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Background: The purpose of this study was to assess impingement-free internal rotation (IR) in a virtual reverse shoulder arthroplasty simulation using a Statistical Shape Model based on scapula size. Methods: A database of over 10,000 scapulae utilized for preoperative planning for shoulder arthroplasty was analyzed with a Statistical Shape Model to obtain 5 scapula sizes including the mean and 2 standard deviations. For each scapula model, one glenosphere size (33-42 mm) was selected as the best fit based on consensus among 3 shoulder surgeons. Virtual implantation variables included 1) lateral offset (0-12 mm in 2-mm increments), 2) inferior eccentricity (0, 2.5, 5, and 7.5 mm), and 3) posterior eccentricity (0, 2.5, and 5 mm). The neck shaft angle was fixed at 135° with an inlay design humeral prosthesis. IR at the side (IR0) and in abduction (IRABD) were then simulated. Results: Maximum impingement-free IR0 was reached with increasing inferior offset in combination with increasing lateralization. Lateralization was the most important variable in increasing impingement-free IRABD. Maximum IRABD was reached at 4-6 mm of lateralization with smaller scapula (−2 to 0 standard deviation). Increasing lateralization up to 12 mm continues to increase IRABD for larger-sized scapula (+1 to +2 standard deviation). Optimal inferior offset and lateralization to maximize IR did have a small loss of external rotation in neutral abduction. There was no loss of external rotation in 60° of abduction. Conclusion: In a virtual model, the glenosphere position required to maximize IR varied by scapula size. For smaller scapulae, maximum IR0 was reached with a combination of 2.5-mm inferior offset and 0- 4 mm of lateralization. For larger scapulae, maximum IR0 was reached with a combination of 2.5 mm of inferior offset and 4 mm of lateralization. The amount of lateralization required to maximize IRABD also varies by scapula size. Maximum IRABD was reached in smaller scapula with 4-6 mm of lateralization and at least 12 mm of lateralization in larger scapula. These findings may be applied in the clinical decision-making process knowing that impingement-free IR and IRABD can be maximized with combinations of inferior offset and lateralization based on scapula size with minimal effect on external rotation and external rotation in 60° of abduction.

Introduction: Articular cartilage injuries of the knee are a complex and challenging clinical pathology. Objectives: The purpose of this study was to establish consensus statements via a Delphi process on clinical and research follow-up for knee cartilage injuries. Methods: A consensus process on knee cartilage injuries utilizing a modified Delphi technique was conducted. Seventy-seven surgeons across 17 countries were invited to participate in these consensus statements. Nine questions were generated on clinical and research follow-up, with 3 rounds of questionnaires and final voting occurring. Consensus was defined as achieving 80% to 89% agreement, whereas strong consensus was defined as 90% to 99% agreement, and unanimous consensus was defined as 100% agreement with a proposed statement. Results: Of the 9 total questions and consensus statements on clinical and research follow-up developed from 3 rounds of voting, 1 achieved unanimous consensus, 5 achieved strong consensus, 1 achieved consensus, and 2 did not achieve consensus. Conclusions: The statement that achieved unanimous consensus was on physical examination findings. The statements that achieved strong consensus were related to defining and monitoring treatment success, patient-reported outcomes, research follow-up, and second-look arthroscopy in the setting of recurrence. The statements that did not achieve consensus were related to routine imaging and length of clinical follow-up after operative intervention.

Inpatient treatment of hyperkalaemia with insulin and dextrose can be complicated by iatrogenic hypoglycaemia. We sought to assess the incidence of hypoglycaemia in hospitalised patients with renal disease and assess the impact of the introduction of a local guideline incorporating the use of sodium zirconium cyclosilicate (SZC) for patients with moderate hyperkalaemia. After establishing a significant burden of hypoglycaemia in the initial observation period, a requirement for hourly capillary blood glucose monitoring (for up to 6 h) following the administration of insulin for hyperkalaemia was incorporated into the guidelines. The two-fold introduction of SZC alongside changes in patient care after the administration of insulin/dextrose resulted in more appropriate use of insulin/dextrose, as well as a significant (73%) reduction in the iatrogenic burden of hypoglycaemia (P = 0.04).

Background: Conservative management of atypical endometrial hyperplasia (AEH) or endometrial cancer (EMCA) often relies on the treatment of synthetic progestins, which show varied success and response rates. We evaluate the correlation between steroid receptor expression and response to progestin therapy in patients with AEH and EMCA. Methods: Retrospective cohort study collected data for patients with AEH or EMCA who had an endometrial sample after receiving conservative therapy utilizing either Megestrol acetate or Levonorgestrel Intrauterine device (IUD). Immunohistochemistry (IHC) was performed on pre- and post- treatment biopsy samples to assess androgen receptor (AR), estrogen receptor (ER), and progesterone receptor (PR) expression. IHC scores (1–12) were calculated based on staining intensity and percentage of positive cells. Results and analysis: We identified 15 patients with AEH and EMCA between 2015 and 2023 with the majority of African American ethnicity (53 %). Fourteen patients (93 %) received Megestrol acetate, and 1 patient received Levonorgestrel IUD alone. Three patients ultimately underwent hysterectomy. Seven (46.6 %) endometrial samples had strong positivity for AR, PR and ER expression on pre-treatment biopsies, and only 3 (20 %) of them maintained strong positivity for the 3 receptors in the post-treatment. Patients who successfully responded to the treatment demonstrated a significantly greater decrease in IHC scores after the treatment compared to those who did not respond (p = 0.009). Conclusion: Steroid receptor expression could be used as a possible biomarker for response to progestin therapy in patients undergoing conservative management for AEH and EMCA.

This research aims to investigate the approximate controllability of multivalued impulsive stochastic fractional differential inclusions in Hilbert space with ABC fractional-order derivatives. First, we confirm the existence of mild solutions for the proposed control system using stochastic analysis, resolvent operator theory, and the fixed point technique. Secondly, we discuss a new set of sufficient conditions for the approximate controllability of the systems. The results are obtained under the assumption that the associated linear system is approximately controllable. Finally, an example is provided to illustrate the obtained results.

Background: Improvements in pain control after shoulder arthroplasty with a reduction in narcotic use continues to be an important postoperative goal. With the increased utilization of stemless anatomic total shoulder arthroplasty (aTSA), it is relevant to compare between stemmed and stemless arthroplasty to assess if there is any association between this implant design change and early postoperative pain. Methods: Patients from a multicenter, prospectively-maintained database who had undergone a stemless aTSA with a minimum of two year clinical follow-up were retrospectively identified. Patients who underwent aTSA with a short stem were identified in the same registry, and matched to the stemless aTSA patients by age, sex and preoperative pain score. The primary study outcome was the Visual Analog Scale pain score. Secondary pain outcomes were the American Shoulder and Elbow Surgeons shoulder pain subscore, Western Ontario Osteoarthritis of the Shoulder physical symptoms subscore, and the Single Assessment Numeric Evaluation score. Finally, the percentage of patients who could sleep on the affected shoulder was assessed for each group. These pain-related clinical outcomes were assessed and compared preoperatively, and postoperatively at 9 weeks, 26 weeks, one year and two years. For all statistical comparisons, P > .05 was considered significant. Results: 124 patients were included in the study; 62 in each group. At 9 weeks after surgery, statistically significantly improved pain control was reported by patients undergoing stemless aTSA, as assessed by the Visual Analog Scale (stemless: 1.5, stemmed: 2.5, P = .001), American Shoulder and Elbow Surgeons pain subscore (stemless: 42.4, stemmed: 37.3, P

Introduction: Cauda equina syndrome (CES), conus medullaris syndrome (CMS), and sciatica-like syndromes or “sciatica mimics” (SM) may present as diagnostic and/or therapeutic dilemmas for the practicing spine surgeon. There is considerable controversy regarding the appropriate definition and diagnosis of these entities, as well as indications for and timing of surgery. Our goal is to formulate the most current, evidence-based recommendations for the definition, diagnosis, and management of CES, CMS, and SM syndromes. Methods: We performed a systematic literature search in PubMed from 2012 to 2022 using the keywords “cauda equina syndrome”, “conus medullaris syndrome”, “sciatica”, and “sciatica mimics”. Standardized screening criteria yielded a total of 43 manuscripts, whose data was summarized and presented at two international consensus meetings of the World Federation of Neurosurgical Societies (WFNS) Spine Committee. Utilizing the Delphi method, we generated seven final consensus statements. Results and conclusion: s: We provide standardized definitions of cauda equina, cauda equina syndrome, conus medullaris, and conus medullaris syndrome. We advocate for the use of the Lavy et al classification system to categorize different types of CES, and recommend urgent MRI in all patients with suspected CES (CESS), considering the low sensitivity of clinical examination in excluding CES. Surgical decompression for CES and CMS is recommended within 48 h, preferably within less than 24 h. There is no data regarding the role of steroids in acute CES or CMS. The treating physician should be cognizant of a variety of other pathologies that may mimic sciatica, including piriformis syndrome, and how to manage these.

Purpose: To determine whether low resilience is predictive of worse patient-reported outcomes (PROs) or diminished improvements in clinical outcomes after joint preserving and arthroscopic surgery. Methods: A comprehensive search of PubMed, Medline, Embase, and Science Direct was performed on September 28, 2022, for studies investigating the relationship between resilience and PROs after arthroscopic surgery in accordance with the Preferred Reported Items for Systematic Reviews and Meta-analyses guidelines. Results: Nine articles (level II-IV studies) were included in the final analysis. A total of 887 patients (54% male, average age 45 years) underwent arthroscopic surgery, including general knee (n = 3 studies), ACLR-only knee (n = 1 study), rotator cuff repair (n = 4 studies), and hip (n = 1 study). The Brief Resilience Scale was the most common instrument measuring resilience in 7 of 9 studies (78%). Five of 9 studies (56%) stratified patients based on high, normal, or low resilience cohorts, and these stratification threshold values differed between studies. Only 4 of 9 studies (44%) measured PROs both before and after surgery. Three of 9 studies (33%) reported rates of return to activity, with 2 studies (22%) noting high resilience to be associated with a higher likelihood of return to sport/duty, specifically after knee arthroscopy. However, significant associations between resilience and functional outcomes were not consistently observed, nor was resilience consistently observed to be predictive of subjects’ capacity to return to a preinjury level of function. Conclusions: Patient resilience is inconsistently demonstrated to affect clinical outcomes associated with joint preserving and arthroscopic surgery. However, substantial limitations in the existing literature including underpowered sample sizes, lack of standardization in stratifying patients based on pretreatment resilience, and inconsistent collection of PROs throughout the continuum of care, diminish the strength of most conclusions that have been drawn. Level of Evidence: Level IV, systematic review of level II-IV studies.

Left ventricular assist devices are known for the treatment of heart failure. We present a patient who underwent emergent decommissioning of his left ventricular assist device after experiencing life-threatening hemorrhage. In this case, the patient's outflow graft was avulsed from his left subclavian artery. We used a covered stent to first exclude the outflow graft and an Amplatzer II plug (Abbott Cardiovascular) to then occlude the inflow cannula. Accessing the inflow cannula of the left ventricular assist device was challenging. In hindsight, we could have accessed and occluded the outflow graft via the left subclavian artery before deploying the covered stent.

Peripheral arterial disease (PAD) affects 12 % of adult population and is increasing globally and in India. Peripheral arterial disease when associated with atherosclerosis in two or more other arterial beds such as coronary artery disease (CAD), mesenteric/renal artery and cerebrovascular disease (CVD), is known as polyvascular disease. The Reduction of Atherothrombosis for Continued Health (REACH) registry reported that 1 out of 6 patients had multi-vascular bed involvement. Progression of PAD to critical limb ischaemia (CLI) is seen in 1 % of affected patients per year, but patients who progress to CLI may have a 10- to 15-fold increased risk of cardiovascular death.The 2019 ECS/EAS guidelines for the management of dyslipidaemias have suggested that for primary or secondary prevention in very high risk, patients should follow a therapeutic regimen that achieves >50 % LDL-C reduction from baseline and an LDL-C goal of

With the increase in digital communication, images have become indispensable media for carrying obscured communication these days. Unraveling the presence or details of obscured transmission also known as steganography is termed as steganalysis. Passive steganalysis focuses only on classification of object as clean or adulterated. Finding the length of payload and regions where the message is hidden, in a stego object is a challenging task and forms a part of Active or Forensic Steganalysis. Many researchers have worked towards finding the length of message, but not much work has been done on finding region where message is hidden. This motivated us to work towards finding the region of payload in stego images. Hence this paper proposes a novel technique for detection of payload regions in a stego image combining Denoising Autoencoder with Local Binary Pattern (LBP) Operator. Denoising Autoencoder is used to learn inter relationships between pixels of an image for estimating cover image from the given stego image. LBP operator capable of capturing local inter-relationships within neighborhood coordinates, have been used to compare corresponding blocks in input stego image and estimated cover image for unraveling payload locations. The major advantage of the proposed technique is that it is universal and it does not require cover image or knowledge about steganographic algorithm used. Accuracy of 96.5% and 97.7% respectively was achieved in the experimental study conducted with spatial and JPEG domain images from BOSSBase dataset.

Background & Aims: Inactivating mutations of KDM6A, a histone demethylase, were frequently found in pancreatic ductal adenocarcinoma (PDAC). We investigated the role of KDM6A (lysine demethylase 6A) in PDAC development. Methods: We performed a pancreatic tissue microarray analysis of KDM6A protein levels. We used human PDAC cell lines for KDM6A knockout and knockdown experiments. We performed bromouridine sequencing analysis to elucidate the effects of KDM6A loss on global transcription. We performed studies with Ptf1aCre; LSL-KrasG12D; Trp53R172H/+; Kdm6afl/fl or fl/Y, Ptf1aCre; Kdm6afl/fl or fl/Y, and orthotopic xenograft mice to investigate the impacts of Kdm6a deficiency on pancreatic tumorigenesis and pancreatitis. Results: Loss of KDM6A was associated with metastasis in PDAC patients. Bromouridine sequencing analysis showed up-regulation of the epithelial–mesenchymal transition pathway in PDAC cells deficient in KDM6A. Loss of KDM6A promoted mesenchymal morphology, migration, and invasion in PDAC cells in vitro. Mechanistically, activin A and subsequent p38 activation likely mediated the role of KDM6A loss. Inhibiting either activin A or p38 reversed the effect. Pancreas-specific Kdm6a-knockout mice pancreata showed accelerated PDAC progression, developed a more aggressive undifferentiated type of PDAC, and increased metastases in the background of Kras and p53 mutations. Kdm6a-deficient pancreata in a pancreatitis model had a delayed recovery with increased PDAC precursor lesions compared with wild-type pancreata. Conclusions: Loss of KDM6A accelerates PDAC progression and metastasis, most likely by a noncanonical p38-dependent activin A pathway. KDM6A also promotes pancreatic tissue recovery from pancreatitis. Activin A might be used as a therapeutic target for KDM6A-deficient PDACs.

Out of all emerging infectious diseases, approximately 75% are of zoonotic origin, with their source often traced back to animals. The emergence of zoonoses is driven by a complex interplay between anthropogenic, genetic, ecological, socioeconomic, and climatic factors. This intricate web of influences poses significant challenges for the prediction and prevention of zoonotic outbreaks. Effective coordination and collaboration among the animal, human, and environmental health sectors are essential for proactively addressing major zoonotic diseases. Despite advancements in surveillance and diagnostic practices, the emergence of zoonoses continues to be a pressing global concern. Therefore, prioritizing zoonotic disease surveillance is of paramount importance as part of a comprehensive disease prevention and containment strategy. Furthermore, evaluating existing surveillance systems provides insights into the challenges faced, which can be mitigated through implementation of One Health principles involving relevant stakeholders. To initiate multisectoral partnerships, it is crucial to identify the priorities and core themes of surveillance systems with equitable inputs from various sectors. Strengthening surveillance, promoting data sharing, enhancing laboratory testing capabilities, and fostering joint outbreak responses in both the human and animal health sectors will establish the necessary infrastructure to effectively prevent, predict, detect, and respond to emerging health threats, thereby reinforcing global health security. This review assesses existing surveillance approaches by offering an overview of global agencies engaged in monitoring zoonoses and outlines the essential components required at the human–animal–environment interface for designing comprehensive surveillance networks. Additionally, it discusses the key steps necessary for executing effective zoonotic disease surveillance through a One Health approach, while highlighting the key challenges encountered in establishing such a robust surveillance system.

Summary: Recent breakthroughs in cancer immunotherapy have provided unprecedented clinical benefits to human cancer patients. Cancer is also one of the most common causes of death in pet dogs. Thus, canine-specific immune therapies targeting similar signaling pathways can provide better treatment options for canine cancer patients. Here, we describe the development and characterization of two canine-specific anti-OX40 agonists to activate OX40 signaling. We show that canine OX40, like human OX40, is not expressed on resting T cells, and its expression is markedly increased on canine CD4 T cells and Tregs after stimulation with concanavalin A (Con-A). cOX40 is also expressed on tumor-infiltrating lymphocytes (TILs) in canine osteosarcoma patients. The canine-specific OX40 agonists strongly activates cPBMCs by increasing IFN-γ expression and do not require Fc receptor-mediated cross-linking for OX40 agonism. Together, these results suggest that cFcOX40L proteins are potent OX40 agonists and have the potential to enhance antitumor immunity in canine cancer patients.

Summary: Background: More than 3 billion people do not have access to clean energy and primarily use solid fuels to cook. Use of solid fuels generates household air pollution, which was associated with more than 2 million deaths in 2019. Although local patterns in cooking vary systematically, subnational trends in use of solid fuels have yet to be comprehensively analysed. We estimated the prevalence of solid-fuel use with high spatial resolution to explore subnational inequalities, assess local progress, and assess the effects on health in low-income and middle-income countries (LMICs) without universal access to clean fuels. Methods: We did a geospatial modelling study to map the prevalence of solid-fuel use for cooking at a 5 km × 5 km resolution in 98 LMICs based on 2·1 million household observations of the primary cooking fuel used from 663 population-based household surveys over the years 2000 to 2018. We use observed temporal patterns to forecast household air pollution in 2030 and to assess the probability of attaining the Sustainable Development Goal (SDG) target indicator for clean cooking. We aligned our estimates of household air pollution to geospatial estimates of ambient air pollution to establish the risk transition occurring in LMICs. Finally, we quantified the effect of residual primary solid-fuel use for cooking on child health by doing a counterfactual risk assessment to estimate the proportion of deaths from lower respiratory tract infections in children younger than 5 years that could be associated with household air pollution. Findings: Although primary reliance on solid-fuel use for cooking has declined globally, it remains widespread. 593 million people live in districts where the prevalence of solid-fuel use for cooking exceeds 95%. 66% of people in LMICs live in districts that are not on track to meet the SDG target for universal access to clean energy by 2030. Household air pollution continues to be a major contributor to particulate exposure in LMICs, and rising ambient air pollution is undermining potential gains from reductions in the prevalence of solid-fuel use for cooking in many countries. We estimated that, in 2018, 205 000 (95% uncertainty interval 147 000–257 000) children younger than 5 years died from lower respiratory tract infections that could be attributed to household air pollution. Interpretation: Efforts to accelerate the adoption of clean cooking fuels need to be substantially increased and recalibrated to account for subnational inequalities, because there are substantial opportunities to improve air quality and avert child mortality associated with household air pollution. Funding: Bill & Melinda Gates Foundation.

Summary: The cyclin-dependent kinase CDK12 has garnered interest as a cancer therapeutic target as DNA damage response genes are particularly suppressed by loss of CDK12 activity. In this study, we assessed the acute effects of CDK12 inhibition on transcription and RNA processing using nascent RNA Bru-seq and BruChase-seq. Acute transcriptional changes were overall small after CDK12 inhibition but over 600 genes showed intragenic premature termination, including DNA repair and cell cycle genes. Furthermore, many genes showed reduced transcriptional readthrough past the end of genes in the absence of CDK12 activity. RNA turnover was dramatically affected by CDK12 inhibition and importantly, caused increased degradation of many transcripts from DNA damage response genes. We also show that co-transcriptional splicing was suppressed by CDK12 inhibition. Taken together, these studies reveal the roles of CDK12 in regulating transcription elongation, transcription termination, co-transcriptional splicing, and RNA turnover.

Anabolic metabolism of carbon in mammals is mediated via the one- and two-carbon carriers S-adenosyl methionine and acetyl-coenzyme A. In contrast, anabolic metabolism of three-carbon units via propionate has not been shown to extensively occur. Mammals are primarily thought to oxidize the three-carbon short chain fatty acid propionate by shunting propionyl-CoA to succinyl-CoA for entry into the TCA cycle. Here, we found that this may not be absolute as, in mammals, one nonoxidative fate of propionyl-CoA is to condense to two three-carbon units into a six-carbon trans-2-methyl-2-pentenoyl-CoA (2M2PE-CoA). We confirmed this reaction pathway using purified protein extracts provided limited substrates and verified the product via LC-MS using a synthetic standard. In whole-body in vivo stable isotope tracing following infusion of 13C-labeled valine at steady state, 2M2PE-CoA was found to form via propionyl-CoA in multiple murine tissues, including heart, kidney, and to a lesser degree, in brown adipose tissue, liver, and tibialis anterior muscle. Using ex vivo isotope tracing, we found that 2M2PE-CoA also formed in human myocardial tissue incubated with propionate to a limited extent. While the complete enzymology of this pathway remains to be elucidated, these results confirm the in vivo existence of at least one anabolic three- to six-carbon reaction conserved in humans and mice that utilizes propionate.

Purpose: Management of adult soft tissue sarcomas entails a multidisciplinary approach with surgery and radiation therapy with or without chemotherapy. The use of preoperative irradiation has been well established, and although conventional fractionation involves daily treatments over the course of 5 weeks, higher doses per fraction may be beneficial due to the radiobiologic profile of sarcoma. In this study we report long-term oncologic outcomes from a single-institution, phase II study evaluating a 5-fraction hypofractionated course of preoperative radiation. Methods and materials: Preoperative hypofractionated radiation therapy was administered to 35 Gy in 5 fractions every other day followed by resection 4 to 6 weeks later. If given, chemotherapy consisted of a doxorubicin-ifosfamide-based regimen delivered neoadjuvantly. The primary endpoint was local control. Additional survival and pathologic outcomes, including overall and distant metastasis-free survival, tumor, and treatment-related pathology, as well as acute and late toxicity were examined. Results: Thirty-two patients were enrolled in this prospective, single-arm phase II trial. At a median follow-up of 36.4 months (range, 3-56), no patient developed a local recurrence, and the 3-year overall and distant metastasis-free survival was 82.2% and 69%, respectively. Major acute postoperative wound complications occurred in 25% of patients. Grade 2 and 3 fibrosis occurred in 21.7% and 13% of patients, respectively. The 2-year median and mean Musculoskeletal Tumor Society score for all patients was 28 and 27.4, respectively. Conclusions: A condensed course of preoperative hypofractionated radiation therapy leads to excellent rates of local control and survival with acceptable toxicity profiles. Potential studies ideally with phase II or III randomized trials would help corroborate these findings and other preoperative hypofractionated results in soft tissue sarcomas.

Because of its critical role in HDL formation, significant efforts have been devoted to studying apolipoprotein A-I (APOA1) structural transitions in response to lipid binding. To assess the requirements for the conformational freedom of its termini during HDL particle formation, we generated three dimeric APOA1 molecules with their termini covalently joined in different combinations. The dimeric (d)-APOA1C-N mutant coupled the C-terminus of one APOA1 molecule to the N-terminus of a second with a short alanine linker, whereas the d-APOA1C-C and d-APOA1N-N mutants coupled the C-termini and the N-termini of two APOA1 molecules, respectively, using introduced cysteine residues to form disulfide linkages. We then tested the ability of these constructs to generate reconstituted HDL by detergent-assisted and spontaneous phospholipid microsolubilization methods. Using cholate dialysis, we demonstrate WT and all APOA1 mutants generated reconstituted HDL particles of similar sizes, morphologies, compositions, and abilities to activate lecithin:cholesterol acyltransferase. Unlike WT, however, the mutants were incapable of spontaneously solubilizing short chain phospholipids into discoidal particles. We found lipid-free d-APOA1C-N and d-APOA1N-N retained most of WT APOA1’s ability to promote cholesterol efflux via the ATP binding cassette transporter A1, whereas d-APOA1C-C exhibited impaired cholesterol efflux. Our data support the double belt model for a lipid-bound APOA1 structure in nascent HDL particles and refute other postulated arrangements like the “double super helix.” Furthermore, we conclude the conformational freedom of both the N- and C-termini of APOA1 is important in spontaneous microsolubilization of bulk phospholipid but is not critical for ABCA1-mediated cholesterol efflux.

The concept of returning to sport for a professional athlete is still under debate for the professional athlete in today’s sports environment. It is critical for the professional athlete to be able to return to sport at a highly competitive level but also to return in a safe and timely measure. With no “gold standard” of sport testing, it is difficult to determine what the right progression or testing regimen should be. The Return to Sport Clearance Continuum does not look at one moment in time, but looks throughout the continuum of healing to determine readiness for sport. The purpose of this article is to explore the concept of RTS being part of an evolving continuum rather than the traditional notion that RTS is a single decision made at a discrete point in time. The principles of progressive but regular testing procedures including qualitative and quantitative movement are presented to help the professional athlete return to sport at their maximal performance level. Level of Evidence: V, expert opinion.

Shoulder and elbow injuries during athletic participation are very common and may require operative intervention if refractory to conservative care. In recovering from these upper extremity injuries, proper postoperative rehabilitation and setting reasonable expectations regarding return to play are very important. This review article focuses on the most common surgically treated shoulder and elbow injuries, including rotator cuff tears, SLAP tears, anterior and posterior shoulder instability, and elbow ulnar collateral ligament tears. Rates of return to play after surgical intervention are encouraging in most professional and recreational athletes but are highly dependent on the severity of injury, as well as the demands and position in sport. Real-world strategies for staged successful rehabilitation are presented and discussed.

Objectives: Paternally inherited alterations in epigenetic programming are emerging as relevant factors in numerous disease states, including the growth and metabolic defects observed in fetal alcohol spectrum disorders. In rodents, chronic paternal alcohol use induces fetal growth restriction, as well as sex-specific alterations in insulin signaling and lipid homeostasis in the offspring. Based on previous studies, we hypothesized that the observed metabolic irregularities are the consequence of paternally inherited alterations liver x receptor (LXR) activity. Methods: Male offspring of alcohol-exposed sires were challenged with a high-fat diet and the molecular pathways controlling glucose and lipid homeostasis assayed for LXR-induced alterations. Results: Similar to findings in studies employing LXR agonists we found that the male offspring of alcohol-exposed sires display resistance to diet-induced obesity and improved glucose homeostasis when challenged with a high-fat diet. This improved metabolic adaptation is mediated by LXRα trans-repression of inflammatory cytokines, releasing IKKβ inhibition of the insulin signaling pathway. Interestingly, paternally programmed increases in LXRα expression are liver-specific and do not manifest in the pancreas or visceral fat. Conclusions: These studies identify LXRα as a key mediator of the long-term metabolic alterations induced by preconception paternal alcohol use. Keywords: Epigenetic programming, Liver X receptor, Nuclear receptor, Insulin signaling, Inflammation, Paternal alcohol exposure, Metabolic programming, Preconception, Developmental origins of adult disease

Traumatic amputation of the penis is a rare but disabling condition that can occur during self-inflicted injury, felonious assault, accidental trauma, or circumcision. This report aims to access the cosmetic and functional results of a penile replantation without micro-anastomosis after a penile traumatic amputation during circumcision in a limited resource setting. A one-year-old child presented penile amputation located at 2mm below the neck of the glans penis during circumcision. We admitted the child to the theatre of the Campus Teaching Hospital of Lomé (Togo) 3 h after the trauma. Under general anaesthesia, we performed an end-to-end urethra, corpus spongiosum, corpora cavernosa, and skin to mucosa anastomosis. We positioned a Foley catheter for 12 days and established an anticoagulation treatment for a week. During the postoperative course, there was progressive necrosis of the skin and the glans mucosa. We performed debridement. The glans and corpora cavernosa were viable. Non-microsurgical anastomosis of the glans showed to preserve the cosmetic and genital function of the victim.

Background: Lack of treatment of novel Coronavirus disease led to the search of specific antivirals that are capable to inhibit the replication of the virus. The plant kingdom has demonstrated to be an important source of new molecules with antiviral potential. Purpose: The present study aims to utilize various computational tools to identify the most eligible drug candidate that have capabilities to halt the replication of SARS-COV-2 virus by inhibiting Main protease (Mpro) enzyme Methods: We have selected plants whose extracts have inhibitory potential against previously discovered coronaviruses. Their phytoconstituents were surveyed and a library of 100 molecules was prepared. Then, computational tools such as molecular docking, ADMET and molecular dynamic simulations were utilized to screen the compounds and evaluate them against Mpro enzyme. Results: All the phytoconstituents showed good binding affinities towards Mpro enzyme. Among them laurolitsine possesses the highest binding affinity i.e. -294.1533 kcal/mol. On ADMET analysis of best three ligands were simulated for 1.2 ns, then the stable ligand among them was further simulated for 20 ns. Results revealed that no conformational changes were observed in the laurolitsine w.r.t. protein residues and low RMSD value suggested that the Laurolitsine-protein complex was stable for 20 ns. Conclusion: Laurolitsine, an active constituent of roots of Lindera aggregata, was found to be having good ADMET profile and have capabilities to halt the activity of the enzyme. Therefore, this makes laurolitsine a good drug candidate for the treatment of COVID-19.

Objective: To prepare a novel nanoemulsion- Carbopol® 934 gel for Eugenol, in order to prevent the periodontitis. Material and methods: Spontaneous emulsification method was used for the preparation of nanoemulsion in which it contain Eugenol (oil phase), Tween-80 (surfactant), and PEG (co-surfactant). To the development of best nanoemulsion, three-factor three-level central composite design was used in which %oil; %Smix and % water were optimized as independent variables. An optimized–nanoemulsion were converted to nanoemulsion–Carbopol® 934 gel. Results: 5.5% oil, 35.5% Smix and 59.0% water were optimized as independent and dependent variables. Finally dependent variables optimized as a particle size (nm), PDI and %transmittance were observed 79.92 ± 6.33 nm, 0.229 ± 0.019, and 98.88 ± 1.31% respectively. The values of final results for dependent variables like particle size (nm), PDI and % transmittance were evaluated as 79.92 ± 6.33 nm, 0.229 ± 0.019, and 98.88 ± 1.31%, respectively. TEM and SEM showed a spherical shape of developed nanoemulsion with refractive index (1.63 ± 0.038), zeta potential (−19.16 ± 0.11), pH (7.4 ± 0.06), viscosity (34.28 ± 6 cp), and drug content of 98.8 ± 0.09%. After that a final optimized EUG–NE–Gel was assessed on the basis of their pH measurement, drug content, syringeability, and mucoadhesion on the goat buccal mucosa. Optimized EUG-NE-Gel (Tween-80 and Carbopol® 934 used) showed the results, to improve the periodontal drug delivery of EUG in future. Conclusion: EUG-NE-Gel showed a significant role in anti-inflammatory activity, analgesic, and anesthetic, antibacterial, and treatment of periodontal disease. Keywords: Eugenol, Nanoemulsion–gel, Mucoadhesion, Anti-inflammatory & periodontal disease

Duplication of the inferior vena cava (IVC) with coagulation mutations in the form of factor V Leiden and MTHFR mutations represents an unusual subset of patients. We are reporting a case of a 43-year-old man who presented with left iliofemoral deep venous thrombosis diagnosed on duplex ultrasound scan. At the time of catheter-directed thrombolysis with prophylactic IVC filter placement, a duplicated IVC system was observed. After thrombolysis, a stenotic lesion in the left common iliac vein and IVC was stented. IVC filters were retrieved after 6 weeks. On thrombophilia profile testing at 3 months, he was also found to have factor V Leiden and MTHFR mutations. After 12 months of follow-up, the patient is asymptomatic with a patent iliocaval venous system and is receiving lifelong anticoagulation. Keywords: Duplicated IVC, Catheter-directed thrombolysis, Deep venous thrombosis

PURPOSE: Despite the availability of current standards of care treatments for triple negative breast cancer (TNBC), many patients still die from this disease. Quadruple negative tumors, which are TNBC tumors that lack androgen receptor (AR), represent a more aggressive subtype of TNBC; however, the molecular features are not well understood. METHODS: Immunohistochemistry of estrogen receptor (ER), progesterone receptor (PR), HER2, and AR was determined in 244 primary and 630 recurrent/metastatic site biopsies. Expression was correlated with a panel of 25 cancer-related genes and proteins by IHC and in situ hybridization (ISH). RESULTS: We observed that 80.2% (65 of 81) of primary TNBC tumors and 75.7% (159 of 210) of recurrent/metastatic TNBC tumors are QNBC. Bivariate fit analysis demonstrated that QNBC (n = 224) significantly (P

Human high-density lipoproteins (HDLs) are a complex mixture of structurally related nanoparticles that perform distinct physiological functions. We previously showed that human HDL containing apolipoprotein A-I (APOA1) but not apolipoprotein A-II (APOA2), designated LpA-I, is composed primarily of two discretely sized populations. Here, we isolated these particles directly from human plasma by antibody affinity chromatography, separated them by high-resolution size-exclusion chromatography and performed a deep molecular characterization of each species. The large and small LpA-I populations were spherical with mean diameters of 109 Å and 91 Å, respectively. Unexpectedly, isotope dilution MS/MS with [15N]-APOA1 in concert with quantitation of particle concentration by calibrated ion mobility analysis demonstrated that the large particles contained fewer APOA1 molecules than the small particles; the stoichiometries were 3.0 and 3.7 molecules of APOA1 per particle, respectively. MS/MS experiments showed that the protein cargo of large LpA-I particles was more diverse. Human HDL and isolated particles containing both APOA1 and APOA2 exhibit a much wider range and variation of particle sizes than LpA-I, indicating that APOA2 is likely the major contributor to HDL size heterogeneity. We propose a ratchet model based on the trefoil structure of APOA1 whereby the helical cage maintaining particle structure has two “settings”—large and small—that accounts for these findings. This understanding of the determinants of HDL particle size and protein cargo distribution serves as a basis for determining the roles of HDL subpopulations in metabolism and disease states.

Summary: Background: Universal access to safe drinking water and sanitation facilities is an essential human right, recognised in the Sustainable Development Goals as crucial for preventing disease and improving human wellbeing. Comprehensive, high-resolution estimates are important to inform progress towards achieving this goal. We aimed to produce high-resolution geospatial estimates of access to drinking water and sanitation facilities. Methods: We used a Bayesian geostatistical model and data from 600 sources across more than 88 low-income and middle-income countries (LMICs) to estimate access to drinking water and sanitation facilities on continuous continent-wide surfaces from 2000 to 2017, and aggregated results to policy-relevant administrative units. We estimated mutually exclusive and collectively exhaustive subcategories of facilities for drinking water (piped water on or off premises, other improved facilities, unimproved, and surface water) and sanitation facilities (septic or sewer sanitation, other improved, unimproved, and open defecation) with use of ordinal regression. We also estimated the number of diarrhoeal deaths in children younger than 5 years attributed to unsafe facilities and estimated deaths that were averted by increased access to safe facilities in 2017, and analysed geographical inequality in access within LMICs. Findings: Across LMICs, access to both piped water and improved water overall increased between 2000 and 2017, with progress varying spatially. For piped water, the safest water facility type, access increased from 40·0% (95% uncertainty interval [UI] 39·4–40·7) to 50·3% (50·0–50·5), but was lowest in sub-Saharan Africa, where access to piped water was mostly concentrated in urban centres. Access to both sewer or septic sanitation and improved sanitation overall also increased across all LMICs during the study period. For sewer or septic sanitation, access was 46·3% (95% UI 46·1–46·5) in 2017, compared with 28·7% (28·5–29·0) in 2000. Although some units improved access to the safest drinking water or sanitation facilities since 2000, a large absolute number of people continued to not have access in several units with high access to such facilities (>80%) in 2017. More than 253 000 people did not have access to sewer or septic sanitation facilities in the city of Harare, Zimbabwe, despite 88·6% (95% UI 87·2–89·7) access overall. Many units were able to transition from the least safe facilities in 2000 to safe facilities by 2017; for units in which populations primarily practised open defecation in 2000, 686 (95% UI 664–711) of the 1830 (1797–1863) units transitioned to the use of improved sanitation. Geographical disparities in access to improved water across units decreased in 76·1% (95% UI 71·6–80·7) of countries from 2000 to 2017, and in 53·9% (50·6–59·6) of countries for access to improved sanitation, but remained evident subnationally in most countries in 2017. Interpretation: Our estimates, combined with geospatial trends in diarrhoeal burden, identify where efforts to increase access to safe drinking water and sanitation facilities are most needed. By highlighting areas with successful approaches or in need of targeted interventions, our estimates can enable precision public health to effectively progress towards universal access to safe water and sanitation. Funding: Bill & Melinda Gates Foundation.

Summary: Background: Lymphatic filariasis is a neglected tropical disease that can cause permanent disability through disruption of the lymphatic system. This disease is caused by parasitic filarial worms that are transmitted by mosquitos. Mass drug administration (MDA) of antihelmintics is recommended by WHO to eliminate lymphatic filariasis as a public health problem. This study aims to produce the first geospatial estimates of the global prevalence of lymphatic filariasis infection over time, to quantify progress towards elimination, and to identify geographical variation in distribution of infection. Methods: A global dataset of georeferenced surveyed locations was used to model annual 2000–18 lymphatic filariasis prevalence for 73 current or previously endemic countries. We applied Bayesian model-based geostatistics and time series methods to generate spatially continuous estimates of global all-age 2000–18 prevalence of lymphatic filariasis infection mapped at a resolution of 5 km2 and aggregated to estimate total number of individuals infected. Findings: We used 14 927 datapoints to fit the geospatial models. An estimated 199 million total individuals (95% uncertainty interval 174–234 million) worldwide were infected with lymphatic filariasis in 2000, with totals for WHO regions ranging from 3·1 million (1·6–5·7 million) in the region of the Americas to 107 million (91–134 million) in the South-East Asia region. By 2018, an estimated 51 million individuals (43–63 million) were infected. Broad declines in prevalence are observed globally, but focal areas in Africa and southeast Asia remain less likely to have attained infection prevalence thresholds proposed to achieve local elimination. Interpretation: Although the prevalence of lymphatic filariasis infection has declined since 2000, MDA is still necessary across large populations in Africa and Asia. Our mapped estimates can be used to identify areas where the probability of meeting infection thresholds is low, and when coupled with large uncertainty in the predictions, indicate additional data collection or intervention might be warranted before MDA programmes cease. Funding: Bill & Melinda Gates Foundation.

Summary: Background: Oral rehydration solution (ORS) is a form of oral rehydration therapy (ORT) for diarrhoea that has the potential to drastically reduce child mortality; yet, according to UNICEF estimates, less than half of children younger than 5 years with diarrhoea in low-income and middle-income countries (LMICs) received ORS in 2016. A variety of recommended home fluids (RHF) exist as alternative forms of ORT; however, it is unclear whether RHF prevent child mortality. Previous studies have shown considerable variation between countries in ORS and RHF use, but subnational variation is unknown. This study aims to produce high-resolution geospatial estimates of relative and absolute coverage of ORS, RHF, and ORT (use of either ORS or RHF) in LMICs. Methods: We used a Bayesian geostatistical model including 15 spatial covariates and data from 385 household surveys across 94 LMICs to estimate annual proportions of children younger than 5 years of age with diarrhoea who received ORS or RHF (or both) on continuous continent-wide surfaces in 2000–17, and aggregated results to policy-relevant administrative units. Additionally, we analysed geographical inequality in coverage across administrative units and estimated the number of diarrhoeal deaths averted by increased coverage over the study period. Uncertainty in the mean coverage estimates was calculated by taking 250 draws from the posterior joint distribution of the model and creating uncertainty intervals (UIs) with the 2·5th and 97·5th percentiles of those 250 draws. Findings: While ORS use among children with diarrhoea increased in some countries from 2000 to 2017, coverage remained below 50% in the majority (62·6%; 12 417 of 19 823) of second administrative-level units and an estimated 6 519 000 children (95% UI 5 254 000–7 733 000) with diarrhoea were not treated with any form of ORT in 2017. Increases in ORS use corresponded with declines in RHF in many locations, resulting in relatively constant overall ORT coverage from 2000 to 2017. Although ORS was uniformly distributed subnationally in some countries, within-country geographical inequalities persisted in others; 11 countries had at least a 50% difference in one of their units compared with the country mean. Increases in ORS use over time were correlated with declines in RHF use and in diarrhoeal mortality in many locations, and an estimated 52 230 diarrhoeal deaths (36 910–68 860) were averted by scaling up of ORS coverage between 2000 and 2017. Finally, we identified key subnational areas in Colombia, Nigeria, and Sudan as examples of where diarrhoeal mortality remains higher than average, while ORS coverage remains lower than average. Interpretation: To our knowledge, this study is the first to produce and map subnational estimates of ORS, RHF, and ORT coverage and attributable child diarrhoeal deaths across LMICs from 2000 to 2017, allowing for tracking progress over time. Our novel results, combined with detailed subnational estimates of diarrhoeal morbidity and mortality, can support subnational needs assessments aimed at furthering policy makers' understanding of within-country disparities. Over 50 years after the discovery that led to this simple, cheap, and life-saving therapy, large gains in reducing mortality could still be made by reducing geographical inequalities in ORS coverage. Funding: Bill & Melinda Gates Foundation.

Summary: Background: Availability of data to assess the population health and provision and quality of health care in Saudi Arabia has been lacking. In 2010, Saudi Arabia began a major investment and transformation programme in the health-care sector. Here we assess the impact of this investment era on mortality, health loss, risk factors, and health-care services in the country. Methods: We used results of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to describe the levels and temporal patterns in deaths, health loss, risk factors, and health-care access and quality in the Saudi Arabian population during 1990–2010 (before the health-care investments and reform) and 2010–17 (during health-care investments and reform). We also compared patterns in health outcomes between these periods with those in the north Africa and the Middle East GBD region and the Gulf Cooperation Council countries. Findings: Age-standardised mortality in Saudi Arabia decreased from 1990 to 2010 (annualised rate of change of −0·58%), and this decrease was further accelerated from 2010 to 2017 (–2·20%). The north Africa and the Middle East GBD region also had decreases in mortality during these periods, but for 2010–17 the decrease was not as low as in Saudi Arabia (–1·29%). Transport injuries decreased from third ranked cause of disability-adjusted life-years in 2010 to fifth ranked cause in 2017 in Saudi Arabia, below cardiovascular diseases (ranked first) and musculoskeletal disorders (ranked second). Years lived with disability (YLDs) due to mental disorders, substance use disorders, neoplasms, and neurological disorders consistently increased over the periods 1990–2010 and 2010–17. Between 1990 and 2017, attributable YLDs due to metabolic, behavioural, and environmental or occupational risk factors remained almost unchanged in Saudi Arabia, with high body-mass index, high fasting plasma glucose concentration, and drug use increasing across all age groups. Health-care Access and Quality (HAQ) Index levels increased in Saudi Arabia during this period with similar patterns to the rest of the Gulf Cooperation Council countries and the north Africa and the Middle East GBD region. Interpretation: Decreases in mortality continued at greater rates in Saudi Arabia during the period of 2010–17 than in 1990–2010. HAQ Index levels have also improved. Public health policy makers in Saudi Arabia need to increase efforts to address preventable risk factors that are major contributors to the burden of ill health and disability. Funding: Bill & Melinda Gates Foundation.

Seafood is a major source of human exposure to polybrominated diphenyl ethers (PBDEs). The intake of these globally distributed and bioaccumulative contaminants depends on both consumption patterns (which seafoods are consumed) and on their origins. Here, we investigate exposure to PBDEs through seafood consumption as a function of species, origins and consumption levels. We estimate the contribution of seafood consumption to PBDE exposures in the Swiss population using two approaches. The first approach estimates exposures by estimating the composition of the Swiss seafood diet using trade data and national statistics on total seafood consumption. This naïve approach could be used for any country for which no individually reported consumption data are available for a population. The second approach uses dietary survey data provided by the Swiss Federal Statistical Office as part of the menuCH study for exposure estimates. To support region- and species-specific estimates of exposures for both approaches, we built a database of PBDE concentrations in seafood by analysis of published PBDE levels in fish from food markets or freshwater resources from various countries. We find estimated PBDE exposures ranging from 0.15 to 0.65 ng/kg bw/day for the trade data-based diet. These were close to the median exposures of 0.68 ng/kg bw/day for the Swiss population based on the menuCH survey, indicating that the composition and consumption rate derived from trade data are appropriate for calculating exposures in the average adult population. However, it could not account for PBDE exposures of more vulnerable (high seafood consuming) populations captured only by the survey data. All estimates were lower than the PBDE Chronic Oral Reference Doses (RfD’s) suggested by the EPA, but could increase substantially to a value of 7 ng/kg bw/day if fish are sourced from the most contaminated origins, as in the case of Vietnamese shrimp/prawn, Norwegian salmon, and Swiss whitefish. Exposures as high as 8.50 ng/kg bw/day are estimated for the survey-based diet, which better captures the variability in consumption by individuals, including extreme high and low values. In general, the most frequently consumed species reported by Swiss consumers are consistent with those predicted using trade data. Keywords: Exposure, e-waste, International food trade, Polybrominated diphenyl ethers (PBDE), Seafood, Diet

The mortality rate in patients suffering from non-small cell lung cancer (NSCLC) is quite high. This type of cancer mainly occurs due to rearrangements in the anaplastic lymphoma kinase (ALK) gene which leads to form an oncogene of fused gene NPM-ALK. Brigatinib is recently approved by FDA in April 2017 as a potent tyrosine kinase inhibitor (TKI) for the NSCLC therapy. In the present scenario, it is no less than a wonder drug because it is indicated for the treatment of advanced stages of metastatic ALK positive NSCLC, a fatal disease to overcome the resistance of various other ALK inhibitors such as crizotinib, ceritinib and alectinib. In addition to ALK, it is also active against multiple types of kinases such as ROS1, Insulin like growth factor-1Receptor and EGFR. It can be synthesized by using N-[2-methoxy-4-[4-(dimethylamino) piperidin-1-yl] aniline] guanidine and 2,4,5-trichloropyrimidine respectively in two different ways. Its structure consists of mainly dimethylphosphine oxide group which is responsible for its pharmacological activity. It is active against various cell lines such as HCC78, H2228, H23, H358, H838, U937, HepG2 and Karpas- 299. Results of ALTA (ALK in Lung Cancer Trial of AP26113) phase ½ trial shows that 90 mg of brigatinib for 7 days and then 180 mg for next days is effective in the treatment of NSCLC. Brigatinib has been shown to have favorable risk benefit profile and is a safer drug than the available cytotoxic chemotherapeutic agents. In comparison to other FDA approved drugs for the same condition, it causes fewer minor adverse reactions which can be easily managed either by changing the dose or by providing good supportive care. This article is intended to provide readers with an overview of chemistry, pharmacokinetic, pharmacodynamic and safety profile of brigatinib, which addresses an unmet medical need. Keywords: ALK inhibitors, Brigatinib, Lung cancer, Kinase, Lymphoma

Objective: Omega-3 fatty acids, especially alpha-linolenic acid (ALA), which are present in nuts may reduce cardiovascular disease (CVD) risk, by changing vascular inflammation and improving endothelial dysfunction. The objective of the study was to evaluate the acute effects of two different diets, one containing walnuts and the other almonds on endothelial function. Methods: Twenty-seven overweight volunteers underwent a randomized 2-period, crossover, controlled intervention study. The subjects were given either walnut or almond diets which varied in monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA) content. The walnut diet provided 23.1% energy from PUFA and the almond diet provided 7.6% energy from PUFA. Endothelial function was assessed physiologically by flow-mediated dilation (FMD) and biochemically by sVCAM (soluble vascular cell adhesion molecules). Results: The walnut diet significantly improved FMD (p = 0.004) and decreased sVCAM (p = 0.009) whereas the almond diet tended to improve FMD (p = 0.06) and significantly decreased sVCAM (p = 0.004). Conclusion: Both walnut and almond diets improved FMD and sVCAM and there was no significant difference in physiological and biochemical markers between the two diets. Keywords: Almonds, Walnuts, Endothelial Function, sVCAM, Flow mediated dilation (FMD), MUFA, PUFA

Background: Brucellosis is one of the neglected zoonotic diseases in humans. The serological methods based on antibody detections are unable to detect the effectiveness of treatment in humans as antibodies persist for long time in humans even after therapy. Therefore, we developed qPCR technique to overcome such discrepancy and device a rapid and efficient test for both diagnosis and follow up of the brucellosis affected individuals. Methods: High risk suspected individuals with positive serology (RBPT, STAT and iELISA) and PCR were mainly analyzed for DNA quantification by qPCR assay. The bcsp-31 gene, a shared gene of Brucella species was amplified by genus specific primers and cloned to pGEMT™ easy vector and the cloned plasmid were used to construct a standard curve (R2 = 0.99, efficiency = 1.98) over 7 orders of magnitude with sensitivity of ≈10 copy number. The assay was found 100% specific. Results: Overall 85 individuals were found positive out of 188. Out of them, 23 serological, PCR and qPCR positive individuals were recommended for 45 days therapy according to WHO regimen (Doxycycline and Rifampin) and each case was further followed by qPCR. The mean threshold cycle (Cq) before treatment was 26.05 ± 0.347 (3940.5 copies/μl), which increased significantly to 32.7 ± 0.66 (259.13 copies/μl) on 4th week during treatment, 35.12 ± 3.12 (38.52 copies/μl) at 6th week on day of treatment completion, 35.6 ± 0.66 (34.21 copies/μl) on 21st day after treatment depicting a significant reduction in DNA load over the course of treatment. Serological follow up showed that only 3 individuals had decreased STAT titre but no change in RBPT results. Out of 17 symptomatic individuals under therapy, 10 improved clinically, 5 improved clinically with persistent weakness and 2 had no effect of therapy. Conclusion: The study suggests that qPCR is more useful and rapid test to follow treated individuals than serology. Keywords: Brucella, qPCR, Cq value, High-risk individuals, Copy number

Nowadays, applications of nanosized materials have been an important issue in basic and applied sciences. In this investigation, Zinc Oxide (ZnO) nanoparticles were prepared by two different techniques (simple heat treatment, thermal evaporation-two zone furnaces). In order to control shape and size – ZnO nanoparticles prepared from heat treatment were used as a source for thermal evaporation method by using two zone split furnace by varying zone temperature (Zone 1–800 °C and Zone 2–400 °C). For both techniques 0.17 M of Zn acetate dihydrate is used as main precursor and film is deposited on glass substrate. Synthesized ZnO were characterized for XRD, FESEM, FTIR and UV–Vis spectrophotometer and LCR meter. XRD revealed hexagonal wurtzite structure with preferential orientation along (1 0 1) plane. FESEM observed that grain size in the range of range of ∼50 ± 5 nm. FTIR spectra showed that the peaks between 400 and 500 cm−1 for ZnO stretching modes. Optical properties has been studied and found that the observed band gap lies in the range of 3.32–3.36 eV. The higher value of capacitance is observed at lower frequency. Gas sensing properties showed the higher response in case of thermal evaporation as compared to simple heat treatment at an operating temperature of 250 °C. Keywords: ZnO nanoparticles, Simple heat treatment, Thermal evaporation, Gas sensor

The data presented in this article are related to the research paper titled, “The impact of a household biogas programme on energy use and expenditure in East Java” (A.S. Bedi, R. Sparrow, L. Tasciotti, 2017) [1]. This Data in Brief article presents two rounds of survey data conducted in 2011 and 2012 for a panel of 677 dairy farm households in the province of East Java, Indonesia. The survey relied on structured questionnaires to collect data on the production and use of biogas, the use of other non-renewable energy sources, farm characteristics, and socioeconomic and demographic characteristics of households. The panel data set in STATA format and do files are made publicly available to promote replicability and extended analyses of a sustainable energy initiative.

Background: Human multipotent adult progenitor cells (MAPC®) are an emerging therapy for traumatic brain injury (TBI); however, clinically translating a therapy involves overcoming many factors in vivo which are not present in pre-clinical testing. In this study we examined clinical parameters in vitro that may impact cell therapy efficacy. Methods: MAPC were infused through varying gauged needles and catheters with and without chlorhexidine, and their viability tested with trypan blue exclusion. MAPC were co-cultured with phenytoin and celecoxib at relevant clinical concentrations for 1 h and 24 h. Anti-inflammatory potency was tested using a stimulated rat splenocyte co-culture and ELISA for TNF-α production. MAPC were cultured under different osmolar concentrations and stained with propidium iodide for viability. Anti-inflammatory potency was tested by co-culture of MAPC with naïve lymphocytes activated by CD3/CD28 beads, and Click-iT® Plus EdU was used to quantify proliferation by flow cytometry. Results: The mean viability of the MAPC infused via needles was 95 ± 1%; no difference was seen with varying flow rate, but viability was notably reduced by chlorhexidine. MAPC function was not impaired by co-culture with phenytoin, celecoxib, or combination with both. Co-culture with phenytoin showed a decrease in TNF-α production as compared to the MAPC control. MAPC cultured at varying osmolar concentrations all had viabilities greater than 90% with no statistical difference between them. Co-culture of MAPC with CD3/CD28 activated PBMCs showed a significant reduction in proliferation as measured by EdU uptake. Discussion: Needle diameter, phenytoin, celecoxib, and a relevant range of osmolarities do not impair MAPC viability or anti-inflammatory potency in vitro.

Background: Endoprosthesis are being used in the everyday clinical practice either as a permanent solution or transient. They can be used in both benign and malignant situations. Case presentation: We report a case in which a temporary Montgomery cannula is used in conjunction with therapeutic bronchoscopy to manage a patient with failed tracheostomy decannulation secondary to a distal complex tracheal stenosis. Conclusions: This innovative use of the Montgomery cannula allowed for successful management of the patient's tracheal stenosis and subsequent tracheostomy tube decannulation.

The estrogen receptor α (ERα) controls cell proliferation and tumorigenesis by recruiting various cofactors to estrogen response elements (EREs) to control gene transcription. A deeper understanding of these transcriptional mechanisms may uncover therapeutic targets for ERα-dependent cancers. We show that BRD4 regulates ERα-induced gene expression by affecting elongation-associated phosphorylation of RNA polymerase II (RNAPII) and histone H2B monoubiquitination. Consistently, BRD4 activity is required for proliferation of ER+ breast and endometrial cancer cells and uterine growth in mice. Genome-wide studies revealed an enrichment of BRD4 on transcriptional start sites of active genes and a requirement of BRD4 for H2B monoubiquitination in the transcribed region of estrogen-responsive genes. Importantly, we demonstrate that BRD4 occupancy on distal EREs enriched for H3K27ac is required for recruitment and elongation of RNAPII on EREs and the production of ERα-dependent enhancer RNAs. These results uncover BRD4 as a central regulator of ERα function and potential therapeutic target.

Background: The eastern Mediterranean region is comprised of 22 countries: Afghanistan, Bahrain, Djibouti, Egypt, Iran, Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Pakistan, Palestine, Qatar, Saudi Arabia, Somalia, Sudan, Syria, Tunisia, the United Arab Emirates, and Yemen. Since our Global Burden of Disease Study 2010 (GBD 2010), the region has faced unrest as a result of revolutions, wars, and the so-called Arab uprisings. The objective of this study was to present the burden of diseases, injuries, and risk factors in the eastern Mediterranean region as of 2013. Methods: GBD 2013 includes an annual assessment covering 188 countries from 1990 to 2013. The study covers 306 diseases and injuries, 1233 sequelae, and 79 risk factors. Our GBD 2013 analyses included the addition of new data through updated systematic reviews and through the contribution of unpublished data sources from collaborators, an updated version of modelling software, and several improvements in our methods. In this systematic analysis, we use data from GBD 2013 to analyse the burden of disease and injuries in the eastern Mediterranean region specifically. Findings: The leading cause of death in the region in 2013 was ischaemic heart disease (90·3 deaths per 100 000 people), which increased by 17·2% since 1990. However, diarrhoeal diseases were the leading cause of death in Somalia (186·7 deaths per 100 000 people) in 2013, which decreased by 26·9% since 1990. The leading cause of disability-adjusted life-years (DALYs) was ischaemic heart disease for males and lower respiratory infection for females. High blood pressure was the leading risk factor for DALYs in 2013, with an increase of 83·3% since 1990. Risk factors for DALYs varied by country. In low-income countries, childhood wasting was the leading cause of DALYs in Afghanistan, Somalia, and Yemen, whereas unsafe sex was the leading cause in Djibouti. Non-communicable risk factors were the leading cause of DALYs in high-income and middle-income countries in the region. DALY risk factors varied by age, with child and maternal malnutrition affecting the younger age groups (aged 28 days to 4 years), whereas high bodyweight and systolic blood pressure affected older people (aged 60–80 years). The proportion of DALYs attributed to high body-mass index increased from 3·7% to 7·5% between 1990 and 2013. Burden of mental health problems and drug use increased. Most increases in DALYs, especially from non-communicable diseases, were due to population growth. The crises in Egypt, Yemen, Libya, and Syria have resulted in a reduction in life expectancy; life expectancy in Syria would have been 5 years higher than that recorded for females and 6 years higher for males had the crisis not occurred. Interpretation: Our study shows that the eastern Mediterranean region is going through a crucial health phase. The Arab uprisings and the wars that followed, coupled with ageing and population growth, will have a major impact on the region's health and resources. The region has historically seen improvements in life expectancy and other health indicators, even under stress. However, the current situation will cause deteriorating health conditions for many countries and for many years and will have an impact on the region and the rest of the world. Based on our findings, we call for increased investment in health in the region in addition to reducing the conflicts. Funding: Bill & Melinda Gates Foundation.

We report a 55-year-old man who underwent off-pump bypass surgery and had diffuse oozing and bruising postoperatively. His hematological profile had been normal preoperatively and he had been off antiplatelets for a week prior to surgery. Postoperatively, a detailed talk revealed that he had been on dietary supplements containing fish oil and garlic – both of which are known to affect platelet function. It behooves the surgeon and anesthetist to screen all patients preoperatively for the possibility of intake of any dietary supplements taken by the patient.

Treatment cost is a major concern for modern medicine in developing countries like India and systematic innovative means to reduce these costs are needed. This article reviews the concept of bioenhancers to reduce treatment costs by increasing drug bioavailability. This concept, based on the Ayurvedic system of medicine, works for a wide range of ingested substances, and has been applied to modern drugs, particularly single chemicals. It offers a fine example of the benefit of integrating an ancient system with modern medicine in both theory and practice.

Antimicrobial resistance is an emerging global threat to public health. The resistant bacteria in food animals can be transferred to humans through the food chain. Limited information on antimicrobial usage and resistance in food animals is available in Southeast Asia due to inadequate monitoring or surveillance systems. A literature review was conducted on antimicrobial use and resistance in food animal production in Southeast Asia for the period 2011–2020, to assess the scope and extent of antibiotic use and resistance. The countries included in the study were Bangladesh, Bhutan, Democratic People’s Republic of Korea, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand and Timor-Leste. The information was categorised by country, production type and findings regarding antibiotic use and resistance. A total of 108 publications were included in the review. Results showed widespread use of critically and highly important antibiotics in livestock, poultry and aquacultured fish and their products. To curb the growing threat of antibiotic resistance, Southeast Asian countries need to strengthen surveillance and regulatory controls of antimicrobial use in food animal production through “One Health” approach.

The primary focus of this article is to provide sufficient conditions for the Ulam–Hyers stability of neutral delay fractional differential equations involving Hilfer fractional derivatives and Erdelyi–Kober fractional integral boundary conditions. The fixed point approach is utilized to prove the existence and uniqueness of mild solutions for the proposed problem. In the end, the derived results are validated through an illustrative example.