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Path loss modeling is a crucial consideration in radio engineering for wireless networks. Over the years, diverse techniques have been implemented in attempts to accurately predict path loss across a given terrain. In this study, path loss predictors created on the bases of artificial neural networks (ANN) were used to estimate path loss across a rural section of the Nigerian middle-belt grassland. The ANN structures considered were the Generalized Regression Neural network (GRNN) and the Radial Basis Function Neural Network (RBFNN), which exhibit a few differences and similarities. These ANN based predictors were trained, validated and tested for path loss prediction using path loss values computed from received power measured at 900MHz from six Base Transceiver Stations (BTSs) situated along the rural terrain. Findings show that the RBFNN predictor with a Root Mean Squared Error (RMSE) of 5.17dB and the GRNN with 4.9dB are slightly more accurate than the COST 231 Hata model with 6.64dB, while the Hata-Okumura with 25.78dB is simply not suitable for the terrain under investigation. Overall, the GRNN, which proffers a 26.21% improvement over the COST 231 Hata is recommended for the terrain in question.

Catastrophic forgetting (CF) refers to the sudden and severe loss of prior information in learning systems when acquiring new information. CF has been an Achilles heel of standard artificial neural networks (ANNs) when learning multiple tasks sequentially. The brain, by contrast, has solved this problem during evolution. Modellers now use a variety of strategies to overcome CF, many of which have parallels to cellular and circuit functions in the brain. One common strategy, based on metaplasticity phenomena, controls the future rate of change at key connections to help retain previously learned information. However, the metaplasticity properties so far used are only a subset of those existing in neurobiology. We propose that as models become more sophisticated, there could be value in drawing on a richer set of metaplasticity rules, especially when promoting continual learning in agents moving about the environment.

The importance of creation of geodatabase and mapping of healthcare facilities in Northeast Nigeria, Gombe state cannot be over emphasis, an adequate and equity access to healthcare facilities in Gombe state, Northeast Nigeria. study uses geospatial techniques to collect geoinformation of healthcare facilities, creation of geodatabase mapped and identified new suitable sites of healthcare facilities in Gombe state. Spatial queried database questions such as what, how much, what is where. Euclidean Distance used to generate distancehealthcare centersin the study area. Delineation ofareas falls within 4 km radius from healthcare centers used as criterion.Findings, research revealed 669 healthcare facilities in the study area, 661 primary, 52 secondary and 1 tertiary healthcare, 569 primary healthcare, 28public healthcareand 47 are private. secondary healthcare facilities 28 and 1 tertiary public owners and 24 secondary private owners, 16 new sites identified in all 4 in Nafada, 3 each in Akko, Dukku, Kwami and Yamaltu/Deba LGAs respectively. Research recommends universal health coverage strategy, rehabilitations of other social amenities, needs for the provision of 16 more healthcare facilities in Gombe state.&nbsp

Introduction: Sonographic scan tests are real-time procedures but the female reproductive systems are subject to continued changes beyond the mid-menstrual period. Therefore a second test may be useful after mid-menstrual ultrasound tests among women with infertility who first had normal ultrasound tests during the mid-menstrual period. Aim: The aim of this study is to find out whether physiological changes beyond the mid-menstrual period in the female reproductive system could develop into findings that could be missed at the first ultrasound test among women with infertility during mid menstrual period. Method: One hundred and forty (140) women participated in this study, over a period of 12 months. The inter-observer correlations were carried out. The ultrasound test measured the diameters of the endometrium and ovarian follicle. The study was carried out during the mid-menstrual cycle when normal changes are optimal. The subjects were women of childbearing age (18 years - 40 years) with 28 days cycles who were referred from the fertility clinic. Women who had previous pelvic surgery, women on fertility therapy, and women who were unsure of the date were excluded from the study. Only women who met the inclusion criteria were selected for the study. The selection was by convenience sampling method. The women underwent the first phase of the ultrasound test during the mid-menstrual cycle. Those who had ultrasonographic-positive infertility reports were returned to the referral clinic. Only women who had normal ultrasonographic fertility reports were included in the second phase of further ultrasonographic tests. The scans were carried out further for four days for this second phase study and the result was again compared with normal values. (Endometrium Normal range 7.4 mm - 13.5 mm and ovarian follicles normal range 17.4 mm to 23.5 mm). Results: The first phase of the scan showed 108 (77%) of the women had positive infertility results for endometrium and ovarian follicles, while 32 (23%) of the women had a normal ultrasonographic result and were rescanned over days. The findings of the second phase scan showed that 10 subjects (7.30%) showed new abnormalities, Findings were distributed in three sub-groups in this second phase of the study. Sub-group A, 4 (2.67%) had enlarged unruptured follicles, sub-group B, 6 (4.30%) had an endometrial cavity filled with fluid, sub-group C, 22 (15.70%) subjects still had normal scans who may be referred for other studies. Conclusion: Women with infertility who had a normal scan at the mid-menstrual cycle should be followed up with a second-phase ultrasound scan before other tests.

Microtubules deliver essential resources to and from synapses. Three-dimensional reconstructions in rat hippocampus reveal a sampling bias regarding spine density that needs to be controlled for dendrite caliber and resource delivery based on microtubule number. The strength of this relationship varies across dendritic arbors, as illustrated for area CA1 and dentate gyrus. In both regions, proximal dendrites had more microtubules than distal dendrites. For CA1 pyramidal cells, spine density was greater on thicker than thinner dendrites in stratum radiatum, or on the more uniformly thin terminal dendrites in stratum lacunosum moleculare. In contrast, spine density was constant across the cone shaped arbor of tapering dendrites from dentate granule cells. These differences suggest that thicker dendrites supply microtubules to subsequent dendritic branches and local dendritic spines, whereas microtubules in thinner dendrites need only provide resources to local spines. Most microtubules ran parallel to dendrite length and associated with long, presumably stable mitochondria, which occasionally branched into lateral dendritic branches. Short, presumably mobile, mitochondria were tethered to microtubules that bent and appeared to direct them into a thin lateral branch. Prior work showed that dendritic segments with the same number of microtubules had elevated resources in subregions of their dendritic shafts where spine synapses had enlarged, and spine clusters had formed. Thus, additional microtubules were not required for redistribution of resources locally to growing spines or synapses. These results provide new understanding about the potential for microtubules to regulate resource delivery to and from dendritic branches and locally among dendritic spines.

Long-term potentiation (LTP) is regulated in part by metaplasticity, the activity-dependent alterations in neural state that coordinate the direction, amplitude, and persistence of future synaptic plasticity. Previously, we documented a heterodendritic metaplasticity effect whereby high-frequency priming stimulation in stratum oriens (SO) of hippocampal CA1 suppressed subsequent LTP in the stratum radiatum (SR). The cytokine tumor necrosis factor (TNF) mediated this heterodendritic metaplasticity in wild-type rodents and in a mouse model of Alzheimer’s disease. Here, we investigated whether LTP at other afferent synapses to CA1 pyramidal cells were similarly affected by priming stimulation. We found that priming stimulation in SO inhibited LTP only in SR and not in a second independent pathway in SO, nor in stratum lacunosum moleculare (SLM). Synapses in SR were also more sensitive than SO or SLM to the LTP-inhibiting effects of pharmacological TNF priming. Neither form of priming was sex-specific, while the metaplasticity effects were absent in TNFR1 knock-out mice. Our findings demonstrate an unexpected pathway specificity for the heterodendritic metaplasticity in CA1. That Schaffer collateral/commissural synapses in SR are particularly susceptible to such metaplasticity may reflect an important control of information processing in this pathway in addition to its sensitivity to neuroinflammation under disease conditions.

The growth of the skeleton depends on the transmission of contractile muscle forces from tendon to bone across the extracellular matrix-rich enthesis. Loss of muscle loading leads to significant impairments in enthesis development. However, little is known about how the enthesis responds to increased loading during postnatal growth. To study the cellular and matrix adaptations of the enthesis in response to increased muscle loading, we used optogenetics to induce skeletal muscle contraction and unilaterally load the Achilles tendon and enthesis in young (i.e., during growth) and adult (i.e., mature) mice. In young mice, daily bouts of unilateral optogenetic loading led to expansion of the calcaneal apophysis and growth plate, as well as increased vascularization of the normally avascular enthesis. Daily loading bouts, delivered for 3 weeks, also led to a mechanically weaker enthesis with increased molecular-level accumulation of collagen damage in young mice. However, adult mice did not exhibit impaired mechanical properties or noticeable structural adaptations to the enthesis. We then focused on the transcriptional response of the young tendon and bone following optogenetic-induced loading. After 1 or 2 weeks of loading, we identified, in tendon, transcriptional activation of canonical pathways related to glucose metabolism (glycolysis) and inhibited pathways associated with cytoskeletal remodeling (e.g., RHOA and CREB signaling). In bone, we identified activation of inflammatory signaling (e.g., NFkB and STAT3 signaling) and inhibition of ERK/MAPK and PTEN signaling. Thus, we have demonstrated the utility of optogenetic-induced skeletal muscle contraction to elicit structural, functional, and molecular adaptation of the enthesisin vivoespecially during growth.

Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g. hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year-old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.

Bone Marrow IC50s broken into cell type.

Association of PARP1 and H2A.X detected by Proximity Ligation Assay (PLA).

Structures and PC3 viability IC50 data for compounds in Figure 2.

Association of PARP1 and other histone proteins detected by Proximity Ligation Assay (PLA).

IC50 values of PARPi vs BM-CFU and BM-PAR

Clinical RP2D concentrations for PARP inhibitors.

Supplementary methods, tables S1-S3, and supplementary figures 1-7

TRAIL can activate cell surface death receptors, resulting in potent tumor cell death via induction of the extrinsic apoptosis pathway. Eftozanermin alfa (ABBV-621) is a second generation TRAIL receptor agonist engineered as an IgG1-Fc mutant backbone linked to two sets of trimeric native single-chain TRAIL receptor binding domain monomers. This hexavalent agonistic fusion protein binds to the death-inducing DR4 and DR5 receptors with nanomolar affinity to drive on-target biological activity with enhanced caspase-8 aggregation and death-inducing signaling complex formation independent of FcγR-mediated cross-linking, and without clinical signs or pathologic evidence of toxicity in nonrodent species. ABBV-621 induced cell death in approximately 36% (45/126) of solid cancer cell lines in vitro at subnanomolar concentrations. An in vivo patient-derived xenograft (PDX) screen of ABBV-621 activity across 15 different tumor indications resulted in an overall response (OR) of 29% (47/162). Although DR4 (TNFSFR10A) and/or DR5 (TNFSFR10B) expression levels did not predict the level of response to ABBV-621 activity in vivo, KRAS mutations were associated with elevated TNFSFR10A and TNFSFR10B and were enriched in ABBV-621–responsive colorectal carcinoma PDX models. To build upon the OR of ABBV-621 monotherapy in colorectal cancer (45%; 10/22) and pancreatic cancer (35%; 7/20), we subsequently demonstrated that inherent resistance to ABBV-621 treatment could be overcome in combination with chemotherapeutics or with selective inhibitors of BCL-XL. In summary, these data provide a preclinical rationale for the ongoing phase 1 clinical trial (NCT03082209) evaluating the activity of ABBV-621 in patients with cancer.Significance:This study describes the activity of a hexavalent TRAIL-receptor agonistic fusion protein in preclinical models of solid tumors that mechanistically distinguishes this molecular entity from other TRAIL-based therapeutics.

Supplementary file containing all supplementary figures and tables

Ashleigh Barrett-Young,1 Wickliffe C Abraham,1 Carol Y Cheung,2 Jesse Gale,3 Sean Hogan,1 David Ireland,1 Ross Keenan,4– 6 Annchen R Knodt,7 Tracy R Melzer,6,8,9 Terrie E Moffitt,7,10 Sandhya Ramrakha,1 Yih Chung Tham,11,12 Graham A Wilson,13 Tien Yin Wong,12,14 Ahmad R Hariri,7 Richie Poulton1 1Department of Psychology, University of Otago, Dunedin, New Zealand; 2Department of Ophthalmology and Visual Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong; 3Department of Surgery & Anaesthesia, University of Otago, Wellington, New Zealand; 4Department of Radiology, Christchurch Hospital, Christchurch, New Zealand; 5Pacific Radiology Group, Christchurch, New Zealand; 6New Zealand Brain Research Institute, Christchurch, New Zealand; 7Department of Psychology and Neuroscience, Duke University, Durham, NC, USA; 8Department of Medicine, University of Otago, Christchurch, New Zealand; 9School of Psychology, Speech and Hearing, University of Canterbury, Christchurch, New Zealand; 10Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK; 11Singapore Eye Research Institute, Singapore National Eye Centre, Duke-NUS Medical School, Singapore; 12Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 13Department of Medicine, University of Otago, Dunedin, New Zealand; 14Tsinghua Medicine, Tsinghua University, Beijing, People’s Republic of ChinaCorrespondence: Ashleigh Barrett-Young, Department of Psychology, University of Otago, PO Box 56, Dunedin, 9054, New Zealand, Email Ashleigh.barrett-young@otago.ac.nzPurpose: The retina has potential as a biomarker of brain health and Alzheimer’s disease (AD) because it is the only part of the central nervous system which can be easily imaged and has advantages over brain imaging technologies. Few studies have compared retinal and brain measurements in a middle-aged sample. The objective of our study was to investigate whether retinal neuronal measurements were associated with structural brain measurements in a middle-aged population-based cohort.Participants and Methods: Participants were members of the Dunedin Multidisciplinary Health and Development Study (n=1037; a longitudinal cohort followed from birth and at ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32, 38, and most recently at age 45, when 94% of the living Study members participated). Retinal nerve fibre layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness were measured by optical coherence tomography (OCT). Brain age gap estimate (brainAGE), cortical surface area, cortical thickness, subcortical grey matter volumes, white matter hyperintensities, were measured by magnetic resonance imaging (MRI).Results: Participants with both MRI and OCT data were included in the analysis (RNFL n=828, female n=413 [49.9%], male n=415 [50.1%]; GC-IPL n=825, female n=413 [50.1%], male n=412 [49.9%]). Thinner retinal neuronal layers were associated with older brain age, smaller cortical surface area, thinner average cortex, smaller subcortical grey matter volumes, and increased volume of white matter hyperintensities.Conclusion: These findings provide evidence that the retinal neuronal layers reflect differences in midlife structural brain integrity consistent with increased risk for later AD, supporting the proposition that the retina may be an early biomarker of brain health.Keywords: optical coherence tomography, retina, Alzheimer’s, magnetic resonance imaging, brain aging

BACKGROUND: The appropriate antibiotic treatment for severe scrub typhus, a neglected but widespread reemerging zoonotic infection, is unclear. METHODS: In this multicenter, double-blind, randomized, controlled trial, we compared the efficacy of intravenous doxycycline, azithromycin, or a combination of both in treating severe scrub typhus. Patients who were 15 years of age or older with severe scrub typhus with at least one organ involvement were enrolled. The patients were assigned to receive a 7-day course of intravenous doxycycline, azithromycin, or both (combination therapy). The primary outcome was a composite of death from any cause at day 28, persistent complications at day 7, and persistent fever at day 5. RESULTS: Among 794 patients (median age, 48 years) who were included in the modified intention-to-treat analysis, complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%). The use of combination therapy resulted in a lower incidence of the composite primary outcome than the use of doxycycline (33% and 47%, respectively), for a risk difference of −13.3 percentage points (95% confidence interval [CI], −21.6 to −5.1; P = 0.002). The incidence with combination therapy was also lower than that with azithromycin (48%), for a risk difference of −14.8 percentage points (95% CI, −23.1 to −6.5; P

Background: Achieving climate targets will require a rapid transition to clean energy. However, renewable energy (RE) firms face financial, policy, and economic barriers to mobilizing sufficient investment in low-carbon technologies, especially in low- and middle-income countries. Here, we analyze the challenges and successes of financing the energy transition in Nigeria and Brazil using three empirically grounded levers: financing environments, channels, and instruments. Results: While Brazil has leveraged innovative policy instruments to mobilize large-scale investment in RE, policy uncertainty and weak financing mechanisms have hindered RE investments in Nigeria. Specifically, Brazil’s energy transition has been driven by catalytic finance from the Brazilian Development Bank (BNDES). In contrast, bilateral agencies and multilateral development banks (MDBs) have been the largest financiers of renewables in Nigeria. Policy instruments and public–private partnerships need to be redesigned to attract finance and scale market opportunities for RE project developers in Nigeria. Conclusions: We conclude that robust policy frameworks, a dynamic public bank, strategic deployment of blended finance, and diversification of financing instruments would be essential to accelerate RE investment in Nigeria. Considering the crucial role of donors and MDBs in Nigeria, we propose a multi-stakeholder model to consolidate climate finance and facilitate the country’s energy transition., Energy, Sustainability and Society, 13 (1), ISSN:2192-0567

We present six advanced tutorials instructing users in the best practices of using key new features and plugins/extensions of the WESTPA 2.0 software package, which consists of major upgrades for enabling applications of the weighted ensemble (WE) path sampling strategy to even larger systems and/or slower processes. The tutorials demonstrate the use of the following key features: (i) a generalized resampler module for the creation of “binless” schemes, (ii) a minimal adaptive binning scheme for more efficient surmounting of free energy barriers, (iii) streamlined handling of large simulation datasets using an HDF5 framework, (iv) two different schemes for more efficient rate-constant estimation, (v) a Python API for simplified analysis of WE simulations, and (vi) plugins/extensions for Markovian Weighted Ensemble Milestoning and WE rule-based modeling at the system biology level. Applications of the tutorials range from atomistic to residue-level to non-spatial models, and include complex processes such as protein folding and the membrane permeability of a drug-like molecule. Users are expected to already have significant experience with running conventional molecular dynamics simulations and completed the previous suite of WESTPA tutorials.

We investigated the extent to which measures of retinal neuronal thickness capture variability in the structural integrity of the brain in a large population-based cohort followed from birth to midlife. Using data from the Dunedin Multidisciplinary Health and Development Study (n=1037; analyticn=828, aged 45 years), we specifically tested for associations between optical coherence tomography-measured retinal neuronal layers and MRI-measured structural brain integrity. We found that Study members who had thinner retinal neuronal layers had thinner average cortex, smaller total cortical surface area, smaller subcortical grey matter volumes, larger volume of white matter hyperintensities as well as older looking brains. This suggests that retinal neuronal thickness reflects differences in midlife structural brain integrity consistent with accelerated cognitive decline and increased risk for later dementia, further supporting the proposition that the retina may be a biomarker of brain aging as early as midlife.

Knowledge of a person’s risk for Alzheimer’s disease and related dementias (ADRDs) is required to triage candidates for preventive interventions, surveillance, and treatment trials. ADRD risk indexes exist for this purpose, but each includes only a subset of known risk factors. Information missing from published indexes could improve risk prediction. In the Dunedin Study of a population-representative New Zealand-based birth cohort followed to midlife (N = 938, 49.5% female), we compared associations of four leading risk indexes with midlife antecedents of ADRD against a novel benchmark index comprised of nearly all known ADRD risk factors, the Dunedin ADRD Risk Benchmark (DunedinARB). Existing indexes included the Cardiovascular Risk Factors, Aging, and Dementia index (CAIDE), LIfestyle for BRAin health index (LIBRA), Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI), and risks selected by the Lancet Commission on Dementia. The Dunedin benchmark was comprised of 48 separate indicators of risk organized into 10 conceptually distinct risk domains. Midlife antecedents of ADRD treated as outcome measures included age-45 measures of brain structural integrity [magnetic resonance imaging-assessed: (i) machine-learning-algorithm-estimated brain age, (ii) log-transformed volume of white matter hyperintensities, and (iii) mean grey matter volume of the hippocampus] and measures of brain functional integrity [(i) objective cognitive function assessed via the Wechsler Adult Intelligence Scale-IV, (ii) subjective problems in everyday cognitive function, and (iii) objective cognitive decline measured as residualized change in cognitive scores from childhood to midlife on matched Weschler Intelligence scales]. All indexes were quantitatively distributed and proved informative about midlife antecedents of ADRD, including algorithm-estimated brain age (β's from 0.16 to 0.22), white matter hyperintensities volume (β's from 0.16 to 0.19), hippocampal volume (β's from −0.08 to −0.11), tested cognitive deficits (β's from −0.36 to −0.49), everyday cognitive problems (β's from 0.14 to 0.38), and longitudinal cognitive decline (β's from −0.18 to −0.26). Existing indexes compared favourably to the comprehensive benchmark in their association with the brain structural integrity measures but were outperformed in their association with the functional integrity measures, particularly subjective cognitive problems and tested cognitive decline. Results indicated that existing indexes could be improved with targeted additions, particularly of measures assessing socioeconomic status, physical and sensory function, epigenetic aging, and subjective overall health. Existing premorbid ADRD risk indexes perform well in identifying linear gradients of risk among members of the general population at midlife, even when they include only a small subset of potential risk factors. They could be improved, however, with targeted additions to more holistically capture the different facets of risk for this multiply determined, age-related disease.

Connectomics is generating an ever-increasing deluge of data, which challenges us to develop new methods for analyzing and extracting insights from these data. We introduce here a powerful method for analyzing three-dimensional reconstruction from serial section electron microscopy (3DEM) to measure synaptic information storage capacity (SISC) and apply it to data followingin vivolong-term potentiation (LTP). Connectomic researchers have focused on the pattern of connectivity between neurons. The strengths of synapses have also been studied by quantifying the sizes of synapses. Importantly, synapses from the same axon onto the same dendrite have a common history of coactivation, making them a candidate for measuring the precision of synaptic plasticity based on the similarity of their dimensions. Quantifying precision is fundamental to understanding information storage and retrieval in neural circuits. We quantify this precision with Shannon information theory, which is a more reliable estimate than prior analyses based on signal detection theory because there is no overlap between states, and outliers do not artificially bias the outcome. Spine head volumes are well correlated with other measures of synaptic weight, thus SISC can be determined by identifying the non-overlapping clusters of dendritic spine head volumes to determine the number of distinguishable synaptic weights. SISC analysis of spine head volumes in the stratum radiatum of hippocampal area CA1 revealed 24 distinguishable states (4.1 bits). In contrast, spine head volumes in the middle molecular layer of control dentate gyrus occupied only 5 distinguishable states (2 bits). Thus, synapses in different hippocampal regions had significantly different SISCs. Moreover, these were not fixed properties but increased by 30 min following induction of LTP in the dentate gyrus to occupy 10 distinguishable states (3 bits), and this increase lasted for at least 2 hours. We also observed a broader and nearly uniform distribution of spine head volumes across the increased number of states, suggesting the distribution evolved towards the theoretical upper bound of SISC following LTP. For dentate granule cells these findings show that the spine size range was broadened by the interplay among synaptic plasticity mechanisms. SISC provides a new analytical measure to probe these mechanisms in normal and diseased brains.

Neuronal hyperexcitability in Alzheimer’s disease (AD) models is thought to either contribute to the formation of amyloid beta plaques or result from their formation. Neuronal hyperexcitability has been shown in the cerebral cortex of the widely used young APPswe/PS1dE9 mice, which have accelerated plaque formation. However, it is currently unclear if hyperexcitability also occurs in CA1 hippocampal neurons of aged animals in this model. In the present work, we have compared intrinsic excitability and spontaneous synaptic inputs from CA1 pyramidal cells of 8-month-old APPswe/PS1dE9 and wildtype control mice. We find no change in intrinsic excitability or spontaneous postsynaptic currents (PSCs) between groups. We did, however, find a reduced input resistance and an increase in hyperpolarization-activated sag current. These results are consistent with findings from other aged AD model mice, including the widely used 5xFAD and 3xTg. Together these results suggest that neuronal hyperexcitability is not a consistent feature of all AD mouse models, particularly at advanced ages.

Healthcare-associated infections (HAIs) in critical patients affect the quality and safety of patient care and increase patient morbidity and mortality. During the COVID-19 pandemic, an increase in the incidence of HAIs, particularly device-associated infections (DAIs), was reported worldwide. In this study, we aimed to estimate the incidence of HAIs in an intensive care unit (ICU) during a 10-year period and compare HAI incidence during the preCOVID-19 and COVID-19 periods.A retrospective, observational study of HAIs in the medical-surgical ICU at The Cuban Hospital was conducted. DAIs included central line-associated bloodstream infections (CLABSI), catheter-associated urinary tract infections (CAUTI), and ventilator-associated pneumonia (VAP). Data included the annual incidence of HAIs, etiology, and antimicrobial resistance, using definitions provided by the Centers for Disease Control and Prevention, except for other respiratory tract infections (RTIs).155 patients with HAI infections were reported, from which 130 (85.5%) were identified during the COVID-19 period. The frequencies of DAIs and non-DAIs were higher during the COVID-19 period, except forThe incidence of DAIs increased during the pandemic period, with limited evidence of antimicrobial resistance observed. The infection control program should evaluate strategies to minimize the impact of the pandemic on HAIs.

Rotator cuff disease pathogenesis is associated with intrinsic (e.g., age, joint laxity, muscle weakness) and extrinsic (e.g., mechanical load, fatigue) factors which lead to chronic degeneration of the cuff tissues. However, etiological studies are difficult to perform in patients due to the long duration of disease onset and progression. Therefore, the purpose of this study was to determine the effects of altered joint loading on the rotator cuff. Mice were subjected to one of three load-dependent rotator cuff tendinopathy models: underuse loading, achieved by injecting botulinum toxin-A into the supraspinatus muscle; overuse loading, achieved using downhill treadmill running; destabilization loading, achieved by surgical excision of the infraspinatus tendon. All models were compared to cage activity animals. Whole joint function was assessed longitudinally using gait analysis. Tissue-scale structure and function were determined using microCT, tensile testing, and histology. The molecular response of the supraspinatus tendon and enthesis was determined by measuring the expression of 84 wound healing associated genes. Underuse and destabilization altered forepaw weight bearing, decreased tendon-to-bone attachment strength, decreased mineral density of the humeral epiphysis, and reduced tendon strength. Transcriptional activity of the underuse group returned to baseline levels by 4 weeks, while destabilization had significant upregulation of inflammation, growth factors, and extracellular matrix remodeling genes. Surprisingly, overuse activity caused changes in walking pattern, increased tendon stiffness, and primarily suppressed expression of wound healing related genes. In summary, the tendinopathy models demonstrated how divergent muscle loading can result in clinically relevant alterations in rotator cuff structure, function, and gene expression. This article is protected by copyright. All rights reserved.

TRAIL can activate cell surface death receptors, resulting in potent tumor cell death via induction of the extrinsic apoptosis pathway. Eftozanermin alfa (ABBV-621) is a second generation TRAIL receptor agonist engineered as an IgG1-Fc mutant backbone linked to two sets of trimeric native single-chain TRAIL receptor binding domain monomers. This hexavalent agonistic fusion protein binds to the death-inducing DR4 and DR5 receptors with nanomolar affinity to drive on-target biological activity with enhanced caspase-8 aggregation and death-inducing signaling complex formation independent of FcγR-mediated cross-linking, and without clinical signs or pathologic evidence of toxicity in nonrodent species. ABBV-621 induced cell death in approximately 36% (45/126) of solid cancer cell lines in vitro at subnanomolar concentrations. An in vivo patient-derived xenograft (PDX) screen of ABBV-621 activity across 15 different tumor indications resulted in an overall response (OR) of 29% (47/162). Although DR4 (TNFSFR10A) and/or DR5 (TNFSFR10B) expression levels did not predict the level of response to ABBV-621 activity in vivo, KRAS mutations were associated with elevated TNFSFR10A and TNFSFR10B and were enriched in ABBV-621–responsive colorectal carcinoma PDX models. To build upon the OR of ABBV-621 monotherapy in colorectal cancer (45%; 10/22) and pancreatic cancer (35%; 7/20), we subsequently demonstrated that inherent resistance to ABBV-621 treatment could be overcome in combination with chemotherapeutics or with selective inhibitors of BCL-XL. In summary, these data provide a preclinical rationale for the ongoing phase 1 clinical trial (NCT03082209) evaluating the activity of ABBV-621 in patients with cancer. Significance: This study describes the activity of a hexavalent TRAIL-receptor agonistic fusion protein in preclinical models of solid tumors that mechanistically distinguishes this molecular entity from other TRAIL-based therapeutics.

Clozapine is a unique atypical anti-psychotic agent with best efficacy for treatment resistant schizophrenia compared to other agents, but with increased metabolic adverse effects. We sought to audit the prevalence of diabetes and pre-diabetes in Northland, New Zealand patients on clozapine.We captured all 287 patients in Northland, New Zealand who were prescribed clozapine in September 2021 and obtained demographic, clinical and laboratory data.We discovered that 26.48% had diabetes (one patient type one, 75 type two diabetes) and 14.63% had pre-diabetes that developed after a median of six years' clozapine treatment. Diabetes prevalence is approximately 6% in the general population. NZ Māori made up 65.85% of the entire cohort (35.8% of the general population) and 85.53% of the diabetes patients. NZ Europeans represented most of the remaining 30.66% on clozapine, consistent with the largely bicultural ethnic mix of our region. Māori on clozapine were younger: mean age 42 years, compared to NZ Europeans, mean age 49 years. The average BMI was 37kg/m2 for Māori, 32 for Europeans (range 21-63, SD 8); there was a moderate relationship between clozapine use and increasing BMI (correlation coefficient of 0.74). For the diabetes patients, glycaemic control was overall suboptimal with a mean Hba1c of 66mmol/mol (range 41-117).Culturally appropriate, flexible and accessible services which integrate both the mental and physical health needs of Northland, New Zealand people with treatment-resistant schizophrenia on clozapine are required to reduce the 41% rate of dysglycaemia in this predominantly Māori group.

Background and Objectives: Studies around the world have shown that incidence of HF is increasing with the highest risk of mortality during their first admission and in the subsequent 1 year. Only a few Indian studies had looked at the predictors of in-hospital mortality in patients admitted with HF in patients admitted in medical wards. We have done a case control study to determine the risk factors for in-hospital mortality, in patients admitted with HF, in general medical ward, in a tertiary care centre in south India. Methods: We collected demographic data, clinical details and outcome data from case records. We performed a univariate analysis comparing those who died as compared to those who did not. Factors that were significant in the above, were entered into a logistic regression analysis to identify factors that independently predicted poor outcomes. Results: The in-hospital mortality rate in patients admitted with HF was 12.19%. On multivariate analysis, Systolic blood pressure < 115 mmHg {OR – 2.82, CI (1.29 – 6.19)}, serum lactate > 2 mmol/l {OR-2.61, CI (1.16 – 5.87)}, and GCS < 15 {OR 6.64, CI (2.26 – 19.51)} were statistically significant. Conclusion: Our study has shown that, in patients admitted with HF in general medical ward, at admission, low systolic blood pressure, high serum lactates, low GCS were predictors of in-hospital mortality.

Adeno-associated viral (AAV) vectors are attractive tools for central nervous system (CNS) gene therapy because some vectors can cross the blood-brain barrier (BBB), allowing them to be used as minimally invasive treatments. A novel AAV vector recently evolved in vivo, AAV-PHP.eB, has been reported to cross the BBB more effectively than the existing gold standard AAV9, but not under all conditions. Here, we compared the efficacy of single-stranded AAV-PHP.eB and AAV9 in targeting mouse CNS and peripheral tissues after administration via various routes, in two different mouse strains (C57BL/6J and B6C3), and after packaging AAV-PHP.eB with a self-complementary genome. We found that AAV-PHP.eB produced higher CNS transduction than AAV9 after intravenous injection, but only in C57BL/6J and not in B6C3 mice. AAV-PHP.eB and AAV9 produced similar CNS transduction when the administration route did not require the vectors to cross the BBB. Packaging AAV-PHP.eB with a self-complementary genome increased overall CNS transduction, but at the expense of strong neuronal tropism. AAV-PHP.eB resulted in less transduction of liver tissue than AAV9 under all conditions. Taken together, these results suggest the potential for AAV-PHP.eB as a vector for CNS gene therapy applications, but consideration will be required for translation beyond mouse models., Graphical Abstract, Engineered AAV vector AAV-PHP.eB has improved ability over AAV9 to transduce mouse CNS after intravenous administration. Using various methods of administration, we show this is due to the increased ability of AAV-PHP.eB to cross the blood-brain barrier; however, this is dependent on the mouse strain used.

One of the most fundamental features of the mammalian brain is its ability to encode, store and retrieve a large amount of information. The neurobiology of this ability has been studied for decades...

Rotator cuff supraspinatus tendon injuries are common with high rates of anatomic failure after surgical repair. The purpose of the study was to define clinically relevant features of a mouse model of supraspinatus tendon injury to determine painful, functional, and structural outcomes; we further investigated two cell populations mediating healing using genetic lineage tracing after full detachment and repair of the supraspinatus tendon in mice. Pain was assessed using the mouse grimace scale and function by gait analysis and tensile testing. Histological and microCT analyses were used to determine enthesis/tendon and bone structure, respectively. Lineage tracing was carried out using inducible Cre lines for ScxCreERT2 (tendon cells) and αSMACreERT2 (myofibroblasts and mesenchymal progenitors). Mice only expressed pain transiently after surgery despite long-term impairment of functional and structural properties. Gait, tensile mechanical properties, and bone properties were significantly reduced after injury and repair. Lineage tracing showed relatively few Scx(lin) tendon cells while αSMA(lin) cells contributed strongly to scar formation. Despite surgical reattachment of healthy tendon, lineage tracing revealed poor preservation of supraspinatus tendon after acute injury and loss of tendon structure, suggesting that tendon degeneration is also a key impediment of successful rotator cuff repair. Scar formation after surgery is mediated largely by αSMA(lin) cells and results in permanently reduced functional and structural properties.