Mechanisms of temperature modulation in mammalian seasonal timing

Global warming is predicted to have major effects on the annual time windows during which species may successfully reproduce. At the organismal level, climatic shifts engage with the control mechanism for reproductive seasonality. In mammals, laboratory studies on neuroendocrine mechanism emphasize photoperiod as a predictive cue, but this is based on a restricted group of species. In contrast, field-oriented comparative analyses demonstrate that proximate bioenergetic effects on the reproductive axis are a major determinant of seasonal reproductive timing. The interaction between proximate energetic and predictive photoperiodic cues is neglected. Here, we focused on photoperiodic modulation of postnatal reproductive development in common voles (Microtus arvalis), a herbivorous species in which a plastic timing of breeding is well documented. We demonstrate that temperature-dependent modulation of photoperiodic responses manifest in the thyrotrophin-sensitive tanycytes of the mediobasal hypothalamus. Here, the photoperiod-dependent expression of type 2 deiodinase expression, associated with the summer phenotype was enhanced by 21°C, whereas the photoperiod-dependent expression of type 3 deiodinase expression, associated with the winter phenotype, was enhanced by 10°C in spring voles. Increased levels of testosterone were found at 21°C, whereas somatic and gonadal growth were oppositely affected by temperature. The magnitude of these temperature effects was similar in voles photoperiodical programmed for accelerated maturation (ie, born early in the breeding season) and in voles photoperiodical programmed for delayed maturation (ie, born late in the breeding season). The melatonin-sensitive pars tuberalis was relatively insensitive to temperature. These data define a mechanistic hierarchy for the integration of predictive temporal cues and proximate thermo-energetic effects in mammalian reproduction

Temperature effects on DNA damage during hibernation

During multiday torpor, deep-hibernating mammals maintain a hypometabolic state where heart rate and ventilation are reduced to 2%–4% of euthermic rates. It is hypothesized that this ischemia-like condition may cause DNA damage through reactive oxygen species production. The reason for intermittent rewarming (arousal) during hibernation might be to repair the accumulated DNA dam-age. Because increasing ambient temperatures (Ta’s) shortens torpor bout duration, we hypothesize that hibernating at higher Ta’swill result in a faster accumulation of genomic DNA damage. To test this, we kept 39 male and female garden dormice at a Ta of either 57C or 107C and obtained tissue at 1, 4, and 8 d in torpor to assess DNA damage and recruitment of DNA repair markers in splenocytes. DNA damage in splenocytes measured by comet assay was significantly higher in almost all torpor groups than in sum-mer euthermic groups. Damage accumulates in the first days of torpor at Ta = 57C (between days 1 and 4) but not at Ta = 107C. At the higher Ta, DNA damage is high at 24 h in torpor, indicating either a faster buildup of DNA damage at higher Ta’soranin-complete repair during arousals in dormice. At 57C, recruitment of the DNA repair protein 53BP1 paralleled the increase in DNA damage over time during torpor. In contrast, after 1 d in torpor at 107C, DNA damage levels were high, but 53BP1 was not re-cruited to the nuclear DNA yet. The data suggest a potential mis-match in the DNA damage/repair dynamics during torpor at higher Ta’s.</p

Incidence of hypertension in people with HIV who are treated with integrase inhibitors versus other antiretroviral regimens in the RESPOND cohort consortium.

OBJECTIVE To compare the incidence of hypertension in people living with HIV receiving integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) versus non-nucleoside reverse transcriptase inhibitors (NNRTIs) or boosted protease inhibitors (PIs) in the RESPOND consortium of HIV cohorts. METHODS Eligible people with HIV were aged ≥18 years who initiated a new three-drug ART regimen for the first time (baseline), did not have hypertension, and had at least two follow-up blood pressure (BP) measurements. Hypertension was defined as two consecutive systolic BP measurements ≥140 mmHg and/or diastolic BP ≥90 mmHg or initiation of antihypertensives. Multivariable Poisson regression was used to determine adjusted incidence rate ratios (aIRRs) of hypertension, overall and in those who were ART naïve or experienced at baseline. RESULTS Overall, 4606 people living with HIV were eligible (INSTIs 3164, NNRTIs 807, PIs 635). The median baseline systolic BP, diastolic BP, and age were 120 (interquartile range [IQR] 113-130) mmHg, 78 (70-82) mmHg, and 43 (34-50) years, respectively. Over 8380.4 person-years (median follow-up 1.5 [IQR 1.0-2.7] years), 1058 (23.0%) participants developed hypertension (incidence rate 126.2/1000 person-years, 95% confidence interval [CI] 118.9-134.1). Participants receiving INSTIs had a higher incidence of hypertension than those receiving NNRTIs (aIRR 1.76; 95% CI 1.47-2.11), whereas the incidence was no different in those receiving PIs (aIRR 1.07; 95% CI 0.89-1.29). The results were similar when the analysis was stratified by ART status at baseline. CONCLUSION Although unmeasured confounding and channelling bias cannot be excluded, INSTIs were associated with a higher incidence of hypertension than were NNRTIs, but rates were similar to those of PIs overall, in ART-naïve and ART-experienced participants within RESPOND

Trends in Cancer Incidence in Different Antiretroviral Treatment-Eras amongst People with HIV

Despite cancer being a leading comorbidity amongst individuals with HIV, there are limited data assessing cancer trends across different antiretroviral therapy (ART)-eras. We calculated age-standardised cancer incidence rates (IRs) from 2006-2021 in two international cohort collaborations (D:A:D and RESPOND). Poisson regression was used to assess temporal trends, adjusted for potential confounders. Amongst 64,937 individuals (31% ART-naïve at baseline) and 490,376 total person-years of follow-up (PYFU), there were 3763 incident cancers (IR 7.7/1000 PYFU [95% CI 7.4, 7.9]): 950 AIDS-defining cancers (ADCs), 2813 non-ADCs, 1677 infection-related cancers, 1372 smoking-related cancers, and 719 BMI-related cancers (groups were not mutually exclusive). Age-standardised IRs for overall cancer remained fairly constant over time (8.22/1000 PYFU [7.52, 8.97] in 2006-2007, 7.54 [6.59, 8.59] in 2020-2021). The incidence of ADCs (3.23 [2.79, 3.72], 0.99 [0.67, 1.42]) and infection-related cancers (4.83 [4.2, 5.41], 2.43 [1.90, 3.05]) decreased over time, whilst the incidence of non-ADCs (4.99 [4.44, 5.58], 6.55 [5.67, 7.53]), smoking-related cancers (2.38 [2.01, 2.79], 3.25 [2.63-3.96]), and BMI-related cancers (1.07 [0.83, 1.37], 1.88 [1.42, 2.44]) increased. Trends were similar after adjusting for demographics, comorbidities, HIV-related factors, and ART use. These results highlight the need for better prevention strategies to reduce the incidence of NADCs, smoking-, and BMI-related cancers

Trends in Cancer Incidence in Different Antiretroviral Treatment-Eras amongst People with HIV

Despite cancer being a leading comorbidity amongst individuals with HIV, there are limited data assessing cancer trends across different antiretroviral therapy (ART)-eras. We calculated age-standardised cancer incidence rates (IRs) from 2006–2021 in two international cohort collaborations (D:A:D and RESPOND). Poisson regression was used to assess temporal trends, adjusted for potential confounders. Amongst 64,937 individuals (31% ART-naïve at baseline) and 490,376 total person-years of follow-up (PYFU), there were 3763 incident cancers (IR 7.7/1000 PYFU [95% CI 7.4, 7.9]): 950 AIDS-defining cancers (ADCs), 2813 non-ADCs, 1677 infection-related cancers, 1372 smoking-related cancers, and 719 BMI-related cancers (groups were not mutually exclusive). Age-standardised IRs for overall cancer remained fairly constant over time (8.22/1000 PYFU [7.52, 8.97] in 2006–2007, 7.54 [6.59, 8.59] in 2020–2021). The incidence of ADCs (3.23 [2.79, 3.72], 0.99 [0.67, 1.42]) and infection-related cancers (4.83 [4.2, 5.41], 2.43 [1.90, 3.05]) decreased over time, whilst the incidence of non-ADCs (4.99 [4.44, 5.58], 6.55 [5.67, 7.53]), smoking-related cancers (2.38 [2.01, 2.79], 3.25 [2.63–3.96]), and BMI-related cancers (1.07 [0.83, 1.37], 1.88 [1.42, 2.44]) increased. Trends were similar after adjusting for demographics, comorbidities, HIV-related factors, and ART use. These results highlight the need for better prevention strategies to reduce the incidence of NADCs, smoking-, and BMI-related cancers

Increased Prevalence of Albuminuria in HIV-Infected Adults with Diabetes

HIV and type 2 diabetes are known risk factors for albuminuria, but no previous reports have characterized albuminuria in HIV-infected patients with diabetes.We performed a cross-sectional study including 73 HIV-infected adults with type 2 diabetes, 82 HIV-infected non-diabetics, and 61 diabetic control subjects without HIV. Serum creatinine >1.5 mg/dL was exclusionary. Albuminuria was defined as urinary albumin/creatinine ratio >30 mg/g.The prevalence of albuminuria was significantly increased among HIV-infected diabetics (34% vs. 13% of HIV non-diabetic vs. 16% diabetic control, p = 0.005). HIV status and diabetes remained significant predictors of albuminuria after adjusting for age, race, BMI, and blood pressure. Albumin/creatinine ratio correlated significantly with HIV viral load (r = 0.28, p = 0.0005) and HIV-infected subjects with albuminuria had significantly greater cumulative exposure to abacavir (p = 0.01). In an adjusted multivariate regression analysis of HIV-infected subjects, the diagnosis of diabetes (p = 0.003), higher HIV viral load (p = 0.03) and cumulative exposure to abacavir (p = 0.0009) were significant independent predictors of albuminuria.HIV and diabetes appear to have additive effects on albuminuria which is also independently associated with increased exposure to abacavir and HIV viral load. Future research on the persistence, progression and management of albuminuria in this unique at-risk population is needed

Phylotyping and Functional Analysis of Two Ancient Human Microbiomes

Background: The Human Microbiome Project (HMP) is one of the U.S. National Institutes of Health Roadmap for Medical Research. Primary interests of the HMP include the distinctiveness of different gut microbiomes, the factors influencing microbiome diversity, and the functional redundancies of the members of human microbiotas. In this present work, we contribute to these interests by characterizing two extinct human microbiotas. Methodology/Principal Findings: We examine two paleofecal samples originating from cave deposits in Durango Mexico and dating to approximately 1300 years ago. Contamination control is a serious issue in ancient DNA research; we use a novel approach to control contamination. After we determined that each sample originated from a different human, we generated 45 thousand shotgun DNA sequencing reads. The phylotyping and functional analysis of these reads reveals a signature consistent with the modern gut ecology. Interestingly, inter-individual variability for phenotypes but not functional pathways was observed. The two ancient samples have more similar functional profiles to each other than to a recently published profile for modern humans. This similarity could not be explained by a chance sampling of the databases. Conclusions/Significance: We conduct a phylotyping and functional analysis of ancient human microbiomes, while providing novel methods to control for DNA contamination and novel hypotheses about past microbiome biogeography. We postulate that natural selection has more of an influence on microbiome functional profiles than it does on the species represented in the microbial ecology. We propose that human microbiomes were more geographically structured during pre-Columbian times than today

Differential activation of the frontal pole to high vs low calorie foods: The neural basis of food preference in Anorexia Nervosa?

Neuroimaging studies in anorexia nervosa (AN) suggest that altered food reward processing may result from dysfunction in both limbic reward and cortical control centers of the brain. This fMRI study aimed to index the neural correlates of food reward in a subsample of individuals with restrictive AN: twelve currently ill, fourteen recovered individuals and sixteen healthy controls. Participants were shown pictures of high and low-calorie foods and asked to evaluate how much they wanted to eat each one following a four hour fast. Whole-brain task-activated analysis was followed by psychophysiological interaction analysis (PPI) of the amygdala and caudate. In the AN group, we observed a differential pattern of activation in the lateral frontal pole: increasing following presentation of high-calorie stimuli and decreasing in during presentation of low-calorie food pictures, the opposite of which was seen in the healthy control (HC) group. In addition, decreased activation to food pictures was observed in somatosensory regions in the AN group. PPI analyses suggested hypo-connectivity in reward pathways, and between the caudate and both somatosensory and visual processing regions in the AN group. No significant between-group differences were observed between the recovered group and the currently ill and healthy controls in the PPI analysis. Taken together, these findings further our understanding of the neural processes which may underpin the avoidance of high-calorie foods in those with AN and might exacerbate the development of compulsive weight-loss behavior, despite emaciation

Diagnosis and management of Silver–Russell syndrome: first international consensus statement

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver–Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups