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Abstract Our study in the Nurses’ Health Study (NHS) and NHS2, a nested case-control study with 1260 cases and 2221 controls, investigated the association between C-peptide levels, mammographic density (MD) parameters, V (a measure of gray scale variation), and breast cancer (BC) risk. We also examined how C-peptide and BC risk vary across quartiles of mammographic features. Linear and logistic regressions were used to study the associations between C-peptide and MD parameters, and breast cancer. C-peptide was inversely associated with percent MD and positively with non-dense area, but no associations were found with dense area and V measure. C-peptide was associated with an increased risk of invasive BC risk (top vs. bottom quartile, odds ratio = 1.46, 95% CI: 1.12–1.91). No multiplicative interactions were found between C-peptide, MD parameters, and BC risk. Our results suggest a positive association between C-peptide and BC risk, and MD parameters do not seem to modify this association.

Abstract Histones are important chromatin-organizing proteins in eukaryotes and archaea. They form superhelical structures around which DNA is wrapped. Recent studies have shown that some archaea and bacteria contain alternative histones that exhibit different DNA binding properties, in addition to highly divergent sequences. However, the vast majority of these histones are identified in metagenomes and thus are difficult to study in vivo. The recent revolutionary breakthroughs in computational protein structure prediction by AlphaFold2 and RoseTTAfold allow for unprecedented insights into the potential function and structure of previously uncharacterized proteins. Here, we categorize the prokaryotic histone space into 17 distinct groups based on AlphaFold2 predictions. We identify a superfamily of histones, termed α3 histones, which are common in archaea and present in several bacteria. Importantly, we establish the existence of a large family of histones throughout archaea and in some bacteriophages that, instead of wrapping DNA, bridge DNA, thereby diverging from conventional nucleosomal histones.

Cell migration is the major driver of invasion and metastasis during cancer progression. For cells to migrate, they utilize the actin–myosin cytoskeleton and adhesion molecules, such as integrins and CD44, to generate traction forces in their environment. CD44 primarily binds to hyaluronic acid (HA) and integrins primarily bind to extracellular matrix (ECM) proteins such as collagen. However, the role of CD44 under integrin-mediated conditions and vice versa is not well known. Here, we performed traction force microscopy (TFM) on U251 cells seeded on collagen I-coated polyacrylamide gels to assess the functional mechanical relationship between integrins and CD44. Performing TFM on integrin-mediated adhesion conditions, i.e., collagen, we found that CD44KO U251 cells exerted more traction force than wild-type (WT) U251 cells. Furthermore, untreated WT and CD44-blocked WT exhibited comparable results. Conversely, in CD44-mediated adhesive conditions, integrin-blocked WT cells exerted a higher traction force than untreated WT cells. Our data suggest that CD44 and integrins have a mutually antagonistic relationship where one receptor represses the other's ability to generate traction force on its cognate substrate.

Usher syndrome (USH) is the most common cause of inherited deaf-blindness. Here, we produced the LEIi020-A and LEIi020-B induced pluripotent stem cell (iPSC) lines from dermal fibroblasts derived from a patient with USH1B caused by inheritance of homozygous c.496del variants in MYO7A using episomal plasmids encoding OCT4, SOX2, KLF4, L-MYC, LIN28, mir302/367 microRNA and shRNA for TP53. Both iPSC lines expressed pluripotency markers, demonstrated trilineage differentiation potential and displayed a 46,XY karyotype. These cell lines represent a valuable resource for the production of retinal and otic tissues to support research into the pathogenesis and treatment of USH1B.

5-Amino salicylic acid (5-ASA) is a known culprit for the development of tubulointerstitial nephritis. Together with impaired kidney function, tubulointerstitial nephritis can lead to specific tubular malfunctions including distal renal tubular acidosis. Distal renal tubular acidosis is an acid-base disorder in which acid secretion in the distal part of the renal tubular system is decreased. Patients with distal renal tubular acidosis are predisposed to recurrently form calcium phosphate kidney stones. This results from the inability to acidify the urine properly as well as from a decreased citrate concentration in the urine, which is another pathognomonic feature of distal renal tubular acidosis. We present the case of a man in his late 40s with Crohn’s disease who developed tubulointerstitial nephritis associated with 5-ASA leading to the development of distal renal tubular acidosis and recurrent calcium phosphate nephrolithiasis. After steroid therapy and partial recovery of kidney function, we observed an increase of citraturia in response to treatment with dapagliflozin, potentially indicating beneficial effects of sodium/glucose cotransporter 2 inhibition on the recurrence of calcium phosphate stone disease in interstitial nephritis-induced distal tubular acidosis.

Abstract Hyperglycemia and rash are expected but challenging adverse events of phosphatidylinositol-3-kinase inhibition (such as with alpelisib). Two modified Delphi panels were conducted to provide consensus recommendations for managing hyperglycemia and rash in patients taking alpelisib. Experts rated the appropriateness of interventions on a 1-to-9 scale; median scores and dispersion were used to classify the levels of agreement. Per the hyperglycemia panel, it is appropriate to start alpelisib in patients with HbA1c 6.5% (diabetes) to

Objective The accuracy of intraoperative neuromonitoring (IONM) during surgery for cervical spondylotic myelopathy (CSM) to detect iatrogenic nervous system injuries while they are reversible remains unknown. We evaluated a cohort of patients who had IONM during surgery to assess accuracy.

Background: Black male students are present but underrepresented in undergraduate engineering programs. They currently make up 2.8% of engineering bachelor’s degree earners. Beyond the typical economic framing of underrepresentation in engineering, this lack of diversity is also an issue of social justice and equity that we must address. Purpose: To address this challenge, we employed an assets-based approach to examine how Barry, a Black male engineering student, acquired and used his Community Cultural Wealth (CCW) to pursue his goal of earning an engineering degree. Design/Methods: We conducted a single semi-structured interview with Barry. We used Yosso’s CCW framework to guide data analysis and retell Barry’s story using a narrative approach. Results: We demonstrated that Barry acquired and used aspirational, familial linguistic, navigational, resistant, and social capital to achieve his goal of earning an engineering degree. We also illustrated the bidirectional and overlapping manifestations of his capital, which gave him the strength and motivation to persist. Conclusions: Barry’s resources helped him become reflective about and enact his CCW. Findings illustrate how the narrative of a Black male engineering student further expands the utility of CCW. As universities seek ways to recruit, retain, and support Black males, assets-based frames provide a perspective to understand how their cultural assets support their educational goals and success and provide a perspective for designing support.

Abstract The prevalence, intensity, or outcome of interference competition and interspecific killing between predominantly solitary species operating on large spatial scales is challenging to document or test. Here, we present a detailed account of inter‐ and intraspecific interactions from contemporaneous GPS location data and in‐field investigation. In June 2018, a GPS‐collared female cougar (Puma concolor) maintained strong site fidelity for a period of 19 days, indicative of parturition behavior and establishment of a nursery site. In early July 2018, three GPS‐collared black bears (Ursus americanus) arrived at the nursery site, after which the female cougar abandoned the site. Site investigation showed that one or more bears predated an unknown number of cougar kittens. The evidence supports ecological theory suggesting that body size, mass, or group number is an important predictor of outcome. Our observation provides an example of bears potentially making risk–reward trade‐offs by eliminating a potential competitor that at the same time provisions carrion as critical food resources. These real‐time inter‐ and intraspecies competitive interactions as documented using GPS collars allow for greater insight into individual fitness and community‐level effects.

Background: Almost all Xylopia species have a long history of being used therapeutically in China due to their potent antioxidant properties. Xylopia parviflora (X. parviflora) is a relatively novel plant comprised mainly of beta-pinene, which has a rich history in Chinese medicine and is a principal active constituent in numerous Chinese herbs such as Rakkyo, the Chinese onions, Huasi Baidu Fang and Ru Xiang which are all native to China. Objective: The study evaluated the antidiabetic potentials of the methanol leaf extract of X. parviflora and its toxicity profile. Methods: A modified version of the OECD guidelines was used to conduct acute and sub-chronic toxicity tests on the plant extract. The extract's effects on glucose, haematological, and biochemical components were evaluated using standard procedures. Using glibenclamide (10 mg/kg) and distilled water as positive and negative controls, the extract was tested for its antidiabetic activity in diabetic rats with streptozotocin induction at 50, 150, and 300 mg/kg for 28 days. Furthermore, vital organs underwent histopathological examination. Analysis of Variance (ANOVA) and the Dunnett multiple comparison tests were used for the statistical analysis, with a significance level of p

Background: Androgen deprivation therapy (ADT) is a common treatment modality for men with prostate cancer. Increases in adipose tissue mass and decreases in skeletal muscle mass are known on-target adverse effects of standard ADT. The effects of newer agents such as abiraterone acetate (ABI) and enzalutamide (ENZA) on body composition and how these compare with standard luteinizing hormone-releasing hormone agonists (aLHRHs) are unclear. Objective: To assess the effects of different forms of androgen deprivation therapy on body composition in men with prostate cancer. Design, setting, and participants: Using a retrospective design, 229 patients receiving aLHRHs alone (n = 120) or in combination with ABI (n = 53) or ENZA (n = 56) were studied. Outcome measurements and statistical analysis: Muscle, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were assessed at baseline, 6 mo, and 18 mo after initiating therapy using a cross-sectional densitometry analysis performed on standard of care computed tomography images. Response trajectories for all treatment groups were calculated via a two-way analysis of variance post hoc test, for both within-group and between-group differences. Results and limitations: Treatment with aLHRHs, ABI, and ENZA was associated with a median muscle volume loss of –1.4%, –4.8%, and –5.5% at 6 mo, and –7.1%, –8.1%, and –8.3% at 18 mo, respectively. Therapy with aLHRHs was associated with minimal changes in VAT (0.3% at 6 mo and –0.1% at 18 mo). ABI therapy was associated with significant increases in VAT at 6 mo (4.9%) but not at 18 mo (0.5%), and ENZA therapy was associated with significant decreases in VAT (–4.6% at 6 mo and –5.4% at 18 mo). With respect to SAT, treatment with aLHRHs was associated with increases over time (8.6% at 6 mo and 4.7% at 18 mo), ABI was associated with decreases over time (–3.6% at 6 mo and –6.8% at 18 mo), and ENZA had no clear effects (1.7% at 6 mo and 3.3% at 18 mo). Conclusions: ADT regimens cause significant short-term losses in muscle mass, with the most rapid effects occurring with ABI and ENZA. The three regimens have disparate effects on SAT and VAT, suggesting distinct roles of androgens in these tissues. Patient summary: Androgen deprivation therapy alters body composition in men with prostate cancer. Abiraterone and enzalutamide are associated with losses in muscle mass compared with luteinizing hormone-releasing hormone agonists. These treatments impact subcutaneous and visceral fat mass, suggesting distinct roles of androgens in these tissues.

The study investigated the antidiabetic potentials of the fruit extract of Parquetina nigrescens with the aim of justifying its folkloric antidiabetic usage in some part of Nigeria. Acute toxicity test of the plant extract was assessed using Lorke’s method. Its antidiabetic activities were assayed in α-amylase, α-glucosidase, glucose, and streptozotocin-induced diabetic rats’ models at various doses with acarbose and glibenclamide (5 mg/kg) as positive controls. Molecular docking studies were performed to identify the antidiabetic constituent of the extract and elucidate its possible mechanism of action. The estimated median lethal dose (LD 50 ) of the extract was above 5000 mg/kg. In the α-amylase, α-glucosidase study, the extract elicited concentration-dependent activity similar to acarbose. In the glucose-induced hyperglycaemic model, 200 mg/kg of the extract was the most effective dose with comparable ( P > .05) antihyperglycaemic activity to glibenclamide (5 mg kg) at 1 to 4 h. Also in the streptozotocin-induced diabetic rats model, 100 and 200 mg/kg of the extract gave comparable ( P > 0.05) activity on days 4 to 14 that were significantly better than that of glibenclamide on days 4 to 7. The n-hexane and ethylacetate fractions of the extract, both at 200 mg/kg were the most active with comparable activity to glibenclamide at all time points. The molecular docking studies identified isorhoifolin as the best binder against alpha amylase with binding energy (−9.1 kcal/mol), alpha glucosidase (−9.4 kcal/mol), sodium-glucose cotransporter-2 (−9.5 kcal/mol), peroxisome proliferator activated receptor gamma (−10.3 kcal/mol), 11β - Hydroxysteroid dehydrogenase (−10.8 kcal/mol), and dipeptidyl peptidase IV (−9.4 kcal/mol). The results of the antidiabetic study of P nigrescence fruit extract justified its usage in ethnomedicne in diabetes management.

Summary: The phosphoinositide 3-kinase p110α is an essential mediator of insulin signaling and glucose homeostasis. We interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110α and found that the Hippo kinases phosphorylate p110α at T1061, which inhibits its activity. This inhibitory state corresponds to a conformational change of a membrane-binding domain on p110α, which impairs its ability to engage membranes. In human primary hepatocytes, cancer cell lines, and rodent tissues, activation of the Hippo kinases MST1/2 using forskolin or epinephrine is associated with phosphorylation of T1061 and inhibition of p110α, impairment of downstream insulin signaling, and suppression of glycolysis and glycogen synthesis. These changes are abrogated when MST1/2 are genetically deleted or inhibited with small molecules or if the T1061 is mutated to alanine. Our study defines an inhibitory pathway of PI3K signaling and a link between epinephrine and insulin signaling.

Objective: Glucose-dependent insulinotropic polypeptide (GIP) has a role in controlling postprandial metabolic tone. In humans, a GIP receptor (GIPR) variant (Q354, rs1800437) is associated with a lower body mass index (BMI) and increased risk for Type 2 Diabetes. To better understand the impacts of GIPR-Q354 on metabolism, it is necessary to study it in an isogeneic background to the predominant GIPR isoform, E354. To accomplish this objective, we used CRISPR-CAS9 editing to generate mouse models of GIPR-Q354 and GIPR-E354. Here we characterize the metabolic effects of GIPR-Q354 variant in a mouse model (GIPR-Q350). Methods: We generated the GIPR-Q350 mice for in vivo studies of metabolic impact of the variant. We isolated pancreatic islets from GIPR-Q350 mice to study insulin secretion ex vivo. We used a β−cell cell line to understand the impact of the GIPR-Q354 variant on the receptor traffic. Results: We found that female GIPR-Q350 mice are leaner than littermate controls, and male GIPR-Q350 mice are resistant to diet-induced obesity, in line with the association of the variant with reduced BMI in humans. GIPR-Q350 mice of both sexes are more glucose tolerant and exhibit an increased sensitivity to GIP. Postprandial GIP levels are reduced in GIPR-Q350 mice, revealing feedback regulation that balances the increased sensitivity of GIP target tissues to secretion of GIP from intestinal endocrine cells. The increased GIP sensitivity is recapitulated ex vivo during glucose stimulated insulin secretion assays in islets. Generation of cAMP in islets downstream of GIPR activation is not affected by the Q354 substitution. However, post-activation traffic of GIPR-Q354 variant in β-cells is altered, characterized by enhanced intracellular dwell time and increased localization to the Trans-Golgi Network (TGN). Conclusions: Our data link altered intracellular traffic of the GIPR-Q354 variant with GIP control of metabolism. We propose that this change in spatiotemporal signaling underlies the physiologic effects of GIPR-Q350/4 and GIPR-E350/4 in mice and humans. These findings contribute to a more complete understanding of the impact of GIPR-Q354 variant on glucose homeostasis that could perhaps be leveraged to enhance pharmacologic targeting of GIPR for the treatment of metabolic disease.

Abstract Mechanical forces drive critical cellular processes that are reflected in mechanical phenotypes, or mechanotypes, of cells and their microenvironment. We present here “Rupture And Deliver” Tension Gauge Tethers (RAD-TGTs) in which flow cytometry is used to record the mechanical history of thousands of cells exerting forces on their surroundings via their propensity to rupture immobilized DNA duplex tension probes. We demonstrate that RAD-TGTs recapitulate prior DNA tension probe studies while also yielding a gain of fluorescence in the force-generating cell that is detectable by flow cytometry. Furthermore, the rupture propensity is altered following disruption of the cytoskeleton using drugs or CRISPR-knockout of mechanosensing proteins. Importantly, RAD-TGTs can differentiate distinct mechanotypes among mixed populations of cells. We also establish oligo rupture and delivery can be measured via DNA sequencing. RAD-TGTs provide a facile and powerful assay to enable high-throughput mechanotype profiling, which could find various applications, for example, in combination with CRISPR screens and -omics analysis.

Renin–angiotensin–aldosterone system (RAAS) inhibitors are standard care in patients with hypertension, heart failure or chronic kidney disease (CKD). Although we have studied the RAAS for decades, there are still circumstances that remain unclear. In this review, we describe the evolution of the RAAS and pose the question of whether this survival trait is still necessary to humankind in the present age. We elucidate the benefits on cardiovascular health and kidney disease of RAAS inhibition and present promising novel medications. Furthermore, we address why more studies are needed to establish a new standard of care away from generally prescribing ACEi or ARB toward an improved approach to combine drugs tailored to the needs of individual patients.

Abstract Background Lung cancer remains the major cause of cancer‐related deaths worldwide. Early stages of lung cancer are characterized by long asymptomatic periods that are ineffectively identified with the current screening programs. This deficiency represents a lost opportunity to improve the overall survival of patients. Serum biomarkers are among the most effective strategies for cancer screening and follow up. Methods Using bead‐based multiplexing assays we screened plasma and tumours of the KrasG12D/+; Lkb1f/f (KL) mouse model of lung cancer for cytokines that could be used as biomarkers. We identified tissue inhibitor of metalloproteinase 1 (TIMP1) as an early biomarker and validated this finding in the plasma of lung cancer patients. We used immunohistochemistry (IHC), previously published single‐cell RNA‐seq and bulk RNA‐seq data to assess the source and expression of TIMP1in the tumour. The prognostic value of TIMP1 was assessed using publicly available human proteomic and transcriptomic databases. Results We found that TIMP1 is a tumour‐secreted protein with high sensitivity and specificity for aggressive cancer, even at early stages in mice. We showed that TIMP1 levels in the tumour and serum correlate with tumour burden and worse survival in mice. We validated this finding using clinical samples from our institution and publicly available human proteomic and transcriptomic databases. These data support the finding that high tumour expression of TIMP1 correlates with an unfavorable prognosis in lung cancer patients. Conclusion TIMP1 is a suitable biomarker for lung cancer detection.

Despite significant advances in the development of therapeutics for hearing loss, drug delivery to the middle and inner ear remains a challenge. As conventional oral or intravascular administration are ineffective due to poor bioavailability and impermeability of the blood-labyrinth-barrier, localized delivery is becoming a preferable approach for certain drugs. Even then, localized delivery to the ear precludes continual drug delivery due to the invasive and potentially traumatic procedures required to access the middle and inner ear. To address this, the preclinical development of controlled release therapeutics and drug delivery devices have greatly advanced, with some now showing promise clinically. This review will discuss the existing challenges in drug development for treating the most prevalent and damaging hearing disorders, in particular otitis media, perforation of the tympanic membrane, cholesteatoma and sensorineural hearing loss. We will then address novel developments in drug delivery that address these including novel controlled release therapeutics such as hydrogel and nanotechnology and finally, novel device delivery approaches such as microfluidic systems and cochlear prosthesis-mediated delivery. The aim of this review is to investigate how drugs can reach the middle and inner ear more efficiently and how recent innovations could be applied in aiding drug delivery in certain pathologic contexts.

Cochlear implants (CIs) allow individuals with profound hearing loss to understand speech and perceive sounds. However, not all patients obtain the full benefits that CIs can provide and the cause of this disparity is not fully understood. One possible factor for the variability in outcomes after cochlear implantation, is the development of fibrotic scar tissue around the implanted electrode. It has been hypothesised that limiting the extent of fibrosis after implantation may improve overall CI function, and longevity of the device. Currently, histology is often used to quantify the extent of intracochlear tissue growth after implantation however this method is labour intensive, time-consuming, often involves significant user bias, and causes physical distortion of the fibrosis. Therefore, this study aimed to evaluate x-ray micro computed tomography (μCT) as a method to measure the amount and distribution of fibrosis in a guinea pig model of cochlear implantation. Adult guinea pigs were implanted with an inactive electrode, and cochleae harvested eight weeks later (n = 7) and analysed using μCT, to quantify the extent of tissue reaction, followed by histological analysis to confirm that the tissue was indeed fibrotic. Cochleae harvested from an additional six animals following implantation were analysed by μCT, before and after contrast staining with osmium tetroxide (OsO4), to enhance the visualisation of soft tissues within the cochlea, including the tissue reaction. Independent analysis by two observers showed that the quantification method was robust and provided additional information on the distribution of the response within the cochlea. Histological analysis revealed that μCT visualised dense collagenous material and new bone formation but did not capture loose, areolar fibrotic tissue. Treatment with OsO4 significantly enhanced the visible tissue reaction detected using μCT. Overall, μCT is an alternative and reliable method that can be used to quantify the extent of the CI-induced intracochlear tissue response and will be a useful tool for the in vivo assessment of novel anti-fibrotic treatments.

The goal of metagenomic binning is to reconstruct genomes from a mixture of DNA sequences into genomic bins, which can be considered a clustering task. Multiple methods have been proposed for this task, such as distance-based metrics, machine learning, and ensemble approaches. We propose BinChill, a metagenomic ensemble method, based on the generic co-occurrence ensembler method, ACE. BinChill incorporates domain information in the form of Single-Copy Genes (SCG) with a co-occurrence strategy. This strategy combines multiple clustering partitions according to how often two items co-occur in the same cluster. BinChill was able to reconstruct more or equally as many high- and medium quality while having an equal or faster runtime than other metagenomics-specific methods on a smaller simulated dataset. On larger datasets, both simulated and real-world, BinChill outperformed other methods in reconstructing high-quality bins, at the cost of an increased processing time when compared to generic ensemble clustering algorithms. This is due to the domain-specific steps that our method implements. Our results show that the strengths of multiple partitions can be combined to generate a partition of higher quality.

Different location of adipose tissue may have different consequences to cardiometabolic risk. Here the authors report that deep learning enabled accurate prediction of specific adipose tissue volumes, and that after adjustment for BMI, visceral adiposity was associated with increased risk of cardiometabolic disease, while gluteofemoral adiposity was associated with reduced risk.

The advent of proteolysis-targeting chimaeras (PROTACs) mandates that new ligands for the recruitment of E3 ligases are discovered. The traditional immunomodulatory drugs (IMiDs) such as thalidomide and its analogues (all based on the phthalimide glutarimide core) bind to Cereblon, the substrate receptor of the CRL4ACRBN E3 ligase. We designed a thalidomide analogue in which the phthalimide moiety was replaced with benzotriazole, using an innovative synthesis strategy. Compared to thalidomide, the resulting “benzotriazolo thalidomide” has a similar binding mode, but improved properties, as revealed in crystallographic analyses, affinity assays and cell culture.

Abstract Lattice and electronic structure interactions for f-electrons are fundamental challenges for lanthanide equation of state development. Difficulties in first-principles calculations, such as density functional theory (DFT), emphasize the need for well-characterized experimental data. Here, we measure in-situ x-ray diffraction of shocked samarium (Sm) and temperature along the Hugoniot for the first time, providing direct evidence for phase transitions. We report direct evidence of a distorted fcc (dfcc) phase at 23 GPa. Shocked samarium melts from the dfcc phase starting at 33 GPa (1333 K), with complete melt at 40 GPa (1468 K). Previous work indicated shock melt at 27 GPa (1200 K), underscoring the significance of x-ray measurements for detecting phase transitions. Interestingly, our observed melting is in sharp contrast with the melting reported by a diamond anvil cell study. These experimental data can tightly constrain first principles calculations and serve as key touchstones for equation of state modeling.

Abstract Large gaps in reef distribution may hinder the dispersal of marine organisms, interrupting processes vital to the maintenance of biodiversity. Here we show the presence and location of extensive reef habitats on the continental shelf between the Amazon Reef System (ARS) and the Eastern Brazilian Reef System (ERS), two reef complexes off eastern South America. Formations located 20–50 m deep include both biogenic and geogenic structures. The presence of diverse reef assemblages suggests the widespread occurrence of rocky substrates below 50 m. These habitats represent an expansion of both the ARS and ERS and the closure of the only remaining large-scale gap (~ 1000 km) among West Atlantic reef environments. This indicates that the SW Atlantic harbors a single, yet heterogeneous, reef system that stretches for about 4000 km, and thus, represents one of the largest semi-continuous tropical marine ecosystems in the world.

Lipid droplets (LDs) are ubiquitous organelles that facilitate neutral lipid storage in cells, including energy-dense triglycerides. They are found in all investigated metazoan embryos where they are thought to provide energy for development. Intriguingly, early embryos of diverse metazoan species asymmetrically allocate LDs amongst cellular lineages, a process which can involve massive intracellular redistribution of LDs. However, the biological reason for asymmetric lineage allocation is unknown. To address this issue, we utilize the Drosophila embryo where the cytoskeletal mechanisms that drive allocation are well characterized. We disrupt allocation by two different means: Loss of the LD protein Jabba results in LDs adhering inappropriately to glycogen granules; loss of Klar alters the activities of the microtubule motors that move LDs. Both mutants cause the same dramatic change in LD tissue inheritance, shifting allocation of the majority of LDs to the yolk cell instead of the incipient epithelium. Embryos with such mislocalized LDs do not fully consume their LDs and are delayed in hatching. Through use of a dPLIN2 mutant, which appropriately localizes a smaller pool of LDs, we find that failed LD transport and a smaller LD pool affect embryogenesis in a similar manner. Embryos of all three mutants display overlapping changes in their transcriptome and proteome, suggesting that lipid deprivation results in a shared embryonic response and a widespread change in metabolism. Excitingly, we find abundant changes related to redox homeostasis, with many proteins related to glutathione metabolism upregulated. LD deprived embryos have an increase in peroxidized lipids and rely on increased utilization of glutathione-related proteins for survival. Thus, embryos are apparently able to mount a beneficial response upon lipid stress, rewiring their metabolism to survive. In summary, we demonstrate that early embryos allocate LDs into specific lineages for subsequent optimal utilization, thus protecting against oxidative stress and ensuring punctual development.

Up to 1.5 billion people worldwide suffer from various forms of hearing loss, with an additional 1.1 billion people at risk from various insults such as increased consumption of recreational noise-emitting devices and ageing. The most common type of hearing impairment is sensorineural hearing loss caused by the degeneration or malfunction of cochlear hair cells or spiral ganglion nerves in the inner ear. There is currently no cure for hearing loss. However, emerging frontier technologies such as gene, drug or cell-based therapies offer hope for an effective cure. In this review, we discuss the current therapeutic progress for the treatment of hearing loss. We describe and evaluate the major therapeutic approaches being applied to hearing loss and summarize the key trials and studies.

Cancer-associated cachexia is characterized by loss of body weight, skeletal muscle and adipose tissue which relates to higher mortality in cancer patients. Here, the authors show in a lung cancer murine model that both ActRIIB signalling inhibition and restoring appetite are necessary to revert cachexia and improve survival in female mice.

Abstract Inter-individual variation in fat distribution is increasingly recognized as clinically important but is not routinely assessed in clinical practice, in part because medical imaging has not been practical to deploy at scale for this task. Here, we report a deep learning model trained on an individual’s body shape outline—or “silhouette” —that enables accurate estimation of specific fat depots of interest, including visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) adipose tissue volumes, and VAT/ASAT ratio. Two-dimensional coronal and sagittal silhouettes are constructed from whole-body magnetic resonance images in 40,032 participants of the UK Biobank and used as inputs for a convolutional neural network to predict each of these quantities. Mean age of the study participants is 65 years and 51% are female. A cross-validated deep learning model trained on silhouettes enables accurate estimation of VAT, ASAT, and GFAT volumes (R 2: 0.88, 0.93, and 0.93, respectively), outperforming a comparator model combining anthropometric and bioimpedance measures (ΔR 2 = 0.05–0.13). Next, we study VAT/ASAT ratio, a nearly body-mass index (BMI)—and waist circumference-independent marker of metabolically unhealthy fat distribution. While the comparator model poorly predicts VAT/ASAT ratio (R 2: 0.17–0.26), a silhouette-based model enables significant improvement (R 2: 0.50–0.55). Increased silhouette-predicted VAT/ASAT ratio is associated with increased risk of prevalent and incident type 2 diabetes and coronary artery disease independent of BMI and waist circumference. These results demonstrate that body silhouette images can estimate important measures of fat distribution, laying the scientific foundation for scalable population-based assessment.

The inherited basis of body fat distribution is not fully understood. Here, the authors use genetic data and MRI-derived measures of local adiposity to highlight fat depot-specific genetic architecture with implications for cardiometabolic health.

Abstract Purpose The phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) pathway controls insulin sensitivity and glucose metabolism. Hyperglycemia is one of the most common on‐target adverse effects (AEs) of PI3K/AKT inhibitors. As several PI3K and AKT inhibitors are approved by the United States Food and Drug Administration or are being studied in clinical trials, characterizing this AE and developing a management strategy is essential. Methods Patients with hematologic or solid malignancies treated at Memorial Sloan Kettering Cancer Center with a PI3K or AKT inhibitor were included in this retrospective analysis. A search for patients experiencing hyperglycemia was performed. The frequency, management interventions and outcomes were characterized. Results Four hundred and ninety‐one patients with 10 unique cancer types who received a PI3K or AKT inhibitor were included. Twelve percent of patients required a dose interruption, 6% of patients required a dose reduction and 2% of patients were hospitalized to manage hyperglycemia. No events occurred among patients receiving β‐, γ‐, or δ‐ specific PI3K inhibitor. There was one case where the PI3K or AKT inhibitor was permanently discontinued due to hyperglycemia. Metformin was the most commonly used antidiabetic medication, followed by insulin, sodium‐glucose transport protein 2 (SGLT2) inhibitors, and sulfonylurea. SGLT2 inhibitors were associated with the greatest reductions in blood sugar, followed by metformin. At least one case of euglycemic diabetic ketoacidosis (DKA) occurred in a patient on PI3K inhibitor and SGLT2 inhibitor. Body mass index ≥ 25 and HbA1c ≥ 5.7 are were independently significant predictors of developing hyperglycemia. Conclusion Hyperglycemia is one of the major on‐target side effects of PI3K and AKT inhibitors. It is manageable with antidiabetic medications, treatment interruption and/or dose modification. We summarize pharmacological interventions that may be considered for PI3K/AKT inhibitor induced hyperglycemia. SGLT2‐inhibitor may be a particularly effective second‐line option after metformin but there is a low risk of euglycemic DKA, which can be deadly. To our knowledge, our report is the largest study of hyperglycemia in patients receiving PI3K/AKT inhibitors.

Abstract Electronic health record (EHR) datasets are statistically powerful but are subject to ascertainment bias and missingness. Using the Mass General Brigham multi-institutional EHR, we approximated a community-based cohort by sampling patients receiving longitudinal primary care between 2001-2018 (Community Care Cohort Project [C3PO], n = 520,868). We utilized natural language processing (NLP) to recover vital signs from unstructured notes. We assessed the validity of C3PO by deploying established risk models for myocardial infarction/stroke and atrial fibrillation. We then compared C3PO to Convenience Samples including all individuals from the same EHR with complete data, but without a longitudinal primary care requirement. NLP reduced the missingness of vital signs by 31%. NLP-recovered vital signs were highly correlated with values derived from structured fields (Pearson r range 0.95–0.99). Atrial fibrillation and myocardial infarction/stroke incidence were lower and risk models were better calibrated in C3PO as opposed to the Convenience Samples (calibration error range for myocardial infarction/stroke: 0.012–0.030 in C3PO vs. 0.028–0.046 in Convenience Samples; calibration error for atrial fibrillation 0.028 in C3PO vs. 0.036 in Convenience Samples). Sampling patients receiving regular primary care and using NLP to recover missing data may reduce bias and maximize generalizability of EHR research.

Abstract Neutrophils are the most abundant circulating leukocyte population with critical roles in immune defense, regulation of innate and adaptive immune systems, and disease pathogenesis. Our progress in understanding precise mechanisms of neutrophil activation, recruitment, and function has been hampered by the lack of optimized and standardized methods for the characterization and phenotyping of this readily activated population. By comparing eight methods of neutrophil characterization, we demonstrate that the level of neutrophil activation and degranulation is associated with specific experimental conditions and the number and type of manipulation steps employed. Staining whole blood at 4 °C and removal of remaining unbound antibodies prior to one-step fixation and red blood cell lysis minimizes neutrophil activation, decreases phenotypic alterations during processing, and prevents nonspecific antibody binding. The effects of anticoagulants used for collection, processing delays, and time and temperature during sample analysis on neutrophil phenotype are addressed. The presented data provide a foundation for higher quality standards of neutrophil characterization improving consistency and reproducibility among studies.

We describe a new species of extinct duck, Miotadorna catrionae sp. nov. (Anatidae, Tadornini, Tadorninae), based on a right humerus from the Miocene lacustrine deposits of St Bathans, Otago, New Zealand. Principal component analysis reveals that the new taxon is distinguished by its large size and relative proportions. This is the eighth and largest species of duck described from the St Bathans fossil assemblage and further underscores the global importance of this site for understanding anatid evolution.

Purpose: The oral, α-specific phosphatidylinositol-3-kinase (PI3Kα) inhibitor alpelisib is the first PI3K inhibitor approved for the treatment of advanced breast cancer. As alpelisib is a relatively new therapeutic option, specific guidance and a multidisciplinary approach are needed to provide optimal patient care. The primary objective of this manuscript is to provide comprehensive guidance on minimizing and managing adverse events (AEs) for patients with advanced breast cancer who are receiving alpelisib. Methods: Clinical studies, prescribing information, published literature, and relevant guidelines were reviewed to provide recommendations on the prevention and management of alpelisib-associated AEs. Results: The most common AEs associated with alpelisib in the phase 3 SOLAR-1 trial were hyperglycemia and rash (which are considered on-target effects of PI3Kα inhibition) and gastrointestinal AEs, including diarrhea, nausea, and decreased appetite. These AEs require regular monitoring, early recognition, and prompt initiation of appropriate treatment. In addition, there are effective strategies to reduce the onset and severity of frequently observed AEs—in particular, onset of hyperglycemia and rash may be reduced by lifestyle changes (such as reduced intake of carbohydrates and regular exercise) and antihistamine prophylaxis, respectively. To reduce risk of severe hyperglycemia, it is essential to achieve adequate glycemic control prior to initiation of alpelisib treatment. Conclusion: Overall, alpelisib-associated AEs are generally manageable with prompt recognition, regular monitoring, and appropriate intervention, preferably with a multidisciplinary approach.

Current U.S. guidelines recommend integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) as initial treatment for people with HIV (PWH). We assessed long-term effects of INSTI use on lipid profiles in routine HIV care. We analyzed medical record data from the HIV Outpatient Study’s participants in care from 2007 to 2021. Hyperlipidemia was defined based on clinical diagnoses, treatments, and laboratory results. We calculated hyperlipidemia incidence rates and rate ratios (RRs) during initial ART and assessed predictors of incident hyperlipidemia by using Poisson regression. Among 349 eligible ART-naïve PWH, 168 were prescribed INSTI-based ART (36 raltegravir (RAL), 51 dolutegravir (DTG), and 81 INSTI-others (elvitegravir and bictegravir)) and 181 non-INSTI-based ART, including 68 protease inhibitor (PI)-based ART. During a median follow-up of 1.4 years, hyperlipidemia rates were 12.8, 22.3, 22.7, 17.4, and 12.6 per 100 person years for RAL-, DTG-, INSTI-others-, non-INSTI-PI-, and non-INSTI-non-PI-based ART, respectively. In multivariable analysis, compared with the RAL group, hyperlipidemia rates were higher in INSTI-others (RR = 2.25; 95% confidence interval (CI): 1.29–3.93) and non-INSTI-PI groups (RR = 1.89; CI: 1.12–3.19) but not statistically higher for the DTG (RR = 1.73; CI: 0.95–3.17) and non-INSTI-non-PI groups (RR = 1.55; CI: 0.92–2.62). Other factors independently associated with hyperlipidemia included older age, non-Hispanic White race/ethnicity, and ART without tenofovir disoproxil fumarate. PWH using RAL-based regimens had lower rates of incident hyperlipidemia than PWH receiving non-INSTI-PI-based ART but had similar rates as those receiving DTG-based ART, supporting federal recommendations for using DTG-based regimens as the initial therapy for ART-naïve PWH.

BackgroundThis study aimed to describe available evidence of cochlear implantation delivery arrangements in adults and the outcomes by which these service models are measured.MethodsScoping review of English language, primary studies conducted on adults (≥18 years) with ten or more subjects, published between January 2000 and June 2022, which assessed the effects of delivery arrangements of cochlear implantation were included. MEDLINE, EMBASE, CINAHL Plus, AMED, PsycINFO, LILACS, KoreaMed, IndMed, Cochrane CRCT, ISRCTN registry, WHO ICTRP and Web of Science were systematically searched. Included studies had to have a method section explicitly measure at least one of the Cochrane Effective Practice and Organization of Care (EPOC) outcome category. Criteria for systematic reviews and delivery arrangement category based on EPOC taxonomy was included in data extraction. Data was narratively synthesized based on EPOC categories.ResultsA total of 8135 abstracts were screened after exclusion of duplicates, of these 357 studies fulfilled the inclusion criteria. Around 40% of the studies investigated how care is delivered, focusing on quality and safety systems. New care pathways to coordinate care and the use of information and communication technology were emerging areas. There was little evidence on continuity, coordination and integration of care, how the workforce is managed, where care is provided and changes in the healthcare environment. The main outcome measure for various delivery arrangements were the health status and performance in a test.ConclusionA substantial body of evidence exists about safety and efficacy of cochlear implantation in adults, predominantly focused on surgical aspects and this area is rapidly growing. There is a lack of evidence on aspects of care delivery that may have more impact on patients' experience such as continuity, coordination and integration of care and should be a focus of future research. This would lead to a better understanding of how patient's view CI experience, associated costs and the value of different care models.

Hematologic malignancies, including multiple myeloma (MM), promote systemic immune dysregulation resulting in an alteration and increased plasticity of myeloid cell subsets. To determine the heterogeneity of the myeloid cell compartment in the peripheral blood of patients with MM, we performed a detailed investigation of the phenotype and function of myeloid subpopulations. We report that a subset of MM patients exhibits a specific myeloid cell phenotype indicative of altered myelopoiesis characterized by significant changes in the properties of circulating granulocytic, monocytic, and eosinophilic populations. The subset, referred to as MM2, is defined by a markedly elevated level of CD64 (FcγRI) on the surface of circulating neutrophils. Compared to healthy controls or MM1 patients displaying intermediate levels of CD64, neutrophils from MM2 patients exhibit a less differentiated phenotype, low levels of CD10 and CXC chemokine receptor 2 (CXCR2), increased capacity for the production of mitochondrial reactive oxygen species, and an expansion of CD16neg immature neutrophil subset. Classical and patrolling monocytes from MM2 patients express elevated levels of CD64 and activation markers. MM2 eosinophils display lower levels of C-C Chemokine receptor 3 (CCR3), Toll-like receptor 4 (TLR4, CD284), and tissue factor (TF, CD142). The MM2 (CD64high) phenotype is independent of age, race, sex, and treatment type. Characteristic features of the MM2 (CD64high) phenotype are associated with myeloma-defining events including elevated involved/uninvolved immunoglobulin free light chain (FLC) ratio at diagnosis. Detailed characterization of the altered myeloid phenotype in multiple myeloma will likely facilitate the identification of patients with an increased risk of disease progression and open new avenues for the rational design of novel therapeutic approaches.

Estimation of hydrological processes is critical to water resource management, water supply planning, ecological protection, and climate change impact assessment. Mountains in Central Asia are the major source of water for rivers and agricultural practices. The disturbance of mountain forests in the region has altered the hydrological processes and accelerated soil erosion, mudflow, landslides, and flooding. We used the SWAT (Soil and Water Assessment Tool) model calibrated and validated with remote sensing data to quantify the mountainous hydrological processes in the Aktash River watershed (ARW) of Uzbekistan, Central Asia. Simulations showed that the daily surface runoff and streamflow closely responded to daily precipitation. Groundwater discharge reached its maximum in winter because of snowmelt. The wet months were from July to December, and the dry months were from January to June. The magnitudes of the seasonal hydrological processes were in the following order: fall > summer > winter > spring for precipitation and surface runoff; summer > spring > fall > winter for evapotranspiration (ET); winter > spring > fall > summer for snowmelt; fall > winter > summer > spring for water yield and streamflow; and winter > fall > spring > summer for groundwater discharge. The Mann–Kendall statistical test revealed a significant increasing trend for the annual precipitation (τ = 0.45, p < 0.01) and surface runoff (τ = 0.41, p < 0.02) over the past 17 years from 2003 to 2019. Compared to rangeland, forested land decreased monthly and annual average surface runoff by 20%, and increased monthly and annual average groundwater recharge by about 5%. Agricultural land had much higher unit-area values (mm/km2/y) of ET, groundwater recharge, and water yield than those of urban, forest, and range lands. Our research findings provide useful information to farmers, foresters, and decision makers for better water resource management in the ARW, Central Asia, and other mountain watersheds with similar conditions.

Abstract Background Fructose is an abundant source of carbon and energy for cells to use for metabolism, but only certain cell types use fructose to proliferate. Tumor cells that acquire the ability to metabolize fructose have a fitness advantage over their neighboring cells, but the proteins that mediate fructose metabolism in this context are unknown. Here, we investigated the determinants of fructose-mediated cell proliferation. Methods Live cell imaging and crystal violet assays were used to characterize the ability of several cell lines (RKO, H508, HepG2, Huh7, HEK293T (293T), A172, U118-MG, U87, MCF-7, MDA-MB-468, PC3, DLD1 HCT116, and 22RV1) to proliferate in fructose (i.e., the fructolytic ability). Fructose metabolism gene expression was determined by RT-qPCR and western blot for each cell line. A positive selection approach was used to “train” non-fructolytic PC3 cells to utilize fructose for proliferation. RNA-seq was performed on parental and trained PC3 cells to find key transcripts associated with fructolytic ability. A CRISPR-cas9 plasmid containing KHK-specific sgRNA was transfected in 293T cells to generate KHK -/- cells. Lentiviral transduction was used to overexpress empty vector, KHK, or GLUT5 in cells. Metabolic profiling was done with seahorse metabolic flux analysis as well as LC/MS metabolomics. Cell Titer Glo was used to determine cell sensitivity to 2-deoxyglucose in media containing either fructose or glucose. Results We found that neither the tissue of origin nor expression level of any single gene related to fructose catabolism determine the fructolytic ability. However, cells cultured chronically in fructose can develop fructolytic ability. SLC2A5, encoding the fructose transporter, GLUT5, was specifically upregulated in these cells. Overexpression of GLUT5 in non-fructolytic cells enabled growth in fructose-containing media across cells of different origins. GLUT5 permitted fructose to flux through glycolysis using hexokinase (HK) and not ketohexokinase (KHK). Conclusions We show that GLUT5 is a robust and generalizable driver of fructose-dependent cell proliferation. This indicates that fructose uptake is the limiting factor for fructose-mediated cell proliferation. We further demonstrate that cellular proliferation with fructose is independent of KHK.

ABSTRACT INTRODUCTIONOver-prescription of antibiotics for common infective conditions is an important health issue. Infective conjunctivitis represents one of the most common eye-related complaints in general practice. Despite its self-limiting nature, there is evidence of frequent general practitioner (GP) antibiotic prescribing for this condition, which is inconsistent with evidence-based guidelines. AIMTo investigate the prevalence and associations of GP registrars' (trainees') prescription of antibiotics for infective conjunctivitis. METHODSWe performed a cross-sectional analysis of the Registrar Encounters in Clinical Training (ReCEnT) ongoing prospective cohort study, which documents GP registrars' clinical consultations (involving collection of information from 60 consecutive consultations, at three points during registrar training). The outcome of the analyses was antibiotic prescription for a new diagnosis of conjunctivitis. Patient, registrar, practice and consultation variables were included in uni- and multivariable logistic regression analyses to test associations of these prescriptions. RESULTSIn total, 2333 registrars participated in 18 data collection rounds from 2010 to 2018. There were 1580 new cases of infective conjunctivitis (0.31% of all problems). Antibiotics (mainly topical) were prescribed in 1170 (74%) of these cases. Variables associated with antibiotic prescription included patients' Aboriginal or Torres Strait Islander status, registrar organisation of a follow up (both registrar and other GP follow up), and earlier registrar training term (more junior status). DISCUSSIONGP registrars, like established GPs, prescribe antibiotics for conjunctivitis in excess of guideline recommendations, but prescribing rates are lower in later training. These prescribing patterns have educational, social and economic consequences. Further educational strategies may enhance attenuation of registrars' prescribing during training.

Background There are a paucity of randomised data on the optimal timing of invasive coronary angiography (ICA) in higher-risk patients with non-ST elevation myocardial infarction (N-STEMI). International guideline recommendations for early ICA are primarily based on retrospective subgroup analyses of neutral trials.Aims The RAPID N-STEMI trial aims to determine whether very early percutaneous revascularisation improves clinical outcomes as compared with a standard of care strategy in higher-risk N-STEMI patients.Methods and analysis RAPID N-STEMI is a prospective, multicentre, open-label, randomised-controlled, pragmatic strategy trial. Higher-risk N-STEMI patients, as defined by Global Registry of Acute Coronary Events 2.0 score ≥118, or >90 with at least one additional high-risk feature, were randomised to either: very early ICA±revascularisation or standard of care timing of ICA±revascularisation. The primary outcome is the proportion of participants with at least one of the following events (all-cause mortality, non-fatal myocardial infarction and hospital admission for heart failure) at 12 months. Key secondary outcomes include major bleeding and stroke. A hypothesis generating cardiac magnetic resonance (CMR) substudy will provide mechanistic data on infarct size, myocardial salvage and residual ischaemia post percutaneous coronary intervention. On 7 April 2021, the sponsor discontinued enrolment due to the impact of the COVID-19 pandemic and lower than expected event rates. 425 patients were enrolled, and 61 patients underwent CMR.Ethics and dissemination The trial has been reviewed and approved by the East of England Cambridge East Research Ethics Committee (18/EE/0222). The study results will be submitted for publication within 6 months of completion.Trial registration number NCT03707314; Pre-results.

Abstract Background Globally, about 50 million people were living with dementia in 2015, with this number projected to triple by 2050. With no cure or effective treatment currently insight, it is vital that factors are identified which will help prevent or delay both age-related and pathological cognitive decline and dementia. Observational data have suggested that hearing loss is a potentially modifiable risk factor for dementia, but no conclusive evidence from randomised controlled trials is currently available. Methods The HearCog trial is a 24-month, randomised, controlled clinical trial aimed at determining whether a hearing loss intervention can delay or arrest the cognitive decline. We will randomise 180 older adults with hearing loss and mild cognitive impairment to a hearing aid or control group to determine if the fitting of hearing aids decreases the 12-month rate of cognitive decline compared with the control group. In addition, we will also determine if the expected clinical gains achieved after 12 months can be sustained over an additional 12 months and if losses experienced through the non-correction of hearing loss can be reversed with the fitting of hearing aids after 12 months. Discussion The trial will also explore the cost-effectiveness of the intervention compared to the control arm and the impact of hearing aids on anxiety, depression, physical health and quality of life. The results of this trial will clarify whether the systematic correction of hearing loss benefits cognition in older adults at risk of cognitive decline. We anticipate that our findings will have implications for clinical practice and health policy development. Trial registration Australian and New Zealand Clinical Trials Registry ( ANZCTR: 12618001278224 ), registered on 30.07.2018.

Although loss of BRCA1 leads to defects in DNA double-strand break repair by homologous recombination (HR) and renders cells hypersensitive to PARP inhibitors, resistance to the drugs can arise. Here the authors reveal that PALB2 chromatin recruitment restores HR in BRCA1-deficient cells depleted of 53BP1.

IntroductionDiabetes mellitus is a chronic noncommunicable disease associated with death and major disability, with increasing prevalence in low- and middle-income countries. There is limited population-based data about diabetes in Haiti. The objective of this study was to assess the prevalence of diabetes and associated factors among adults in Port-au-Prince, Haiti using a population-based cohort.MethodsThis study analyzes cross-sectional enrollment data from the population-based Haiti Cardiovascular Disease Cohort Study, conducted using multistage sampling with global positioning system waypoints in census blocks in the metropolitan area of Port-au-Prince, Haiti. A total of 3,005 adults ≥18 years old were enrolled from March 2019 to August 2021. We collected socio-demographic data, health-related behaviors, and clinical data using standardized questionnaires. Diabetes was defined as any of the following criteria: enrollment fasting glucose value ≥ 126 mg/dL or non-fasting glucose ≥ 200 mg/dL, patient self-report of taking diabetes medications, or study physician diagnosis of diabetes based on clinical evaluation.ResultsAmong 2985 (99.3%) with complete diabetes data, median age was 40 years, 58.1% were female, and 17.2% were obese. The prevalence of diabetes was 5.4% crude, and 5.2% age standardized. In unadjusted analysis, older age, higher body mass index (BMI), low physical activity, low education were associated with a higher odds of diabetes. After multivariable logistic regression, older age [60+ vs 18-29, Odds Ratio (OR)17.7, 95% CI 6.6 to 47.9] and higher BMI (obese vs normal/underweight, OR 2.7, 95% CI 1.7 to 4.4) remained statistically significantly associated with higher odds of diabetes.ConclusionThe prevalence of diabetes was relatively low among adults in Port-au-Prince, but much higher among certain groups (participants who were older and obese). The Haitian health system should be strengthened to prevent, diagnose, and treat diabetes among high-risk groups.

Phosphatidylinositol-3-kinase (PI3K) pathway hyperactivation has been associated with the development of cancer and treatment resistance. PI3K inhibitors are now used to treat hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2−), PIK3CA- mutated advanced breast cancer. Hyperglycemia, a frequently observed adverse event with PI3K inhibitors (PI3Ki), is regarded as an on-target effect because inhibition of the PI3K pathway has been shown to decrease glucose transport and increase glycogenolysis and gluconeogenesis. PI3Ki-induced hyperglycemia results in a compensatory increase in insulin release, which has been shown to reduce the efficacy of treatment by reactivating the PI3K pathway in preclinical models. Patients with an absolute or relative deficiency in insulin, and those with insulin resistance or pancreatic dysfunction, may experience exacerbated or prolonged hyperglycemia. Therefore, the effective management of PI3Ki-associated hyperglycemia depends on early identification of patients at risk, frequent monitoring to allow prompt recognition of hyperglycemia and its sequelae, and initiating appropriate management strategies. Risk factors for the development of hyperglycemia include older age (≥75 years), overweight/obese at baseline, and family history of diabetes. Consultation with an endocrinologist is recommended for patients considered high risk. The management of PI3Ki-induced hyperglycemia requires an integrative approach that combines diets low in carbohydrates and glucose-lowering medications. Medications that do not affect the PI3K pathway are preferred as the primary and secondary agents for the management of hyperglycemia. These include metformin, sodium-glucose co-transporter 2 inhibitors, thiazolidinediones, and α-glucosidase inhibitors. Insulin should only be considered as a last-line agent for PI3Ki-associated hyperglycemia due to its stimulatory effect of PI3K signaling. Clinical studies show that alpelisib-associated hyperglycemia is reversible and manageable, rarely leading to treatment discontinuation. Management of PI3Ki-associated hyperglycemia in patients with breast cancer should focus on the prevention of acute and subacute complications of hyperglycemia, allowing patients to remain on anticancer treatment longer.

Introduction Nurse-run preanaesthesia assessment is well established in ambulatory surgery. However, in the Middle East the implementation of such a service is new and needed careful preparation. Aim of this audit is to assess the feasibility and the quality of preoperative assessments by the specially trained nurses, patient and nurse satisfaction and overall perioperative quality of recovery.Methods The nurses were selected and trained first in an accredited programme. Then an implementation period of 3 month was used for them to gain experience. Hereafter, we performed a four-step audit on the quality of preassessment, the patient’s satisfaction, the quality of recovery and adverse events if any. Finally, we also monitored the nurse’s satisfaction of their new advanced role.Results The quality of preanaesthesia assessment was high as with 95% compliance to the accepted standards. In the patient satisfaction survey, all 152 patients were either highly satisfied or satisfied with the nurse-run service. The nurses were also highly satisfied and felt that they were either highly or moderately valued. All the patients who were operated at the ambulatory care services were followed up postoperatively by telephone calls which revealed that most of them were highly satisfied. No major or minor adverse events occurred.Conclusion Our specially trained nurses perform preoperative assessments on high standard without adverse events, while patient and staff satisfaction is very high. Future projects will focus on reducing the rate of cancellation of surgeries, investigating the cost-effectiveness of this approach as well as training the specialised nurses for paediatric preoperative anaesthesia assessments. This model of care could induce further nurse-run models of care in the Middle East.

This study aimed to determine the specific cytokine profile in peripheral blood during the early onset of COVID-19 infection. This was a cross-sectional exploratory, single center study. A total of 55 plasma samples were studied. Serum samples of adults showing symptoms of COVID-19 infection who were tested positive for SARS-CoV-2 infection (CoV+, n=18) at the COVID-19 outpatient clinic of the Medical University of Vienna were screened for immune activation markers by Luminex technology. Additionally, age and gender-matched serum samples of patients displaying COVID-19 associated symptoms, but tested negative for SARS-CoV-2 (CoV-, n=16) as well as healthy controls (HC, n=21) were analyzed. COVID-19 positive (CoV+) patients showed a specific upregulation of BLC (141; 74-189 pg/mL), SCD30 (273; 207-576 pg/mL), MCP-2 (18; 12-30 pg/mL) and IP-10 (37; 23-96 pg/mL), compared to patients with COVID19-like symptoms but negative PCR test (CoV-), BLC (61; 22-100 pg/mL), sCD30L (161; 120-210 pg/mL), MCP-2 (8; 5-12 pg/mL) and IP-10 (9; 6-12 pg/mL) and healthy controls (HC) (BLC 22; 11-36 pg/mL, sCD30 74; 39-108 pg/mL, MCP-2 6; 3-9. pg/mL, IP-10 = 8; 5-13). The markers APRIL, sIL-2R, IL7, MIF, MIP-1b, SCF, SDF-1a, sTNF-RII were elevated in both CoV+ and CoV- patient groups compared to healthy controls. HGF, MDC and VEGF-A were elevated in CoV- but not CoV+ compared to healthy controls. BLC, sCD30, MCP-2 and IP-10 are specifically induced during early stages of COVID-19 infection and might constitute attractive targets for early diagnosis and treatment of this disease.

Background: Historically, choledochal cyst excision has been performed as an open procedure. Controversy remains regarding managing this technically challenging entity in a minimally invasive fashion. Methods: A novel mechanically-designed intuitive, articulating instrument is used to facilitate intracorporeal suturing when there is limited working space. The mechanical design of the three-axis Gimbal cuff facilitates intracorporeal suturing by providing intuitive wristed function to the surgeon by translating the surgeon's wrist movement to the end effector. Results: We describe the adoption of a novel articulating instrument to facilitate a primary hepaticoduodenostomy within the limited space of a pediatric porta and a redo hepaticojejunostomy. Conclusions: These cases demonstrate the use of a novel articulating needle driver to sew an intracorporeal bilio-enteric anastomosis which obviates the need for robotic technology while expanding a laparoscopic surgeon's armamentarium.

Alpelisib is a α-selective phosphatidylinositol 3-kinase (PI3K) inhibitor approved for treatment of postmenopausal women, and men, with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–), PIK3CA-mutated, advanced breast cancer (ABC). Hyperglycemia is a common, on-target adverse effect that impairs treatment efficacy and increases the rate of treatment delays, dose reductions, and discontinuation. Currently, there are no clear guidelines on how to manage hyperglycemia due to alpelisib when metformin is not effective. In this case series, we review 3 subjects with ABC that developed hyperglycemia during alpelisib-fulvestrant therapy and were successfully managed with dietary and pharmacologic interventions. These cases provide anecdotal evidence to support the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and very low carbohydrate diets to minimize hyperglycemia during alpelisib therapy.

This study investigated how acute exercise and mindfulness meditation impacts executive functioning and psycho-emotional well-being in 16 children and youth with ADHD aged 10–14 (male = 11; White = 80%). Participants completed three interventions: 10 min of exercise, 10 min of mindfulness meditation, and 10 min of reading (control). Before and after each intervention, executive functioning (inhibitory control, working memory, task-switching) and psycho-emotional well-being (mood, self-efficacy) were assessed. Mindfulness meditation increased performance on all executive functioning tasks whereas the other interventions did not (d = 0.55–0.86). Exercise enhanced positive mood and self-efficacy whereas the other interventions did not (d = 0.22–0.35). This work provides preliminary evidence for how acute exercise and mindfulness meditation can support differential aspects of executive and psycho-emotional functioning among children and youth with ADHD.