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Background: A decline in skeletal muscle mass and function known as skeletal muscle sarcopenia is an inevitable consequence of aging. Sarcopenia is a major cause of decreased muscle strength, physical frailty and increased muscle fatigability, contributing significantly to an increased risk of physical disability and functional dependence among the elderly. There remains a significant need for a novel therapy that can improve sarcopenia and related problems in aging. Iron accumulation, especially catalytic iron (labile iron) through increased oxidative stress, could be one of the contributing factors to sarcopenia. Our study aimed to examine the effect of an iron chelator on age-related sarcopenia in mice., Methods: We investigated the effect of iron chelation (deferiprone, DFP) in sarcopenia, using mice with klotho deficiency (kl/kl), an established mouse model for aging. Four weeks old Klotho -/- male mice were treated with 25 mg/kg body weight of iron chelator deferiprone in drinking water for 8-14 weeks (n = 12/group, treated and untreated). At the end of the study, gastrocnemius, quadriceps and bicep muscles were dissected and used for western blot and immunohistochemistry analysis, histopathology and iron staining. Serum total iron, catalytic iron and cytokine ELISAs were performed with established methods., Results: Treatment with DFP significantly reduced loss of muscle mass in gastrocnemius and quadriceps muscles (p < 0.0001). Total and catalytic iron content of serum and iron in muscles were significantly (both p < 0.0001) lower in the treated animals. The inhibitory factor of myogenesis, the myostatin protein in gastrocnemius muscles (p = 0.019) and serum (p = 0.003) were downregulated after 8 weeks of therapy accompanied by an increased in muscle contractile protein myosin heavy chain (~2.9 folds, p = 0.0004). Treatment decreased inflammation (serum IL6 and TNFα) (p < 0.0001, p = 0.005), respectively, and elevated insulin-like growth factor levels (p = 0.472). This was associated with reduced DNA damage and reduced 8-hydroxy 2 deoxyguanosine in muscle and HO-1 protein (p < 0.001, p = 079), respectively. Significant weight loss (p < 0.001) and decreased water intake (p = 0.012) were observed in untreated mice compared to treatment group. Kaplan-Meier survival curves show the median life span of treated mice was 108 days as compared to 63 days for untreated mice (p = 0.0002)., Conclusions: In summary, our research findings indicate that deferiprone reduced age-related sarcopenia in the muscles of Klotho -/- mice. Our finding suggests chelation of excess iron could be an effective therapy to counter sarcopenia. However, additional studies are needed to evaluate and determine the efficacy in humans., (© 2025 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Aim: To evaluate the impact of heart rate-guided basic resuscitation compared to Helping Babies Breathe on neonatal outcomes and resuscitation practices in the Democratic Republic of the Congo., Methods: We conducted a pre-post clinical trial comparing heart rate-guided basic resuscitation to Helping Babies Breathe in three facilities, enrolling in-born neonates ≥28 weeks gestation. We collected observational data during a convenience sample of resuscitations and extracted clinical data from the medical record for all participants. We evaluated our primary outcome of effective breathing at three minutes after birth among newborns not breathing well at 30 seconds after birth employing generalized linear models using maximum likelihood estimation., Results: Among 1,284 newborns with observational data, there was no difference in the proportion effectively breathing at three minutes (adjusted relative risk 1.08 [95% CI 0.81, 1.45]). Among 145 receiving bag mask ventilation, time to bag mask ventilation decreased 64.3 seconds during heart rate-guided resuscitation (p<0.001). Among 10,906 enrolled in the trial, perinatal mortality was unchanged (adjusted relative risk 1.19 [95% CI 0.96, 1.48]) and death before discharge increased (adjusted relative risk 1.43 [95% CI 1.03, 1.99]). Expert review of stillborn cases demonstrated a stillbirth misclassification rate of 33.3% during Helping Babies Breathe versus 5.9% in heart rate-guided resuscitation., Conclusion: During heart rate-guided basic resuscitation, time to bag mask ventilation was reduced by greater than one minute. The increase in death before discharge and unchanged perinatal mortality may be due to resuscitation of newborns with a higher risk of mortality who were previously presumed stillborn. A cluster-randomized trial of heart rate-guided basic resuscitation is needed to evaluate its impact on neonatal mortality in low-resource settings., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Jackie K. Patterson is the recipient of a Laerdal Global Health gift and in-kind personnel support for an NIH-funded clinical trial in resuscitation in the DRC. Joar Eilevstjønn, Ingunn Haug and Helge Myklebust are all employed by Laerdal Medical, the company that developed NeoBeat. Beena Kamath-Rayne is an employee of the American Academy of Pediatrics, and was an Associate Editor for the Helping Babies Breathe, 2nd Edition. The other authors have no relevant conflicts of interest to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2025 Patterson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Approximately 40-50% of municipal solid waste is organic and causing biogenic malodor and infections, due to inefficient treatment methods. Biorefinery-based bioremediation and valorization is in vogue against these conventional strategies since it combines unit operations for better efficiency and productivity. Deriving inspiration, the proposed strategy puts together a unique and compatible combination of processes. This novel two-step valorization workflow involves the extraction of small molecules using organic solvents, and fermentation of resulting denatured residues (increased biodegradability or decreased recalcitrance) of reduced microbial load. The extraction step also doubles up as a sterilization event, with different solvents (petroleum ether, chloroform, ethyl methyl ketone and methanol) exhibiting varied efficiency, methanol and ethyl methyl ketone being the most effective. Different recalcitrant plant organic wastes resulting from four plants ( Cocos nucifera , Allium cepa , Artocarpus hirsutus and Swietenia mahagoni ) were used as feedstocks in the preliminary exploratory study using chosen pathogenic bacteria. Onion peel ( Allium cepa ) ethyl methyl ketone extract was chosen for further studies, as it inhibits Salmonella enterica , which is associated with infection and malodour (due to biogenic H 2 S) in wastewater. Further, fractionation of the extract yielded quercetin and its glycoside. The onion peel residue, after solvent extraction was fortified with peptone and essential minerals to promote the growth of Bacillus clausii . Fortified post-extraction residue supported the growth better than the pre-extraction residue. The residue resultant after solvent extraction was fermented with Bacillus clausii and with release of bioactive supernatants. The concentrated supernatant showed significant inhibition of Salmonella enterica and Shigella dysenteriae . Additionally, all the exudates showed considerable inhibition in H 2 S production, respectively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Meppoyilam, Madhavan, Bose, Pooja, Suresh, Nair and Pal.)

LGBTQ+ people (e.g., lesbian, gay, bisexual, transgender, and queer or questioning people) experience systemic marginalisation and discrimination globally and throughout India. In October 2023, the Indian Supreme Court rejected the legal recognition of same-sex marriage, blocking marriage equality for LGBTQ+ people and contending that the right to marry neither qualifies as a fundamental right accorded by the Indian Constitution nor falls under the Supreme Court's purview. Although the Supreme Court declared opposition to discrimination based on sexual orientation, its failure to recognise same-sex marriage legally is a substantial obstruction to full LGBTQ+ equality. We propose that the refusal of the Indian legal system to honour same-sex marriage while calling for an end to societal violence and discriminatory behaviour against the LGBTQ+ community is inherently flawed and counterintuitive. Informed by our team's multidisciplinary orientation as healthcare professionals, researchers, and advocates, we delineate explicit challenges that LGBTQ+ people in India may encounter due to the Supreme Court's recent ruling. We subsequently put forth a series of interprofessional and intersectoral recommendations to mitigate this decision's immediate and long-term consequences, providing an actionable path toward LGBTQ+ inclusion, justice, and equity in India., Competing Interests: SCB and WER are both partially funded by 10.13039/100000054NCI/10.13039/100000002NIH Comprehensive Cancer Centre award number P30 CA008748. The authors have no other conflicts of interest to disclose., (© 2024 The Author(s).)

Aims/introduction: Deficiency of neurotropic factors is implicated in diabetic neuropathy (DN). Netrin-1 is a neurotropic factor, but its association with DN has not been explored. We have assessed the association between serum netrin-1 levels and early diabetic neuropathy assessed by quantifying corneal nerve fiber loss using corneal confocal microscopy., Materials and Methods: A total of 72 participants with type 2 diabetes, without and with corneal nerve fiber loss (DN- n = 42, DN+ n = 30), and 45 healthy controls were studied. Serum netrin-1 levels were measured by enzyme-linked immunosorbent assay, and corneal nerve morphology was assessed using corneal confocal microscopy., Results: Corneal nerve fiber density, branch density, fiber length and serum netrin-1 levels were significantly lower in the DN- and DN+ groups compared with controls (P < 0.001). Netrin-1 levels correlated with corneal nerve fiber length in the DN+ group (r = 0.51; P < 0.01). A receiver operating characteristic curve analysis showed that a netrin-1 cut-off value of 599.6 (pg/mL) had an area under the curve of 0.85, with a sensitivity of 76% and specificity of 74% (P < 0.001; 95% confidence interval 0.76-0.94) for differentiating patients with and without corneal nerve loss., Conclusions: Serum netrin-1 levels show a progressive decline with increasing severity of small nerve fiber damage in patients with diabetes. Netrin-1 could act as a biomarker for small nerve fiber damage in DN., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Surveys in neonatal perinatal medicine are practical instruments for gathering information about medical practices, and outcomes related to the care of newborns and infants. This includes research for identifying needs, assessing requirements, analyzing the effects of change, creating policies, and developing curriculum initiatives. Surveys also provide useful data for enhancing the provision of healthcare services, assessing medical specialties, and evaluating training programs. However, creating a high-quality survey can be difficult for many practitioners, particularly when deciding how to formulate the right questions, whether to utilize various types of questions and how best to arrange or format the survey tool for effective responses. Problems with design principles have been evident in many surveys submitted for dissemination to the members of the Section of Neonatal Perinatal Medicine (SoNPM). To prevent potential measurement errors and increase the quality of surveys, it is crucial to follow a systematic approach in developing surveys by adhering to the principles of effective survey design. This review article provides a brief summary of survey use within the SoNPM, and offers guidance for creating high-quality surveys, including identifying important factors to consider in survey development and characteristics of well-written and effective questions. We briefly note techniques that optimize survey design for distribution through digital media., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Natural products have been a long-standing source for exploring health-beneficial components from time immemorial. Modern science has had a renewed interest in natural-products-based drug discovery. The quest for new potential secondary metabolites or exploring enhanced activities for existing molecules remains a pertinent topic for research. Resveratrol belongs to the stilbenoid polyphenols group that encompasses two phenol rings linked by ethylene bonds. Several plant species and foods, including grape skin and seeds, are the primary source of this compound. Resveratrol is known to possess potent anti-inflammatory, antiproliferative, and immunoregulatory properties. Among the notable bioactivities associated with resveratrol, its pivotal role in safeguarding the intestinal barrier is highlighted for its capacity to prevent intestinal inflammation and regulate the gut microbiome. A better understanding of how oxidative stress can be controlled using resveratrol and its capability to protect the intestinal barrier from a gut microbiome perspective can shed more light on associated physiological conditions. Additionally, resveratrol exhibits antitumor activity, proving its potential for cancer treatment and prevention. Moreover, cardioprotective, vasorelaxant, phytoestrogenic, and neuroprotective benefits have also been reported. The pharmaceutical industry continues to encounter difficulties administering resveratrol owing to its inadequate bioavailability and poor solubility, which must be addressed simultaneously. This report summarizes the currently available literature unveiling the pharmacological effects of resveratrol.

Context: A subset of polycystic ovary syndrome (PCOS) individuals also have type 2 diabetes (T2D); an unmet need to identify this subgroup exists., Objective: We looked at the potential role of serum chemerin, a proinflammatory adipokine, in identifying dysglycemic PCOS., Methods: A total of 93 PCOS and 33 healthy controls were classified, based on fasting and 2-hour plasma glucose levels (2hPGPG) and glycated hemoglobin A 1c (HbA 1c ) (%) into normoglycemic (n = 34), dysglycemic (n = 33), and T2D (n = 26). Serum chemerin were measured by enzyme-linked immunosorbent assay. Homeostatic model 2 assessment of insulin resistance (HOMA-2IR) and homeostatic model 2 assessment of β-cell function (HOMA-2β) were computed using serum C-peptide., Results: Metabolic syndrome was present in 9.7% (National Cholesterol Education Program) of PCOS. Waist circumference, body fat (%), 2hPGPG, and HbA 1c levels were significantly higher in T2D group. Serum triglycerides/high-density lipoprotein cholesterol (TGs/HDL-c) ratio was increased in PCOS individuals with T2D; no significant changes in total cholesterol and LDL-c levels were seen. Serum chemerin levels were significantly higher ( P < .001) in the PCOS group. Total body fat (%), 2hPGPG, HbA 1c , and TG/HDL-c ratio correlated positively with chemerin levels. Serum chemerin levels correlated positively with HOMA2IR and negatively with HOMA-2β. On receiver operating characteristic curve analysis, a serum chemerin cutoff level of greater than 309.3 ng/mL differentiated PCOS individuals with dysglycemia from those without (sensitivity 85.71%, specificity 89.47%). The Cohen kappa test revealed a substantial agreement ( P < .001) between chemerin cutoff and 2hPGPG levels greater than 200 mg/dL. The present study is arguably the first ever to define a serum chemerin cutoff to distinguish PCOS individuals with T2D from those without., Conclusion: Elevated serum chemerin levels reliably identify PCOS individuals with dysglycemia. Further, longitudinal studies with larger samples are required to confirm this association., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: To determine the cardiometabolic risk of adolescents and adults with Turner syndrome (TS) and whether and how anthropometry and body composition predict this risk., Methods: We compared the anthropometric, biochemical, and dual-energy x-ray absorptiometry-derived body composition parameters of 103 girls and women with TS aged 12 to 30 years and 103 controls of the same age and body mass index: (1) between TS with and without metabolic syndrome (MetS), (2) between the different karyotypes of TS, and (3) between growth hormone recipients and nonrecipients., Results: Individuals with TS had higher prevalence rates of truncal obesity (57.2%), MetS (37.9%), prediabetes (20.4%), dyslipidemia (73.8%), hypertension (9.7%), and hepatic steatosis (15.5%) and a greater total body fat percentage (38.43% vs 34.26%) and fat mass index (9.15 vs 6.71 kg/m 2 ) but a lower lean mass index (11.05 vs 12.49 kg/m 2 ) than controls (P <.001). Individuals with TS and MetS (n = 39) had a higher total body fat percentage (41.74% vs 36.42%, P <.0001), truncal fat percentage (44.66% vs 36.09%, P <.0001), and visceral adipose tissue mass (495.57 vs 276 g, P <.0001) than those with TS but without MetS. Those with classic TS (45,X) had a higher prevalence of prediabetes (32.6% vs 10.5%, P =.01). Growth hormone recipients had a lower prevalence of MetS and lesser truncal obesity. Altered body composition was significantly correlated with metabolic risk. The truncal fat percentage independently predicted MetS (odds ratio, 1.12; 95% confidence interval, 1.003-1.24; P =.04). Waist circumference and waist-hip ratio predicted metabolic risk with good sensitivity and specificity., Conclusion: Adverse cardiometabolic risk and altered body composition start early in life in TS. Postpubertal women with TS should be routinely assessed for truncal obesity, dysglycemia, dyslipidemia, and liver steatosis, irrespective of body mass index and karyotype., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)

Background: Non-invasive clinic-based tools for assessing PAD are not without limitations. Therefore, costly tests like Doppler study, CT angiography and MR angiography are often required to make a diagnosis. Ankle brachial index (ABI), commonly used for assessment of PAD, has high false positivity rates in sclerosed, calcified arteries which render them non-compressible. Toe brachial index (TBI) can be an alternative, as digital arteries are relatively unaffected by these changes., Aim: To compare the reliability of ABI and TBI in diagnosing PAD in type 2 diabetes using CT angiography (CTA) as the reference., Methods: 175 adults with T2D were selected. ABI &TBI were measured with an automated vascular Doppler XT 6 ports bilaterally for all subjects. For any subject, the limb with lower ABI and TBI was included for analysis. ABI < 0.9 & TBI < 0.6 were taken as evidence of PAD. CTA showing > 50% narrowing was taken as evidence of PAD., Results: 24% of our study subjects had CTA confirmed PAD. ABI has low sensitivity of 35.29% (95% CI 0.21-0.52) compared to TBI being 82.35% (95% CI 0.66-0.92). The specificity however was similar. ABI < 0.9 was able to detect CTA confirmed PAD, but ABI > 0.9, including the so-called normal ABI (0.9-1.3) was unable to detect PAD. ROC showed ABI at 1.005 has sensitivity 64.71% (95% CI 0.48- 0.79) and specificity 61.7% (95% CI 0.53-0.69) and TBI at 0.6 has sensitivity 82.35% (95% CI 0.66-0.92) & specificity 92% (95% CI 0.87-0.96). Utilizing Cohen's Kappa, the reliability of ABI with respect to CTA showed fair agreement (K = 0.225, p = 0.001), whereas the reliability of TBI with respect to CTA showed substantial agreement (K = 0.759, p < 0.0001)., Conclusion: ABI < 0.9 detects PAD reliably, but presence of PAD in patients with ABI > 9.0 including the normal of ABI (0.9-1.3) can be confirmed with TBI, which correlated strongly with CTA. TBI is also non-inferior for PAD detection, when ABI < 0.9. TBI and not ABI can be utilized for initial assessment of PAD in subjects with T2D., (© 2024. The Author(s).)

Several converging lines of evidence from our group support a potential role of RLIP76 (AKA Rlip) in neurodegenerative disorders, including Alzheimer's Disease (AD). However, the role of Rlip in Alzheimer's and other neurodegenerative diseases is not well understood. The purpose of the present study is to determine the role of Rlip in the brains of AD patients and control subjects. To achieve our goals, we used frozen tissues and formalin-fixed paraffin-embedded postmortem brains from AD patients of different Braak stages and age-matched control subjects. Our immunohistology and immunoblotting blotting analysis revealed that expression of Rlip protein gradually and significantly decreased (p = 0.0001) with AD progression, being lowest in Braak stage IV-V. Rlip was colocalized with Amyloid beta (Aβ) and phosphorylated tau (p-Tau) as observed by IHC staining and co-immunoprecipitation studies. Lipid peroxidation (4-HNE generation) and H 2 O 2 production were significantly higher (p = 0.004 and 0.0001 respectively) in AD patients compared to controls, and this was accompanied by lower ATP production in AD (p = 0.0009). Oxidative DNA damage was measured by 8-Hydroxyguanosine (8-OHdG) in tissue lysates by ELISA and COMET assay. AD 8-OHdG levels were significantly higher (p = 0.0001) compared to controls. COMET assay was performed in brain cells, isolated from frozen postmortem samples. The control samples showed minimal DNA in comets representing few DNA strand breaks (<20 %), (score-0-1). However, the AD group showed an average of 50 % to 65 % of DNA in comet tails (score-4-5) indicating numerous DNA strand breaks. The difference between the two groups was significant (p = 0.001), as analyzed by Open Comet by ImageJ. Elevated DNA damage was further examined by western blot analysis for phosphorylated histone variant H2AX (γH2AX). Induction of γH2AX was very significant (p < 0.0001) and confirmed the presence of double-strand breaks in DNA. Overall, our results indicate an important role for Rlip in maintaining neuronal health and homeostasis by suppressing cellular oxidative stress and DNA damage. Based on our findings, we cautiously conclude that Rlip is a promising therapeutic target for Alzheimer's disease., Competing Interests: Declaration of competing interest Authors declare that a pending disclosure is in progress with contents of this study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Children all over the world are subjected to torture, but few are identified as victims of these actions. Knowledge that facilitates identification, documentation, and treatment of torture injuries in children can allow redress and rehabilitation for more children in need., Objective: To synthesise research regarding screening, documentation, and treatment of child survivors of torture., Methods: A systematic literature review was conducted. A total of 4795 titles and/or abstracts were screened, of which 80 articles were included. Grey literature was also included., Results: Screening for torture exposure usually consisted of questions that were included in trauma questionnaires. Questions about perpetrators in the traumatic events were missing from more than half of the studies. Although children were screened mainly for psychological injuries, it was primarily physical injuries that were documented. The evidence on treatment effects was limited. However, there was a tendency that Trauma-Focused Cognitive Behavioral Therapy (TF-CBT) and Narrative Exposure Therapy (NET) significantly reduced PTSD up to three months to one year after the end of treatment. Treatments with individual and group-based formats, as well as those with normal and more intensified approaches, were found to have an effect on PTSD.

Background: The second most frequent cancer in the world and the most common malignancy in women is breast cancer. Breast cancer is a significant health concern in India with a high mortality-to-incidence ratio and presentation at a younger age., Recent Findings: Recent studies have identified gut microbiota as a significant factor that can have an influence on the development, treatment, and prognosis of breast cancer. This review article aims to describe the influence of microbial dysbiosis on breast cancer occurrence and the possible interactions between oncobiome and specific breast cancer molecular subtypes. The review further also discusses the role of epigenetics and diet/nutrition in the regulation of the gut and breast microbiome and its association with breast cancer prevention, therapy, and recurrence. Additionally, the recent technological advances in microbiome research, including next-generation sequencing (NGS) technologies, genome sequencing, single-cell sequencing, and microbial metabolomics along with recent advances in artificial intelligence (AI) have also been reviewed. This is an attempt to present a comprehensive status of the microbiome as a key cancer biomarker., Conclusion: We believe that correlating microbiome and carcinogenesis is important as it can provide insights into the mechanisms by which microbial dysbiosis can influence cancer development and progression, leading to the potential use of the microbiome as a tool for prognostication and personalized therapy., (© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Alzheimer's disease (AD) is a neurodegenerative disease that affects a large proportion of the aging population. RalBP1 (Rlip) is a stress-activated protein that plays a crucial role in oxidative stress and mitochondrial dysfunction in aging and neurodegenerative diseases but its precise role in the progression of AD is unclear. The purpose of our study is to understand the role of Rlip in the progression and pathogenesis of AD in mutant APP/amyloid beta (Aβ)-expressed mouse primary hippocampal (HT22) hippocampal neurons. In the current study, we used HT22 neurons that express mAPP, transfected with Rlip-cDNA and/or RNA silenced, and studied cell survival, mitochondrial respiration, mitochondrial function, immunoblotting & immunofluorescence analysis of synaptic and mitophagy protein's and colocalization of Rlip and mutant APP/Aβ proteins and mitochondrial length and number. We also assessed Rlip levels in autopsy brains from AD patients and control subjects. We found cell survival was decreased in mAPP-HT22 cells and RNA-silenced HT22 cells. However, cell survival was increased in Rlip-overexpressed mAPP-HT22 cells. Oxygen consumption rate (OCR) was decreased in mAPP-HT22 cells and RNA-silenced Rlip-HT22 cells. OCR was increased in Rlip-overexpressed in mAPP-HT22 cells. Mitochondrial function was defective in mAPP-HT22 cells and RNA silenced Rlip in HT22 cells, however, it was rescued in Rlip overexpressed mAPP-HT22 cells. Synaptic and mitophagy proteins were decreased in mAPP-HT22 cells, further reducing RNA-silenced Rlip-HT22 cells. However, these were increased in mAPP+Rlip-HT22 cells. Colocalization analysis revealed Rlip is colocalized with mAPP/Aβ. An increased number of mitochondria and decreased mitochondrial length were found in mAPP-HT22 cells. These were rescued in Rlip overexpressed mAPP-HT22 cells. Reduced Rlip levels were found in autopsy brains from AD patients. These observations strongly suggest that Rlip deficiency causes oxidative stress/mitochondrial dysfunction and Rlip overexpression reduced these defects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aim: To explore the experiences of Nigerian nurses in research and scholarly endeavours., Design: Descriptive phenomenological qualitative study design., Method: In-depth interviews were conducted among 30 nurses until data saturation was reached. Data were analysed using the thematic analysis method, and consolidated criteria for reporting qualitative research guidelines (COREQ) were adhered to in reporting this study., Results: Three themes emerged: (1) challenges of nurses with research; (2) the state of nursing research in Lagos state; (3) strategies to improve the state of nursing research in Lagos state. Some challenges nurses in Lagos State encounter with research include heavy workload and nursing shortage due to brain drain, faulty research foundation, lack of continuing education in research and the stressful nature of conducting research in Lagos., Conclusion: As research is essential in addressing healthcare challenges, policymakers are encouraged to employ more nurses to reduce the workload and provide time for research activities. Training and continuing education in research can be incorporated into professional development programmes. Lagos State will benefit from nursing research units in the hospitals, and a coordinating centre for the units should be provided with adequate funding. Support could be obtained from the Institute of Nursing Research Nigeria in establishing these structures. Hospital management should embrace and welcome research output from nurses and ensure such results are implemented to improve patients' care. Nurses who excel in research might be recognised with awards and other incentives to inspire their peers., (© 2023 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

Introduction: Maternal and neonatal infections are among the most frequent causes of maternal and neonatal mortality, and current antibiotic strategies have been ineffective in preventing many of these deaths. A randomised clinical trial conducted in a single site in The Gambia showed that treatment with an oral dose of 2 g azithromycin versus placebo for all women in labour reduced certain maternal and neonatal infections. However, it is unknown if this therapy reduces maternal and neonatal sepsis and mortality. In a large, multinational randomised trial, we will evaluate the impact of azithromycin given in labour to improve maternal and newborn outcomes., Methods and Analysis: This randomised, placebo-controlled, multicentre clinical trial includes two primary hypotheses, one maternal and one neonatal. The maternal hypothesis is to test whether a single, prophylactic intrapartum oral dose of 2 g azithromycin given to women in labour will reduce maternal death or sepsis. The neonatal hypothesis will test whether this intervention will reduce intrapartum/neonatal death or sepsis. The intervention is a single, prophylactic intrapartum oral dose of 2 g azithromycin, compared with a single intrapartum oral dose of an identical appearing placebo. A total of 34 000 labouring women from 8 research sites in sub-Saharan Africa, South Asia and Latin America will be randomised with a one-to-one ratio to intervention/placebo. In addition, we will assess antimicrobial resistance in a sample of women and their newborns., Ethics and Dissemination: The study protocol has been reviewed and ethics approval obtained from all the relevant ethical review boards at each research site. The results will be disseminated via peer-reviewed journals and national and international scientific forums., Trial Registration Number: NCT03871491 (https://clinicaltrials.gov/ct2/show/NCT03871491?term=NCT03871491&draw=2&rank=1)., Competing Interests: Competing interests: None declared., (Link or Companion Paper: bmjopen-2022-067581"Copyright may not be established in the United States for works of government employees (17 U.S.C. § 105). The NIH Public Access Policy requires NIH authors to submit final, peer-reviewed journal manuscripts to the digital archive PubMed Central upon acceptance for publication but no later than 12 months after publication.''.)

Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the contents of this article.

Background: Individuals with Turner syndrome (TS) have a high risk for prediabetes/type 2 Diabetes Mellitus (T2DM). There is scarce data regarding risk factors for prediabetes in TS, specially from South Asia., Methods: We conducted a cross-sectional study on girls with TS aged 12-30 years who had achieved pubertal stage B3 and above-spontaneously or with oestrogen. Anthropometric measurements and biochemical tests were conducted, and medical records were reviewed for details about pubertal onset and progression, growth hormone (GH) and oestrogen therapy., Results: Out of 129 patients with TS in our database, 99 met the criteria for inclusion, mean age 18.33+/-3.78 years and mean BMI 20.57+/- 3.71 kg/m 2 . Prevalence of prediabetes was 23.23%. Plasma-glucose measured after 75 g-oral-anhydrous-glucose-load (OGTT-PPG) identified five additional prediabetes cases, who had normal fasting plasma glucose (FPG) or HbA1c%. Compared to those without prediabetes, TS with prediabetes (n = 23) had higher mean body weight, BMI, waist circumference (WC) [42.02+/- 5.83 vs 36.22+/-8.07, 22.77+/-2.78 vs 19.91+/- 3.72, 85.26+/- 3.52 vs 81.08+/- 4.59, pall < 0.03 ], higher median WC-to-height ratio (WHtR) and WC-to-hip ratio (WHR)((0.64 [0.6-0.69] vs 0.59[0.56- 0.66], 0.9[0.84-1.12] vs 0.85[0.75-1.01], p both < 0.02), and higher LDL-cholesterol, triglycerides, and greater prevalence of hepatosteatosis (47.1% vs 21.1%, P < 0.01). Among GH recipients (n = 36), those with prediabetes had delayed initiation and shorter duration of GH therapy. There were no differences in cardiometabolic parameters or the prevalence of diabetes between different karyotypic variants of TS. BMI, WC and WHR had significant positive correlation with FBG, OGTT-PPG and HbA1c% (p all < 0.004). Delay in oestrogen initiation had a significant correlation with OGTT-PPG (Spearman's-rho = 0.69, P < 0.004). BMI, WHR and pubertal status were independent predictors for prediabetes (OR: 1.27 [1.03-1.57]), 1.18 [1.04-1.34]) and 0.09[0.02-0.38], respectively, pall < 0.02), but karyotype was not. BMI had the highest sensitivity [cut-off: 21.04 kg/m 2 (sensitivity: 82.6%, specificity: 62.2%) and WHR had the highest specificity [cut-off: 0.89 (sensitivity: 73.9%, specificity 78.4%)] for predicting prediabetes., Conclusion: Indian girls with TS have a high risk for prediabetes, irrespective of underlying karyotype and should be screened with oral glucose challenge to identify prediabetes. Timely intervention against central obesity and early initiation of GH and oestrogen should be ensured in TS. Late presenting girls should be closely monitored for dysglycaemia before and during treatment with GH and/or oestrogen., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Endocrinology and Metabolism.)

RalBP1 (Rlip) is a stress-activated protein that is believed to play a large role in aging and neurodegenerative diseases such as Alzheimer's disease (AD) and other tauopathies. The purpose of our study was to understand the role of Rlip in mutant Tau-expressed immortalized hippocampal HT22 cells. In the current study, we used mutant Tau (mTau)-expressed HT22 neurons and HT22 cells transfected with Rlip-cDNA and/or silenced RNA, and studied the cell survival, mitochondrial respiration, mitochondrial function, immunoblotting, and immunofluorescence analysis of synaptic and mitophagy proteins and the colocalization of Rlip and mTau proteins. We found Rlip protein levels were reduced in mTau-HT22 cells, Rlip silenced HT22 cells, and mTau + Rlip RNA silenced HT22 cells; on the other hand, increased Rlip levels were observed in Rlip cDNA transfected HT22 cells. We found cell survival was decreased in mTau-HT22 cells and RNA-silenced HT22 cells. However, cell survival was increased in Rlip-overexpressed mTau-HT22 cells. A significantly reduced oxygen consumption rate (OCR) was found in mTau-HT22 cells and in RNA-silenced Rlip-HT22 cells, with an even greater reduction in mTau-HT22 + Rlip RNA-silenced HT22 cells. A significantly increased OCR was found in Rlip-overexpressed HT22 cells and in all groups of cells that overexpress Rlip cDNA. Mitochondrial function was defective in mTau-HT22 cells, RNA silenced Rlip in HT22 cells, and was further defective in mTau-HT22 + Rlip RNA-silenced HT22 cells; however, it was rescued in Rlip overexpressed in all groups of HT22 cells. Synaptic and mitophagy proteins were decreased in mTau-HT22 cells, and further reductions were found in RNA-silenced mTau-HT22 cells. However, these were increased in mTau + Rlip-overexpressed HT22 cells. An increased number of mitochondria and decreased mitochondrial length were found in mTau-HT22 cells. These were rescued in Rlip-overexpressed mTau-HT22 cells. These observations strongly suggest that Rlip deficiency causes oxidative stress/mitochondrial dysfunction and Rlip overexpression reverses these defects. Overall, our findings revealed that Rlip is a promising new target for aging, AD, and other tauopathies/neurological diseases.

The obesity epidemic is not only limited to high-income or urbanized societies, but has also become prevalent among rural communities, even in India. Approaches to modifiable behaviors, like unhealthy dietary habits or a sedentary lifestyle, could bring positive results among obese populations. This research aimed to assess the effectiveness of lifestyle intervention programs to prevent obesity and cardio-metabolic risks among Bengali obese adults (Body Mass Index of 25-30kg/m 2 ). The population was selected from rural and urban communities of Hooghly district in west Bengal, India and included 121 participants (20-50 years), divided into four groups (rural male, rural female, urban male, and urban female) who underwent a 12-month intervention program. Anthropometric parameters, systolic and diastolic blood pressure, biochemical parameters (fasting blood glucose, fasting plasma insulin, Homeostatic Model Assessment for Insulin Resistance [HOMA-IR] and lipid profile), dietary habits, and physical activity profiles were assessed before the study (baseline), after 12 months of intervention (post-intervention), and after 24 months (follow-up), among all groups, to evaluate changes in data within and between the groups (rural vs. urban). The results showed a significant decline in anthropometric parameters and fasting blood glucose levels among all intervention groups, HOMA-IR in rural females, and serum triglyceride levels in urban groups. A significant improvement was noted regarding dietary habits and physical activity, even during follow-up. The impact of the intervention program did not show any rural-urban difference. The lifestyle intervention program was effective in reducing obesity and related health risks and promoting a healthy lifestyle among the target population., Competing Interests: The authors declare no conflict of interest., (©2023 JOURNAL of MEDICINE and LIFE.)

Background: To evaluate if treating maternal periodontal disease, a pro-inflammatory condition, during pregnancy (intervention) compared to after pregnancy (control) reduces the likelihood of offspring screening positive for autism spectrum disorder (ASD)., Methods: In a follow-up study to the MOTOR randomized trial, we compared rates of positive screens on the Modified Checklist for Autism in Toddlers (M-CHAT) among n = 306 two-year-old toddlers and correlated findings to maternal and cord blood pro-inflammatory interleukin-6 (IL-6)., Results: Toddlers in the intervention group had decreased risk of a positive M-CHAT screen (adjusted RR = 0.53, 95% CI 0.29-0.99). Toddlers screening positive compared to negative had higher mean IL-6 in cord blood (1.58 ± 1.14 vs. 1.09 ± 0.72 p = 0.001) and maternal IL-6 change from baseline (1.30 ± 0.61 vs 0.96 ± 0.62 p = 0.03)., Conclusions: Treating periodontal disease during pregnancy reduced risk of a positive ASD screen. M-CHAT positivity was associated with increased IL-6 in maternal and cord blood., Clinical Trial: Trial Registration numbers: Clinicaltrials.gov NCT03423836., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The use of azithromycin reduces maternal infection in women during unplanned cesarean delivery, but its effect on those with planned vaginal delivery is unknown. Data are needed on whether an intrapartum oral dose of azithromycin would reduce maternal and offspring sepsis or death., Methods: In this multicountry, placebo-controlled, randomized trial, we assigned women who were in labor at 28 weeks' gestation or more and who were planning a vaginal delivery to receive a single 2-g oral dose of azithromycin or placebo. The two primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis. During an interim analysis, the data and safety monitoring committee recommended stopping the trial for maternal benefit., Results: A total of 29,278 women underwent randomization. The incidence of maternal sepsis or death was lower in the azithromycin group than in the placebo group (1.6% vs. 2.4%), with a relative risk of 0.67 (95% confidence interval [CI], 0.56 to 0.79; P<0.001), but the incidence of stillbirth or neonatal death or sepsis was similar (10.5% vs. 10.3%), with a relative risk of 1.02 (95% CI, 0.95 to 1.09; P = 0.56). The difference in the maternal primary outcome appeared to be driven mainly by the incidence of sepsis (1.5% in the azithromycin group and 2.3% in the placebo group), with a relative risk of 0.65 (95% CI, 0.55 to 0.77); the incidence of death from any cause was 0.1% in the two groups (relative risk, 1.23; 95% CI, 0.51 to 2.97). Neonatal sepsis occurred in 9.8% and 9.6% of the infants, respectively (relative risk, 1.03; 95% CI, 0.96 to 1.10). The incidence of stillbirth was 0.4% in the two groups (relative risk, 1.06; 95% CI, 0.74 to 1.53); neonatal death within 4 weeks after birth occurred in 1.5% in both groups (relative risk, 1.03; 95% CI, 0.86 to 1.24). Azithromycin was not associated with a higher incidence in adverse events., Conclusions: Among women planning a vaginal delivery, a single oral dose of azithromycin resulted in a significantly lower risk of maternal sepsis or death than placebo but had little effect on newborn sepsis or death. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; A-PLUS ClinicalTrials.gov number, NCT03871491.)., (Copyright © 2023 Massachusetts Medical Society.)

There is a substantial gap in our understanding of resuscitation practices following Helping Babies Breathe (HBB) training. We sought to address this gap through an analysis of observed resuscitations following HBB 2nd edition training in the Democratic Republic of the Congo. This is a secondary analysis of a clinical trial evaluating the effect of resuscitation training and electronic heart rate monitoring on stillbirths. We included in-born, liveborn neonates ≥28 weeks gestation whose resuscitation care was directly observed and documented. For the 2592 births observed, providers dried/stimulated before suctioning in 97% of cases and suctioned before ventilating in 100%. Only 19.7% of newborns not breathing well by 60 s (s) after birth ever received ventilation. Providers initiated ventilation at a median 347 s (>five minutes) after birth; no cases were initiated within the Golden Minute. During 81 resuscitations involving ventilation, stimulation and suction both delayed and interrupted ventilation with a median 132 s spent drying/stimulating and 98 s suctioning. This study demonstrates that HBB-trained providers followed the correct order of resuscitation steps. Providers frequently failed to initiate ventilation. When ventilation was initiated, it was delayed and interrupted by stimulation and suctioning. Innovative strategies targeting early and continuous ventilation are needed to maximize the impact of HBB.

Phosphorodiamidate morpholino oligonucleotide (PMO)-based antisense reagents cannot enter cells without the help of a delivery technique, which limits their clinical applications. To overcome this problem, self-transfecting guanidinium-linked morpholino (GMO)-PMO or PMO-GMO chimeras have been explored as antisense agents. GMO facilitates cellular internalization and participates in Watson-Crick base pairing. Targeting NANOG in MCF7 cells resulted in decline of the whole epithelial to mesenchymal transition (EMT) and stemness pathway, evident through its phenotypic manifestations, all of which were promulgated in combination with Taxol due to downregulation of MDR1 and ABCG2. GMO-PMO-mediated knockdown of no tail gene resulted in desired phenotypes in zebrafish even upon delivery after 16-cell stages. In BALB/c mice, 4T1 allografts were found to regress via intra-tumoral administration of NANOG GMO-PMO antisense oligonucleotides (ASOs), which was associated with occurrence of necrotic regions. GMO-PMO-mediated tumor regression restored histopathological damage in liver, kidney, and spleen caused by 4T1 mammary carcinoma. Serum parameters of systemic toxicity indicated that GMO-PMO chimeras are safe. To the best of our knowledge, self-transfecting antisense reagent is the first report since the discovery of guanidinium-linked DNA (DNG), which could be useful as a combination cancer therapy and, in principle, can render inhibition of any target gene without using any delivery vehicle., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Introduction: Chronic heart failure is a severe condition that influences not just the physical dimension but also the mental dimension in patients. Comorbidity of depression and anxiety are prevalent and the quality of life is reduced. Despite the psychological impact there are no recommendations in the guidelines for psychosocial interventions for people with heart failure. The aim of this meta-review is to synthesize results of systematic reviews and meta-analyses on the outcomes of psychosocial interventions in heart failure., Methods: Searches were conducted in PubMed, PsychInfo, Cinahl and the Cochrane Library. In total, seven articles were included after screening 259 studies for eligibility., Results: The included reviews had, in total, 67 original studies included. The measured outcomes in the systematic reviews and meta-analyses were; depression, anxiety, quality of life, hospitalization, mortality, self-care and physical capacity. The results are inconsistent but show some short-term benefit of psychosocial interventions for reduced depression and anxiety and improved quality of life. However, the long-term effects were sparsely followed up., Discussion: This meta-review appears to be the first in the field of the efficacy of psychosocial interventions in chronic heart failure. This meta-review identifies gaps in the current available evidence that need to be further explored, such as booster sessions, longer follow-up time for evaluation and incorporating clinical outcomes and measures of stress processes., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nahlén Bose.)

On January 30, 2020, the COVID-19 epidemic was declared an international public health emergency by the World Health Organization. Given the growing impact of the pandemic, there is great interest in finding potential targets for treating infected or hospitalized COVID-19 patients. Therapeutic studies have been conducted on pre-existing drugs, which vary by country, including anti-malarial agents, antiviral agents, and convalescent plasma. However, many of these agents are ineffective at reducing mortality or only shorten the severity or duration of COVID-19 illness in hospitalized patients. As such, other alternatives for treating COVID-19 are being investigated. One such target of interest has been clathrin-dependent endocytosis (CDE). Clathrin-dependent endocytosis is the most commonly observed mechanism of viral entry into cells. However, there have been no published studies to date on CDE inhibition strategies against COVID-19. One such target is Rlip or RLIP76 (human gene RALBP1, 18p11.22). Among its many functions, Rlip is a stress-protective, Ral-regulated ATPase of the mercapturic acid pathway that transports glutathione-electrophile conjugates of electrophilic toxins, which are precursors of mercapturic acid that precedes de-glutamylation by gamma-glutamyl transferase. Rlip is also regulated by several G-proteins that coordinate movement of cells, organelles, membranes, cytoskeleton, macromolecules, and other small molecules. Previous studies have link Rlip in the pathogenesis of several viral illness. In this paper, we want to propose that RLIP76 (Rlip or RALBP1) may be a novel target for treating SARS-CoV-2 viral infections., Competing Interests: Conflict of interest SA has a conflict of interest because of intellectual property in company (Avesta76 Therapeutics)., (© 2022 Greater Baltimore Medical Center.)

Background: 900,000 newborns die from respiratory depression each year; nearly all of these deaths occur in low- and middle-income countries. Deaths from respiratory depression are reduced by evidence-based resuscitation. Electronic heart rate monitoring provides a sensitive indicator of the neonate's status to inform resuscitation care, but is infrequently used in low-resource settings. In a recent trial in the Democratic Republic of the Congo, midwives used a low-cost, battery-operated heart rate meter (NeoBeat) to continuously monitor heart rate during resuscitations. We explored midwives' perceptions of NeoBeat including its utility and barriers and facilitators to use., Methods: After a 20-month intervention in which midwives from three facilities used NeoBeat during resuscitations, we surveyed midwives and conducted focus group discussions (FGDs) regarding the incorporation of NeoBeat into clinical care. FGDs were conducted in Lingala, the native language, then transcribed and translated from Lingala to French to English. We analyzed data by: (1) coding of transcripts using Nvivo, (2) comparison of codes to identify patterns in the data, and (3) grouping of codes into categories by two independent reviewers, with final categories determined by consensus., Results: Each midwife from Facility A used NeoBeat on an estimated 373 newborns, while each midwife at facilities B and C used NeoBeat an average 24 and 47 times, respectively. From FGDs with 30 midwives, we identified five main categories of perceptions and experiences regarding the use of NeoBeat: (1) Providers' initial skepticism evolved into pride and a belief that NeoBeat was essential to resuscitation care, (2) Providers viewed NeoBeat as enabling their resuscitation and increasing their capacity, (3) NeoBeat helped providers identify flaccid newborns as liveborn, leading to hope and the perception of saving of lives, (4) Challenges of use of NeoBeat included cleaning, charging, and insufficient quantity of devices, and (5) Providers desired to continue using the device and to expand its use beyond resuscitation and their own facilities., Conclusion: Midwives perceived that NeoBeat enabled their resuscitation practices, including assisting them in identifying non-breathing newborns as liveborn. Increasing the quantity of devices per facility and developing systems to facilitate cleaning and charging may be critical for scale-up., Competing Interests: Authors JE and HM were both employed by Laerdal Global Health (LGH), the company that developed NeoBeat. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Thornton, Ishoso, Lokangaka, Berkelhamer, Bauserman, Eilevstjønn, Iyer, Kamath-Rayne, Mafuta, Myklebust, Patterson, Tshefu, Bose and Patterson.)

MicroRNAs (miRNAs) are found in nerve terminals, synaptic vesicles, and synaptosomes, but it is unclear whether synaptic and cytosolic miRNA populations differ in Alzheimer's disease (AD) or if synaptosomal miRNAs affect AD synapse activity. To address these questions, we generated synaptosomes and cytosolic fractions from postmortem brains of AD and unaffected control (UC) samples and analyzed them using a global Affymetrix miRNAs microarray platform. A group of miRNAs significantly differed (P < 0.0001) with high fold changes variance (+/- >200-fold) in their expressions in different comparisons: (1) UC synaptosome vs UC cytosol, (2) AD synaptosomes vs AD cytosol, (3) AD cytosol vs UC cytosol, and (4) AD synaptosomes vs UC synaptosomes. MiRNAs data analysis revealed that some potential miRNAs were consistently different across sample groups. These differentially expressed miRNAs were further validated using AD postmortem brains, brains of APP transgenic (Tg2576), Tau transgenic (P301L), and wild-type mice. The miR-501-3p, miR-502-3p, and miR-877-5p were identified as potential synaptosomal miRNAs upregulated with disease progression based on AD Braak stages. Gene Ontology Enrichment and Ingenuity Pathway Analysis of synaptosomal miRNAs showed the involvement of miRNAs in nervous system development, cell junction organization, synapse assembly formation, and function of GABAergic synapse. This is the first description of synaptic versus cytosolic miRNAs in AD and their significance in synapse function., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

This study focuses on characterizing the bifurcation scenario and the underlying synchrony behavior in a nonlinear aeroelastic system under deterministic as well as stochastic inflow conditions. Wind tunnel experiments are carried out for a canonical pitch-plunge aeroelastic system subjected to dynamic stall conditions. The system is observed to undergo a subcritical Hopf bifurcation, giving way to large-amplitude limit cycle oscillations (LCOs) in the stall flutter regime under the deterministic flow conditions. At this condition, we observe intermittent phase synchronization between pitch and plunge modes near the fold point, whereas synchronization via phase trapping is observed near the Hopf point. Repeating the experiments under stochastic inflow conditions, we observe two different aeroelastic responses: low amplitude noise-induced random oscillations (NIROs) and high-amplitude random LCOs (RLCOs) during stall flutter. The present study shows asynchrony between pitch and plunge modes in the NIRO regime. At the onset of RLCOs, asynchrony persists even though the relative phase distribution changes. With further increase in the flow velocity, we observe intermittent phase synchronization in the flutter regime. To the best of the authors' knowledge, this is the first study reporting the experimental evidence of phase synchronization between pitch and plunge modes of an aeroelastic system, which is of great interest to the nonlinear dynamics community. Furthermore, given the ubiquitous presence of stall behavior and stochasticity in a variety of engineering systems, such as wind turbine blades, helicopter blades, and unmanned aerial vehicles, the present findings will be directly beneficial for the efficient design of futuristic aeroelastic systems.

Introduction: Neonates with serious bacterial infections should be treated with injectable antibiotics after hospitalization, which may not be feasible in many low resource settings. In 2015, the World Health Organization (WHO) launched a guideline for the management of young infants (0-59 days old) with possible serious bacterial infection (PSBI) when referral for hospital treatment is not feasible. We evaluated the feasibility of the WHO guideline implementation in the Democratic Republic of the Congo (DRC) to achieve high coverage of PSBI treatment., Methods: From April 2016 to March 2017, in a longitudinal, descriptive, mixed methods implementation research study, we implemented WHO PSBI guideline for sick young infants (0-59 dyas of age) in the public health programme setting in five health areas of North and South Ubangi Provinces with an overall population of about 60,000. We conducted policy dialogue with national and sub-national level government planners, decision-makers, academics and other stakeholders. We established a Technical Support Unit to provide implementation support. We built the capacity of health workers and managers and ensured the availability of necessary medicines and commodities. We followed infants with PSBI signs up to 14 days. The research team systematically collected data on adherence to treatment and outcomes., Results: We identified 3050 live births and 285 (9.3%) young infants with signs of PSBI in the study area, of whom 256 were treated. Published data have reported 10% PSBI incidence rate in young infants. Therefore, the estimated coverage of treatment was 83.9% (256/305). Another 426 from outside the study catchment area were also identified with PSBI signs by the nurses of a health centre within the study area. Thus, a total of 711 young infants with PSBI were identified, 285 (40%) 7-59 days old infants had fast breathing (pneumonia), 141 (20%) 0-6 days old had fast breathing (severe pneumonia), 233 (33%) had signs of clinical severe infection (CSI), and 52 (7%) had signs of critical illness. Referral to a hospital was advised to 426 (60%) infants with CSI, critical illness or severe pneumonia. The referral was refused by 282 families who accepted simplified antibiotic treatment on an outpatient basis at the health centres. Treatment failure among those who received outpatient treatment occurred in 10/128 (8%) with severe pneumonia, 25/147 (17%) with CSI, including one death, and 2/7 (29%) young infants with a critical illness. Among 285 infants with pneumonia, 257 (90%) received oral amoxicillin treatment, and 8 (3%) failed treatment. Adherence to outpatient treatment was 98% to 100% for various PSBI sub-categories. Among 144 infants treated in a hospital, 8% (1/13) with severe pneumonia, 23% (20/86) with CSI and 40% (18/45) with critical illness died., Conclusion: Implementation of the WHO PSBI guideline when a referral was not possible was feasible in our context with high coverage. Without financial and technical input to strengthen the health system at all levels, including the community and the referral level, it may not be possible to achieve and sustain the same high treatment coverage., Competing Interests: Rajiv Bahl and Yasir Bin Nisar are staff members of the World Health Organization. The expressed views and opinions do not necessarily express the policies of the World Health Organization. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Biomarker directed selection of targeted anti-neoplastic agents such as immune checkpoint inhibitors, small molecule inhibitors and monoclonal antibodies form an important aspect of cancer treatment. Immunohistochemistry (IHC) analysis of the tumor tissue is the method of choice to evaluate the presence of these biomarkers. However, a significant barrier to biomarker testing on tissue is the availability of an adequate amount of tissue and need for repetitive sampling due to tumor evolution. Also, tumor tissue testing is not immune to inter- and intra-tumor heterogeneity. We describe the analytical and clinical validation of a Circulating Tumor Cell (CTC) assay to accurately assess the presence of PD-L1 22C3 and PD-L1 28.8, ER, PR and HER2, from patients with solid tumors to guide the choice of suitable targeted therapies. Analytically, the test has high sensitivity, specificity, linearity and precision. Based on a blinded case control study, the clinical sensitivity and specificity for PD-L1 (22C3 and 28.8) was determined to be 90% and 100% respectively. The clinical sensitivity and specificity was 83% and 89% for ER; 80% and 94% for PR; 63% and 89% for HER2 (by ICC); and 100% and 92% for HER2 (by FISH), respectively. The performance characteristics of the test support its suitability and adaptability for routine clinical use., Competing Interests: The author – Raymond Page declares no competing interests. The authors – Darshana Patil, Dadasaheb Akolkar, Sudha S Murthy, Kiran Bendale, Revati Patil, Pradeep Fulmali, Pooja Fulmali, Archana Adhav, Sneha Puranik, Sachin Apurwa, Vineet Datta, Chirantan Bose, Stefan Schuster, Jinumary John and Ajay Srinivasan are employees of the Study Sponsor. The author – Rajan Datar is the founder of the Study Sponsor. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: To assess the association of lipid and lipid-derived toxic molecules in pathogenesis and severity of diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM)., Methods: The present cross-sectional study included 14 healthy individuals (HC) without T2DM, 22 T2DM subjects without DR (DNR), 24 T2DM subjects with mild non-proliferative DR (MNPDR), and 24 T2DM subjects with high-risk proliferative DR (HRPDR). All subjects underwent plasma and vitreous analysis for estimation of total lipid (TL), free fatty acid (FFA), lipid peroxides (LPOs) like malondialdehyde (MDA), 4-Hydroxy-noneal (HNE), the advanced lipoxidation end product (ALE) like Hexanoyl-lysine (HLY) and vascular endothelial growth factor (VEGF) following standard spectrophotometric and enzyme-linked immunosorbent assay (ELISA) methods respectively., Results: The concentration of TL, FFA, markers of lipid peroxidation and lipoxidation as well as VEGF in plasma and vitreous were found to be significantly elevated stepwise inT2DM subjects (HRPDR > MNPDR > DNR) compared to healthy controls (HC).Further, plasma conventional lipid components like total cholesterol (TCH), low density lipoprotein cholesterol (LDL-C) and triglycerides (TG), FFA and TL showed their significant positive correlations with vitreous level of different LPOs, ALE and VEGF in the DR group., Conclusion: Total lipid and lipid-derived detrimental biomolecules ultimately result in increased secretion of VEGF and thus not only add as associated mediators in the pathogenesis of DR, these also accelerate the severity of microangiopathy in T2DM., (© 2022. The Author(s).)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in older people. AD is associated with the loss of synapses, oxidative stress, mitochondrial structural and functional abnormalities, microRNA deregulation, inflammatory responses, neuronal loss, accumulation of amyloid-beta (Aβ) and phosphorylated tau (p-tau). AD occurs in two forms: early onset, familial AD and late-onset, sporadic AD. Causal factors are still unknown for a vast majority of AD patients. Genetic polymorphisms are proposed to contribute to late-onset AD via age-dependent increases in oxidative stress and mitochondrial abnormalities. Recent research from our lab revealed that reduced levels of Rlip76 induce oxidative stress, mitochondrial dysfunction and synaptic damage, leading to molecular and behavioral phenotypes resembling late-onset AD. Rlip76 is a multifunctional 76 kDa protein encoded by the RALBP1 gene, located on chromosome 18. Rlip is a stress-protective ATPase of the mercapturic acid pathway that couples clathrin-dependent endocytosis with the efflux of glutathione-electrophile conjugates. Rlip is evolutionarily highly conserved across species and is ubiquitously expressed in all tissues, including AD-affected brain regions, the cerebral cortex and hippocampus, where highly active neuronal metabolisms render the cells highly susceptible to intracellular oxidative damage. In the current article, we summarize molecular and cellular features of Rlip and how depleted Rlip may exacerbate oxidative stress, mitochondrial dysfunction and synaptic damage in AD. We also discuss the possible role of Rlip in aspects of learning and memory via axonal growth, dendritic remodeling, and receptor regulation. We conclude with a discussion of the potential for the contribution of genetic polymorphisms in Rlip to AD progression and the potential for Rlip-based therapies.

Cananginones, a family of linear acetogenins found as secondary metabolites in the plant kingdom, show cytotoxicity against several types of cancer cells. We aimed to investigate the efficacy of cananginone and its mechanism as an anti-cancer agent. Our initial screening of Cananginone against HepG2, PC3, A549, and MCF7 cells showed anti-cancer activities and is more potent against MCF7 cells, consistent with the previous report. Next, cell-based assays have revealed that cananginone abrogates cancer stem cell renewal as well as Epithelial-Mesenchymal Transition (EMT) and increased the ROS level beyond the threshold level thus reducing the viability of cancer cells. In the connection of Hh-Gli to EMT, our study indicated that cananginone inhibits Gli1 in a non-canonical pathway. Presumably, this is the first report on the inhibitory activity of cananginone in the Hh pathway and is different from Hh-antagonists cyclopamine and GANT 61 considering the mechanism., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

The purpose of our study is to determine DDQ (diethyl (3,4-dihydroxyphenethylamino) (quinolin-4-yl) methylphosphonate)-a newly discovered molecule that has been shown to protect against phosphorylated tau (p-tau) in Alzheimer's disease (AD) pathogenesis. We used a well-studied tau (P301L) transgenic mouse model to achieve our goal. We administered DDQ into 12-month-old Tau mice, at 20 mg/kg body weight intraperitoneally two times per week for 2 months. We also assessed DDQ levels in the blood, skeletal muscle and brain using biochemical and molecular techniques. We investigated the mRNA and protein levels of mitochondrial dynamics, biogenesis, synaptic, p-tau and longevity genes sirtuins in DDQ-treated tau mice using real-time quantitative PCR (q-RT-PCR), immunoblotting and immunofluorescence techniques. Our extensive pharmacodynamics investigations revealed that skeletal muscle had the greatest peak levels of DDQ, followed by serum and brain. Interestingly, DDQ-treated tau mice had higher levels of mitochondrial fusion, biogenesis, synaptic genes and sirtuins than DDQ-untreated tau mice. In addition, DDQ-treated tau mice had lower levels of mitochondrial fission and p-tau than untreated tau mice. The current findings, combined with our prior findings, firmly show that DDQ possesses anti-aging, anti-amyloid-beta and anti-p-tau properties, making it a promising molecule for reducing age-related, amyloid-beta and p-tau-induced synaptic and mitochondrial toxicities in AD., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: Diabetic retinopathy (DR), the leading cause of blindness among working adults, is an urgent public health problem as diabetes mellitus (DM) is increasing at an alarming rate. Hyperglycemia-induced endothelial dysfunction is the principal contributing factor leading to the development of microangiopathy. Altered levels of microRNA (miR), the negative regulator of protein-coding genes, have been observed and considered to be markers for DR. Present study aimed to find out whether miR levels in plasma could be effective biomarkers to differentiate between type 2 diabetes mellitus (T2DM) with non-proliferative retinopathy (NPDR) from T2DM with no-DR (DNR)., Methods: We recruited 50 T2DM subjects comprising 31 NPDR and 19 DNR individuals. Surrogate markers of systemic oxidative stress and vascular endothelial growth factor (VEGF) were measured in plasma. Levels of miR-126 and miR-132 were determined in plasma and vitreous fluid using real-time PCR., Results: We observed that levels of miR-126 and miR-132 were decreased in NPDR subjects in comparison to DNR. Plasma levels of miRs were inversely correlated with secreted levels of VEGF and oxidative stress marker. The levels of these miRs showed discriminating ability between NPDR and DNR., Conclusion: Circulating miRs 126 and 132 in plasma or vitreous may serve as biomarkers for early diabetic retinopathy risk prediction, provided validated in a larger cohort and other forms of retinal vasculopathy or retinopathy in the future., Competing Interests: The authors declare no conflicts of interest for this work., (© 2022 Pramanik et al.)

Aim: To evaluate the effect of resuscitation training and continuous electronic heart rate (HR) monitoring of non-breathing newborns on identification of stillbirth., Methods: We conducted a pre-post interventional trial in three health facilities in the Democratic Republic of the Congo. We collected data on a retrospective control group of newborns that reflected usual resuscitation practice (Epoch 1). In the prospective, interventional group, skilled birth attendants received resuscitation training in Helping Babies Breathe and implemented continuous electronic HR monitoring of non-breathing newborns (Epoch 2). Our primary outcome was the incidence of stillbirth with secondary outcomes of fresh or macerated stillbirth, neonatal death before discharge and perinatal death. Among a subset, we conducted expert review of electronic HR data to estimate misclassification of stillbirth in Epoch 2. We used a generalized estimating equation, adjusted for variation within-facility, to compare risks between EPOCHs., Results: There was no change in total stillbirths following resuscitation training and continuous electronic HR monitoring of non-breathing newborns (aRR 1.15 [0.95, 1.39]). We observed an increased rate of macerated stillbirth (aRR 1.58 [1.24, 2.02]), death before discharge (aRR 3.31 [2.41, 4.54]), and perinatal death (aRR 1.61 [1.38, 1.89]) during the intervention period. In expert review, 20% of newborns with electronic HR data that were classified by SBAs as stillborn were liveborn., Conclusion: Resuscitation training and use of continuous electronic HR monitoring did not reduce stillbirths nor eliminate misclassification., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Joar Eilevstjønn, Ingunn Haug and Helge Myklebust are all employed by Laerdal Global Health (LGH), the company that developed NeoBeat. At LGH, Joar Eilevstjønn is a senior scientist, Ingunn Haug is a senior product developer and Helge Myklebust is the director of strategic research., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Rlip76 (Rlip) is a multifunctional membrane protein that facilitates the high metabolic rates of cancer cells through the efflux of toxic metabolites and other functions. Rlip inhibition or depletion results in broad-spectrum anti-cancer effects in vitro and in vivo. Rlip depletion effectively suppresses malignancy and causes global reversion of characteristic CpG island methylomic and transcriptomic aberrations in the p53-null mouse model of spontaneous carcinogenesis through incompletely defined signaling and transcriptomic mechanisms. The methylome and transcriptome are normally regulated by the concerted actions of several mechanisms that include chromatin remodeling, promoter methylation, transcription factor interactions, and miRNAs. The present studies investigated the interaction of Rlip depletion or inhibition with the promoter methylation and transcription of selected cancer-related genes identified as being affected by Rlip depletion in our previous studies. We constructed novel promoter CpG island/luciferase reporter plasmids that respond only to CpG methylation and transcription factors. We found that Rlip depletion regulated expression by a transcription factor-based mechanism that functioned independently of promoter CpG methylation, lipid peroxidation, and p53 status.

Alzheimer's disease (AD) is a devastating illness in elderly individuals, that currently has no known cure. Causal genetic factors only account for 1-2% of AD patients. However, other causal factors are still unknown for a majority of AD patients. Currently, multiple factors are implicated in late-onset AD, including unhealthy diet, physical inactivity, traumatic brain injury, chronic conditions, epigenetic factors, and environmental exposures. Although clinical symptoms of dementia are common to all races and ethnic groups, conditions that lead to dementia are different in terms of lifestyle, genetic profile, and socio-economic conditions. Increasing evidence also suggests that some elderly individuals age without cognitive impairments in their 60-90s as seen in rural West Texas, while some individuals progress with chronic conditions and cognitive impairments into their 60s. To understand these discriminations, we assessed current literature on demographic features of health in rural West Texas. This paper also outlines our initiated clinical study with a purpose of understanding the factors that allow some individuals to live without cognitive impairments at the age of 60-90 years, whereas others develop deficits in cognitive function around or above 60 years. Our ongoing study hopes to determine the factors that delay aging in some individuals by investigating various aspects including genetics, epigenetics, ethnicity, biology, culture, and lifestyle. This will be achieved by gathering information about participants' ethnographic profiles, cognitive assessments, blood-profiles, brain scans, and blood-based genomic analyses in relation to lifestyle. The outcomes of our study will provide insights into healthy aging in rural West Texas.

Her2-amplified breast cancers resistant to available Her2-targeted therapeutics continue to be a challenge in breast cancer therapy. Dox is the mainstay of chemotherapy of all types of breast cancer, but its usefulness is limited by cumulative cardiotoxicity. Because oxidative stress caused by dox generates the pro-apoptotic Ω-6 PUFA metabolite 4-hydroxynonenal (4-HNE), we surmised that Ω-6 PUFAs would increase the effectiveness of dox chemotherapy. Since the mercapturic acid pathway enzyme RALBP1 (also known as RLIP76 or Rlip) that limits cellular accumulation of 4-HNE also mediates dox resistance, the combination of Ω-6 PUFAs and Rlip depletion could synergistically improve the efficacy of dox. Thus, we studied the effects of the Ω-6 PUFA arachidonic acid (AA) and Rlip knockdown on the antineoplastic activity of dox towards Her2-amplified breast cancer cell lines SK-BR-3, which is sensitive to Her2 inhibitors, and AU565, which is resistant. AA increased lipid peroxidation, 4-HNE generation, apoptosis, cellular dox concentration and dox cytotoxicity in both cell lines while sparing cultured immortalized cardiomyocyte cells. The known functions of Rlip including clathrin-dependent endocytosis and dox efflux were inhibited by AA. Our results support a model in which 4-HNE generated by AA overwhelms the capacity of Rlip to defend against apoptosis caused by dox or 4-HNE. We propose that Ω-6 PUFA supplementation could improve the efficacy of dox or Rlip inhibitors for treating Her2-amplified breast cancer.

One third of all neonatal deaths are caused by intrapartum-related events, resulting in neonatal respiratory depression (i.e., failure to breathe at birth). Evidence-based resuscitation with stimulation, airway clearance, and positive pressure ventilation reduces mortality from respiratory depression. Improving adherence to evidence-based resuscitation is vital to preventing neonatal deaths caused by respiratory depression. Standard resuscitation training programs, combined with frequent simulation practice, have not reached their life-saving potential due to ongoing gaps in bedside performance. Complex neonatal resuscitations, such as those involving positive pressure ventilation, are relatively uncommon for any given resuscitation provider, making consistent clinical practice an unrealistic solution for improving performance. This review discusses strategies to allow every birth to act as a learning event within the context of both high- and low-resource settings. We review strategies that involve clinical-decision support during newborn resuscitation, including the visual display of a resuscitation algorithm, peer-to-peer support, expert coaching, and automated guidance. We also review strategies that involve post-event reflection after newborn resuscitation, including delivery room checklists, audits, and debriefing. Strategies that make every birth a learning event have the potential to close performance gaps in newborn resuscitation that remain after training and frequent simulation practice, and they should be prioritized for further development and evaluation.

Neonatal-perinatal medicine (NPM) trainees are expressing an increased interest in global health. NPM fellowship programs are tasked with ensuring that interested fellows receive appropriate training and mentorship to participate in the global health arena. Global health engagement during fellowship varies based on a trainee's experience level, career goals, and academic interests. Some trainees may seek active learning opportunities through clinical rotations abroad whereas others may desire engagement through research or quality improvement partnerships. To accommodate these varying interests, NPM fellows and training programs may choose to explore institutional partnerships, opportunities through national organizations with global collaborators, or domestic opportunities with high-risk populations. During any global health project, the NPM trainee needs robust mentorship from professionals at both their home institution and their partner international site. Trainees intending to use their global health project to fulfill the American Board of Pediatrics (ABP) scholarly activity requirement must also pay particular attention to selecting a project that is feasible during fellowship and also meets ABP criteria for board eligibility. Above all, NPM fellows and training programs should strive to ensure equitable, sustainable, and mutually beneficial collaborations., Competing Interests: AUTHOR DISCLOSURES Drs Rent, North, Diego, and Bose have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device., (Copyright © 2021 by the American Academy of Pediatrics.)

Visible impairments in skin appearance, as well as a subtle decline in its functionality at the molecular level, are hallmarks of skin aging. Activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-pathway, which is important in controlling inflammation and oxidative stress that occur during aging, can be triggered by sulforaphane (SFN), an isothiocyanate found in plants from the Brassicaceae family. This study aimed to assess the effects of SFN intake on age-related skin alterations. Male C57BL6 young (2 months) and old (21 months) mice were treated for 3 months with SFN diet (442.5 mg per kg) or control diet. The antioxidant capacities of the skin were increased in old SFN-treated animals as measured by mRNA levels of Nrf2 (P<.001) and its target genes NQO1 (P<.001) and HO1 (P<.01). Protein expression for Nrf2 was also increased in old SFN fed animals (P<.01), but not the protein expression of NQO1 or HO1. Additionally, ROS and MMP9 protein levels were significantly decreased (P<.05) in old SFN fed animals. Histopathological analysis confirmed that there was no difference in epidermal thickness in old, when compared to young, SFN treated animals, while the dermal layer thickness was lower in old vs. young, treated animals (P<.05). Moreover, collagen deposition was improved with SFN treatment in young (P<.05) and structurally significantly improved in the old mice (P<.001). SFN dietary supplementation therefore ameliorates skin aging through activation of the Nrf2-pathway., (Copyright © 2021. Published by Elsevier Inc.)

The purpose of our study is to understand the role of the RALBP1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer's disease (AD) pathogenesis. The RALPB1 gene encodes the 76 kDa protein RLIP76 (Rlip). Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. We hypothesized that Rlip may play an important role in maintaining cognitive function. The aim of this study is to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype (WT) and Rlip +/- mice were analyzed for OS markers, expression of genes that regulate mitochondrial fission/fusion, and synaptic integrity. We also examined mitochondrial ultrastructure in brains obtained from these mice and further analyzed the impact of Rlip deficiency on gene networks of AD, aging, stress response, mitochondrial function, and CREB signaling. Our studies revealed a significant increase in the levels of OS markers and alterations in the expression of genes and proteins involved in mitochondrial biogenesis, dynamics and synapses in brain tissues from these mice. Furthermore, we compared the cognitive function of WT and Rlip +/- mice. Behavioral, basic motor and sensory function tests in Rlip +/- mice revealed cognitive decline, similar to AD. Gene network analysis indicated dysregulation of stress-activated gene expression, mitochondrial function and CREB signaling genes in the Rlip +/- mouse brain. Our results suggest that Rlip deficiency-associated increases in OS and mitochondrial dysfunction could contribute to the development or progression of OS-related AD processes.

Angiogenesis inhibitors (AGI) are not presently used for the treatment of gastric cancers. This report demonstrates that angiogenesis inhibitor can be safely and effectively used in combination with cytotoxic anti-cancer agents for treatment of Gastric cancers., Competing Interests: SL, PN, and PK have no potential conflicts of interest to declare. DP, DA, NS, RP, SA, SP, JJ, RG, VD, CB, ZR, and AS are in full‐time employment of the Study Sponsor who offers commercial services in oncology. RD is the founder and CMD of the Study Sponsor., (© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Value-added phytochemicals from food by-products and waste materials have gained much interest and among them, dietary polyphenolic compounds with potential biological properties extend a promising sustainable approach. Oxyresveratrol (Oxy), a stilbenoid polyphenol, possesses great therapeutic potential, though its pharmacokinetic issues need attention. A good source of oxyresveratrol was found in underutilized coconut shells and the synbiotic applications of the compound in combination with a potential probiotic isolate Limosilactobacillus fermentum ASBT-2 was investigated. The compound showed lower inhibitory effects on the strain with minimum inhibitory concentration (MIC) of 1000 µg/mL. Oxyresveratrol at sub-MIC concentrations (500 µg/mL and 250 µg/mL) enhanced the probiotic properties without exerting any inhibitory effects on the strain. The combination at sub- MIC concentration of the compound inhibited Salmonella enterica and in silico approaches were employed to elucidate the possible mode of action of oxy on the pathogen. Thus, the combination could target pathogens in the gut without exerting negative impacts on growth of beneficial strains. This approach could be a novel perspective to address the poor pharmacokinetic properties of the compound.

Background: Angiogenic factors are commonly activated in solid tumors and present a viable therapeutic target. However, anticancer treatment with angiogenesis inhibitors (AGI) is limited to a few cancers, mostly as monotherapy and not selected based on molecular indications. We aimed to determine whether patient-specific combination regimens with AGI and other anticancer agents when selected based on multi-analyte tumor interrogation (ETA: Encyclopedic Tumor Analysis) can expand the scope of AGIs in advanced refractory solid organ cancers with improved treatment responses. Methods: We evaluated treatment outcomes in 60 patients with advanced, refractory solid organ cancers who received ETA-guided combination regimens of AGI with other targeted, endocrine or cytotoxic agents. Radiological evaluation of treatment response was followed by determination of Objective Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS). Results: Among the 60 patients, Partial Response (PR) was observed in 28 cases (46.7%), Stable Disease (SD) was observed in 29 cases (48.3%) and Disease Progression (PD, within 60 days) was observed in 3 cases (5.0%). The ORR was 46.7% and DCR was 95.0%. At the most recent follow-up the median PFS (mPFS) was 5.0 months and median OS (mOS) was 8.9 months. There were no Grade 4 therapy related adverse events or treatment related deaths. Conclusion: ETA-guided patient-specific combination regimens with AGI and other anti-neoplastic agents, can yield improved outcomes over AGI monotherapy. Trial Registration: Details of all trials are available at WHO-ICTRP: https://apps.who.int/trialsearch/. RESILIENT ID CTRI/2018/02/011,808. LIQUID IMPACT ID CTRI/2019/02/017,548., Competing Interests: DP, NS, DA, VD, CB, SA, SP and AS are employees of the Study Sponsor; RD is the founder of the Study Sponsor. AG was employed by the HCA Healthcare UK. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Crook, Patil, Nagarkar, Gaya, Plowman, Limaye, Srivastava, Akolkar, Ranade, Bhatt, Datta, Bose, Apurwa, Patil, Kumar, Srinivasan and Datar.)