A community-based mentoring scheme for pregnant and parenting adolescents in Sierra Leone: Protocol for a hybrid pilot cluster randomised controlled trial.

BACKGROUND: Sierra Leone has a very high maternal mortality rate, and this burden falls heavily on adolescents, a particularly vulnerable group; this is usually driven by poverty, lack of education and employment opportunities. In 2017, a local grassroots organisation, Lifeline Nehemiah Projects, developed a community-based mentoring intervention '2YoungLives' (2YLs) for adolescent girls in Eastern Freetown. We aim to formally assess the feasibility and implementation of the 2YL mentorship scheme in new communities in Sierra Leone. METHODS: A hybrid type 2 pilot cluster randomised controlled trial of the 2YL mentoring scheme in urban and rural communities living around twelve peripheral health units (PHU) across five districts in Sierra Leone. Clusters will be matched into pairs and randomisation will be determined by computer-generated random numbers via a secure web-based system hosted by MedSciNet. All under-eighteen adolescents identified as pregnant in the community and/or the PHU are included. Feasibility (recruitment, retention, and attrition rates; data collection and completeness; sample calculation) and primary clinical outcome data (composite of maternal deaths, stillbirths, neonatal deaths) will be collected. A mixed-methods process evaluation will explore implementation outcomes, mechanisms of change, contextual factors, experiences of care, and health and wellbeing. A concurrent cost-consequence analysis will be undertaken. Main trial analysis will be pragmatic, by intention to treat, and a complementary per protocol analysis will also be included. DISCUSSION: Improving health and wellbeing for adolescent girls (including sexual and reproductive health) remains a top priority in Sierra Leone indicated by several government policies targeted to this group, in which maternal and infant mortality are still persistently high. Supporting these girls and facilitating their wellbeing is imperative, along with sensitisation of communities, strengthening of youth friendly services and collaboration with stakeholders at all levels (government, regional, community, family). We believe 2YL supports the global holistic agenda to integrate and implement interventions across health, education, and social systems in order to protect, nurture, and support the health and development potential of every adolescent girl, and thus become a model of good practice for adolescent pregnancy, to be adopted more widely in Sierra Leone and elsewhere. TRIAL REGISTRATION: ISRCTN registry ISRCTN32414369. Prospectively registered on 14/03/2022.

Region Convolutional Neural Network for Brain Tumor Segmentation.

Gliomas are often difficult to find and distinguish using typical manual segmentation approaches because of their vast range of changes in size, shape, and appearance. Furthermore, the manual annotation of cancer tissue segmentation under the close supervision of a human professional is both time-consuming and exhausting to perform. It will be easier and faster in the future to get accurate and quick diagnoses and treatments thanks to automated segmentation and survival rate prediction models that can be used now. In this article, a segmentation model is designed using RCNN that enables automatic prognosis on brain tumors using MRI. The study adopts a U-Net encoder for capturing the features during the training of the model. The feature extraction extracts geometric features for the estimation of tumor size. It is seen that the shape, location, and size of a tumor are significant factors in the estimation of prognosis. The experimental methods are conducted to test the efficacy of the model, and the results of the simulation show that the proposed method achieves a reduced error rate with increased accuracy than other methods.

The Potential of Strategic Environmental Assessment to Improve Urban Planning in Sierra Leone.

Strategic Environmental Assessment (SEA) is a proactive and collaborative method for environmental management designed to integrate environmental considerations into decision-making; and it is good for Sierra Leone. To understand whether SEA would be useful in the context of Sierra Leone, the authors interviewed 64 out of 78 experts face to face from March to July 2019. In addition, government policies and regulatory documents on environmental management and sustainable development, published articles served as secondary sources of data. Data were analyzed using descriptive statistics. These Sierra Leonean experts agreed that SEA would be useful for integration and achievement of improved sustainable urban planning strategies. However, the barriers identified to integrating SEA include: not addressing environmental issues during the preparation of policies and programs, insufficient political will, the absence of clear objectives, targets, principles and approaches, overlapping mandates among environmental institutions, and inadequate institutional coordination and non-integrated development framework as barriers to integrating SEA into their work. The study shows that SEA has the potential to have a positive impact on environmental concerns in decision-making, but it would need to be supported by stronger political will, legal frameworks, and improved technical guidance from the policy perspective. Moreover, we propose a conceptual framework for the inclusion of SEA into the urban planning process in Sierra Leone.

Evidence of exposure to SARS-CoV-2 in cats and dogs from households in Italy.

SARS-CoV-2 emerged from animals and is now easily transmitted between people. Sporadic detection of natural cases in animals alongside successful experimental infections of pets, such as cats, ferrets and dogs, raises questions about the susceptibility of animals under natural conditions of pet ownership. Here, we report a large-scale study to assess SARS-CoV-2 infection in 919 companion animals living in northern Italy, sampled at a time of frequent human infection. No animals tested PCR positive. However, 3.3% of dogs and 5.8% of cats had measurable SARS-CoV-2 neutralizing antibody titers, with dogs from COVID-19 positive households being significantly more likely to test positive than those from COVID-19 negative households. Understanding risk factors associated with this and their potential to infect other species requires urgent investigation.

Evidence of exposure to SARS-CoV-2 in cats and dogs from households in Italy.

SARS-CoV-2 originated in animals and is now easily transmitted between people. Sporadic detection of natural cases in animals alongside successful experimental infections of pets, such as cats, ferrets and dogs, raises questions about the susceptibility of animals under natural conditions of pet ownership. Here we report a large-scale study to assess SARS-CoV-2 infection in 817 companion animals living in northern Italy, sampled at a time of frequent human infection. No animals tested PCR positive. However, 3.4% of dogs and 3.9% of cats had measurable SARS-CoV-2 neutralizing antibody titers, with dogs from COVID-19 positive households being significantly more likely to test positive than those from COVID-19 negative households. Understanding risk factors associated with this and their potential to infect other species requires urgent investigation. ONE SENTENCE SUMMARY: SARS-CoV-2 antibodies in pets from Italy.

Candidate Electromagnetic Counterpart to the Binary Black Hole Merger Gravitational-Wave Event S190521g.

We report the first plausible optical electromagnetic counterpart to a (candidate) binary black hole merger. Detected by the Zwicky Transient Facility, the electromagnetic flare is consistent with expectations for a kicked binary black hole merger in the accretion disk of an active galactic nucleus [B. McKernan, K. E. S. Ford, I. Bartos et al., Astrophys. J. Lett. 884, L50 (2019)AJLEEY2041-821310.3847/2041-8213/ab4886] and is unlikely [

Drug-induced keratin 9 interaction with Hsp70 in bladder cancer cells.

A pull-down experiment (co-immunoprecipitation) was performed on a T24 human bladder cancer cell lysate treated with the Hsp inhibitor VER155008 using an Hsp70 antibody attached to Dynabeads. Keratin 9, a cytoskeleton intermediate filament protein, was identified by LC MS/MS analysis. This novel finding was confirmed by Western blotting, RT-PCR, and immunocytochemistry. Other members of the keratin family of proteins have been shown to be involved in cancer progression, most recently identified to be associated with cell invasion and metastasis. The specific role of keratin 9 expression in these cells is yet to be determined.

Effect of feeding three lysine to energy diets on growth, body composition and age at puberty in replacement gilts.

This study evaluated the effect of diets differing in standard ileal digestible (SID) lysine on lysine intake, growth rate, body composition and age at puberty on maternal line gilts. Crossbred Large White×Landrace gilts (n=641) were fed corn-soybean diets differing in SID lysine concentration (%, g SID lysine:Mcal ME); diets were not isocaloric. Gilts received three grower, finisher diet combinations: low (0.68% lysine grower, 0.52% lysine finisher), medium (0.79% lysine grower, 0.60% lysine finisher) or high (0.90% lysine grower, 0.68% lysine finisher). Grower diets were fed from 100 until 142days of age, and finisher diets were fed until they reached 220days of age. Body weight (BW), backfat thickness (BF), and loin depth (LD) were recorded every 28days. From 160-220days of age, gilts were exposed daily to vasectomized boars and observed for behavioral estrus. Gilts fed the low lysine diet had lower average daily gain and BW (P<0.05), but not fat depth:LD ratio. The percentage of gilts that displayed natural estrus by 220days of age was low but not different among dietary treatments (low 27.7%, medium 31.0% and high 37.7%, respectively; P=0.1201). Gilts fed the high and medium diets reached puberty 10 and 6days earlier, however, than gilts fed the low lysine diet (P<0.05). The rate of puberty attainment may have been less because all gilts contracted porcine epidemic diarrhea (PEDv) just as boar exposure was to begin for the first group of gilts. Results from the present study indicate that growth rate and age at puberty can be altered by ad libitum fed diets that differ in SID lysine concentration.

What is the mechanism of Ketamine's rapid-onset antidepressant effect? A concise overview of the surprisingly large number of possibilities.

WHAT IS KNOWN AND OBJECTIVE: Abundant clinical data now confirm that ketamine produces a remarkable rapid-onset antidepressant effect - hours or days - in contrast to the delayed onset (typically weeks) of current antidepressant drugs. This surprising and revolutionary finding may lead to the development of life-saving pharmacotherapy for depressive illness by reducing the high suicide risk associated with the delayed onset of effect of current drugs. As ketamine has serious self-limiting drawbacks that restrict its widespread use for this purpose, a safer alternative is needed. Our objective is to review the proposed mechanism(s) of ketamine's rapid-onset antidepressant action for new insights into the physiological basis of depressive illness that may lead to new and novel targets for antidepressant drug discovery. METHODS: A search was conducted on published literature (e.g. PubMed) and Internet sources to identify information relevant to ketamine's rapid-acting antidepressant action and, specifically, to the possible mechanism(s) of this action. Key search words included 'ketamine', 'antidepressant', 'mechanism of action', 'depression' and 'rapid acting', either individually or in combination. Information was sought that would include less well-known, as well as well-known, basic pharmacologic properties of ketamine and that identified and evaluated the several hypotheses about ketamine's mechanism of antidepressant action. RESULTS: Whether the mechanistic explanation for ketamine's rapid-onset antidepressant action is related to its well-known antagonism of the NMDA (N-Methyl-d-aspartate) subtype of glutamate receptor or to something else has not yet been fully elucidated. The evidence from pharmacologic, medicinal chemistry, animal model and drug-discovery sources reveals a wide variety of postulated mechanisms. WHAT IS NEW AND CONCLUSION: The surprising discovery of ketamine's rapid-onset antidepressant effect is a game-changer for the understanding and treatment of depressive illness. There is some convergence on NMDA receptor antagonism as a likely, but to date unproven, common mechanism. The surprising number of other mechanisms, and the several novel biochemical aetiologies of depression proposed, suggests exciting new drug-discovery targets.

Pharmacological evidence for a role of the transient receptor potential canonical 3 (TRPC3) channel in endoplasmic reticulum stress-induced apoptosis of human coronary artery endothelial cells.

Unresolved endoplasmic reticulum (ER) stress, with the subsequent persistent activation of the unfolded protein response (UPR) is a well-recognized mechanism of endothelial cell apoptosis with a major impact on the integrity of the endothelium during the course of cardiovascular diseases. As in other cell types, Ca(2+) influx into endothelial cells can promote ER stress and/or contribute to mechanisms associated with it. In previous work we showed that in human coronary artery endothelial cells (HCAECs) the Ca(2+)-permeable non-selective cation channel Transient Receptor Potential Canonical 3 (TRPC3) mediates constitutive Ca(2+) influx which is critical for operation of inflammatory signaling in these cells, through a mechanism that entails coupling of TRPC3 constitutive function to activation of Ca(2+)/calmodulin-dependent protein kinase II (CAMKII). TRPC3 has been linked to UPR signaling and apoptosis in cells other than endothelial, and CAMKII is a mediator of ER stress-induced apoptosis in various cell types, including endothelial cells. In the present work we used a pharmacological approach to examine whether in HCAECs TRPC3 and CAMKII also contribute to mechanisms of ER stress-induced apoptosis. The findings show for the first time that in HCAECs activation of the UPR and the subsequent ER stress-induced apoptosis exhibit a strong requirement for constitutive Ca(2+) influx and that TRPC3 contributes to this process. In addition, we obtained evidence indicating that, similar to its roles in non-endothelial cells, CAMKII participates in ER stress-induced apoptosis in HCAECs.

Optimal dietary energy and amino acids for gilt development: Growth, body composition, feed intake, and carcass composition traits.

The objective of this study was to determine if body composition of developing gilts could be altered at the onset of estrus by ad libitum feeding diets differing in standard ileal digestible (SID) lysine and ME using levels that are within those used in practice by pig producers in the United States. Crossbred Large White × Landrace gilts ( = 1,221), housed in groups, were randomly allotted to 6 corn-soybean diets in a 2 × 3 factorial arrangement formulated to provide 2 SID lysine and 3 ME levels. Gilts received grower diets formulated to provide 0.86 (low) or 1.02% (high) SID lysine and 2.94 (low), 3.25 (medium), or 3.57 (high) Mcal of ME/kg from 100 d of age until approximately 90 kg BW. Then, gilts were fed finisher diets containing 0.73 (low) or 0.85% (high) SID lysine and 2.94 (low), 3.26 (medium) or 3.59 (high) Mcal of ME/kg until 260 d of age. The medium SID lysine and medium-ME diets were based on an informal survey from the U.S. commercial swine industry to obtain average levels that are currently being formulated for developing gilts. Gilts were weighed and backfat thickness and loin area were recorded at the beginning of the trial and then every 28 d. Feed intake (FI) was recorded as feed disappearance within the pen at 2-wk intervals. Lysine (g) and ME (Mcal) consumed were calculated based on diet formulations. At approximately 260 d of age, gilts were slaughtered and warm carcass weight and fat thickness were recorded. There were no differences between lysine or ME levels for growth and body composition, except for backfat, which was slightly greater for gilts fed a high-ME diet. Gilts fed high-ME diets had a lower FI but a greater ME intake compared with gilts fed low ME ( < 0.05). Additionally, gilts fed the high-ME diet had lower FI and lysine intake per kilogram of BW gain when compared with gilts fed low- or medium-ME diets ( < 0.05). However, there was no difference in the megacalories consumed per kilogram of BW gain among treatments ( > 0.05). Carcasses from gilts fed the high-ME diet were 3.3 and 2.5 kg heavier than those from gilts fed the low- or medium-ME diets ( < 0.05). Despite significant differences in the lysine:ME ratio in the diets, no changes in growth or body composition occurred, likely due to compensatory changes in FI in response to dietary ME content. Caloric efficiency (Mcal to deposit 1 kg of BW) was similar among treatments.

Four-dimensional Fano toric complete intersections.

We find at least 527 new four-dimensional Fano manifolds, each of which is a complete intersection in a smooth toric Fano manifold.

Tumor-intrinsic and tumor-extrinsic factors impacting hsp90- targeted therapy.

In 1994 the first heat shock protein 90 (Hsp90) inhibitor was identified and Hsp90 was reported to be a target for anticancer therapeutics. In the past 18 years there have been 17 distinct Hsp90 inhibitors entered into clinical trial, and the small molecule Hsp90 inhibitors have been highly valuable as probes of the role of Hsp90 and its client proteins in cancer. Although no Hsp90 inhibitor has achieved regulatory approval, recently there has been significant progress in Hsp90 inhibitor clinical development, and in the past year RECIST responses have been documented in HER2-positive breast cancer and EML4-ALK-positive non-small cell lung cancer. All of the clinical Hsp90 inhibitors studied to date are specific in their target, i.e. they bind exclusively to Hsp90 and two related heat shock proteins. However, Hsp90 inhibitors are markedly pleiotropic, causing degradation of over 200 client proteins and impacting critical multiprotein complexes. Furthermore, it has only recently been appreciated that Hsp90 inhibitors can, paradoxically, cause transient activation of the protein kinase clients they are chaperoning, resulting in initiation of signal transduction and significant physiological events in both tumor and tumor microenvironment. An additional area of recent progress in Hsp90 research is in studies of the posttranslational modifications of Hsp90 itself and Hsp90 co-chaperone proteins. Together, a picture is emerging in which the impact of Hsp90 inhibitors is shaped by the tumor intracellular and extracellular milieu, and in which Hsp90 inhibitors impact tumor and host on a microenvironmental and systems level. Here we review the tumor intrinsic and extrinsic factors that impact the efficacy of small molecules engaging the Hsp90 chaperone machine.

Signal Transduction Pathways Leading to Heat Shock Transcription.

Heat shock proteins (HSP) are essential for intracellular protein folding during stress and protect cells from denaturation and aggregation cascades that can lead to cell death. HSP genes are regulated at the transcriptional level by heat shock transcription factor 1 (HSF1) that is activated by stress and binds to heat shock elements in HSP genes. The activation of HSF1 during heat shock involves conversion from an inert monomer to a DNA binding trimer through a series of intramolecular folding rearrangements. However, the trigger for HSF1 at the molecular level is unclear and hypotheses for this process include reversal of feedback inhibition of HSF1 by molecular chaperones and heat-induced binding to large non-coding RNAs. Heat shock also causes a profound modulation in cell signaling pathways that lead to protein kinase activation and phosphorylation of HSF1 at a number of regulatory serine residues. HSP genes themselves exist in an accessible chromatin conformation already bound to RNA polymerase II. The RNA polymerase II is paused on HSP promoters after transcribing a short RNA sequence proximal to the promoter. Activation by heat shock involves HSF1 binding to the promoter and release of the paused RNA polymerase II followed by further rounds of transcriptional initiation and elongation. HSF1 is thus involved in both initiation and elongation of HSP RNA transcripts. Recent studies indicate important roles for histone modifications on HSP genes during heat shock. Histone modification occurs rapidly after stress and may be involved in promoting nucleosome remodeling on HSP promoters and in the open reading frames of HSP genes. Understanding these processes may be key to evaluating mechanisms of deregulated HSP expression that plays a key role in neurodegeneration and cancer.

Respiratory symptom reporting error in occupational surveillance of older farmers.

OBJECTIVE: Agricultural health studies often use respiratory symptom report as a surrogate measure of disease and exposure; little data exists on the accuracy of symptom report in a work-motivated population. METHODS: Screening spirometry and telephone survey data for Kentucky male farmers >55 year (n = 134) in the NIOSH Farm Family Health and Hazard Surveillance Project were compared to investigate the accuracy of symptom report as a measure of respiratory disease risk in older farmers. RESULTS: The prevalence of reported obstructive respiratory symptoms was 0.24 (95% CI = 0.17 to 0.31); objective measures increased prevalence to 0.35 (95% CI = 0.27 to 0.43). Customary symptom questions did not reliably reflect objective indicators of respiratory impairment. CONCLUSIONS: Older farmers may not accurately report respiratory symptoms. Whether by intention or misinterpretation of physical cues, self-reporting errors in this population may introduce misclassification bias.

Trichloroethylene: Parkinsonism and complex 1 mitochondrial neurotoxicity.

OBJECTIVE: To analyze a cluster of 30 industrial coworkers with Parkinson's disease and parkinsonism subjected to long-term (8-33 years) chronic exposure to trichloroethylene. METHODS: Neurological evaluations were conducted on the 30 coworkers, including a general physical and neurological examination and the Unified Parkinson's Disease Rating Scale. In addition, fine motor speed was quantified and an occupational history survey was administered. Next, animal studies were conducted to determine whether trichloroethylene exposure is neurotoxic to the nigrostriatal dopamine system that degenerates in Parkinson's disease. The experiments specifically analyzed complex 1 mitochondrial neurotoxicity because this is a mechanism of action of other known environmental dopaminergic neurotoxins. RESULTS: The three workers with workstations adjacent to the trichloroethylene source and subjected to chronic inhalation and dermal exposure from handling trichloroethylene-soaked metal parts had Parkinson's disease. Coworkers more distant from the trichloroethylene source, receiving chronic respiratory exposure, displayed many features of parkinsonism, including significant motor slowing. Neurotoxic actions of trichloroethylene were demonstrated in accompanying animal studies showing that oral administration of trichloroethylene for 6 weeks instigated selective complex 1 mitochondrial impairment in the midbrain with concomitant striatonigral fiber degeneration and loss of dopamine neurons. INTERPRETATION: Trichloroethylene, used extensively in industry and the military and a common environmental contaminant, joins other mitochondrial neurotoxins, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and some pesticides, as a risk factor for parkinsonism.

Disinfection with 10% povidone-iodine versus 0.5% chlorhexidine gluconate in 70% isopropanol in the neonatal intensive care unit.

AIM: The finding that 10% povidone-iodine skin disinfectant may compromise thyroid function in premature infants prompted its replacement with 0.5% chlorhexidine gluconate solution in 70% isopropanol. The objective of this study was to compare the incidence rates of true infection and contamination associated with the use of these two disinfectants in the neonatal intensive care unit. METHODS: The study population comprised two cohorts of infants admitted to our neonatal intensive care unit: 1) in 1992-1993 when only 10% povidone-iodine was used as a skin disinfectant, and 2) in 1995-1996 when only 0.5% chlorhexidine gluconate solution in 70% isopropanol was used. A retrospective chart review was conducted to determine whether all documented positive blood, CSF and suprapubic aspirate cultures indicated true infection or contamination. True infection was defined as clinical symptoms and/or laboratory abnormalities suggestive of sepsis, with positive blood, CSF or suprapubic aspirate cultures. RESULTS: 1146 infants were admitted during the study periods, 507 during the first period and 639 during the second. In the early group, 17.6% of infants had major malformations, 72.0% were premature and 25.2% had weights of < 1500 g. Corresponding percentages for the latter group were 16.0%, 80.6% and 32.9%, respectively. No statistically significant differences were found between the two research periods in rate of infants with positive blood cultures, true infections, or contamination. CONCLUSION: The use of 0.5% chlorhexidine gluconate solution in 70% isopropanol as a skin disinfectant is justified in neonatal intensive care units because it is not associated with an increased incidence of infections as opposed to 10% povidone-iodine and is devoid of detrimental effects.