized by 63% of students experiencing fear or anxiety during and after the laboratory visit. The findings from this program evaluation provide a better understanding of student emotional preparedness and utilization of coping strategies, which may help prepare and guide future students for the dissection experience.

The effects of simulated monocular and binocular vision impairment on football penalty kick performance.

Sports performance is relatively robust under high levels of binocular blur. However, the limited research studies investigating monocular impairments has shown it has a larger impact on sport performance. This research study is relevant for classification in sports for athletes with vision impairment (VI), where visual acuity (VA) from the better eye is used during classification. Across two experiments, we aimed to establish the point at which binocular and monocular impairments affected performance in a football penalty kick (PK) through simulating varying severities of degraded VA and contrast sensitivity (CS) in active football players. In experiment one, 25 footballers performed PKs as VA and CS were systematically decreased in both eyes, and in one condition, visual field (VF) was reduced. The most severe VA/CS condition and reduced VF significantly impacted outcome, ball velocity and placement (ball kicked closer to the centre of the goal) (p < 0.05). In experiment two, 29 different footballers performed PKs as VA and CS of only the dominant eye were systematically decreased and in one condition the dominant eye was occluded, and participants viewed their environment through the non-dominant eye (monocular viewing). No differences were observed when assessing monocular impairments influence on outcome, velocity and ball placement. PKs have a high resilience to VI, but binocular impairment has a more immediate effect, suggesting binocular measures should be used in classification processes in football.

Germline prediction of immune checkpoint inhibitor discontinuation for immune-related adverse events.

Introduction: Immune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors but can also often lead to immune-related adverse events (irAEs). Predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Using data from 1,327 patients with lung cancer treated with ICIs between 2009 and 2022 at four academic medical centers, we evaluated the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs. Methods: Using Cox proportional hazards model, we assessed the association between a polygenic risk score for autoimmune disease (PRSAD) and cessation of ICI therapy due to irAEs. All models were adjusted for age at diagnosis, sex, lung cancer histology, type of therapy, recruiting center, and the first 5 principal components. To further understand the differential effects of type of therapy and disease stage on the association between PRSAD and cessation of ICI due to irAEs, we conducted stratified logistic regression analysis by type of ICI therapy and disease stage. Results: We found an association between PRSAD and ICI cessation due to irAEs (HR per SD = 1.18, 95% CI = 1.02 - 1.37, P = 0.03). This association was particularly strong in patients who had ICI cessation due to irAEs within three months of therapy initiation (HR per SD = 1.38, 95% CI = 1.08 - 1.78, P = 0.01). Individuals in the top 20th percentile of PRSAD had 7.2% ICI discontinuation for irAEs by three months, compared to 3.9% discontinuation by three months among patients in the bottom 80th percentile (log-rank P = 0.02). In addition, among patients who received combination PD-1/PD-L1 and CTLA-4 inhibitor therapy, PRSAD had an OR per SD of 1.86 (95% CI = 1.08 - 3.51, P = 0.04). Conclusions: We demonstrate an association between a polygenic risk score for autoimmune disease and early ICI discontinuation for irAEs, particularly among patients treated with combination ICI therapy. Our results suggest that germline genetics may be used as an adjunctive tool for risk stratification around ICI clinical decision-making in solid tumor oncology.

Impact of automated alerts on discharge opioid overprescribing after general surgery.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: The objectives of this study were to identify the most performed surgical procedures associated with the highest rates of discharge opioid overprescribing and to implement an electronic health record (EHR) alert to reduce discharge opioid overprescribing. METHODS: This quality improvement, before-and-after study included patients undergoing one of the identified target procedures-laparoscopic cholecystectomy, unilateral open inguinal hernia repair, and laparoscopic appendectomy-at an academic medical center. The alert notified providers when the prescribed opioid quantity exceeded guideline recommendations. The preimplementation cohort included surgical encounters from January 2020 to December 2021. The EHR alert was implemented in May 2022 following provider education via email and in-person presentations. The postimplementation cohort included surgical encounters from May to August 2022. The primary outcome was the proportion of patients with a discharge opioid supply exceeding guideline recommendations (overprescribing). RESULTS: A total of 1,478 patients were included in the preimplementation cohort, and 141 patients were included in the postimplementation cohort. The rate of discharge opioid overprescribing decreased from 48% in the preimplementation cohort to 3% in the postimplementation cohort, with an unadjusted absolute reduction of 45% (95% confidence interval, 41% to 49%; P < 0.001) and an adjusted odds ratio of 0.03 (95% confidence interval, 0.01 to 0.08; P < 0.001). Among patients who received opioids, the mean (SD) opioid supply at discharge decreased from 92 (43) oral morphine milligram equivalents (MME) (before implementation) to 57 (20) MME (after implementation) (P < 0.001). The proportion of patients who received additional opioid prescriptions within 1 to 14 days of hospital discharge did not change (P = 0.76). CONCLUSION: Implementation of an EHR alert along with provider education can reduce discharge opioid overprescribing following general surgery.

Neuromodulation with Ultrasound: Hypotheses on the Directionality of Effects and a Community Resource.

Low-intensity Transcranial Ultrasound Stimulation (TUS) is a promising non-invasive technique for deep-brain stimulation and focal neuromodulation. Research with animal models and computational modelling has raised the possibility that TUS can be biased towards enhancing or suppressing neural function. Here, we first conduct a systematic review of human TUS studies for perturbing neural function and alleviating brain disorders. We then collate a set of hypotheses on the directionality of TUS effects and conduct an initial meta-analysis on the human TUS study reported outcomes to date ( n = 32 studies, 37 experiments). We find that parameters such as the duty cycle show some predictability regarding whether the targeted area's function is likely to be enhanced or suppressed. Given that human TUS sample sizes are exponentially increasing, we recognize that results can stabilize or change as further studies are reported. Therefore, we conclude by establishing an Iowa-Newcastle (inTUS) resource for the systematic reporting of TUS parameters and outcomes to support further hypothesis testing for greater precision in brain stimulation and neuromodulation with TUS. Highlights: Systematic review of human TUS studies for enhancing or suppressing neural functionCollated set of hypotheses on using TUS to bias towards enhancement or suppressionMeta-analysis results identify parameters that may bias the directionality of effectsTUS resource established for systematic reporting of TUS parameters and outcomes.

Mental Health and Autosomal Dominant Polycystic Kidney Disease: A Narrative Review.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder marked by the development of cysts in the kidneys and other organs, leading to diverse clinical manifestations, including kidney failure. The psychological burden of ADPKD is substantial, with significant contributors including pain, daily life disruptions, depression, anxiety, and the guilt associated with transmitting ADPKD to offspring. This review details the psychological impacts of ADPKD on patients, addressing how they navigate physical and emotional challenges, including pain management, genetic guilt, mood disorders, and disease acceptance. This review also underscores the need for comprehensive research into the psychological aspects of ADPKD, focusing on the prevalence and contributing factors of emotional distress, and identifying effective strategies for managing anxiety and depression. Furthermore, it highlights the importance of understanding the diverse factors that influence patients' quality of life and advocates for holistic interventions to address these psychological challenges.

Uncovering measurement bias: Differential item functioning by income in the Couples Satisfaction Index.

Relationship satisfaction is among the most popular constructs in family science. As the study of families and romantic couples continues to include more diverse samples, it is imperative to ensure the measures scholars use do not significantly vary in psychometric quality across groups. The goal of this study was to examine the psychometric utility of the four-item Couples Satisfaction Index (CSI-4; Funk & Rogge, 2007) for individuals across the income spectrum. This study uses data from the National Couples' Health and Time Study, which sampled married and cohabiting adults in the United States from late 2020 to early 2021. Differential item functioning in the CSI-4 was assessed based on income (N = 3,497) using item response theory. For individuals experiencing lower incomes, the CSI-4 demonstrated differential functioning compared to their more affluent peers, with a bias against individuals experiencing lower incomes equating to average scores 1.38 units lower than higher income participants on the CSI-4 despite having the same true levels of relationship satisfaction. Differential item functioning was less pronounced when comparing item performance of lower- and middle-income participants, equating to lower income participants scoring .21 units lower than middle-income individuals despite having the same true levels of relationship satisfaction. While advancing diversity in family science, researchers should employ psychometric methods to understand how measures perform across groups, which will help prevent the misinterpretation of statistical bias as real group differences. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Impact of a point-of-care urine tenofovir assay on adherence to HIV pre-exposure prophylaxis among women in Kenya: a randomised pilot trial.

BACKGROUND: Adherence challenges with oral tenofovir-based pre-exposure prophylaxis (PrEP) are common. We developed a point-of-care assay to objectively assess tenofovir in urine and conducted a pilot trial examining the impact of counselling informed by use of this urine assay on long-term PrEP adherence. METHODS: This randomised trial enrolled women not in serodiscordant partnerships 3 months after PrEP initiation at the Kenya Medical Research Institute to compare standard-of-care adherence counselling versus counselling informed by the urine assay (urine-test counselling group) every 3 months for 12 months. In the standard of care group, urine samples were stored and tested at study end without participant feedback. Here we report the adherence primary outcome of hair concentrations of tenofovir at 12 months as a long-term metric (undetectable levels defined long-term non-adherence), as well as urine concentrations of tenofovir at each visit as a short-term adherence metric and acceptability of the assay assessed by quantitative surveys. Data were analysed by randomisation group. This completed trial was registered with ClinicalTrials.gov (NCT03935464). FINDINGS: From March 17, 2021 to Jan 18, 2022 we enrolled 49 women in the urine-test counselling group and 51 in the standard of care group; retention was 86 (86%) of 100. Nine (21%) of 42 in the urine-test counselling group had hair samples at 12 months with tenofovir concentrations below the limit of quantification compared with 15 (37%) of 41 in the standard of care group. The relative odds of long-term non-adherence in the standard of care group compared with urine-test counselling were 3·53 (95% CI 1·03-12·03; p=0·044). Pre-intervention, urine tenofovir was detectable in 65% in the urine-test counselling group and 71% in the standard of care group (p=0·68). At 12 months, 31 (72%) of 43 in the intervention group had detectable urine tenofovir compared with 19 (45%) of 42 in the standard of care group (p=0·0015). 40 (93%) of 43 participants liked the test very much and only one disliked the test. One participant in the standard of care group was withdrawn at the 6-month visit due to HIV seroconversion. INTERPRETATION: A low-cost urine tenofovir assay to inform PrEP counselling resulted in improvement in both short-term and long-term metrics of adherence. This urine tenofovir assay could help to improve long-term PrEP adherence. FUNDING: National Institute of Allergy and Infectious Diseases and National Institutes of Health.

Low uveitis rates in patients with axial spondyloarthritis treated with bimekizumab: pooled results from phase 2b/3 trials.

OBJECTIVES: Acute anterior uveitis ('uveitis') is a common axial spondyloarthritis (axSpA) extramusculoskeletal manifestation. Interleukin (IL)-17 is implicated in its pathogenesis, however, there is conflicting evidence for IL-17A inhibition in uveitis management. We report pooled analyses of uveitis incidence in patients receiving bimekizumab (BKZ), a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A, from phase 2b/3 trials. METHODS: Data were pooled for patients receiving BKZ 160 mg or placebo in the double-blind treatment period of the phase 3 BE MOBILE 1 (NCT03928704; non-radiographic axSpA) and BE MOBILE 2 (NCT03928743; radiographic axSpA) trials. Data were separately pooled for patients treated with at least one BKZ dose in the BE MOBILE trials and their ongoing open-label extension (OLE; NCT04436640), and the phase 2b BE AGILE trial (NCT02963506; radiographic axSpA) and its ongoing OLE (NCT03355573). Uveitis rates and exposure-adjusted incidence rates (EAIR)/100 patient-years (PYs) are reported. RESULTS: In the BE MOBILE 1 and 2 double-blind treatment period, 0.6% (2/349) of patients receiving BKZ experienced uveitis vs 4.6% (11/237) receiving placebo (nominal p=0.001; EAIR (95% CI): 1.8/100 PYs (0.2 to 6.7) vs 15.4/100 PYs (95% CI 7.7 to 27.5)). In patients with history of uveitis, EAIR was lower in patients receiving BKZ (6.2/100 PYs (95% CI 0.2 to 34.8); 1.9%) vs placebo (70.4/100 PYs (95% CI 32.2 to 133.7); 20.0%; nominal p=0.004). In the phase 2b/3 pool (N=848; BKZ exposure: 2034.4 PYs), EAIR remained low (1.2/100 PYs (95% CI 0.8 to 1.8)). CONCLUSIONS: Bimekizumab, a dual-IL-17A/F inhibitor, may confer protective effects for uveitis in patients with axSpA.

A toolkit for a modern gynecologic oncology tissue bank.

OBJECTIVES: Tissue banking procedures have evolved to keep pace with precision medicine, technology, emerging understanding of racial disparities, and regulatory requirements. However, there is little published guidance regarding strategies to create and maintain a successful biorepository. Our objective is to describe the infrastructure and protocols used by our Gynecologic Oncology Tissue Bank. METHODS: Our Tissue Bank was founded in 1992. In August 2022, internal funding was used to modernize the Tissue Bank. We hired three full-time employees, implemented universal screening of patients treated by gynecologic oncology faculty, updated consenting protocols, and standardized communication with providers. Tumor tissue, blood derivatives, ascites, and pleural fluid were collected from eligible, consenting patients and processed. Patient-derived cell lines and organoids were generated. For quality control purposes, one formalin-fixed, paraffin-embedded (FFPE) sample per tissue site was analyzed by a board-certified pathologist. All samples were labeled and tracked in an OpenSpecimen collection protocol and clinically annotated in a secure database. RESULTS: From August 2022 to October 2023, 227 patients (83% white, 15% Black, 1% Asian) were enrolled and 4249 specimens were collected. Adherent cell lines were generated from 15 patients with ovarian cancer and cell suspensions for organoid generation were collected from 46 patients with ovarian cancer. A recharge center was established to self-sustain the Tissue Bank. Samples have been shared with academic and commercial collaborators. CONCLUSIONS: Our Tissue Bank has enrolled a large number of diverse patients, collected numerous specimen types, and collaborated widely. The procedures described here provide guidance for other institutions establishing similar resources.

Kv beta complex facilitates exercise-induced augmentation of myocardial perfusion and cardiac growth.

The oxygen sensitivity of voltage-gated potassium (Kv) channels regulates cardiovascular physiology. Members of the Kv1 family interact with intracellular Kvß proteins, which exhibit aldo-keto reductase (AKR) activity and confer redox sensitivity to Kv channel gating. The Kvß proteins contribute to vasoregulation by controlling outward K+ currents in smooth muscle upon changes in tissue oxygen consumption and demand. Considering exercise as a primary physiological stimulus of heightened oxygen demand, the current study tested the role of Kvß proteins in exercise performance, exercise-induced adaptations in myocardial perfusion, and physiological cardiac growth. Our findings reveal that genetic ablation of Kvß2 proteins diminishes baseline exercise capacity in mice and attenuates the enhancement in exercise performance observed after long-term training. Moreover, we demonstrate that Kvß2 proteins are critical for exercise-mediated enhancement in myocardial perfusion during cardiac stress as well as adaptive changes in cardiac structure. Our results underscore the importance of Kvß proteins in metabolic vasoregulation, highlighting their role in modulating both exercise capacity and cardiovascular benefits associated with training. Furthermore, our study sheds light on a novel molecular target for enhancing exercise performance and improving the health benefits associated with exercise training in patients with limited capacity for physical activity.

Point-of-Care Kidney and Genitourinary Ultrasound in Adults: Image Acquisition.

A range of conditions involving the kidneys and urinary bladder can cause organ-threatening complications that are preventable if diagnosed promptly with diagnostic imaging. Common imaging modalities include either computed tomography or diagnostic ultrasound. Traditionally, ultrasound of the kidney-genitourinary system has required consultative teams consisting of a sonographer performing image acquisition and a radiologist performing image interpretation. However, diagnostic point-of-care ultrasound (POCUS) has recently emerged as a useful tool to troubleshoot acute kidney injury at the bedside. Studies have shown that non-radiologists can be trained to perform diagnostic POCUS of the kidneys and bladder with high accuracy for a set number of important conditions. Currently, diagnostic POCUS of the kidney-genitourinary system remains underused in actual clinical practice. This is likely because image acquisition for this organ system is unfamiliar to most clinicians in specialties that encounter acute kidney injury, including primary care, emergency medicine, intensive care, anesthesiology, nephrology, and urology. To address this multi-specialty educational gap, this narrative review was developed by a multi-disciplinary group to provide a specialty-agnostic framework for kidney-genitourinary POCUS image acquisition: indications/contraindications, patient positioning, transducer selection, acquisition sequence, and exam limitations. Finally, we describe foundational concepts in kidney-genitourinary ultrasound image interpretation, including key abnormal findings that every bedside clinician performing this modality should know.

Characterization of Ligilactobacillus salivarius CRISPR-Cas systems.

Ligilactobacillus is a diverse genus among lactobacilli with phenotypes that reflect adaptation to various hosts. CRISPR-Cas systems are highly prevalent within lactobacilli, and Ligilactobacillus salivarius, the most abundant species of Ligilactobacillus, possesses both DNA- and RNA-targeting CRISPR-Cas systems. In this study, we explore the presence and functional properties of I-B, I-C, I-E, II-A, and III-A CRISPR-Cas systems in over 500 Ligilactobacillus genomes, emphasizing systems found in L. salivarius. We examined the I-E, II-A, and III-A CRISPR-Cas systems of two L. salivarius strains and observed occurrences of split cas genes and differences in CRISPR RNA maturation in native hosts. This prompted testing of the single Cas9 and multiprotein Cascade and Csm CRISPR-Cas effector complexes in a cell-free context to demonstrate the functionality of these systems. We also predicted self-targeting spacers within L. salivarius CRISPR-Cas systems and found that nearly a third of L. salivarius genomes possess unique self-targeting spacers that generally target elements other than prophages. With these two L. salivarius strains, we performed prophage induction coupled with RNA sequencing and discovered that the prophages residing within these strains are inducible and likely active elements, despite targeting by CRISPR-Cas systems. These findings deepen our comprehension of CRISPR-Cas systems in L. salivarius, further elucidating their relationship with associated prophages and providing a functional basis for the repurposing of these Cas effectors for bacterial manipulation. IMPORTANCE: Ligilactobacillus salivarius is a diverse bacterial species widely used in the food and dietary supplement industries. In this study, we investigate the occurrence and diversity of their adaptive immune systems, CRISPR-Cas, in over 500 genomes. We establish their function and provide insights into their role in the interplay between the bacterial host and the predatory phages that infect them. Such findings expand our knowledge about these important CRISPR-Cas immune systems widespread across the bacterial tree of life and also provide a technical basis for the repurposing of these molecular machines for the development of molecular biology tools and the manipulation and engineering of bacteria and other life forms.

A Plain Language Summary of "Dostarlimab for primary advanced or recurrent endometrial cancer".

What is this summary about? Dostarlimab, also known by the brand name JEMPERLI, is a medicine that uses a patient's own immune system to treat endometrial cancer. Dostarlimab is a type of medicine called an immunotherapy. Immunotherapies help the immune system find and attack cancer cells. Dostarlimab stops cancer cells from being able to hide from the immune system, which allows the patient to have a boosted immune response against their cancer.The RUBY study is a phase 3 clinical study of primary advanced (cancer that has spread outside the uterus) or recurrent (cancer that has come back) endometrial cancer. A phase 3 clinical study looks at how well a new treatment works compared to the standard, or usual, treatment in a large patient population. The RUBY study is testing how well dostarlimab given with chemotherapy, followed by dostarlimab alone, works at delaying primary advanced or recurrent endometrial cancer from getting worse and preventing patients from dying, compared to chemotherapy given alone (the current standard treatment for primary advanced or recurrent endometrial cancer).What were the results? When dostarlimab was given with chemotherapy, this combination was found to delay primary advanced or recurrent endometrial cancer from getting worse and to prevent patients from dying, compared with chemotherapy given alone (without dostarlimab). Patients in the study who received dostarlimab with chemotherapy had a 36% lower risk of dying or having their cancer get worse.What do the results mean? The results from this study contributed to the approval of dostarlimab with chemotherapy as a new treatment option for patients with mismatch repair deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer. As of the publication of this plain language summary of publication (PLSP), this combination of dostarlimab with chemotherapy has been approved in the United States of America, the United Kingdom, the European Union and Hong Kong.Clinical Trial Registration: NCT03981796 (RUBY).

Functional performance of a vibrotactile sensory substitution device in people with profound vision loss.

SIGNIFICANCE: This study has shown a vibrotactile sensory substitution device (SSD) prototype, VibroSight, has the potential to improve functional outcomes (i.e., obstacle avoidance, face detection) for people with profound vision loss, even with brief familiarization (<20 minutes). PURPOSE: Mobility aids such as long canes are still the mainstay of support for most people with vision loss, but they do have limitations. Emerging technologies such as SSDs are gaining widespread interest in the low vision community. The aim of this project was to assess the efficacy of a prototype vibrotactile SSD for people with profound vision loss in the face detection and obstacle avoidance tasks. METHODS: The VibroSight device was tested in a movement laboratory setting. The first task involved obstacle avoidance, in which participants were asked to walk through an obstacle course. The second was a face detection task, in which participants were asked to step toward the first face they detected. Exit interviews were also conducted to gather user experience data. Both people with low vision (n = 7) and orientation and mobility instructors (n = 4) completed the tasks. RESULTS: In obstacle avoidance task, participants were able to use the device to detect (p<0.001) and avoid (p<0.001) the obstacles within a significantly larger range, but were slower (p<0.001), when compared with without the device. In face detection task, participants demonstrated a great level of accuracy, precision, and sensitivity when using the device. Interviews revealed a positive user experience, although participants identified that they would require a lighter and compact design for real-world use. CONCLUSIONS: Overall, the results verified the functionality of vibrotactile SSD prototype. Further research is warranted to evaluate the user performance after an extended training program and to add new features, such as object recognition software algorithms, into the device.