C13orf31 (FAMIN) is a central regulator of immunometabolic function.

Single-nucleotide variations in C13orf31 (LACC1) that encode p.C284R and p.I254V in a protein of unknown function (called 'FAMIN' here) are associated with increased risk for systemic juvenile idiopathic arthritis, leprosy and Crohn's disease. Here we set out to identify the biological mechanism affected by these coding variations. FAMIN formed a complex with fatty acid synthase (FASN) on peroxisomes and promoted flux through de novo lipogenesis to concomitantly drive high levels of fatty-acid oxidation (FAO) and glycolysis and, consequently, ATP regeneration. FAMIN-dependent FAO controlled inflammasome activation, mitochondrial and NADPH-oxidase-dependent production of reactive oxygen species (ROS), and the bactericidal activity of macrophages. As p.I254V and p.C284R resulted in diminished function and loss of function, respectively, FAMIN determined resilience to endotoxin shock. Thus, we have identified a central regulator of the metabolic function and bioenergetic state of macrophages that is under evolutionary selection and determines the risk of inflammatory and infectious disease.

Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes.

Mutations in whole organisms are powerful ways of interrogating gene function in a realistic context. We describe a program, the Sanger Institute Mouse Genetics Project, that provides a step toward the aim of knocking out all genes and screening each line for a broad range of traits. We found that hitherto unpublished genes were as likely to reveal phenotypes as known genes, suggesting that novel genes represent a rich resource for investigating the molecular basis of disease. We found many unexpected phenotypes detected only because we screened for them, emphasizing the value of screening all mutants for a wide range of traits. Haploinsufficiency and pleiotropy were both surprisingly common. Forty-two percent of genes were essential for viability, and these were less likely to have a paralog and more likely to contribute to a protein complex than other genes. Phenotypic data and more than 900 mutants are openly available for further analysis. PAPERCLIP:

A cornucopia of candidates for deafness.

Many genes involved in deafness are yet to be discovered. Here, Senthilan et al. focus on the Drosophila Johnston's organ to uncover a wide variety of genes, including several unexpected candidates as well as those already known to underlie deafness in mice and humans.

Reversal of an existing hearing loss by gene activation in Spns2 mutant mice.

Hearing loss is highly heterogeneous, but one common form involves a failure to maintain the local ionic environment of the sensory hair cells reflected in a reduced endocochlear potential. We used a genetic approach to ask whether this type of pathology can be reversed, using the Spns2tm1a mouse mutant known to show this defect. By activating Spns2 gene transcription at different ages after the onset of hearing loss, we found that an existing auditory impairment can be reversed to give close to normal thresholds for an auditory brainstem response (ABR), at least at low to mid stimulus frequencies. Delaying the activation of Spns2 led to less effective recovery of ABR thresholds, suggesting that there is a critical period for intervention. Early activation of Spns2 not only led to improvement in auditory function but also to protection of sensory hair cells from secondary degeneration. The genetic approach we have used to establish that this type of hearing loss is in principle reversible could be extended to many other diseases using available mouse resources.

Accurate phenotypic classification and exome sequencing allow identification of novel genes and variants associated with adult-onset hearing loss.

Adult-onset progressive hearing loss is a common, complex disease with a strong genetic component. Although to date over 150 genes have been identified as contributing to human hearing loss, many more remain to be discovered, as does most of the underlying genetic diversity. Many different variants have been found to underlie adult-onset hearing loss, but they tend to be rare variants with a high impact upon the gene product. It is likely that combinations of more common, lower impact variants also play a role in the prevalence of the disease. Here we present our exome study of hearing loss in a cohort of 532 older adult volunteers with extensive phenotypic data, including 99 older adults with normal hearing, an important control set. Firstly, we carried out an outlier analysis to identify genes with a high variant load in older adults with hearing loss compared to those with normal hearing. Secondly, we used audiometric threshold data to identify individual variants which appear to contribute to different threshold values. We followed up these analyses in a second cohort. Using these approaches, we identified genes and variants linked to better hearing as well as those linked to worse hearing. These analyses identified some known deafness genes, demonstrating proof of principle of our approach. However, most of the candidate genes are novel associations with hearing loss. While the results support the suggestion that genes responsible for severe deafness may also be involved in milder hearing loss, they also suggest that there are many more genes involved in hearing which remain to be identified. Our candidate gene lists may provide useful starting points for improved diagnosis and drug development.

Neonatal Docosahexaenoic Acid in Preterm Infants and Intelligence at 5 Years.

BACKGROUND: Docosahexaenoic acid (DHA) is a component of neural tissue. Because its accretion into the brain is greatest during the final trimester of pregnancy, infants born before 29 weeks' gestation do not receive the normal supply of DHA. The effect of this deficiency on subsequent cognitive development is not well understood. METHODS: We assessed general intelligence at 5 years in children who had been enrolled in a trial of neonatal DHA supplementation to prevent bronchopulmonary dysplasia. In the previous trial, infants born before 29 weeks' gestation had been randomly assigned in a 1:1 ratio to receive an enteral emulsion that provided 60 mg of DHA per kilogram of body weight per day or a control emulsion from the first 3 days of enteral feeds until 36 weeks of postmenstrual age or discharge home, whichever occurred first. Children from 5 of the 13 centers in the original trial were invited to undergo assessment with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) at 5 years of corrected age. The primary outcome was the full-scale intelligence quotient (FSIQ) score. Secondary outcomes included the components of WPPSI. RESULTS: A total of 1273 infants underwent randomization in the original trial; of the 656 surviving children who had undergone randomization at the centers included in this follow-up study, 480 (73%) had an FSIQ score available - 241 in the DHA group and 239 in the control group. After imputation of missing data, the mean (±SD) FSIQ scores were 95.4±17.3 in the DHA group and 91.9±19.1 in the control group (adjusted difference, 3.45; 95% confidence interval, 0.38 to 6.53; P = 0.03). The results for secondary outcomes generally did not support that obtained for the primary outcome. Adverse events were similar in the two groups. CONCLUSIONS: In infants born before 29 weeks' gestation who had been enrolled in a trial to assess the effect of DHA supplementation on bronchopulmonary dysplasia, the use of an enteral DHA emulsion until 36 weeks of postmenstrual age was associated with modestly higher FSIQ scores at 5 years of age than control feeding. (Funded by the Australian National Health and Medical Research Council and Nu-Mega Ingredients; N3RO Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820.).

Efficacy of a Dual-Epitope Dendritic Cell Vaccine as Part of Combined Immunotherapy for HER2-Expressing Breast Tumors.

Previous work from our group and others has shown that patients with breast cancer can generate a T cell response against specific human epidermal growth factor 2 (HER2) epitopes. In addition, preclinical work has shown that this T cell response can be augmented by Ag-directed mAb therapy. This study evaluated the activity and safety of a combination of dendritic cell (DC) vaccination given with mAb and cytotoxic therapy. We performed a phase I/II study using autologous DCs pulsed with two different HER2 peptides given with trastuzumab and vinorelbine to a study cohort of patients with HER2-overexpressing and a second with HER2 nonoverexpressing metastatic breast cancer. Seventeen patients with HER2-overexpressing and seven with nonoverexpressing disease were treated. Treatment was well tolerated, with one patient removed from therapy because of toxicity and no deaths. Forty-six percent of patients had stable disease after therapy, with 4% achieving a partial response and no complete responses. Immune responses were generated in the majority of patients but did not correlate with clinical response. However, in one patient, who has survived >14 y since treatment in the trial, a robust immune response was demonstrated, with 25% of her T cells specific to one of the peptides in the vaccine at the peak of her response. These data suggest that autologous DC vaccination when given with anti-HER2-directed mAb therapy and vinorelbine is safe and can induce immune responses, including significant T cell clonal expansion, in a subset of patients.

Cohesin is required for meiotic spindle assembly independent of its role in cohesion in C. elegans.

Accurate chromosome segregation requires a cohesin-mediated physical attachment between chromosomes that are to be segregated apart, and a bipolar spindle with microtubule plus ends emanating from exactly two poles toward the paired chromosomes. We asked whether the striking bipolar structure of C. elegans meiotic chromosomes is required for bipolarity of acentriolar female meiotic spindles by time-lapse imaging of mutants that lack cohesion between chromosomes. Both a spo-11 rec-8 coh-4 coh-3 quadruple mutant and a spo-11 rec-8 double mutant entered M phase with separated sister chromatids lacking any cohesion. However, the quadruple mutant formed an apolar spindle whereas the double mutant formed a bipolar spindle that segregated chromatids into two roughly equal masses. Residual non-cohesive COH-3/4-dependent cohesin on separated sister chromatids of the double mutant was sufficient to recruit haspin-dependent Aurora B kinase, which mediated bipolar spindle assembly in the apparent absence of chromosomal bipolarity. We hypothesized that cohesin-dependent Aurora B might activate or inhibit spindle assembly factors in a manner that would affect their localization on chromosomes and found that the chromosomal localization patterns of KLP-7 and CLS-2 correlated with Aurora B loading on chromosomes. These results demonstrate that cohesin is essential for spindle assembly and chromosome segregation independent of its role in sister chromatid cohesion.

Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice.

Discovery of deafness genes and elucidating their functions have substantially contributed to our understanding of hearing physiology and its pathologies. Here we report on DNA variants in MINAR2, encoding membrane integral NOTCH2-associated receptor 2, in four families underlying autosomal recessive nonsyndromic deafness. Neurologic evaluation of affected individuals at ages ranging from 4 to 80 y old does not show additional abnormalities. MINAR2 is a recently annotated gene with limited functional understanding. We detected three MINAR2 variants, c.144G > A (p.Trp48*), c.412_419delCGGTTTTG (p.Arg138Valfs*10), and c.393G > T, in 13 individuals with congenital- or prelingual-onset severe-to-profound sensorineural hearing loss (HL). The c.393G > T variant is shown to disrupt a splice donor site. We show that Minar2 is expressed in the mouse inner ear, with the protein localizing mainly in the hair cells, spiral ganglia, the spiral limbus, and the stria vascularis. Mice with loss of function of the Minar2 protein (Minar2tm1b/tm1b) present with rapidly progressive sensorineural HL associated with a reduction in outer hair cell stereocilia in the shortest row and degeneration of hair cells at a later age. We conclude that MINAR2 is essential for hearing in humans and mice and its disruption leads to sensorineural HL. Progressive HL observed in mice and in some affected individuals and as well as relative preservation of hair cells provides an opportunity to interfere with HL using genetic therapies.

Management of Acute Coronary Syndrome in the Older Adult Population: A Scientific Statement From the American Heart Association.

Diagnostic and therapeutic advances during the past decades have substantially improved health outcomes for patients with acute coronary syndrome. Both age-related physiological changes and accumulated cardiovascular risk factors increase the susceptibility to acute coronary syndrome over a lifetime. Compared with younger patients, outcomes for acute coronary syndrome in the large and growing demographic of older adults are relatively worse. Increased atherosclerotic plaque burden and complexity of anatomic disease, compounded by age-related cardiovascular and noncardiovascular comorbid conditions, contribute to the worse prognosis observed in older individuals. Geriatric syndromes, including frailty, multimorbidity, impaired cognitive and physical function, polypharmacy, and other complexities of care, can undermine the therapeutic efficacy of guidelines-based treatments and the resiliency of older adults to survive and recover, as well. In this American Heart Association scientific statement, we (1) review age-related physiological changes that predispose to acute coronary syndrome and management complexity; (2) describe the influence of commonly encountered geriatric syndromes on cardiovascular disease outcomes; and (3) recommend age-appropriate and guideline-concordant revascularization and acute coronary syndrome management strategies, including transitions of care, the use of cardiac rehabilitation, palliative care services, and holistic approaches. The primacy of individualized risk assessment and patient-centered care decision-making is highlighted throughout.

Sarcopenia and Cardiovascular Diseases.

Sarcopenia is the loss of muscle strength, mass, and function, which is often exacerbated by chronic comorbidities including cardiovascular diseases, chronic kidney disease, and cancer. Sarcopenia is associated with faster progression of cardiovascular diseases and higher risk of mortality, falls, and reduced quality of life, particularly among older adults. Although the pathophysiologic mechanisms are complex, the broad underlying cause of sarcopenia includes an imbalance between anabolic and catabolic muscle homeostasis with or without neuronal degeneration. The intrinsic molecular mechanisms of aging, chronic illness, malnutrition, and immobility are associated with the development of sarcopenia. Screening and testing for sarcopenia may be particularly important among those with chronic disease states. Early recognition of sarcopenia is important because it can provide an opportunity for interventions to reverse or delay the progression of muscle disorder, which may ultimately impact cardiovascular outcomes. Relying on body mass index is not useful for screening because many patients will have sarcopenic obesity, a particularly important phenotype among older cardiac patients. In this review, we aimed to: (1) provide a definition of sarcopenia within the context of muscle wasting disorders; (2) summarize the associations between sarcopenia and different cardiovascular diseases; (3) highlight an approach for a diagnostic evaluation; (4) discuss management strategies for sarcopenia; and (5) outline key gaps in knowledge with implications for the future of the field.

A novel role for endoplasmic reticulum protein 46 (ERp46) in platelet function and arterial thrombosis in mice.

Although several members of protein disulfide isomerase (PDI) family support thrombosis, other PDI family members with the CXYC motif remain uninvestigated. ERp46 has 3 CGHC redox-active sites and a radically different molecular architecture than other PDIs. Expression of ERp46 on the platelet surface increased with thrombin stimulation. An anti-ERp46 antibody inhibited platelet aggregation, adenosine triphosphate (ATP) release, and αIIbß3 activation. ERp46 protein potentiated αIIbß3 activation, platelet aggregation, and ATP release, whereas inactive ERp46 inhibited these processes. ERp46 knockout mice had prolonged tail-bleeding times and decreased platelet accumulation in thrombosis models that was rescued by infusion of ERp46. ERp46-deficient platelets had decreased αIIbß3 activation, platelet aggregation, ATP release, and P-selectin expression. The defects were reversed by wild-type ERp46 and partially reversed by ERp46 containing any of the 3 active sites. Platelet aggregation stimulated by an αIIbß3-activating peptide was inhibited by the anti-ERp46 antibody and was decreased in ERp46-deficient platelets. ERp46 bound tightly to αIIbß3 by surface plasmon resonance but poorly to platelets lacking αIIbß3 and physically associated with αIIbß3 upon platelet activation. ERp46 mediated clot retraction and platelet spreading. ERp46 more strongly reduced disulfide bonds in the ß3 subunit than other PDIs and in contrast to PDI, generated thiols in ß3 independently of fibrinogen. ERp46 cleaved the Cys473-Cys503 disulfide bond in ß3, implicating a target for ERp46. Finally, ERp46-deficient platelets have decreased thiols in ß3, implying that ERp46 cleaves disulfide bonds in platelets. In conclusion, ERp46 is critical for platelet function and thrombosis and facilitates αIIbß3 activation by targeting disulfide bonds.

Advances and knowledge gaps on climate change impacts on honey bees and beekeeping: A systematic review.

The Western honey bee Apis mellifera is a managed species that provides diverse hive products and contributing to wild plant pollination, as well as being a critical component of crop pollination systems worldwide. High mortality rates have been reported in different continents attributed to different factors, including pesticides, pests, diseases, and lack of floral resources. Furthermore, climate change has been identified as a potential driver negatively impacting pollinators, but it is still unclear how it could affect honey bee populations. In this context, we carried out a systematic review to synthesize the effects of climate change on honey bees and beekeeping activities. A total of 90 articles were identified, providing insight into potential impacts (negative, neutral, and positive) on honey bees and beekeeping. Interest in climate change's impact on honey bees has increased in the last decade, with studies mainly focusing on honey bee individuals, using empirical and experimental approaches, and performed at short-spatial (<10 km) and temporal (<5 years) scales. Moreover, environmental analyses were mainly based on short-term data (weather) and concentrated on only a few countries. Environmental variables such as temperature, precipitation, and wind were widely studied and had generalized negative effects on different biological and ecological aspects of honey bees. Food reserves, plant-pollinator networks, mortality, gene expression, and metabolism were negatively impacted. Knowledge gaps included a lack of studies at the apiary and beekeeper level, a limited number of predictive and perception studies, poor representation of large-spatial and mid-term scales, a lack of climate analysis, and a poor understanding of the potential impacts of pests and diseases. Finally, climate change's impacts on global beekeeping are still an emergent issue. This is mainly due to their diverse effects on honey bees and the potential necessity of implementing adaptation measures to sustain this activity under complex environmental scenarios.

La abeja occidental Apis mellifera es una especie manejada que proporciona diversos productos de la colmena y servicios de polinización, los cuales son cruciales para plantas silvestres y cultivos en todo el mundo. En distintos continentes se han registrado altas tasas de mortalidad, las cuales son atribuidas a diversos factores, como el uso de pesticidas, plagas, enfermedades y falta de recursos florales. Además, el cambio climático ha sido identificado como un potencial factor que afecta negativamente a los polinizadores, pero aún no está claro cómo podría afectar a las poblaciones de abejas melíferas. En este contexto, realizamos una revisión sistemática de la literatura disponible para sintetizar los efectos del cambio climático en las abejas melíferas y las actividades apícolas. En total, se identificaron 90 artículos que proporcionaron información sobre los posibles efectos (negativos, neutros y positivos) en las abejas melíferas y la apicultura. El interés por el impacto del cambio climático en las abejas melíferas ha aumentado en la última década, con estudios centrados principalmente en individuos de abejas melíferas, utilizando enfoques empíricos y experimentales y realizados a escalas espaciales (<10 km) y temporales (<5 años) cortas. Además, los análisis ambientales fueron basaron principalmente en datos a corto plazo (meteorológicos) y se concentraron sólo en algunos países. Variables ambientales como la temperatura, las precipitaciones y el viento fueron ampliamente estudiadas y tuvieron efectos negativos generalizados sobre distintos aspectos biológicos y ecológicos de las abejas melíferas. Además, las reservas alimenticias, las interacciones planta-polinizador, la mortalidad, la expresión génica y el metabolismo se vieron afectados negativamente. Entre los vacios de conocimiento cabe mencionar la falta de estudios a nivel de colmenar y apicultor, la escasez de estudios de predicción y percepción, la escasa representación de las grandes escalas espaciales y a mediano plazo, el déficit de análisis climáticos y la escasa comprensión de los impactos potenciales de plagas y enfermedades. Por último, las repercusiones del cambio climático en la apicultura mundial siguen siendo un tema emergente, que debe estudiarse en los distintos países. Esto se debe principalmente a sus diversos efectos sobre las abejas melíferas y a la necesidad potencial de aplicar medidas de adaptación para mantener esta actividad crucial en escenarios medioambientales complejos.

Too Much Too Little: Clarifying the Relationship Between Maternal Iodine Intake and Neurodevelopmental Outcomes.

BACKGROUND: In 2009, the Australian government mandated the fortification of bread salt with iodine. In 2010, pregnant and lactating women were also advised to take an iodine-containing supplement. Our assessment of this policy in an iodine-sufficient population showed that children whose mothers were in the highest and lowest quartiles of iodine intake performed more poorly on early childhood tests of cognition and language than those in the second quartile. However, we did not quantify the iodine intake associated with optimal neurodevelopment. OBJECTIVES: The aim was to establish the iodine intake range in pregnancy associated with optimal child neurodevelopment. METHODS: A prospective cohort study of pregnant women and their young children (n = 699). Iodine intake was assessed by a validated food frequency questionnaire at 16 and 28 wk of gestation. Child neurodevelopment at 18 mo of age was measured using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). The relationship between average iodine intake during pregnancy and child neurodevelopment was assessed using linear regression with fractional polynomials and adjustment for confounders. RESULTS: Mean (SD) iodine intake was similar at study entry and 28 wk, 308 (120) µg/d, with 82% of women taking iodine supplements at study entry. The relationship between iodine intake during pregnancy and Bayley-III cognitive and language scores was curvilinear (P = 0.001 and P = 0.004, respectively), with the lowest Bayley-III scores observed at lower and higher iodine intakes. The inflection point that drove the association between lower iodine intake in pregnancy and poorer child neurodevelopment scores was around 185 µg/d; for the higher pregnancy iodine intakes, language and cognitive scores were negatively affected from ∼350 µg/d to 370 µg/d, respectively. Higher iodine intakes were being driven by supplement use. CONCLUSIONS: Targeted, not blanket, iodine supplementation may be needed for pregnant women with low-iodine intake from food.

The Effect of Iron Supplements on the Gut Microbiome of Females of Reproductive Age: A Randomized Controlled Trial.

BACKGROUND: Iron deficiency is the most common nutritional deficiency worldwide, particularly for young children and females of reproductive age. Although oral iron supplements are routinely recommended and generally considered safe, iron supplementation has been shown to alter the fecal microbiota in low-income countries. Little is known about the effect of iron supplementation on the fecal microbiota in high-income settings. OBJECTIVES: To assess the effect of oral iron supplementation compared with placebo on the gut microbiome in nonpregnant females of reproductive age in a high-income country. METHODS: A 21-d prospective parallel design double-blind, randomized control trial conducted in South Australia, Australia. Females (18-45 y) were randomly assigned to either iron (65.7 mg ferrous fumarate) or placebo. Fecal samples were collected prior to commencing supplements and after 21 d of supplementation. The primary outcome was microbiota ß-diversity (paired-sample weighted unique fraction metric dissimilarity) between treatment and placebo groups after 21 d of supplementation. Exploratory outcomes included changes in the relative abundance of bacterial taxa. RESULTS: Of 82 females randomly assigned, 80 completed the trial. There was no significant difference between the groups for weighted unique fraction metric dissimilarity (mean difference: 0.003; 95% confidence interval: -0.007, 0.014; P = 0.52) or relative abundance of common bacterial taxa or Escherichia-Shigella (q > 0.05). CONCLUSIONS: Iron supplementation did not affect the microbiome of nonpregnant females of reproductive age in Australia. This trial was registered at clinicaltrials.gov as NCT05033483.

Predictors of outcomes after PCI with incomplete revascularization: Impact of CTO and LAD vessel.

BACKGROUND: Incomplete revascularization (ICR) after percutaneous coronary intervention (PCI) is associated with mortality and morbidity. AIM: We sought to investigate whether ICR in the left anterior descending artery (LAD) is worse than ICR of the right coronary artery (RCA) or left circumflex artery (LCX); and whether ICR in patients with a chronic total occlusion (CTO) is worse than in those without. METHODS: In the RIVER-PCI trial, 2651 patients with ICR after PCI were randomly assigned to ranolazine or placebo. Angiograms were assessed at an independent core laboratory in 2501 patients (94.3%). The primary endpoint was the composite of ischemia-driven revascularization or hospitalization. RESULTS: A total of 1664 patients (66.5%) had ICR involving the LAD, whereas 837 (33.5%) had ICR limited to the RCA or LCX. At median follow-up of 643 days, the primary endpoint occurred in 26.9% versus 26.5% of patients (adjusted HR [aHR]: 1.03, 95% confidence interval [CI]: 0.88-1.21). A nonrecanalized CTO was present in 854 patients (34.1%) with ICR after PCI. The primary endpoint occurred in 28.6% versus 25.9% of ICR patients with versus without a CTO (aHR: 1.10, 95% CI: 0.94-1.29). However, patients with a CTO had higher rates of ischemia-driven hospitalization without revascularization (aHR: 1.27, 95% CI: 1.04-1.56), heart failure hospitalization (aHR: 2.69, 95% CI: 1.61-4.59) and myocardial infarction (aHR: 1.46, 95% CI: 1.11-1.92) compared with those without. CONCLUSIONS: The 2-year prognosis was similar in post-PCI patients with ICR whether the LAD was versus was not involved. ICR patients with a CTO had more frequent hospitalizations for ischemia and myocardial infarctions compared with those without.

Physical and psychological distress amongst patients undergoing neoadjuvant chemotherapy for advanced ovarian cancer.

OBJECTIVE: This study compares baseline clinical characteristics, physical function testing, and patient-reported outcomes for patients undergoing primary cytoreductive surgery versus neoadjuvant chemotherapy, with the goal of better understanding unique patient needs at diagnosis. METHODS: Patients with suspected advanced stage (IIIC/IV) epithelial ovarian cancer undergoing either primary cytoreductive surgery or neoadjuvant chemotherapy were enrolled in a single-institution, non-randomized prospective behavioral intervention trial of prehabilitation. Baseline clinical characteristics were abstracted. Physical function was evaluated using the Short Physical Performance Battery, Fried Frailty Index, gait speed, and grip strength. Patient-reported outcomes were evaluated using Patient-Reported Outcomes Measurement Information System metrics and the Perceived Stress Scale. RESULTS: There were no significant differences in demographics or clinical characteristics between cohorts at enrollment, with the exception of performance status, clinical stage, and albumin. While gait speed and grip strength were lower amongst neoadjuvant chemotherapy patients, there were no significant differences in physical function using the Short Physical Performance Battery and Fried Frailty Index. Patients in the neoadjuvant chemotherapy cohort reported decreased perception of physical function and increased fatigue on Patient-Reported Outcomes Measurement Information System metrics. A larger proportion of patients in the neoadjuvant cohort reported severe levels of emotional distress and anxiety, as well as greater perceived stress at diagnosis. CONCLUSIONS: Our findings suggest that patients undergoing neoadjuvant chemotherapy for advanced ovarian cancer present with increased psychosocial distress and decreased perception of physical function at diagnosis and may benefit most from early introduction of supportive care.

Differential G Protein-Coupled Estrogen Receptor-1 Regulation of Counter-Regulatory Transmitter Marker and 5'-AMP-Activated Protein Kinase Expression in Ventrolateral versus Dorsomedial Ventromedial Hypothalamic Nucleus.

INTRODUCTION: The ventromedial hypothalamic nucleus (VMN) is an estrogen receptor (ER)-rich structure that regulates glucostasis. The role of nuclear but not membrane G protein-coupled ER-1 (GPER) in that function has been studied. METHODS: Gene silencing and laser-catapult microdissection/immunoblot tools were used to examine whether GPER regulates transmitter and energy sensor function in dorsomedial (VMNdm) and/or ventrolateral (VMNvl) VMN counter-regulatory nitrergic and γ-Aminobutyric acid (GABA) neurons. RESULTS: Intra-VMN GPER siRNA administration to euglycemic animals did not affect VMNdm or -vl nitrergic neuron nitric oxide synthase (nNOS), but upregulated (VMNdm) or lacked influence on (VMNvl) GABA nerve cell glutamate decarboxylase65/67 (GAD) protein. Insulin-induced hypoglycemia (IIH) caused GPER knockdown-reversible augmentation of nNOS, 5'-AMP-activated protein kinase (AMPK), and phospho-AMPK proteins in nitrergic neurons in both divisions. IIH had dissimilar effects on VMNvl (unchanged) versus VMNdm (increased) GABAergic neuron GAD levels, yet GPER knockdown affected these profiles. GPER siRNA prevented hypoglycemic upregulation of VMNvl and -dm GABA neuron AMPK without altering pAMPK expression. CONCLUSIONS: Outcomes infer that GPER exerts differential control of VMNdm versus -vl GABA transmission during glucostasis and is required for hypoglycemic upregulated nitrergic (VMNdm and -vl) and GABA (VMNdm) signaling. Glycogen metabolism is reported to regulate VMN nNOS and GAD proteins. Data show that GPER limits VMNvl glycogen phosphorylase (GP) protein expression and glycogen buildup during euglycemia but mediates hypoglycemic augmentation of VMNvl GP protein and glycogen content; VMNdm glycogen mass is refractory to GPER control. GPER regulation of VMNvl glycogen metabolism infers that this receptor may govern local counter-regulatory transmission in part by astrocyte metabolic coupling.

Neutral vs. non-neutral genetic footprints of Plasmodium falciparum multiclonal infections.

At a time when effective tools for monitoring malaria control and eradication efforts are crucial, the increasing availability of molecular data motivates their application to epidemiology. The multiplicity of infection (MOI), defined as the number of genetically distinct parasite strains co-infecting a host, is one key epidemiological parameter for evaluating malaria interventions. Estimating MOI remains a challenge for high-transmission settings where individuals typically carry multiple co-occurring infections. Several quantitative approaches have been developed to estimate MOI, including two cost-effective ones relying on molecular data: i) THE REAL McCOIL method is based on putatively neutral single nucleotide polymorphism loci, and ii) the varcoding method is a fingerprinting approach that relies on the diversity and limited repertoire overlap of the var multigene family encoding the major Plasmodium falciparum blood-stage antigen PfEMP1 and is therefore under selection. In this study, we assess the robustness of the MOI estimates generated with these two approaches by simulating P. falciparum malaria dynamics under three transmission conditions using an extension of a previously developed stochastic agent-based model. We demonstrate that these approaches are complementary and best considered across distinct transmission intensities. While varcoding can underestimate MOI, it allows robust estimation, especially under high transmission where repertoire overlap is extremely limited from frequency-dependent selection. In contrast, THE REAL McCOIL often considerably overestimates MOI, but still provides reasonable estimates for low and moderate transmission. Regardless of transmission intensity, results for THE REAL McCOIL indicate that an inaccurate tail at high MOI values is generated, and that at high transmission, an apparently reasonable estimated MOI distribution can arise from some degree of compensation between overestimation and underestimation. As many countries pursue malaria elimination targets, defining the most suitable approach to estimate MOI based on sample size and local transmission intensity is highly recommended for monitoring the impact of intervention programs.

Mindfulness-Based Stress Reduction for Symptom Management in Older Individuals with HIV-Associated Neurocognitive Disorder.

The growing number of people aging with HIV represents a group vulnerable to the symptom burdens of HIV-associated neurocognitive disorder (HAND). Among younger groups, Mindfulness-Based Stress Reduction (MBSR) has been shown to help people living with HIV manage HIV-related and other life stress, and although there is some theoretical and empirical evidence that it may be effective among those with cognitive deficits, the approach has not been studied in older populations with HAND. Participants (n = 180) 55 years or older with HIV and cognitive impairment were randomly assigned to either an 8-week MBSR arm or a waitlist control. We assessed the impact of MBSR compared to a waitlist control on psychological outcomes [stress, anxiety, depression, and quality of life (QOL)] and cognitive metrics (e.g., speed of information processing, working memory, attention, impulsivity) measured at baseline, immediately post intervention (8 weeks) and one month later (16 weeks). Intent to treat analyses showed significant improvement in the MBSR group compared to control on symptoms of depression from baseline to 8 weeks, however, the difference was not sustained at 16 weeks. The MBSR group also showed improvement in perceived QOL from baseline to 16 weeks compared to the waitlist control group. Cognitive performance did not differ between the two treatment arms. MBSR shows promise as a tool to help alleviate the symptom burden of depression and low QOL in older individuals living with HAND and future work should address methods to better sustain the beneficial impact on depression and QOL.