The thienopyridine A-769662 and benzimidazole 991 inhibit human TASK-3 potassium channels in an AMPK-independent manner.

Heteromeric Tandem pore domain Acid Sensitive (TASK)-1/3 channels are critical to oxygen-sensing by carotid body type 1 cells, where hypoxia-induced inhibition of TASK-3 and/or TASK-1/3 potassium currents leads to voltage-gated calcium entry, exocytotic transmitter release and increases in carotid body afferent input responses that initiate corrective changes in breathing patterns. It was proposed that, in response to hypoxia, the AMP-activated protein kinase (AMPK) might directly phosphorylate and inhibit TASK channels, in particular TASK-3, but studies on rat type I cells questioned this view. However, sequence alignment identified a putative AMPK recognition motif in human (h) TASK-3, but not hTASK-1, with Ser55 representing a potential phosphorylation site. We therefore studied the effects of five different AMPK activators on recombinant hTASK-3 potassium channels expressed in human embryonic kidney (HEK)-293 cells. Two structurally unrelated AMPK activators, the thienopyridine A-769662 (100-500 µM) and the benzimidazole 991 (3-30 µM) inhibited hTASK-3 currents in a concentration-dependent manner, while the 4-azabenzimidazole MK-8722 (3-30 µM) partially inhibited hTASK-3 at concentrations above those required for maximal AMPK activation. By contrast, the 4-azabenzimidazole, BI-9774 (10-100 µM; a closely related analogue of MK8722) and the pro-drug AICA-riboside (1 mM; metabolised to ZMP, an AMP-mimetic) had no significant effect on hTASK-3 currents at concentrations sufficient to maximally activate AMPK. Importantly, A-769662 (300 µM) also inhibited hTASK-3 channel currents in HEK-293 cells that stably over-expressed an AMPK-ß1 subunit mutant (S108A) that renders AMPK insensitive to activators that bind to the Allosteric Drug and Metabolite site, such as A-769662. We therefore identify A-769662 and 991 as novel hTASK-3 channel inhibitors and provide conclusive evidence that AMPK does not regulate hTASK-3 channel currents.

"I must make the grade!": the role of cognitive appraisals, irrational beliefs, exam anxiety, and affect, in the academic self-concept of undergraduate students.

BACKGROUND AND OBJECTIVES: Examination anxiety is a common occurrence, and is potentially detrimental to student attainment. In recent theorizing, it has been suggested that cognitive appraisals, as put forth in cognitive appraisal theory, and irrational beliefs, as put forth in rational emotive behavior therapy, may interact to predict affectivity. The current research examines the antecedents and associates of examination affect and academic self-concept in undergraduate students. DESIGN: A preliminary study applied confirmatory factor analysis (CFA) to test the factor structure of an irrational beliefs inventory. Study 1 utilized a cross-sectional and correlational approach to testing core theoretical assumptions. Study 2 took a two-wave longitudinal and path analytical approach to examine temporal effects between target variables. METHOD: All self-report data collection took place in the United Kingdom with university students. We recruited n = 1150, n = 362, n = 662 for preliminary, study 1, and study 2, respectively. RESULTS: Across studies, data indicated that a pattern of adaptive cognitive appraisal was associated with more advantageous affectivity, and better academic self-concept. CONCLUSIONS: Reciprocal temporal relationships were revealed between many variables, supporting an interactive and bidirectional view of how cognition and affect are related pertaining to examination anxiety.

Injection-induced basement seismicity beneath the Raton Basin: constraints from refined fault architectures and basin structure.

Intraplate earthquakes induced by anthropogenic fluid injection present unexpected seismic risk to previously quiescent or low seismicity-rate regions. Despite many studies of induced seismicity, there are relatively few with detailed openly accessible constraints on the interaction between seismic sources and subsurface structures. In this study of the Raton Basin, we refine source observations from a dense nodal array and constrain basin structure using teleseismic receiver functions. The cross-correlation-based relocated hypocentres and a new set of focal mechanisms light up active fault segments and show clear spatiotemporal patterns. The geometric complexity of reactivated fault clusters appears greatest near higher rate injection wells. Simpler normal fault structure is found farther from injection wells and near abrupt structural transitions suggested by receiver functions. While less induced seismicity in the crystalline basement is expected when injection is >1 km from the top of the basement (like Raton), our receiver function analysis identified a basin thickness ~3 km beneath the nodal array and lateral variations in sedimentary structures. Our results explain potential fluid connectivity between the injection depths focused at ~1-1.5 km below the surface and basement fault activity that begins at ~3 km and reaches peak activity at ~4-8 km depths. This article is part of the theme issue 'Induced seismicity in coupled subsurface systems'.

SubSol-HIe is an AMPK-dependent hypoxia-responsive subnucleus of the nucleus tractus solitarius that coordinates the hypoxic ventilatory response and protects against apnoea in mice.

Functional magnetic resonance imaging (fMRI) suggests that the hypoxic ventilatory response is facilitated by the AMP-activated protein kinase (AMPK), not at the carotid bodies, but within a subnucleus (Bregma -7.5 to -7.1 mm) of the nucleus tractus solitarius that exhibits right-sided bilateral asymmetry. Here, we map this subnucleus using cFos expression as a surrogate for neuronal activation and mice in which the genes encoding the AMPK-α1 (Prkaa1) and AMPK-α2 (Prkaa2) catalytic subunits were deleted in catecholaminergic cells by Cre expression via the tyrosine hydroxylase promoter. Comparative analysis of brainstem sections, relative to controls, revealed that AMPK-α1/α2 deletion inhibited, with right-sided bilateral asymmetry, cFos expression in and thus activation of a neuronal cluster that partially spanned three interconnected anatomical nuclei adjacent to the area postrema: SolDL (Bregma -7.44 mm to -7.48 mm), SolDM (Bregma -7.44 mm to -7.48 mm) and SubP (Bregma -7.48 mm to -7.56 mm). This approximates the volume identified by fMRI. Moreover, these nuclei are known to be in receipt of carotid body afferent inputs, and catecholaminergic neurons of SubP and SolDL innervate aspects of the ventrolateral medulla responsible for respiratory rhythmogenesis. Accordingly, AMPK-α1/α2 deletion attenuated hypoxia-evoked increases in minute ventilation (normalised to metabolism), reductions in expiration time, and increases sigh frequency, but increased apnoea frequency during hypoxia. The metabolic response to hypoxia in AMPK-α1/α2 knockout mice and the brainstem and spinal cord catecholamine levels were equivalent to controls. We conclude that within the brainstem an AMPK-dependent, hypoxia-responsive subnucleus partially spans SubP, SolDM and SolDL, namely SubSol-HIe, and is critical to coordination of active expiration, the hypoxic ventilatory response and defence against apnoea.

Association between diet quality and risk of stunting among school-aged children in Schistosoma mansoni endemic area of western Kenya: a cross-sectional study.

BACKGROUND: Healthy eating habits are essential for improving nutritional status and strengthening immunity against infectious diseases. This study examined the relationship between diet quality and stunting in school-aged children in an infectious disease-endemic area of western Kenya. METHODS: This cross-sectional study included 260 school-aged children (age 9-17 years) enrolled in primary schools in Mbita Sub-county, western Kenya. The nutritional status was assessed using anthropometric measurements. Dietary intake was measured using food frequency questionnaires and evaluated using the Food Pyramid (FP) score, which indicates adherence to the Kenyan food-based dietary guideline. Information on the children's age, sex, maternal education, and household wealth index was collected using a household-based questionnaire. Infections with the predominant parasites, such as Schistosoma (S.) mansoni, were detected via microscopy. The trend associations of the FP score with food group intake were examined to characterize the dietary intake of this population. Logistic regression analysis was performed to investigate the relationship between stunting and FP score tertiles, adjusted for sociodemographic and economic indicators and parasitic infection status. RESULTS: Among the studied schoolchildren, 15.0% exhibited stunting, while 76.2% were infected with S. mansoni. The mean FP score was 25.6 out of 50 points. A higher FP score was characterized by a high intake of roots and tubers, dairy products, pulses, and fruits and a low intake of cereals and animal-source foods. The analysis revealed a trend: a lower risk of stunting was evident in groups with elevated FP scores (p for trend = 0.065). However, these trend associations were observable among subjects with either negative or light S. mansoni infection (p for trend = 0.016). CONCLUSIONS: A higher quality diet, as evaluated by FP scores, was associated with a low risk of stunting among school-aged children. Notably, this association seemed to weaken in the presence of a high burden of S. mansoni infection. It highlights the importance of enhancing dietary quality through the promotion of diverse nutrient-dense foods alongside effective S. mansoni infection control for improved growth. This study contributes fundamental knowledge for understanding the diet-malnutrition relationship in areas endemic for S. mansoni infection.

Observation of the effect of gravity on the motion of antimatter.

Einstein's general theory of relativity from 19151 remains the most successful description of gravitation. From the 1919 solar eclipse2 to the observation of gravitational waves3, the theory has passed many crucial experimental tests. However, the evolving concepts of dark matter and dark energy illustrate that there is much to be learned about the gravitating content of the universe. Singularities in the general theory of relativity and the lack of a quantum theory of gravity suggest that our picture is incomplete. It is thus prudent to explore gravity in exotic physical systems. Antimatter was unknown to Einstein in 1915. Dirac's theory4 appeared in 1928; the positron was observed5 in 1932. There has since been much speculation about gravity and antimatter. The theoretical consensus is that any laboratory mass must be attracted6 by the Earth, although some authors have considered the cosmological consequences if antimatter should be repelled by matter7-10. In the general theory of relativity, the weak equivalence principle (WEP) requires that all masses react identically to gravity, independent of their internal structure. Here we show that antihydrogen atoms, released from magnetic confinement in the ALPHA-g apparatus, behave in a way consistent with gravitational attraction to the Earth. Repulsive 'antigravity' is ruled out in this case. This experiment paves the way for precision studies of the magnitude of the gravitational acceleration between anti-atoms and the Earth to test the WEP.

Review: The ovarian follicular reserve - implications for fertility in ruminants.

Ruminants are born with a finite number of healthy ovarian follicles and oocytes (ovarian reserve) and germ cell proliferation in the developing foetal gonad predominantly occurs during early gestation. Two markers have been established to reliably estimate the size of the ovarian reserve in cattle: the number of antral follicles ≤3 mm in diameter recruited per follicular wave (Antral Follicle Count, AFC) and peripheral concentrations of the Anti-Müllerian hormone (AMH). Studies that used one or both indicators show that the size of ovarian reserve varies greatly among age-matched individuals, but is highly repeatable in the same animal. Conditions during prenatal life are likely among the causes of such variation in the ovarian reserve. In addition, the size of the ovarian reserve is a moderately heritable trait in cattle. The association between ovarian reserve and fertility is controversial. Several studies indicate that cattle with a low ovarian reserve have phenotypic characteristics that are associated with suboptimal fertility. On the contrary, the presence and absence of a positive association between AFC and/or AMH and fertility measures (i.e. no. on services/conception, pregnancy rates, pregnancy loss) have been equally reported in cattle. In conclusion, the size of the ovarian reserve in the progeny can be enhanced by improving management of the dam from preconception to early gestation and also through genetic selection. However, although the ovarian reserve may be among the determinants of reproductive success in ruminants, the use of AFC/AMH as reliable predictors of fertility is yet to be established. Furthermore, the possibility that there is a complex interaction of AFC, AMH and reproduction has yet to be fully characterised and exploited to improve fertility in cattle.

Cardiometabolic syndrome among general adult population in Ghana: The role of lipid accumulation product, waist circumference-triglyceride index, and triglyceride-glucose index as surrogate indicators.

Background: Visceral obesity and insulin resistance contribute to developing cardiometabolic syndrome (MetS). We investigated the predictive abilities of lipid accumulation product (LAP), waist circumference-triglyceride index (WTI), and triglyceride-glucose (TyG) index for MetS screening among the general Ghanaian adults. Methods: The final prospective analysis included 4740 healthy adults aged 30-90 years from three communities comprising Ejisu, Konongo, and Ashanti Akim Agogo in Ghana. Self-structured questionnaire pretested was used to collect sociodemographic, anthropometric, and clinical data. Blood samples were taken after fasting to measure glucose and lipid levels. LAP, WTI, and TyG were calculated from standard equations. MetS was defined by the International Diabetes Federation criteria. Receiver operating characteristic (ROC) curves and multivariable logistic regression were utilized to evaluate the potential of the three indices in identifying MetS. Results: Of the 4740 participants, 39.7% had MetS. MetS was more common in females (50.3%) than in males (22.2%). Overall, LAP ≥ 27.52 yielded as the best index for MetS with the highest area under the ROC curve (AUC) (0.866). At cut-off LAP point of ≥23.87 in males and ≥33.32 in females, an AUC of 0.951 and 0.790 was identified in MetS prediction, respectively. LAP was an independent risk measure of MetS for both males (45.6-fold) and females (3.7-fold) whereas TyG was an independent risk measure for females (3.7-fold) only. Conclusions: MetS is increasing among the general adult population. LAP and TyG are important sex-specific risk measures to screen for MetS among the general adult population in our cohort.

Of Mice and Men and Plethysmography Systems: Does LKB1 Determine the Set Point of Carotid Body Chemosensitivity and the Hypoxic Ventilatory Response?

Our recent studies suggest that the level of liver kinase B1 (LKB1) expression in some way determines carotid body afferent discharge during hypoxia and to a lesser extent during hypercapnia. In short, phosphorylation by LKB1 of an as yet unidentified target(s) determines a set point for carotid body chemosensitivity. LKB1 is the principal kinase that activates the AMP-activated protein kinase (AMPK) during metabolic stresses, but conditional deletion of AMPK in catecholaminergic cells, including therein carotid body type I cells, has little or no effect on carotid body responses to hypoxia or hypercapnia. With AMPK excluded, the most likely target of LKB1 is one or other of the 12 AMPK-related kinases, which are constitutively phosphorylated by LKB1 and, in general, regulate gene expression. By contrast, the hypoxic ventilatory response is attenuated by either LKB1 or AMPK deletion in catecholaminergic cells, precipitating hypoventilation and apnea during hypoxia rather than hyperventilation. Moreover, LKB1, but not AMPK, deficiency causes Cheyne-Stokes-like breathing. This chapter will explore further the possible mechanisms that determine these outcomes.

Histology of Convergent Probing Appendages in Mormyridae.

Mormyridae is an early diverging family of Teleostean fishes that produce an electric field for navigation and communication using an electric organ. This clade has a diverse array of soft-tissue rostral appendages, such as the chin-swelling, the Schnauzenorgan, and the tubesnout combined with a Schnauzenorgan, that have evolved multiple times. Here we assess if macroscopically convergent, soft-tissue rostral appendages are also histologically convergent. Further, we investigate how the histology of these appendages can inform their function. We sampled independent gains of the chin-swelling and Schnauzenorgan to understand similarities and differences in their anatomies. We show that macroscopically convergent rostral appendages are also convergent at a histological level, and different types of rostral appendages share a similar anatomy; that said, minor differences likely relate to their specific functions. Based on a comparison of the skeletal muscle distribution and the differing attachment shapes of each appendage to the dentary, we conclude that the Schnauzenorgan is capable of a wider range of movements than the chin swelling. Furthermore, the anatomy suggests that these soft-tissue rostral appendages likely function as electrosensory foveas (i.e., an appendage that focuses a sensory system). Lastly, these histological data support the hypothesis that the chin swelling may be a precursor to the Schnauzenorgan.

ResumenMormyridae es una de las primeras familias divergentes de peces teleósteos que producen un campo eléctrico para la navegación y la comunicación mediante un órgano eléctrico. Este clado tiene una variedad diversa de apéndices rostrales de tejidos blandos, como el mentón hinchado, el Schnauzenorgan y el hocico tubular combinado con un Schnauzenorgan, que han evolucionado varias veces. Aquí evaluamos si los apéndices rostrales de tejido blando macroscópicamente convergentes también son histológicamente convergentes. Además, investigamos cómo la histología de estos apéndices puede informar sus funciones. Tomamos muestras de ganancias independientes del mentón hinchado y del Schnauzenorgan para comprender las similitudes y diferencias en sus anatomías. Mostramos que los apéndices rostrales macroscópicamente convergentes también lo son a nivel histológico, y diferentes tipos de apéndices rostrales comparten una anatomía similar; dicho esto, es probable que las diferencias menores se relacionen con sus funciones específicas. Con base en una comparación de la distribución del músculo esquelético y las diferentes formas de unión de cada apéndice al dentario, concluimos que el Schnauzenorgan es capaz de realizar una gama más amplia de movimientos que el mentón hinchado. Además, la anatomía sugiere que estos apéndices rostrales de tejido blando probablemente funcionen como fóveas electrosensoriales (es decir, un apéndice que enfoca un sistema sensorial). Por último, estos datos histológicos apoyan la hipótesis de que el mentón hinchado puede ser un precursor del Schnauzenorgan.

Protocol for a parallel group, two-arm, superiority cluster randomised trial to evaluate a community-level complementary-food safety and hygiene and nutrition intervention in Mali: the MaaCiwara study (version 1.3; 10 November 2022).

BACKGROUND: Diarrhoeal disease remains a significant cause of morbidity and mortality among the under-fives in many low- and middle-income countries. Changes to food safety practices and feeding methods around the weaning period, alongside improved nutrition, may significantly reduce the risk of disease and improve development for infants. We describe a protocol for a cluster randomised trial to evaluate the effectiveness of a multi-faceted community-based educational intervention that aims to improve food safety and hygiene behaviours and enhance child nutrition. METHODS: We describe a mixed-methods, parallel group, two-arm, superiority cluster randomised controlled trial with baseline measures. One hundred twenty clusters comprising small urban and rural communities will be recruited in equal numbers and randomly allocated in a 1:1 ratio to either treatment or control arms. The community intervention will be focussed around an ideal mother concept involving all community members during campaign days with dramatic arts and pledging, and follow-up home visits. Participants will be mother-child dyads (27 per cluster period) with children aged 6 to 36 months. Data collection will comprise a day of observation and interviews with each participating mother-child pair and will take place at baseline and 4 and 15 months post-intervention. The primary analysis will estimate the effectiveness of the intervention on changes to complementary-food safety and preparation behaviours, food and water contamination, and diarrhoea. Secondary outcomes include maternal autonomy, enteric infection, nutrition, child anthropometry, and development scores. A additional structural equation analysis will be conducted to examine the causal relationships between the different outcomes. Qualitative and health economic analyses including process evaluation will be done. CONCLUSIONS: The trial will provide evidence on the effectiveness of community-based behavioural change interventions designed to reduce the burden of diarrhoeal disease in the under-fives and how effectiveness varies across different contexts. TRIAL REGISTRATION: ISRCTN14390796. Registration date December 13, 2021.

AMPK facilitates the hypoxic ventilatory response through non-adrenergic mechanisms at the brainstem.

We recently demonstrated that the hypoxic ventilatory response (HVR) is facilitated by the AMP-activated protein kinase (AMPK) in catecholaminergic neural networks that likely lie downstream of the carotid bodies within the caudal brainstem. Here, we further subcategorise the neurons involved, by cross-comparison of mice in which the genes encoding the AMPK-α1 (Prkaa1) and AMPK-α2 (Prkaa2) catalytic subunits were deleted in catecholaminergic (TH-Cre) or adrenergic (PNMT-Cre) neurons. As expected, the HVR was markedly attenuated in mice with AMPK-α1/α2 deletion in catecholaminergic neurons, but surprisingly was modestly augmented in mice with AMPK-α1/α2 deletion in adrenergic neurons when compared against a variety of controls (TH-Cre, PNMT-Cre, AMPK-α1/α2 floxed). Moreover, AMPK-α1/α2 deletion in catecholaminergic neurons precipitated marked hypoventilation and apnoea during poikilocapnic hypoxia, relative to controls, while mice with AMPK-α1/α2 deletion in adrenergic neurons entered relative hyperventilation with reduced apnoea frequency and duration. We conclude, therefore, that AMPK-dependent modulation of non-adrenergic networks may facilitate increases in ventilatory drive that shape the classical HVR, whereas AMPK-dependent modulation of adrenergic networks may provide some form of negative feedback or inhibitory input to moderate HVR, which could, for example, protect against hyperventilation-induced hypocapnia and respiratory alkalosis.

Knowledge of Nutrition and Physical Activity Guidelines is Not Associated with Physical Function in Dutch Older Adults Attending a Healthy Ageing Public Engagement Event.

Purpose: Evidence-based guidelines on nutrition and physical activity are used to increase knowledge in order to promote a healthy lifestyle. However, actual knowledge of guidelines is limited and whether it is associated with health outcomes is unclear. Participants and Methods: This inception cohort study aimed to investigate the association of knowledge of nutrition and physical activity guidelines with objective measures of physical function and physical activity in community-dwelling older adults attending a public engagement event in Amsterdam, The Netherlands. Knowledge of nutrition and physical activity according to Dutch guidelines was assessed using customized questionnaires. Gait speed and handgrip strength were proxies of physical function and the Minnesota Leisure Time Physical Activity Questionnaire was used to assess physical activity in minutes/week. Linear regression analysis, stratified by gender and adjusted for age, was used to study the association between continuous and categorical knowledge scores with outcomes. Results: In 106 older adults (mean age=70.1 SD=6.6, years) who were highly educated, well-functioning, and generally healthy, there were distinct knowledge gaps in nutrition and physical activity which did not correlate with one another (R2=0.013, p=0.245). Knowledge of nutrition or physical activity guidelines was not associated with physical function or physical activity. However, before age-adjustment nutrition knowledge was positively associated with HGS in males (B= 0.64 (95% CI: 0.05, 1.22)) and having knowledge above the median was associated with faster gait speed in females (B=0.10 (95% CI: 0.01, 0.19)). Conclusion: Our findings may represent a ceiling effect of the impact knowledge has on physical function and activity in the this high performing and educated population and that there may be other determinants of behavior leading to health status such as attitude and perception to consider in future studies.

Detection of karakin poisoning using a targeted mass spectrometric workflow.

Treatment and management of plant toxicosis is made more difficult when an alien plant species is ingested, as identification of the toxin may pose a challenge. High-resolution mass spectrometers are required for the toxicological analysis of samples in these cases owing to their ability to scan large mass ranges and accurately identify mass features. We present this case to highlight the value of this technology in clinical toxicology. A middle-aged woman reported visual impairment, dizziness and numbness of her mouth and tongue following the ingestion of a berry. Over time her condition deteriorated, warranting toxicological analysis. The tree the berry came from was identified as Cornynocarpus laevigatus, which is known to produce the karakin neurotoxin. The patient's samples and the husk and pulp of the berries were analysed using a high-resolution mass spectrometer. This resulted in the identification of the toxin in the berry kernel and husk and patient's hair, suggesting that karakin could have contributed to the patient's condition.

Fat, adipokines, bone structure and bone regulatory factors associations in obesity.

Context: Obese (OB) adults (BMI ≥ 30) have a higher bone mineral density (BMD) and more favourable bone microarchitecture than normal-weight (NW) adults (BMI 18.5-24.9). Objective: The objective of this study was to identify which fat compartments have the strongest association with bone density and bone turnover and whether biochemical factors (adipokines, hormones and bone regulators) are likely to be important mediators of the effect of obesity on bone. Design: This was a cross-sectional, observational, matched case-control study. Setting: Participants were recruited from the local community. Participants: Two hundred healthy men and women aged 25-40 or 55-75 were recruited in individually matched OB and NW pairs. Body composition, BMD and bone microarchitecture were determined by dual-energy X-ray absorptiometry (DXA), computed tomography (CT) and high-resolution peripheral CT (HR-pQCT). Bone turnover and potential regulators such as C-terminal cross-linking telopeptide (CTX), type 1 procollagen N-terminal peptide (PINP), sclerostin, periostin, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), insulin-like growth factor 1 (IGF1), adiponectin, leptin and insulin were assessed. Main outcome: Planned exploratory analysis of the relationships between fat compartments, areal and volumetric BMD, bone microarchitecture, bone turnover markers and bone regulators. Results: Compared with NW, OB had lower CTX, PINP, adiponectin, IGF1, and 25OHD and higher leptin, PTH and insulin (all P < 0.05). CTX and subcutaneous adipose tissue (SAT) were the bone marker and fat compartment most consistently associated with areal and volumetric BMD. In regression models, SAT was negatively associated with CTX (P < 0.001). When leptin was added to the model, SAT was no longer associated with CTX, but leptin (P < 0.05) was negatively associated with CTX. Conclusions: SAT is associated with lower bone resorption and properties favourable for bone strength in obesity. Leptin may be an important mediator of the effects of SAT on the skeleton.

AMPK deficiency in smooth muscles causes persistent pulmonary hypertension of the new-born and premature death.

AMPK has been reported to facilitate hypoxic pulmonary vasoconstriction but, paradoxically, its deficiency precipitates pulmonary hypertension. Here we show that AMPK-α1/α2 deficiency in smooth muscles promotes persistent pulmonary hypertension of the new-born. Accordingly, dual AMPK-α1/α2 deletion in smooth muscles causes premature death of mice after birth, associated with increased muscularisation and remodeling throughout the pulmonary arterial tree, reduced alveolar numbers and alveolar membrane thickening, but with no oedema. Spectral Doppler ultrasound indicates pulmonary hypertension and attenuated hypoxic pulmonary vasoconstriction. Age-dependent right ventricular pressure elevation, dilation and reduced cardiac output was also evident. KV1.5 potassium currents of pulmonary arterial myocytes were markedly smaller under normoxia, which is known to facilitate pulmonary hypertension. Mitochondrial fragmentation and reactive oxygen species accumulation was also evident. Importantly, there was no evidence of systemic vasculopathy or hypertension in these mice. Moreover, hypoxic pulmonary vasoconstriction was attenuated by AMPK-α1 or AMPK-α2 deletion without triggering pulmonary hypertension.

The prevalence of frailty and pre-frailty among geriatric hospital inpatients and its association with economic prosperity and healthcare expenditure: A systematic review and meta-analysis of 467,779 geriatric hospital inpatients.

BACKGROUND: Frailty is a common and clinically significant condition among geriatric populations. Although well-evidenced pooled estimates of the prevalence of frailty exist within various settings and populations, presently there are none assessing the overall prevalence of frailty among geriatric hospital inpatients. The purpose of this review was to systematically search and analyse the prevalence of frailty among geriatric hospital inpatients within the literature and examine its associations with national economic indicators. METHODS: Systematic searches were conducted on Ovid, Web of Science, Scopus, CINAHL Plus, and the Cochrane Library, encompassing all literature published prior to 22 November 2018, supplemented with manual reference searches. Included studies utilised a validated operational definition of frailty, reported the prevalence of frailty, had a minimum age ≥ 65 years, attempted to assess the whole ward/clinical population, and occurred among hospital inpatients. Two reviewers independently extracted data and assessed study quality. RESULTS: Ninety-six studies with a pooled sample of 467,779 geriatric hospital inpatients were included. The median critical appraisal score was 8/9 (range 7-9). The pooled prevalence of frailty, and pre-frailty, among geriatric hospital inpatients was 47.4% (95% CI 43.7-51.1%), and 25.8% (95% CI 22.0-29.6%), respectively. Significant differences were observed in the prevalence of frailty stratified by age, prevalent morbidity, ward type, clinical population, and operational definition. No significant differences were observed in stratified analyses by sex or continent, or significant associations between the prevalence of frailty and economic indicators. CONCLUSIONS: Frailty is highly prevalent among geriatric hospital inpatients. High heterogeneity exists within this setting based on various clinical and demographic characteristics. Pooled estimates reported in this review place the prevalence of frailty among geriatric hospital inpatients between that reported for community-dwelling older adults and older adults in nursing homes, outlining an increase in the relative prevalence of frailty with progression through the healthcare system.