Loss of GPR75 protects against non-alcoholic fatty liver disease and body fat accumulation.

Approximately 1 in 4 people worldwide have non-alcoholic fatty liver disease (NAFLD); however, there are currently no medications to treat this condition. This study investigated the role of adiposity-associated orphan G protein-coupled receptor 75 (GPR75) in liver lipid accumulation. We profiled Gpr75 expression and report that it is most abundant in the brain. Next, we generated the first single-cell-level analysis of Gpr75 and identified a subpopulation co-expressed with key appetite-regulating hypothalamic neurons. CRISPR-Cas9-deleted Gpr75 mice fed a palatable western diet high in fat adjusted caloric intake to remain in energy balance, thereby preventing NAFLD. Consistent with mouse results, analysis of whole-exome sequencing data from 428,719 individuals (UK Biobank) revealed that variants in GPR75 are associated with a reduced likelihood of hepatic steatosis. Here, we provide a significant advance in understanding of the expression and function of GPR75, demonstrating that it is a promising pharmaceutical target for NAFLD treatment.

Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease.

Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.

Key Performance Indicators and Metrics for the Implementation of an Oral Chemotherapy Adherence Program.

BACKGROUND: Oral anticancer agents (OAAs) transformed cancer care for patients, extending survival and delaying progression in certain cases. There are multiple pharmacy-driven models to improve patient knowledge and adherence to OAAs. However, a lack of measurable key performance indicators (KPIs) has limited the adoption, implementation, and maintenance of these models. The objective of this study was to identify a set of KPIs, their metrics, and the target values that indicated improved patient care through an OAA adherence program. METHODS: A literature review was conducted to identify an initial list of defined KPIs, metrics of the KPIs, and targets for success. We assembled an advisory panel of clinicians (n=9), administrators (n=7), and patients (n=2) from across an academic and affiliated community cancer center to gauge agreement on identified KPIs for use within a structured adherence intervention. We used a Qualtrics survey consisting of questions measured using a 5-point Likert scale response that ranged from 1 (strongly disagree) to 5 (strongly agree) and a subsequent consensus-building discussion with the advisory panel to identify agreeability with the definitions, metrics, and targets of identified KPIs. RESULTS: Eleven KPIs were identified: (1) time to intended OAA initiation; (2) adherence rate during active treatment; (3) adverse events; (4) medication-related financial toxicity; (5) patient satisfaction; (6) treatment-related emergency department visits; (7) treatment-related hospital admissions; (8) proportion of patients with adherence, toxicity, and financial barriers assessed; (9) proportion of patients referred to social work; (10) time spent by patient in each phase of care as defined by the intervention's standard operating procedure; and (11) revenue generated by billing for service. CONCLUSIONS: This study identified 11 KPIs that can be used in evaluating the success of an OAA adherence program. Use of these KPIs will be piloted after formal implementation of the program in both academic and community cancer centers.

The vagus nerve mediates the physiological but not pharmacological effects of PYY3-36 on food intake.

Peptide YY (PYY3-36) is a post-prandially released gut hormone with potent appetite-reducing activity, the mechanism of action of which is not fully understood. Unravelling how this system physiologically regulates food intake may help unlock its therapeutic potential, whilst minimising unwanted effects. Here we demonstrate that germline and post-natal targeted knockdown of the PYY3-36 preferring receptor (neuropeptide Y (NPY) Y2 receptor (Y2R)) in the afferent vagus nerve is required for the appetite inhibitory effects of physiologically-released PYY3-36, but not peripherally administered pharmacological doses. Post-natal knockdown of the Y2R results in a transient body weight phenotype that is not evident in the germline model. Loss of vagal Y2R signalling also results in altered meal patterning associated with accelerated gastric emptying. These results are important for the design of PYY-based anti-obesity agents.

Real-World Incidence and Severity of Hypertension Caused by Abiraterone Acetate in Patients With Metastatic Prostate Cancer.

BACKGROUND: Abiraterone acetate (AA) is used in treatment of patients with metastatic prostate cancer. Despite the survival advantage, AA is associated with hypertension due to mineralocorticoid excess syndrome. OBJECTIVE: We conducted a single-center retrospective analysis to evaluate the real-world incidence and severity of AA-induced hypertension. METHODS: Electronic health records were used to collect baseline characteristics and prostate cancer history. Patient data, including blood pressure at each 4 (±2)-week interval, were collected for 24 weeks after the initiation of AA therapy. The primary endpoint was the incidence and severity of AA-induced hypertension. The secondary endpoints include effect of different prednisone dosing regimens and prostate cancer types on hypertensive incidence and the impact of clinical pharmacists' involvement in managing AA-induced hypertension. RESULTS: A total of 142 patients who met our inclusion criteria received AA for metastatic prostate cancer, 73 (51.4%) with metastatic castration-resistant prostate cancer (mCRPC), and 69 (48.6%) with metastatic castration-sensitive prostate cancer (mCSPC). Of all, 43.7% experienced all-grade hypertension, and 28.2% experienced grade 3-4 hypertension. There was no difference in incidence of hypertension between patients receiving 5 mg of prednisone daily and those receiving 5 mg of prednisone twice daily. All-grade hypertension occurred in 39.7% of mCRPC and 47.8% of mCSPC patients (P = 0.33). Thirty-two percent of patients were actively managed by a clinical pharmacist and had an overall trend of reduced hypertension severity after 12 weeks. CONCLUSION AND RELEVANCE: This single-center, retrospective cohort study found that real-world metastatic prostate cancer patients who received AA had substantially higher incidence and severity of hypertension compared with clinical trials regardless of prednisone dose. In patients with mCRPC and mCSPC, the role of prednisone dose in hypertension incidence and severity warrants further investigation. Overall, results indicate the need for closely monitoring hypertension and optimization of anti-hypertensive therapy by multidisciplinary teams in metastatic prostate cancer patients receiving AA.

Changes in the Incidence and Human Papillomavirus-Positive Portion of Oropharyngeal Squamous Cell Carcinoma in Hong Kong.

The incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is rising in the West, but little is known in Asia. This study elucidated changes in the incidence and HPV-positive portion of OPSCC in Hong Kong. Data from population-based cancer registry were used to analyze the incidence of OPSCC in association with other head and neck cancers. Archived tumor tissues were tested for HPV. From 1986 to 2020, there was a marked decrease in the incidence of nasopharyngeal and laryngeal cancers, but a persistent increase in OPSCC from 36 cases in 1986 to 116 cases in 2020. The average positive rate for high-risk HPV was 36.1% (112/310) among OPSCC diagnosed in 2010-2020. The HPV-positive rate in recent years was significantly higher than earlier cases (tonsil SCC: 64.7% (55/85) in 2016-2020 vs. 40.4% (19/47) in 2010-2015, p = 0.007). Patients with HPV-positive tonsil cancers were significantly younger than those negative (mean [SD]: 58.9 [9.9] vs. 64.3 [13.3] years, p = 0.006), but no significant difference was observed between genders. A persistent increase in the incidence of oropharyngeal cancer over the last few decades was observed in Hong Kong, which can be explained by the remarkable increase in HPV-positive tonsil cancers.

Global survey of stigma among physicians and patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Patients with fatty liver disease may experience stigma from the disease or comorbidities. In this cross-sectional study, we aimed to understand stigma among patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and healthcare providers. METHODS: Members of the Global NASH Council created two surveys about experiences/attitudes toward NAFLD and related diagnostic terms: a 68-item patient and a 41-item provider survey. RESULTS: Surveys were completed by 1,976 patients with NAFLD across 23 countries (51% Middle East/North Africa [MENA], 19% Europe, 17% USA, 8% Southeast Asia, 5% South Asia) and 825 healthcare providers (67% gastroenterologists/hepatologists) across 25 countries (39% MENA, 28% Southeast Asia, 22% USA, 6% South Asia, 3% Europe). Of all patients, 48% ever disclosed having NAFLD/NASH to family/friends; the most commonly used term was "fatty liver" (88% at least sometimes); "metabolic disease" or "MAFLD" were rarely used (never by >84%). Regarding various perceptions of diagnostic terms by patients, there were no substantial differences between "NAFLD", "fatty liver disease (FLD)", "NASH", or "MAFLD". The most popular response was being neither comfortable nor uncomfortable with either term (56%-71%), with slightly greater discomfort with "FLD" among the US and South Asian patients (47-52% uncomfortable). Although 26% of patients reported stigma related to overweight/obesity, only 8% reported a history of stigmatization or discrimination due to NAFLD. Among providers, 38% believed that the term "fatty" was stigmatizing, while 34% believed that "nonalcoholic" was stigmatizing, more commonly in MENA (43%); 42% providers (gastroenterologists/hepatologists 45% vs. 37% other specialties, p = 0.03) believed that the name change to metabolic dysfunction-associated steatotic liver disease (or MASLD) might reduce stigma. Regarding the new nomenclature, the percentage of providers reporting "steatotic liver disease" as stigmatizing was low (14%). CONCLUSIONS: The perception of NAFLD stigma varies among patients, providers, geographic locations and sub-specialties. IMPACT AND IMPLICATIONS: Over the past decades, efforts have been made to change the nomenclature of nonalcoholic fatty liver disease (NAFLD) to better align with its underlying pathogenetic pathways and remove any potential stigma associated with the name. Given the paucity of data related to stigma in NAFLD, we undertook this global comprehensive survey to assess stigma in NAFLD among patients and providers from around the world. We found there is a disconnect between physicians and patients related to stigma and related nomenclature. With this knowledge, educational programs can be developed to better target stigma in NAFLD among all stakeholders and to provide a better opportunity for the new nomenclature to address the issues of stigma.

Genome sequences of Arthrobacter globiformis B-2979 phages MidnightRain and Gusanita.

Phages MidnightRain and Gusanita, with siphovirus morphology, were isolated on Arthrobacter globiformis B-2979. MidnightRain's genome consists of 53,674 bp, encoding 101 putative genes and 1 tRNA, whereas Gusanita's genome is 42,742 bp, encoding 68 putative genes and 2 tRNAs.

Severe, Persistent, Disruptive Fatigue Post-SARS-CoV-2 Disproportionately Affects Young Women.

Introduction: Post-acute SARS-CoV-2 (PASC) symptoms are often persistent, disruptive, and difficult to treat effectively. Fatigue is often among the most frequently reported symptoms and may indicate a more challenging road to recovery. Purpose: To describe the natural history, symptomology, and risk profile of long-term post-acute SARS-CoV-2. Patients and Methods: Participants treated for SARS-CoV-2 within a large, community health system in the US were enrolled prospectively in a longitudinal, observational PASC study examining participants at enrollment and 6 months. Medical history, symptom reporting, validated measures of cognition, and patient-reported outcomes (PROs), were performed for all participants and repeated during study follow-up visits. Results: A total of 323 participants completed baseline evaluations. Sixty one participants indicated clinically significant fatigue (23.1% at baseline); a representative sample of 141 enrollees also completed a baseline Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) in-depth fatigue reporting questionnaire, 37 had severe fatigue. The severely fatigued (FACIT-F ≤29.7) were significantly younger, female, had more anxiety and depression, had a higher resting heart rate, reported more sick days, and were less physically active post-COVID. They were more likely to have a diagnosis of chronic kidney disease (13.5% vs 2.9%) but less likely to have a history of cancer (8.1% vs 23.1). Participants who were severely fatigued reported health, diet, weight, and sleep were worse than those not severely fatigued post-COVID (p = 0.02 to 0.0002). Fatigue was significantly correlated with impairment of all PROs administered after COVID-19 infection. Conclusion: Fatigue is a common symptom post-COVID-19 infection and is associated with lower reported well-being and function. Those with severe fatigue tended to be younger and female and have a past medical history of anxiety, depression, kidney disease, and more sedentary lifestyles.

Cerebrospinal fluid camk2a levels at baseline predict long-term progression in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) remains a highly unpredictable disease. Many hope that fluid biomarkers may contribute to better stratification of disease, aiding the personalisation of treatment decisions, ultimately improving patient outcomes. OBJECTIVE: The objective of this study was to evaluate the predictive value of CSF brain-specific proteins from early in the disease course of MS on long term clinical outcomes. METHODS: In this study, 34 MS patients had their CSF collected and stored within 5 years of disease onset and were then followed clinically for at least 15 years. CSF concentrations of 64 brain-specific proteins were analyzed in the 34 patient CSF, as well as 19 age and sex-matched controls, using a targeted liquid-chromatography tandem mass spectrometry approach. RESULTS: We identified six CSF brain-specific proteins that significantly differentiated MS from controls (p < 0.05) and nine proteins that could predict disease course over the next decade. CAMK2A emerged as a biomarker candidate that could discriminate between MS and controls and could predict long-term disease progression. CONCLUSION: Targeted approaches to identify and quantify biomarkers associated with MS in the CSF may inform on long term MS outcomes. CAMK2A may be one of several candidates, warranting further exploration.

Fetal manipulation of maternal metabolism is a critical function of the imprinted Igf2 gene.

Maternal-offspring interactions in mammals involve both cooperation and conflict. The fetus has evolved ways to manipulate maternal physiology to enhance placental nutrient transfer, but the mechanisms involved remain unclear. The imprinted Igf2 gene is highly expressed in murine placental endocrine cells. Here, we show that Igf2 deletion in these cells impairs placental endocrine signaling to the mother, without affecting placental morphology. Igf2 controls placental hormone production, including prolactins, and is crucial to establish pregnancy-related insulin resistance and to partition nutrients to the fetus. Consequently, fetuses lacking placental endocrine Igf2 are growth restricted and hypoglycemic. Mechanistically, Igf2 controls protein synthesis and cellular energy homeostasis, actions dependent on the placental endocrine cell type. Igf2 loss also has additional long-lasting effects on offspring metabolism in adulthood. Our study provides compelling evidence for an intrinsic fetal manipulation system operating in placenta that modifies maternal metabolism and fetal resource allocation, with long-term consequences for offspring metabolic health.

The cichlid pharyngeal jaw novelty enhances evolutionary integration in the feeding apparatus.

The modified pharyngeal jaw system of cichlid fishes is widely viewed as a key innovation that substantially facilitated the evolutionary exuberance of this iconic evolutionary radiation. We conduct comparative phylogenetic analyses of integration, disparity, and rate of evolution among feeding-related, skeletal structures in Neotropical cichlids and North American centrarchids, which lack the specialized pharyngeal jaw. Contrasting evolutionary patterns in these two continental radiations, we test a classic decoupling hypothesis. Specifically, we ask whether the modified pharyngeal jaw in cichlids resulted in enhanced evolutionary independence of the oral and pharyngeal jaws, leading to increased diversity of trophic structures. Contrary to this prediction, we find significantly stronger evolutionary integration between the oral and pharyngeal jaws in cichlids compared to centrarchids, although the two groups do not differ in patterns of integration within each jaw system. Further, though we find no significant differences in disparity, centrarchids show faster rates of morphological evolution. Our results suggest that the modified pharyngeal jaw resulted in less evolutionary independence and slower rates of evolution within the feeding system. Thus, we raise the possibility that the cichlid novelty enhances feeding performance, but does not prompt increased morphological diversification within the feeding apparatus, as has long been thought.

Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty.

CONTEXT: The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. OBJECTIVE: This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). METHODS: We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort. RESULTS: MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07). CONCLUSION: We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

Dax1 modulates ERα-dependent hypothalamic estrogen sensing in female mice.

Coupling the release of pituitary hormones to the developmental stage of the oocyte is essential for female fertility. It requires estrogen to restrain kisspeptin (KISS1)-neuron pulsatility in the arcuate hypothalamic nucleus, while also exerting a surge-like effect on KISS1-neuron activity in the AVPV hypothalamic nucleus. However, a mechanistic basis for this region-specific effect has remained elusive. Our genomic analysis in female mice demonstrate that some processes, such as restraint of KISS1-neuron activity in the arcuate nucleus, may be explained by region-specific estrogen receptor alpha (ERα) DNA binding at gene regulatory regions. Furthermore, we find that the Kiss1-locus is uniquely regulated in these hypothalamic nuclei, and that the nuclear receptor co-repressor NR0B1 (DAX1) restrains its transcription specifically in the arcuate nucleus. These studies provide mechanistic insight into how ERα may control the KISS1-neuron, and Kiss1 gene expression, to couple gonadotropin release to the developmental stage of the oocyte.

Post-Acute SARS-CoV-2 Symptoms are Fewer, Less Intense Over Time in People Treated with Mono-Clonal Antibodies for Acute Infection.

Introduction: Many with post-acute SARS-CoV-2 (PASC) have persistent symptoms impacting physical and cognitive function, decreased health and health-related life quality. Monoclonal antibody (mAb) treatment was available to acutely infected patients which might improve these outcomes. Purpose: To compare patient perception of PASC symptoms for those receiving bamlanivimab or casirivimab and imdevimab (mAbs) to those not receiving this treatment (non-mAbs). To compare changes between these groups in symptoms, function and quality of life over a 6-month follow-up. Patients and Methods: Consented adults >28 days post-infection with positive SARS-CoV-2 qPCR or antigen test and SARS-CoV-2 infection between March of 2020 and July of 2022 were enrolled. This prospective, repeated measure observational study reports baseline through 6-month follow-up. Extensive sociodemographic data, detailed medical history, COVID-19 symptom history, and standardized measures of well-being, depression, anxiety, stigma, cognition, symptom assessment, distress, and health status were collected. Results: 323 participants [101 mAb, 221 non-mAb, 52.7±15.5 years, 47.7% male, body mass index (BMI) 31.4±8.4] were analyzed. Fewer symptoms at baseline were reported in mAb versus non-mAb participants (1.06±1.31 vs 1.78±2.15, respectively p=0.0177) 6 months: (0.911±1.276 mAb vs.1.75±2.22 non-mAb, p=0.0427). Both groups showed significant within-group decreases in symptom number (52 to 21 mAb, 126 to 63 non-mAb) and symptom burden (p=0.0088 mAb, p<0.00001 non-mAb). mAb patients had significantly shorter infection-to-baseline interval (days) (120.4±55.3 mAb vs 194.0±89.3 non-mAb, p<0.00001); less frequent history of myocardial infarction (0.0 vs 3.9%, p=0.0464); headache (2.0% vs.11.8%, p=0.0046), rash (3.1% vs 9.9%, p=0.0377), and miscellaneous muscle complaints (2.0% vs 12.3%, p=0.0035), plus significantly better 6-month mood. (2.2% vs 13.2%, p=0.0390). Conclusion: mAb treated participants had reduced symptom burden and consistently reported fewer symptoms than non-mAb at all time points despite less time since acute illness. Both groups reported a statistically significant decrease in symptoms by 6-month visit with no statistically significant differences between them at follow-up.

Biallelic Mutations in P4HTM Cause Syndromic Obesity.

We previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carry pathogenic variants in known monogenic obesity genes. Here, we have discovered a novel monogenetic recessive form of severe childhood obesity using an in-house computational staged approach. The analysis included whole-exome sequencing data of 366 children with severe obesity, 1,000 individuals of the Pakistan Risk of Myocardial Infarction Study (PROMIS) study, and 200,000 participants of the UK Biobank to prioritize genes harboring rare homozygous variants with putative effect on human obesity. We identified five rare or novel homozygous missense mutations predicted deleterious in five consanguineous families in P4HTM encoding prolyl 4-hydroxylase transmembrane (P4H-TM). We further found two additional homozygous missense mutations in children with severe obesity of Indian and Moroccan origin. Molecular dynamics simulation suggested that these mutations destabilized the active conformation of the substrate binding domain. Most carriers also presented with hypotonia, cognitive impairment, and/or developmental delay. Three of the five probands died of pneumonia during the first 2 years of the follow-up. P4HTM deficiency is a novel form of syndromic obesity, affecting 1.5% of our children with obesity associated with high mortality. P4H-TM is a hypoxia-inducible factor that is necessary for survival and adaptation under oxygen deprivation, but the role of this pathway in energy homeostasis and obesity pathophysiology remains to be elucidated.

The combination of the enhanced liver fibrosis and FIB-4 scores to determine significant fibrosis in patients with nonalcoholic fatty liver disease.

BACKGROUND: The presence of fibrosis in NAFLD is the most significant risk factor for adverse outcomes. We determined the cutoff scores of two non-invasive te sts (NITs) to rule in and rule out significant fibrosis among NAFLD patients. METHODS: Clinical data and liver biopsies were used for NAFLD patients included in this analysis (2001-2020). The enhanced liver fibrosis (ELF) and FIB-4 NITs were calculated. Liver biopsies were read by a single hematopathologist and scored by the NASH CRN criteria. Significant fibrosis was defined as stage F2-F4. RESULTS: There were 463 NAFLD patients included: 48 ± 13 years old, 31% male, 35% type 2 diabetes; 39% had significant fibrosis; mean ELF score was 9.0 ± 1.2, mean FIB-4 score was 1.22 ± 1.05. Patients with significant fibrosis were older, more commonly male, had lower BMI but more components of metabolic syndrome, higher ELF and FIB-4 (p < 0.0001). The performance of the two NITs in identifying significant fibrosis was: AUC (95% CI) = 0.78 (0.74-0.82) for ELF, 0.79 (0.75-0.83) for FIB-4. The combination of ELF score ≥9.8 and FIB-4 ≥ 1.96 returned a positive predictive value of 95% which can reliably rule in significant fibrosis (sensitivity 22%, specificity >99%), while an ELF score ≤7.7 or FIB-4 ≤ 0.30 had a negative predictive value of 95% ruling out significant fibrosis (sensitivity 98%, specificity 22%). CONCLUSIONS: The combination of ELF and FIB-4 may provide practitioners with easily obtained information to risk stratify patients with NAFLD who could be referred to specialists or for enrollment in clinical trials.

A program of successive gene expression in mouse one-cell embryos.

At the moment of union in fertilization, sperm and oocyte are transcriptionally silent. The ensuing onset of embryonic transcription (embryonic genome activation [EGA]) is critical for development, yet its timing and profile remain elusive in any vertebrate species. We here dissect transcription during EGA by high-resolution single-cell RNA sequencing of precisely synchronized mouse one-cell embryos. This reveals a program of embryonic gene expression (immediate EGA [iEGA]) initiating within 4 h of fertilization. Expression during iEGA produces canonically spliced transcripts, occurs substantially from the maternal genome, and is mostly downregulated at the two-cell stage. Transcribed genes predict regulation by transcription factors (TFs) associated with cancer, including c-Myc. Blocking c-Myc or other predicted regulatory TF activities disrupts iEGA and induces acute developmental arrest. These findings illuminate intracellular mechanisms that regulate the onset of mammalian development and hold promise for the study of cancer.

Clinical Significance of Tumour-Infiltrating B Lymphocytes (TIL-Bs) in Breast Cancer: A Systematic Literature Review.

Although T lymphocytes have been considered the major players in the tumour microenvironment to induce tumour regression and contribute to anti-tumour immunity, much less is known about the role of tumour-infiltrating B lymphocytes (TIL-Bs) in solid malignancies, particularly in breast cancer, which has been regarded as heterogeneous and much less immunogenic compared to other common tumours like melanoma, colorectal cancer and non-small cell lung cancer. Such paucity of research could translate to limited opportunities for this most common type of cancer in the UK to join the immunotherapy efforts in this era of precision medicine. Here, we provide a systematic literature review assessing the clinical significance of TIL-Bs in breast cancer. Articles published between January 2000 and April 2022 were retrieved via an electronic search of two databases (PubMed and Embase) and screened against pre-specified eligibility criteria. The majority of studies reported favourable prognostic and predictive roles of TIL-Bs, indicating that they could have a profound impact on the clinical outcome of breast cancer. Further studies are, however, needed to better define the functional role of B cell subpopulations and to discover ways to harness this intrinsic mechanism in the fight against breast cancer.

How long is too long: A retrospective study evaluating the impact of the duration of noninvasive oxygenation support strategies (high flow nasal cannula & BiPAP) on mortality in invasive mechanically ventilated patients with COVID-19.

BACKGROUND/AIM: We investigated the association of noninvasive oxygenation support [high flow nasal cannula (HFNC) and BiPAP], timing of invasive mechanical ventilation (IMV), and inpatient mortality among patients hospitalized with COVID-19. METHODS: Retrospective chart review study of patients hospitalized with COVID-19 (ICD-10 code U07.1) and received IMV from March 2020-October 2021. Charlson comorbidity index (CCI) was calculated; Obesity defined as body mass index (BMI) ≥ 30 kg/m2; morbid obesity was BMI ≥ 40 kg/m2. Clinical parameters/vital signs recorded at time of admission. RESULTS: 709 COVID-19 patients underwent IMV, predominantly admitted from March-May 2020 (45%), average age 62±15 years, 67% male, 37% Hispanic, and 9% from group living settings. 44% had obesity, 11% had morbid obesity, 55% had type II diabetes, 75% had hypertension, and average CCI was 3.65 (SD = 3.11). Crude mortality rate was 56%. Close linear association of age with inpatient-mortality risk was found [OR (95% CI) = 1.35 (1.27-1.44) per 5 years, p<0.0001)]. Patients who died after IMV received noninvasive oxygenation support significantly longer: 5.3 (8.0) vs. 2.7 (SD 4.6) days; longer use was also independently associated with a higher risk of inpatient-mortality: OR = 3.1 (1.8-5.4) for 3-7 days, 7.2 (3.8-13.7) for ≥8 days (reference: 1-2 days) (p<0.0001). The association magnitude varied between age groups: 3-7 days duration (ref: 1-2 days), OR = 4.8 (1.9-12.1) in ≥65 years old vs. 2.1 (1.0-4.6) in <65 years old. Higher mortality risk was associated with higher CCI in patients ≥65 (P = 0.0082); among younger patients, obesity (OR = 1.8 (1.0-3.2) or morbid obesity (OR = 2.8;1.4-5.9) (p<0.05) were associated. No mortality association was found for sex or race. CONCLUSION: Time spent on noninvasive oxygenation support [as defined by high flow nasal cannula (HFNC) and BiPAP] prior to IMV increased mortality risk. Research for the generalizability of our findings to other respiratory failure patient populations is needed.