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Reversal reactions (RRs) in leprosy are characterized by a reduction in the number of bacilli in lesions associated with an increase in cell-mediated immunity against the intracellular bacterium Mycobacterium leprae, the causative pathogen of leprosy. To identify the mechanisms that contribute to cell-mediated immunity in leprosy, we measured changes in the whole blood-derived transcriptome of patients with leprosy before, during and after RR. We identified an 'RR signature' of 1017 genes that were upregulated at the time of the clinical diagnosis of RR. Using weighted gene correlated network analysis (WGCNA), we detected a module of 794 genes, bisque4, that was significantly correlated with RR, of which 434 genes were part of the RR signature. An enrichment for both IFN-γ and IFN-β downstream gene pathways was present in the RR signature as well as the RR upregulated genes in the bisque4 module, including those encoding proteins of the guanylate binding protein (GBP) family that contributes to antimicrobial responses against mycobacteria. Specifically, GBP1, GBP2, GBP3 and GBP5 mRNAs were upregulated in the RR peripheral blood transcriptome, with GBP1, GBP2 and GBP5 mRNAs also upregulated in the RR disease lesion transcriptome. These data indicate that RRs involve a systemic upregulation of IFN-γ downstream genes including GBP family members as part of the host antimicrobial response against mycobacteria. [ABSTRACT FROM AUTHOR]

Background: The presence of infections is one of the main factors that leads to delays in healing or non-closure of cutaneous wounds. Although the goal of antibiotic use is to treat or prevent infection, there is currently no agreement on the effectiveness of these products. Aim: The aim of this study was to evaluate the efficacy of antibiotic use during the healing process of skin wounds in animal models not intentionally infected, as well as to analyze the advances and limitations of the studies carried out in this field. Main methods: This systematic review was performed according to the PRISMA guidelines, using a structured search on the MedLine (PubMed) and Scopus platforms to retrieve studies published until August 29, 2018, 13:35p.m. The studies included were limited to those that used excision or incision wound models and that were not intentionally infected. The data for the animal models, antibiotic used, and the main results of the studies were extracted, and compared where possible. Bias analysis and methodological quality assessments were examined through the SYRCLE's Risk of Bias tool. Key findings: Twenty-seven studies were selected. Overall, the effects of the antibiotic on the wound decreased inflammatory cell infiltration and promoted an increased number of fibroblasts, extracellular matrix constituents, re-epithelialization and tissue strength. A great deal of important information about the methodology was not presented, such as: the statistical analysis used, the animal model (sex and age), antibiotic dosage, blinding and randomization of the animals chosen. Significance: Based on the results found, we believe that antibiotic therapy can be considered a viable alternative for the treatment of cutaneous wounds. However, current evidence obtained from the methodological quality analysis points towards a high risk of bias. This is due to the incomplete characterization of the experimental design and treatment protocol, which compromises the reproducibility of the studies. [ABSTRACT FROM AUTHOR]

This systematic review and meta-analysis aimed to examine the effects of physical exercise cum cognitive-behavioural therapy (CBT) on alleviating pain intensity, functional disabilities, and mood/mental symptoms in those suffering with chronic musculoskeletal pain. MEDLINE, EMBASE, PubMEd, PsycINFO and CINAHL were searched to identify relevant randomised controlled trials from inception to 31 December 2018. The inclusion criteria were: (a) adults ≥18 years old with chronic musculoskeletal pain ≥3 months, (b) randomised controlled design, (c) a treatment arm consisting of physical intervention and CBT combined, (d) the comparison arm being waitlist, usual care or other non-pharmacological interventions such as physical exercise or CBT alone, and (e) outcomes including pain intensity, pain-related functional disabilities (primary outcomes), or mood/mental symptoms (secondary outcome). The exclusion criteria were: (a) the presence of comorbid mental illnesses other than depression and anxiety and (b) non-English publication. The search resulted in 1696 records and 18 articles were selected for review. Results varied greatly across studies, with most studies reporting null or small effects but a few studies reporting very large effects up to 2-year follow-up. Pooled effect sizes (Hedges' g) were ~1.00 for pain intensity and functional disability, but no effect was found for mood/mental symptoms. The effects were mainly driven by several studies reporting unusually large differences between the exercise cum CBT intervention and exercise alone. When these outliers were removed, the effect on pain intensity disappeared at post-intervention while a weak effect (g = 0.21) favouring the combined intervention remained at follow-up assessment. More consistent effects were observed for functional disability, though the effects were small (g = 0.26 and 0.37 at post-intervention and follow-up respectively). More importantly, the value of adding CBT to exercise interventions is questionable, as consistent benefits were not seen. The clinical implications and directions for future research are discussed. [ABSTRACT FROM AUTHOR]

Introduction: While extracorporeal membrane oxygenation (ECMO) is effective in preventing further hypoxemia and maintains blood flow in endotoxin-induced shock, ECMO alone does not reverse the hypotension. In this study, we tested whether concurrent vasopressor use with ECMO would provide increased circulatory support and blood flow, and characterized regional blood flow distribution to vital organs. Methods: Endotoxic shock was induced in piglets to achieve a 30% decrease in mean arterial pressure (MAP). Measurements of untreated pigs were compared to pigs treated with ECMO alone or ECMO and vasopressors. Results: ECMO provided cardiac support during vasodilatory endotoxic shock and improved oxygen delivery, but vasopressor therapy was required to return MAP to normotensive levels. Increased blood pressure with vasopressors did not alter oxygen consumption or extraction compared to ECMO alone. Regional microcirculatory blood flow (RBF) to the brain, kidney, and liver were maintained or increased during ECMO with and without vasopressors. Conclusion: ECMO support and concurrent vasopressor use improve regional blood flow and oxygen delivery even in the absence of full blood pressure restoration. Vasopressor-induced selective distribution of blood flow to vital organs is retained when vasopressors are administered with ECMO. [ABSTRACT FROM AUTHOR]

Background: Worldwide, the number of emerging and re-emerging infectious diseases is increasing, highlighting the importance of global disease pathogen surveillance. Traditional population-based methods may fail to capture important events, particularly in settings with limited access to health care, such as urban informal settlements. In such environments, a mixture of surface water runoff and human feces containing pathogenic microorganisms could be used as a surveillance surrogate. Method: We conducted a temporal metagenomic analysis of urban sewage from Kibera, an urban informal settlement in Nairobi, Kenya, to detect and quantify bacterial and associated antimicrobial resistance (AMR) determinants, viral and parasitic pathogens. Data were examined in conjunction with data from ongoing clinical infectious disease surveillance. Results: A large variation of read abundances related to bacteria, viruses, and parasites of medical importance, as well as bacterial associated antimicrobial resistance genes over time were detected. Significant increased abundances were observed for a number of bacterial pathogens coinciding with higher abundances of AMR genes. Vibrio cholerae as well as rotavirus A, among other virus peaked in several weeks during the study period whereas Cryptosporidium spp. and Giardia spp, varied more over time. Conclusion: The metagenomic surveillance approach for monitoring circulating pathogens in sewage was able to detect putative pathogen and resistance loads in an urban informal settlement. Thus, valuable if generated in real time to serve as a comprehensive infectious disease agent surveillance system with the potential to guide disease prevention and treatment. The approach may lead to a paradigm shift in conducting real-time global genomics-based surveillance in settings with limited access to health care. [ABSTRACT FROM AUTHOR]

Context: Whether all degrees of periventricular leukomalacia (PVL) and peri-intraventricular haemorrhage (PIVH) have a negative impact on neurodevelopment. Objective: To determine the impact of PVL and PIVH in the incidence of cerebral palsy, sensorineural impairment and development scores in preterm neonates. Registered in PROSPERO (CRD42017073113). Data sources: PubMed, Embase, SciELO, LILACS, and Cochrane databases. Study selection: Prospective cohort studies evaluating neurodevelopment in children born preterm which performed brain imaging in the neonatal period. Data extraction: Two independent researchers extracted data using a predesigned data extraction sheet. Statistical methods: A random-effects model was used, with Mantel-Haenszel approach and a Sidik-Jonkman method for the estimation of variances, combined with Hartung-Knapp-Sidik-Jonkman correction. Heterogeneity was assessed through the I2 statistic and sensitivity analysis were performed when possible. No funnel plots were generated but publication bias was discussed as a possible limitation. Results: Our analysis concluded premature children with any degree of PIVH are at increased risk for cerebral palsy (CP) when compared to children with no PIVH (3.4, 95% CI 1.60–7.22; 9 studies), a finding that persisted on subgroup analysis for studies with mean birth weight of less than 1000 grams. Similarly, PVL was associated with CP, both in its cystic (19.12, 95% CI 4.57–79.90; 2 studies) and non-cystic form (9.27, 95% CI 5.93–14.50; 2 studies). We also found children with cystic PVL may be at risk for visual and hearing impairment compared to normal children, but evidence is weak. Limitations: Major limitations were the lack of data for PVL in general, especially for the outcome of neurodevelopment, the high heterogeneity among methods used to assess neurodevelopment and the small number of studies, which led to meta-analysis with high heterogeneity and wide confidence intervals. Conclusions: There was no evidence supporting the hypothesis that PIVH causes impairment in neuropsychomotor development in our meta-analysis, but review of newer studies show an increased risk for lower intelligence scores in children with severe lesions, both PIVH and PVL. There is evidence to support the hypothesis that children with any degree of PIVH, especially those born below 1000 grams and those with severe haemorrhage, are at increased risk of developing CP, as well as children with PVL, both cystic and non-cystic. [ABSTRACT FROM AUTHOR]

Background: In many low- and middle-income countries, data on the prevalence of surgical diseases have been derived primarily from hospital-based studies, which may lead to an underestimation of disease burden within the community. Community-based prevalence studies may provide better estimates of surgical need to enable proper resource allocation and prioritization of needs. This study aims to assess the prevalence of common surgical conditions among children in a diverse rural and urban population in Nigeria. Methods: Descriptive cross-sectional, community-based study to determine the prevalence of congenital and acquired surgical conditions among children in a diverse rural-urban area of Nigeria was conducted. Households, defined as one or more persons 'who eat from the same pot' or slept under the same roof the night before the interview, were randomized for inclusion in the study. Data was collected using an adapted and modified version of the interviewer-administered questionnaire—Surgeons OverSeas Assessment of Surgical Need (SOSAS) survey tool and analysed using the REDCap web-based analytic application. Main results: Eight-hundred-and-fifty-six households were surveyed, comprising 1,883 children. Eighty-one conditions were identified, the most common being umbilical hernias (20), inguinal hernias (13), and wound injuries to the extremities (9). The prevalence per 10,000 children was 85 for umbilical hernias (95% CI: 47, 123), and 61 for inguinal hernias (95% CI: 34, 88). The prevalence of hydroceles and undescended testes was comparable at 22 and 26 per 10,000 children, respectively. Children with surgical conditions had similar sociodemographic characteristics to healthy children in the study population. Conclusion: The most common congenital surgical conditions in our setting were umbilical hernias, while injuries were the most common acquired conditions. From our study, it is estimated that there will be about 2.9 million children with surgically correctable conditions in the nation. This suggests an acute need for training more paediatric surgeons. [ABSTRACT FROM AUTHOR]

Artemisinin resistance is threatening global efforts for malaria control and elimination. Primaquine (PQ) and methylene blue (MB) are gametocytocidal drugs that can be combined with artemisinin-based combination therapy (ACT) to reduce malaria transmission, including resistant strains. Children (6–59 months) with uncomplicated falciparum malaria in Burkina Faso were treated with artesunate-amodiaquine (AS-AQ) and randomized to MB (15 mg/kg/day for 3 days) or PQ (0.25 mg/kg at day 2) with the aim to show non-inferiority of the MB regimen with regard to haematological recovery at day 7 (primary endpoint). MB-AS-AQ could not be shown to be non-inferior to PQ-AS-AQ (mean Hb difference between treatment groups on day 7 was -0.352, 95% CI -0.832–0.128, p = 0.0767), however, haemoglobin recovery following treatment was alike in the two study arms (day 7: mean 0.2±1.4 g/dl vs. 0.5±0.9 g/dl, p = 0.446). Occurrence of adverse events was similar in both groups, except for vomiting, which was more frequent in the MB than in the PQ arm (20/50 vs 7/50, p = 0.003). Adequate clinical and parasitological response was above 95% in both groups, but significantly more asexual parasites were cleared in the MB arm compared to the PQ arm already on day 1 (48/50, 96%, vs 40/50, 80%, p = 0.014). Moreover, P. falciparum gametocyte prevalence and density were lower in the MB arm than in the PQ arm, which reached statistical significance on day 2 (prevalence: 2/50, 4%, vs 15/49, 31%, p<0.001; density: 9.6 vs 41.1/μl, p = 0.024). However, it should be considered that PQ was given only on day 2. MB-ACT appears to be an interesting alternative to PQ-ACT for the treatment of falciparum malaria. While there is a need to further improve MB formulations, MB-ACT may already be considered useful to reduce falciparum malaria transmission intensity, to increase treatment efficacy, and to reduce the risk for resistance development and spread. Trial registration: ClinicalTrials.gov . [ABSTRACT FROM AUTHOR]

Background: The function of the pelvic bones is to transfer load generated by body weight. Proper function of the pelvic bones can be disturbed by alignment changes that occur during pregnancy. Further, misalignment of the pelvic bones can lead to pain, urinary incontinence, and other complications. An understanding of the timing and nature of pelvic alignment changes during pregnancy may aid in preventing and treating these complications. Objective: To investigate the changes in pelvic alignment during pregnancy and one month after childbirth. Methods: This is a prospective, longitudinal cohort study. Pelvic measurements were obtained for 201 women at 12, 24, 30, and 36 weeks of pregnancy, and 1 month after childbirth. The anterior and posterior width of the pelvis (the distance between the bilateral anterior superior iliac spines and the bilateral posterior superior iliac spines), the anterior pelvic tilt, and pelvic asymmetry (the mean left and right pelvic tilt degrees and the bilateral difference of the anterior pelvic tilt) were measured. For the change in pelvic alignment, a Friedman test was conducted to determine any significant difference in the measurements over time. Results: The anterior and posterior width of the pelvis became significantly wider with pregnancy progress and the anterior width of the pelvis at 1 month after childbirth remained wider than that at 12 weeks of pregnancy (p < 0.001). The anterior pelvic tilt increased during pregnancy and decreased after childbirth (p < 0.05). Conclusion: Some changes in pelvic alignment occur continuously during the perinatal period. Changes in the anterior width of the pelvis are not recovered at one month post-childbirth. Understanding these perinatal changes may help clinicians avert complications due to pelvic misalignment. [ABSTRACT FROM AUTHOR]

Cells damaged by mechanical or infectious injury release proinflammatory mitochondrial DNA (mtDNA) fragments into the circulation. We evaluated the relation between plasma levels of mtDNA fragments in obese type 2 diabetes mellitus (T2DM) patients and measures of chronic inflammation and insulin resistance. In 10 obese T2DM patients and 12 healthy control (HC) subjects, we measured levels of plasma cell-free mtDNA with quantitative real-time polymerase chain reaction, and mtDNA damage in skeletal muscle with quantitative alkaline Southern blot. Also, markers of systemic inflammation and oxidative stress in skeletal muscle were measured. Plasma levels of mtDNA fragments, mtDNA damage in skeletal muscle and plasma tumor necrosis factor α levels were greater in obese T2DM patients than HC subjects. Also, the abundance of plasma mtDNA fragments in obese T2DM patients levels positively correlated with insulin resistance. To the best of our knowledge, this is the first published evidence that elevated level of plasma mtDNA fragments is associated with mtDNA damage and oxidative stress in skeletal muscle and correlates with insulin resistance in obese T2DM patients. Plasma mtDNA may be a useful biomarker for predicting and monitoring insulin resistance in obese patients. [ABSTRACT FROM AUTHOR]

Background: Chiropractic maintenance care is effective as secondary/tertiary prevention of non-specific low back pain (LBP), but the potential effect moderation by psychological characteristics is unknown. The objective was to investigate whether patients in specific psychological sub-groups had different responses to MC with regard to the total number of days with bothersome pain and the number of treatments. Method: Data from a two-arm randomized pragmatic multicenter trial with a 12-month follow up, designed to investigate the effectiveness of maintenance care, was used. Consecutive patients, 18–65 years of age, with recurrent and persistent LBP seeking chiropractic care with a good effect of the initial treatment were included. Eligible subjects were randomized to either maintenance care (prescheduled care) or to the control intervention, symptom-guided care. The primary outcome of the trial was the total number of days with bothersome LBP collected weekly for 12 months using an automated SMS system. Data used to classify patients according to psychological subgroups defined by the West Haven-Yale Multidimensional Pain Inventory (adaptive copers, interpersonally distressed and dysfunctional) were collected at the screening visit. Results: A total of 252 subjects were analyzed using a generalized estimating equations linear regression framework. Patients in the dysfunctional subgroup who received maintenance care reported fewer days with pain (-30.0; 95% CI: -36.6, -23.4) and equal number of treatments compared to the control intervention. In the adaptive coper subgroup, patients who received maintenance care reported more days with pain (10.7; 95% CI: 4.0, 17.5) and more treatments (3.9; 95% CI: 3.5, 4.2). Patients in the interpersonally distressed subgroup reported equal number of days with pain (-0.3; 95% CI: -8.7, 8.1) and more treatments (1.5; 95% CI: 0.9, 2.1) on maintenance care. Conclusions: Psychological and behavioral characteristics modify the effect of MC and should be considered when recommending long-term preventive management of patients with recurrent and persistent LBP. [ABSTRACT FROM AUTHOR]

Background: Postpartum hemorrhage (PPH) is a leading cause of maternal mortality in Nigeria and in most low- and middle-income countries. The World Health Organization (WHO) strongly recommends oxytocin as effective, affordable, and the safest drug of first choice in the prevention and treatment of PPH in the third stage of labor. However, there are concerns about its quality. Very high prevalence of poor-quality oxytocin, especially in Africa and Asia, has been reported in literature. Excessive and inappropriate use of oxytocin is also common in low-resource settings. Objective: To assess clinical experiences with quality of oxytocin used by healthcare providers in Lagos State, Nigeria. Methods: This was a descriptive cross-sectional study conducted in 2017, with 705 respondents (doctors and nurses) who use oxytocin for obstetrics and gynecological services recruited from 195 health facilities (public and registered private) across Lagos State. Data collection was quantitative, using a pretested self-administered questionnaire. Data analysis was performed with IBM SPSS version 21. Statistical significance was set at 5 percent (p<0.05). Ethical approval was obtained from Lagos University Teaching Hospital Health Research Ethics Committee. Results: Only 52 percent of the respondents knew oxytocin should be stored at 2°C to 8°C. About 80 percent of respondents used oxytocin for augmentation of labor, 68 percent for induction of labor, 51 percent for stimulation of labor, and 78 percent for management of PPH. Forty-one percent used 20IU and as much as 10% used 30IU to 60IU for management of PPH. About 13 percent of respondents reported believing they had used an ineffective brand of oxytocin in their practice. Just over a third (36%) had an available means of documenting or reporting perceived ineffectiveness of drugs in their facility; of these, only about 12 percent had pharmacovigilance forms in their facilities to report the ineffectiveness. Conclusion: The inappropriate and inconsistent use of oxytocin, especially overdosing, likely led to the high perception of medicine effectiveness among respondents. This is coupled with lack of suspicion of medicine ineffectiveness by clinicians as a possible root cause of poor treatment response or disease progression. Poor knowledge of oxytocin storage and consequent poor storage practices could have contributed to the ineffectiveness reported by some respondents. It is necessary to establish a unified protocol for oxytocin use that is strictly complied with. Continuous training of healthcare providers in medicine safety monitoring is advocated. [ABSTRACT FROM AUTHOR]

The developmental speed of new antimicrobials does not meet the emergence of multidrug-resistant bacteria sufficiently. A potential shortcut is assessing the antimicrobial activity of already approved drugs. Intrudingly, the antibacterial action of glatiramer acetate (GA) has recently been discovered. GA is a well-known and safe immunomodulatory drug particular effective against Gram-negative bacteria, which disrupts biological membranes by resembling the activity of antimicrobial peptides. Thus, GA can potentially be included in treatment strategies used to combat infections caused by multidrug-resistant Gram-negatives. One potential application is chronic respiratory infections caused by Pseudomonas aeruginosa, however the safety of GA inhalation has never been assessed. Here, the safety of inhaling nebulized GA is evaluated in a preclinical pig model. The potential side effects, i.e., bronchoconstriction, respiratory tract symptoms and systemic- and local inflammation were assessed by ventilator monitoring, clinical observation, biochemistry, flowcytometry, and histopathology. No signs of bronchoconstriction assessed by increased airway peak pressure, Ppeak, or decreased oxygen pressure were observed. Also, there were no signs of local inflammation in the final histopathology examination of the pulmonary tissue. As we did not observe any potential pulmonary side effects of inhaled GA, our preliminary results suggest that GA inhalation is safe and potentially can be a part of the treatment strategy targeting chronic lung infections caused by multidrug-resistant Gram-negative bacteria. [ABSTRACT FROM AUTHOR]

Background: Neonatal mortality is a significant contributor to infant mortality. Causes and predictors of neonatal death are known to vary in different settings and across different contexts. This study aimed to assess predictors, causes, and trends of neonatal mortality amongst neonates admitted to Nekemte Referral Hospital neonatal unit between 2010–2014. Methods: Retrospective data was collected for 2090 live born neonates admitted to the neonatal intensive care unit of Nekemte Referral Hospital by reviewing records between 2010 to 2014. Variables were collected from the neonatal registration book and patient card on the predictors, causes, and trends of neonatal death using a standard checklist developed by the World Health Organization (WHO). Data was analyzed using Epi info version 3.5.1, and SPSS version 25 for windows. The level of significance was set at P<0.05 with the corresponding confidence intervals at 95%. A logistic regression model was used for analysis and to control for confounders. Microsoft Excel 2007 was used to construct the trend analysis. Results: There were 183 deaths in the cohort equivalent to 8.8% of deaths among total admitted neonates during the study period. Early neonatal deaths accounted for 8% and late neonatal deaths accounted for 0.71% of deaths among total admitted neonates. Main predictors identified for an increased risk of neonatal mortality were; neonates from rural residents [AOR 1.35, (95% CI, 1.35–1.87)], birth order of greater than five [AOR 5.10, (95% CI, 1.15–22.63)], home delivery [AOR 3.41, (95% CI, 2.24–5.19)], very low birth weight [AOR 6.75, (95% CI, 3.63–12.54)] and low birth weight [AOR 2.81, (95% CI, 1.95–4.05)] and inability to cry at birth [AOR 2.21, (95% CI, 1.51–3.22)]. The trend analysis showed a sharp fall for the neonatal mortality over the last five years with a mean reduction of 16%. Conclusions: Data from the Nekemte Referral Hospital Neonatal Intensive Care Unit analysis revealed majority of the deaths were occurred during early neonatal period. The main predictors of neonatal mortality identified from this study needs strengthening an appropriate public health intervention through addressing antenatal care, curbing home delivery. [ABSTRACT FROM AUTHOR]

Network coupled cells, such as astrocytes, regulate their cellular homeostasis via Ca2+ signals spread between the cells through gap junctions. Intracellular Ca2+ release is controlled by different signaling pathways that can be stimulated by ATP, glutamate and serotonin (5-HT). Based on our findings, all these pathways are influenced by inflammatory agents and must be restored to fully recover the Ca2+ signaling network. An ultralow concentration of the local anesthetic agent bupivacaine reduced 5-HT-evoked intracellular Ca2+ release, and an ultralow concentration of the phosphodiesterase-5 inhibitor sildenafil in combination with vitamin D3 reduced ATP-evoked intracellular Ca2+ release. Combinations of these three substances downregulated 5-HT-, glutamate- and ATP-evoked intracellular Ca2+ release to a more normal Ca2+ signaling state. Furthermore, inflammatory Toll-like receptor 4 expression decreased with a combination of these three substances. Substance P receptor neurokinin (NK)-1 expression was reduced by ultralow concentrations of bupivacaine. Here, bupivacaine and sildenafil (at extremely low concentrations) combined with vitamin D3 have potential anti-inflammatory properties. According to the present study, drug combinations at the right concentrations, especially extremely low concentrations of bupivacaine and sildenafil, affect different cellular biochemical mechanisms and represent a potential solution for downregulating inflammatory parameters, thereby restoring cells or networks to normal physiological homeostasis. [ABSTRACT FROM AUTHOR]

Background: Postural orthostatic tachycardia syndrome is a disorder of the autonomic nervous system. Approximately 30% of patients experience orthostatic headaches. Orthostatic headaches also are a hallmark symptom in spontaneous intracranial hypotension. While the cause of orthostatic headaches in spontaneous intracranial hypotension can be linked to the cerebrospinal fluid loss at the spinal level and consecutively reduced intracranial pressure in the upright position, the cause of orthostatic headaches in postural orthostatic tachycardia syndrome still remains unknown. The present study examined orthostatic changes of intracranial pressure using dynamic ultrasound of the optic nerve and optic nerve sheath diameter in postural orthostatic tachycardia syndrome, spontaneous intracranial hypotension and healthy subjects. Methods: Data was obtained from postural orthostatic tachycardia syndrome patients with (n = 7) and without orthostatic headaches (n = 7), spontaneous intracranial hypotension patients (n = 5) and healthy subjects (n = 8). All participants underwent high-resolution transorbital ultrasound in the supine and upright position to assess optic nerve and optic nerve sheath diameter. Results: Group differences were found in percentage deviations when changing position of optic nerve sheath diameter (p < 0.01), but not regarding the optic nerve diameter. Pairwise comparisons indicated differences in optic nerve sheath diameter only between spontaneous intracranial hypotension and the other groups. No differences were found between postural orthostatic tachycardia syndrome patients with and without orthostatic headaches. Conclusion: This study shows that the size of the optic nerve sheath diameter dynamically decreases during orthostatic stress in spontaneous intracranial hypotension, but not in postural orthostatic tachycardia syndrome with or without orthostatic headaches, which indicates different underlying causes. [ABSTRACT FROM AUTHOR]

Objectives: Aging is associated with low muscle mass and has been linked to adverse health outcomes. The objectives of this cross-sectional study were: (1) to describe anthropometry, body composition, appendicular skeletal muscle mass index (ASMI; appendicular skeletal muscle mass/height2), and prevalence of low ASMI in older people with normal nutritional status (Malnutrition Universal Screening Tool score = 0); (2) to determine factors associated with ASMI, and odds ratios of having low ASMI. Methods: SHIELD is a study of community-dwelling older people aged 65 years and above in Singapore. ASMI was determined using bioelectrical impedance analysis and low ASMI was defined as <7.0 kg/m2 for males and <5.7 kg/m2 for females (Asian Working Group for Sarcopenia, 2014). Results: A total of 400 older people (183 males and 217 females) took part in this study. The overall prevalence of low ASMI was 20.6% (15.5% in males and 24.9% in females). Females had significantly lower ASMI than males (P < 0.0001), age was inversely associated with ASMI (P = 0.0024) while BMI and calf circumference were positively associated with ASMI (both P < 0.0001) in the total cohort. In addition, ASMI was positively associated with bone mass in both genders (both P < 0.0001). After adjusting for covariates, the odds ratios of having low ASMI with every 1 year and 10 years increase in age were 1.13 (95% CI: 1.06, 1.20) and 3.36 (95% CI: 1.82, 6.21) respectively. Conclusions: The high prevalence of low ASMI in community-dwelling older people with normal nutritional status highlights the need for early screening. There was a strong inverse association between age and ASMI while BMI, calf circumference and bone mass were positively associated with ASMI. These findings will give further weight to the importance and development of public health strategies in maintaining and improving muscle health in this population group. [ABSTRACT FROM AUTHOR]

Although there is good evidence to indicate a major role of intrinsic impairment of the contractile apparatus in muscle weakness seen in several pathophysiological conditions, the factors responsible for control of myofibrillar function are not fully understood. To investigate the role of mechanical load in myofibrillar function, we compared the skinned fiber force between denervated (DEN) and dexamethasone-treated (DEX) rat skeletal muscles with or without neuromuscular electrical stimulation (ES) training. DEN and DEX were induced by cutting the sciatic nerve and daily injection of dexamethasone (5 mg/kg/day) for 7 days, respectively. For ES training, plantarflexor muscles were electrically stimulated to produce four sets of five isometric contractions each day. In situ maximum torque was markedly depressed in the DEN muscles compared to the DEX muscles (-74% vs. -10%), whereas there was not much difference in the degree of atrophy in gastrocnemius muscles between DEN and DEX groups (-24% vs. -17%). Similar results were obtained in the skinned fiber preparation, with a greater reduction in maximum Ca2+-activated force in the DEN than in the DEX group (-53% vs. -16%). Moreover, there was a parallel decline in myosin heavy chain (MyHC) and actin content per muscle volume in DEN muscles, but not in DEX muscles, which was associated with upregulation of NADPH oxidase (NOX) 2, neuronal nitric oxide synthase (nNOS), and endothelial NOS expression, translocation of nNOS from the membrane to the cytosol, and augmentation of mRNA levels of muscle RING finger protein 1 (MuRF-1) and atrogin-1. Importantly, mechanical load evoked by ES protects against DEN- and DEX-induced myofibrillar dysfunction and these molecular alterations. Our findings provide novel insights regarding the difference in intrinsic contractile properties between DEN and DEX and suggest an important role of mechanical load in preserving myofibrillar function in skeletal muscle. [ABSTRACT FROM AUTHOR]

Sepsis can be caused by malaria infection, but little is known about the utility of the quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) and SOFA score in malaria. We conducted a prospective observational study from March 2013 to February 2017 to examine adults admitted with community-acquired infection in a tertiary-care hospital in Ubon Ratchathani, Northeast Thailand (Ubon-sepsis). Subjects were classified as having sepsis if they had a modified SOFA score ≥2 within 24 hours of admission. Serum was stored and later tested for malaria parasites using a nested PCR assay. Presence of severe malaria was defined using modified World Health Organization criteria. Of 4,989 patients enrolled, 153 patients (3%) were PCR positive for either Plasmodium falciparum (74 [48%]), P. vivax (69 [45%]), or both organisms (10 [7%]). Of 153 malaria patients, 80 were severe malaria patients presenting with sepsis, 70 were non-severe malaria patients presenting with sepsis, and three were non-severe malaria patients presenting without sepsis. The modified SOFA score (median 5; IQR 4–6; range 1–18) was strongly correlated with malaria severity determined by the number of World Health Organization severity criteria satisfied by the patient (Spearman’s rho = 0.61, p<0.001). Of 80 severe malaria patients, 2 (2.5%), 11 (14%), 62 (77.5%) and 5 (6%), presented with qSOFA scores of 0, 1, 2 and 3, respectively. Twenty eight-day mortality was 1.3% (2/153). In conclusion, qSOFA and SOFA can serve as markers of disease severity in adults with malarial sepsis. Patients presenting with a qSOFA score of 1 may also require careful evaluation for sepsis; including diagnosis of cause of infection, initiation of medical intervention, and consideration for referral as appropriate. [ABSTRACT FROM AUTHOR]

Background: People with advanced cancer experience multiple symptoms during their illness trajectory, which can fluctuate in intensity. Aim: To describe the course of self-reported quality of life, emotional functioning, physical functioning and symptom intensity over time in cancer patients receiving palliative care. Design: Longitudinal study with monthly assessments, using the EORTC QLQ-C15-PAL. Data were analysed (1) prospectively, from baseline to ≥8-month follow-up; and (2) retrospectively, by taking death as index date and comparing results from three cross-sectional subsamples at different stages of illness (time to death ≥6, 5–3 and 2–0 months). Linear mixed models were calculated. Setting/participants: A total of 1739 patients (mean age 66, 50% male) from 30 palliative care centers in 12 countries were included. Results: In prospective analyses, quality of life, functioning and symptoms–except nausea/vomiting–remained generally stable over time. In retrospective analyses, patients 2–0 months before death reported significantly lower quality of life and physical functioning scores than those 5–3 months before death, who in turn scored lower than those ≥6 months before death, suggesting progressive decline. Emotional functioning remained initially unchanged, but decreased in the last months. Pain, fatigue and appetite loss showed a stable increase in intensity towards death. Dyspnea, insomnia and constipation increased from 5–3 to 2–0 months before death. Nausea/vomiting only increased when comparing those ≥6 months before death with those 2–0 months before death. Conclusion: While the prospective approach showed predominantly stable patterns for quality of life, functioning and symptom severity throughout study duration, retrospective analyses indicated that deterioration was already apparent before the terminal phase and accelerated close to death. Our findings support the importance of early symptom identification and treatment in this population, and highlight the need for further studies to explore what characterizes those with either lower or higher symptom burden at different time points towards death. [ABSTRACT FROM AUTHOR]

Hapten contact hypersensitivity (CHS) elicits a well-documented inflammation response that can be used to illustrate training of immune cells through hapten-specific CHS memory. The education of hapten-specific memory T cells has been well-established, recent research in mice has expanded the “adaptive” characteristic of a memory response from solely a function of the adaptive immune system, to innate cells as well. To test whether similar responses are seen in a non-rodent model, we used hapten-specific CHS to measure the ear inflammation response of outbred pigs to dinitrofluorobenzene (DNFB), oxazolone (OXA), or vehicle controls. We adapted mouse innate memory literature protocols to the domestic pig model. Animals were challenged up to 32 days post initial sensitization exposure to the hapten, and specific ear swelling responses to this challenge were significant for 7, 21, and 32 days post-sensitization. We established hapten-specific CHS memory exists in a non-rodent model. We also developed a successful protocol for demonstrating these CHS responses in a porcine system. [ABSTRACT FROM AUTHOR]

Background: Oral anticoagulant therapy (VKA) is nowadays the mainstay of treatment in primary and secondary stroke prevention in patients with atrial fibrillation. Given the limited risk-benefit ratio of vitamin K antagonists, pharmacological research has been directed towards the development of products that could overcome these limits, new oral anticoagulants were recently introduced: dabigatran, rivaroxaban, apixaban, and edoxaban. Aim: Scope of the present study was to examine patterns of use, effectiveness, safety and mean annual cost per patient of anticoagulant treatment for non-valvular AF in real clinical practice. Methods: A retrospective observational cohort study, by using administrative databases (drugs, hospitalizations, clinical visits, lab tests, population registry), was conducted in the Local Health Unit (LHU) of Treviso, Italy, from January 1, 2012 to December 31, 2016. Results: 5597 subjects were selected, 2171 of which satisfied all inclusion criteria. In particular 1355 patients were treated with VKA, 577 patients were treated with NOAC, and 239 patients were treated initially with VKA and subsequently switched to NOAC (switch group). NOAC treatment showed to be superior to VKA and this superiority was statistically significant on both end-points: patients in the NOAC group reported less cardiovascular events (9,9%) and less bleeding episodes (5,5%) versus VKA patients (14,6% and 11,4%; p<,0001 and p = 0,0049, respectively). The mean cost per patient per year was respectively € 1323,9 for patients treated with NOAC versus € 1003,3 for patients treated with VKA. Cost difference appears to be largely driven by drug cost (€ 767,9 for NOAC versus € 17,7 for VKA patients) and by specialist visits and laboratory tests (€ 318,4 for NOAC versus € 733,4 for VKA patients). Conclusion: In this retrospective real-world study treatment with NOAC showed to be associated with significant reductions of CV events and bleeding events compared to VKA use, albeit at a higher NHS’ direct cost per patient/year, mainly due to higher drug therapy cost. [ABSTRACT FROM AUTHOR]

Purpose: Decreasing the risk of catheter related bloodstream infections (CRBSIs) remains a key focus for improving outcomes and reducing cost of care for hemodialysis (HD) patients. Recent studies demonstrate CRBSI rates can be improved by managing bacterial colonization at the catheter exit site. Herein we present the results of a study documenting the clinical performance of the NexSite HD catheter, a new tunneled central venous catheter which incorporates Exit Site Management (ESM) technology. Methods: We conducted an observational study using a prospective, multi-center registry of HD patients implanted with the NexSite HD catheter. The primary endpoint for the study was CRBSI rate for a period up to 180-days following catheter placement. Secondary endpoints included device placement success rate, exit site healing, development of an exit site or tunnel infection, and early or late non-infectious catheter-related complications. All reasons for early non-elective catheter removal were recorded. Results: A total of 115 HD patients at 6 sites were included in the final analysis. Cumulative catheter use was 10,924 days with a mean duration of 95 days. Seven patients experienced CRBSIs during the study period resulting in a CRBSI rate of 0.64 per 1,000 catheter-days. Seventy-four patients (64.3%) had either elective catheter removal (n = 56) or utilized the catheter for the entire 180-day observation period (n = 18). Thirty-five patients (30%) underwent non-elective device removal either due to CRBSI (n = 5), low flow (n = 16), exit site issues (n = 7), or for other causes (n = 7). Six patients died during the observation period with 1 death due to CRBSI-associated complications and the remaining 5 deaths attributed to non-device related causes. Conclusion: Our findings demonstrate that the NexSite HD catheter equipped with ESM technology can achieve a CRBSI rate in compliance with the NKF KDOQI (National Kidney Foundation Kidney Disease Outcome Quality Initiatives) Clinical Performance Guidelines stated goal of less than 1.0/1,000 catheter-days when used in hemodialysis patients using current standard of care nursing protocols. [ABSTRACT FROM AUTHOR]

Background: The partograph has been endorsed by World Health Organization (WHO) since 1994 which presents an algorithm for assessing maternal and foetal conditions and labor progression. Monitoring labour with a partograph can reduce adverse pregnancy outcomes such as prolonged labor, emergency C-sections, birth asphyxia and stillbirths. However, partograph use is still very low, particularly in low and middle income countries (LMICs). In Bangladesh the reported partograph user rate varies from 1.4% to 33.0%. Recently, an electronic version of the partograph, with the provision of online data entry and user aid for emergency clinical support, has been tested successfully in different settings. With this proven evidence, we conducted and operations research to test the feasibility and effectiveness of implementing an e-partograph, for the first time, in 2 public hospitals in Bangladesh Methods: We followed a prospective crossover design. Two secondary level referral hospitals, Jessore and Kushtia District Hospital (DH) were the study sites. All pregnant women who delivered in the study hospitals were the study participants. All nurse-midwives working in the labor ward of study hospitals were trained on appropriate use of both types of partograph along with standard labour management guidelines. Collected quantitative data was analyzed using SPSS 23 statistical software. Discrete variables were expressed as percentages and presented as frequency distribution and cross tabulations. Chi square tests were employed to test the association between exposure and outcome variables. Potential confounding factors were adjusted using multivariate binary logistic regression methods. Ethical approval was obtained from the institutional review board of the International Centre for Diarrheal Disease Research, Bangladesh (icddr,b). Findings: In total 2918 deliveries were conducted at Jessore DH and 2312 at Kushtia DH during one-year study period. Of them, 1012 (506 in each facility) deliveries were monitored using partograph (paper or electronic). The trends of facility based C-section rates was downwards in both the hospitals; 43% to 37% in Jessore and from 36% to 25% in Kushtia Hospital. There was a significant reduction of prolonged labour with e-partograph use. In Kushtia DH, the prolonged labour rate was 42% during phase 1 with the paper version which came down to 29% during phase-2 with the e-partograph use. The similar result was observed in Jessore DH where the prolonged labour rate reduced to 7% with paper partograph from the reported 30% prolonged labour with e-partograph. The e-partograph user rate was higher than the paper partograph during both phases (phase 1: 3.31, CI: 2.04–5.38, p < .001 and in phase 2: 15.20 CI: 6.36–36.33, p < .001) after adjusting for maternal age, parity, gestational age, religion, mother’s education, husband’s education, and fetal sex Conclusion: The partograph user rate has significantly improved with the e- partograph and was associated with an overall reduction in cesarean births. Use of the e-partograph was also associated with reduced rates of prolonged labour. This study has added to the growing body of evidence on the positive impact of e-partograph use. We recommend implementing e-partograph intervention at scale in both public and private hospitals in Bangladesh. Trial registration: ClinicalTrials.gov . [ABSTRACT FROM AUTHOR]

Background: The important role played by intestinal bacterial flora in human health has recently attracted public attention worldwide. Although yogurt is thought to help in preventing the onset of gastroenteritis, this property has rarely been examined in epidemiological studies. Method: This study analyzed data obtained by the Japan Environment and Children’s Study. From a dataset of 103,062 pregnancies, 82,485 were selected for this analysis. Dietary intake of fermented foods (yogurt and cheese) in 1-year-old infants was assessed with a food frequency questionnaire. Parent-reported physician-diagnosed gastroenteritis in early childhood was determined from a questionnaire conducted when the child was 1 year old. Result: The incidence of gastroenteritis was significantly lower in infants who consumed yogurt ≥ 7 and 3–6 times/week than in infants who consumed yogurt < 1 time/week in crude models (n = 82,485) and after adjustment for covariates (adjusted odds ratio [95% confidence interval], 0.78 [0.70–0.86] versus 0.82 [0.76–0.89], respectively; n = 65,051). Frequency of weekly cheese consumption was not associated with the incidence of gastroenteritis. Conclusion: Consumption of yogurt, but not cheese, at 1 year of age was associated with a reduced risk of gastroenteritis. Further studies of this association, including interventional studies, are warranted. [ABSTRACT FROM AUTHOR]

Many drugs can cause hearing loss, leading to sensorineural deafness. The aim of this study was to evaluate the risk of drug-induced hearing loss (DIHL) by using the Japanese Adverse Drug Event Report (JADER) database and to obtain profiles of DIHL onset in clinical settings. We relied on the Medical Dictionary for Regulatory Activities preferred terms and standardized queries, and calculated the reporting odds ratios (RORs). Furthermore, we applied multivariate logistic regression analysis, association rule mining, and time-to-onset analysis using Weibull proportional hazard models. Of 534688 reports recorded in the JADER database from April 2004 to June 2018, adverse event signals were detected for platinum compounds, sulfonamides (plain) (loop diuretics), interferons, ribavirin, other aminoglycosides, papillomavirus vaccines, drugs used in erectile dysfunction, vancomycin, erythromycin, and pancuronium by determining RORs. The RORs of other aminoglycosides, other quaternary ammonium compounds, drugs used in erectile dysfunction, and sulfonamides (plain) were 29.4 (22.4–38.6), 18.5 (11.2–30.6), 15.4 (10.6–22.5), and 12.6 (10.0–16.0), respectively. High lift score was observed for patients with congenital diaphragmatic hernia treated with pancuronium using association rule mining. The median durations (interquartile range) for DIHL due to platinum compounds, sulfonamides (plain), interferons, antivirals for treatment of hepatitis C virus (HCV) infections, other aminoglycosides, carboxamide derivatives, macrolides, and pneumococcal vaccines were 25.5 (7.5–111.3), 80.5 (4.5–143.0), 64.0 (14.0–132.0), 53.0 (9.0–121.0), 11.0 (3.0–26.8), 1.5 (0.3–11.5), 3.5 (1.3–6.8), and 2.0 (1.0–4.5), respectively. Our results demonstrated potential risks associated with several drugs based on their RORs. We recommend to closely monitor patients treated with aminoglycosides for DIHL for at least two weeks. Moreover, individuals receiving platinum compounds, sulfonamides (plain), interferons, and antivirals for HCV infection therapy should be carefully observed for DIHL for at least several months. [ABSTRACT FROM AUTHOR]

It is common to find abundant genetic variation in host resistance and parasite infectivity within populations, with the outcome of infection frequently depending on genotype-specific interactions. Underlying these effects are complex immune defenses that are under the control of both host and parasite genes. We have found extensive variation in Drosophila melanogaster’s immune response against the parasitoid wasp Leptopilina boulardi. Some aspects of the immune response, such as phenoloxidase activity, are predominantly affected by the host genotype. Some, such as upregulation of the complement-like protein Tep1, are controlled by the parasite genotype. Others, like the differentiation of immune cells called lamellocytes, depend on the specific combination of host and parasite genotypes. These observations illustrate how the outcome of infection depends on independent genetic effects on different aspects of host immunity. As parasite-killing results from the concerted action of different components of the immune response, these observations provide a physiological mechanism to generate phenomena like epistasis and genotype-interactions that underlie models of coevolution. [ABSTRACT FROM AUTHOR]

Background: The Global Programme to Eliminate Lymphatic Filariasis (LF) emphasizes hygiene, exercise, and other measures to reduce morbidity and disability related to LF. We recently reported that a portable, three-dimensional, infrared imaging system (3DIS) provides accurate limb volume measurements in patients with filarial lymphedema. To assess the practical utility of repeated 3DIS measurements for longitudinal lymphedema management, we examined intraday and day-to-day leg volume changes in adults with filarial lymphedema in southern Sri Lanka. Methodology and principal findings: We assessed 41 participants with lower extremity lymphedema (stages 1–6) in their homes in the mornings (6:00–9:00 AM) and afternoons (2:00–6:00 PM) of three days within one calendar week. Two examiners performed replicate 3DIS volume measurements at each visit. Median coefficient of variation among replicate volume measurements was 1.7% (IQR 1.1% - 2.3%) for left legs and 2.2% (IQR 1.6% - 2.8%) for right legs. Median intraday volume increase was 3.0%. Range among daily volume measurements tended to be lower for afternoon measurements (median 2.25%, IQR 1.4%– 5.4%) than for morning measurements (median 3.0%, IQR 1.4% - 8.4%). Conclusions and significance: Limb volume measurements by 3DIS are accurate and reproducible, and this technique is feasible for use in patients’ homes. We have developed practical suggestions for optimal outcomes with 3DIS. Duplicate measurements should be performed and repeat assessments should be done at approximately the same time of day to minimize bias. Duplicate measures that vary by more than 8% should prompt review of scanning technique with a repeat measurement. With proper training and attention to technique, 3DIS can be a valuable tool for healthcare workers who work with lymphedema patients. [ABSTRACT FROM AUTHOR]

Background: Maternal morbidity is common in Bangladesh, where the maternal mortality rate has plateaued over the last 6 years. Maternal undernutrition and micronutrient deficiencies contribute to morbidity, but few interventions have measured maternal outcomes. We compared reported prevalence of antepartum, intrapartum, and postpartum complications among recently delivered women between maternal nutrition intervention and control areas in Bangladesh.Methods and Findings: We conducted a cross-sectional assessment nested within a population-based cluster-randomized trial comparing a nutrition counseling and micronutrient supplement intervention integrated within a structured home-based maternal, newborn, and child health (MNCH) program to the MNCH program alone in 10 sub-districts each across 4 Bangladesh districts. Eligible consenting women, delivering within 42-60 days of enrollment and identified by community-level health workers, completed an interviewer-administered questionnaire detailing the index pregnancy and delivery and allowed review of their home-based care register. We compared pooled and specific reported antepartum, intrapartum, and postpartum complications between study groups using hierarchical logistic regression. There were 594 women in the intervention group and 506 in the control group; overall, mean age was 24 years, 31% were primiparas, and 39% reported facility-based delivery, with no significant difference by study group. There were no significant differences between the intervention and control groups in household-level characteristics, including reported mean monthly income (intervention, 6,552 taka, versus control, 6,017 taka; p = 0.48), having electricity (69.6% versus 71.4%, p = 0.84), and television ownership (41.1% versus 38.7%, p = 0.81). Women in the intervention group had higher recorded iron and folic acid and calcium supplement consumption and mean dietary diversity scores, but reported anemia rates were similar between the 2 groups (5.7%, intervention; 6.5%, control; p = 0.83). Reported antepartum (69.4%, intervention; 79.2%, control; p = 0.12) and intrapartum (41.4%, intervention; 48.5%, control; p = 0.18) complication rates were high and not significantly different between groups. Reported postpartum complications were significantly lower among women in the intervention group than the control group (33.5% versus 48.2%, p = 0.02), and this difference persisted in adjusted analysis (adjusted odds ratio [AOR] = 0.51, 95% CI 0.32-0.82; p < 0.001). For specific conditions, odds of retained placenta (AOR = 0.35, 95% CI 0.19-0.67; p = 0.001), postpartum bleeding (AOR = 0.37, 95% CI 0.15-0.92; p = 0.033), and postpartum fever/infection (AOR = 0.27, 95% CI 0.11-0.65; p = 0.001) were significantly lower in the intervention group in adjusted analysis. There were no significant differences in reported hospitalization for antepartum (49.8% versus 45.1%, p = 0.37), intrapartum (69.9% versus 59.8%, p = 0.18), or postpartum (36.1% versus 29.9%, p = 0.49) complications between the intervention and control groups. The main limitations of this study are outcome measures based on participant report, non-probabilistic selection of community-level workers' catchment areas for sampling, some missing data for variables derived from secondary sources (e.g., dietary diversity score), and possible recall bias for reported dietary intake and supplement use.Conclusions: Reported overall postpartum and specific intrapartum and postpartum complications were significantly lower for women in intervention areas than control areas, despite similar rates of facility-based delivery and hospitalization for reported complications, in this exploratory analysis. Maternal nutrition interventions providing intensive counseling and micronutrient supplements may reduce some pregnancy complications or impact women's ability to accurately recognize complications, but more rigorous evaluation is needed for these outcomes. [ABSTRACT FROM AUTHOR]

Objective: The aims of this study were to assess the characteristics of all acute poisoning admissions among adult emergency department (ED) patients, to identify factors associated with admission and to calculate direct medical cost. Methods: Data of 2017 (1st January to 31st December) were collected and analyzed retrospectively using patients’ medical records and hospital invoices. Factors associated with type of hospitalization were identified using appropriate statistics. Results: A total of 1,214 hospital admissions were included, accounting for 3.6% of all ED admissions. Men (62.2%) and the age group 21–40 years (43.0%) accounted for the largest proportion. Substances most commonly involved were ethanol (52.9%), benzodiazepines (9.7%), cocaine (4.9%), cannabis (4.6%), antidepressants (4.6%) and psychostimulants (4.6%). A total of 4,561 treatment acts were recorded, most commonly monitoring of vital signs (63.6%) and medication and/or intravenous drip administration (62.9%). Patients were discharged home after having received care in the emergency department (ED-amb) in 54.5% of admissions, were admitted to the emergency-department-24-hours-observation unit (ED-24h) or were hospitalized (Hosp) in 24.6% and 20.9% of admissions, respectively. Factors found to be associated with hospitalization type were age, hour of admission, victim location, degree of severity, use of antidotes, involvement of antidepressants, antipsychotics, psychostimulants, benzodiazepines and ethanol. Total cost was €1,512,346 with an average of €1,287 per admission. Conclusion: Poisonings entail a considerable percentage of patients admitted to an ED and financial burden. In particular, ethanol poisonings account for the largest proportion of all ED admissions. Comparison of our figures with other data is hampered by the heterogeneity in inclusion criteria. Availability of a uniform template would facilitate comparison and allow better monitoring policies for prevention and cost reduction. [ABSTRACT FROM AUTHOR]

Objective: Little is known about prognostic factors for lung squamous cell carcinoma (SCC). We aimed to explore radiologic and clinical factors affecting prognosis and to compare the prognosis of both central and peripheral lung SCCs. Materials and methods: Radiologic, clinical, and pathologic profiles of surgically confirmed SCCs from 382 patients were retrospectively reviewed. Tumor location, enhancement, necrosis, the presence of obstructive pneumonitis/atelectasis and underlying lung disease were evaluated on chest CT examination. Age, pulmonary function, tumor marker, and cancer stage were also assessed. Univariate and multivariate Cox regression analyses were performed to identify any correlation to overall survival (OS) and disease-free survival (DFS). Hazard rate estimation and competing risk analysis were done to evaluate recurrence pattern. Results: The median follow-up period was 56.2 months. Tumors were located centrally in 230 patients (60.2%) and peripherally in 152 patients (39.8%). Age (p = 0.002, hazard ratio [HR] 1.03, 95% confidence interval [CI] = [1.01, 1.06]) and interstitial lung abnormalities (ILAs) (p<0.001, HR 5.41, 95% CI = [3.08, 9.52]) were associated with poor OS on multivariate analysis. ILAs also had a strong association to DFS (p<0.001, HR 4.25, 95% CI = [3.08, 9.52]). Central cancers had two peaks of local recurrence development at 15 and 60 months after surgery, and peripheral tumors showed rising curves for metastasis development at 60 months. Conclusions: CT-determined ILAs are a strong biomarker predicting poor outcome. Prognosis may not vary according to tumor location, but the two groups exhibited different recurrence patterns. [ABSTRACT FROM AUTHOR]

Objective: To compare the magnetic resonance imaging (MRI) features of deep infiltrating endometriosis (DIE) lesions before and after pregnancy. Design: Retrospective study. Setting: A single French university tertiary referral hospital. Patients: Twenty-one women without a prior history of surgery for endometriosis with a radiological diagnosis by MRI with two sets of examinations performed before and after pregnancy. Interventions: The volumes of the lesions were compared using the same protocol before and after pregnancy based on MRI (1.5 T) examinations by a single experienced radiologist who is a referring practitioner for image-based diagnosis of endometriosis. Main outcome measure(s): The DIE lesion volume. Measurements and main results: Between October 2012 and December 2016, a total of 21 patients (67 lesions) were included and compared before and after pregnancy. The mean time interval between the MRI before pregnancy and delivery was 19.6 ± 8.5 months (median: 17.6, IQR 13.5–25.2 months). The mean time interval between delivery and the MRI after pregnancy was 11.0 ± 6.4 months (median: 8.3, IQR 6–15.2 months). The mean overall DIE lesion volume by MRI was significantly higher before pregnancy compared to after pregnancy (2,552 ± 3,315 mm3 vs. 1,708 ± 3,266 mm3, respectively, p < 0.01). The mean volume by MRI of the largest lesion of each patient was significantly higher before pregnancy compared to after pregnancy (4,728 ± 4,776 mm3 vs. 3165 ± 5299 mm3; p < 0.01). Conclusion: Our data indicate a favorable impact of pregnancy on DIE lesion volumes as measured by MRI. [ABSTRACT FROM AUTHOR]

Purpose: The effects of gravity on bevacizumab or the recommended head position after intraocular bevacizumab injection have not been reported. To evaluate the effect of gravity on bevacizumab in vitro, we added bevacizumab to the upper part of a test tube filled with balanced salt solution (BSS) and examined its distribution over time. Materials and methods: Sixty-four test tubes were divided equally into two groups; group 1 (32, collected from upper part of the tube) and group 2 (32, collected from lower part of the tube). Each test tube was filled with 5 mL BSS before bevacizumab (1.25 mg/0.05 mL) was added, and then stored at 36°C. Bevacizumab concentration in 8 test tubes from each group was measured at 12, 24, 48, and 168 h using an enzyme-linked immunosorbent analysis (ELISA) kit. Mann–Whitney and Jonckheere–Terpstra tests were used for statistical analysis. Results: Bevacizumab concentration was significantly higher in Group 2 than in Group 1 at 12, 24, 48, and 168 h (12, 24, 48, and 168 h; P < 0.01 each; Mann–Whitney test). The mean change in bevacizumab concentration over time tended to increase in Group 1 (P < 0.01; Jonckheere–Terpstra test), but tended to decrease in Group 2 (P < 0.01; Jonckheere–Terpstra test). Conclusions: The significant differences in concentration between the upper and lower parts even after a considerable amount of storage time showed that bevacizumab did not dissolve immediately and diffused evenly throughout the solution. It appeared that more bevacizumab settled in the lower part of the tube than in the upper part because of gravitational force. However, the concentration difference between the upper and lower parts decreased as bevacizumab gradually diffused over time, indicating that the difference in concentration due to gravity was more significant at the beginning of bevacizumab injection. [ABSTRACT FROM AUTHOR]

Introduction: In addition to their role in facilitating leukocyte-mediated inflammation, platelets can dampen leukocyte pro-inflammatory responses in some contexts. Consequently, platelets are increasingly appreciated as regulators of inflammation. Together, platelets and neutrophils play a role in inflammation through Toll-like receptor (TLR) expression, although we do not fully understand how platelets shape neutrophil responses to TLR stimulation. Here, we aimed to determine the extent to which platelets can modulate neutrophil function in response to in vitro stimulation with TLR4, TLR2/1, and TLR2/6 agonists. Methods: Neutrophils from 10 healthy individuals were cultured alone or with autologous platelets. Neutrophils ± platelets were left unstimulated or were stimulated with 1 or 100 ng/mL lipopolysaccharide (LPS; a TLR4 agonist), Pam3CSK4 (a TLR2/1 agonist) and fibroblast-stimulating lipopeptide (FSL)-1 (a TLR2/6 agonist). Neutrophil activation and phagocytic activity were assessed by flow cytometry, and elastase and interleukin-8 secretion were assessed by ELISA. Results: The addition of platelets attenuated neutrophil CD66b and CD11b expression in response to various doses of Pam3CSK4 and FSL-1. Furthermore, platelet co-culture was associated with higher CD62L expression (indicating reduced CD62L shedding) in response to these TLR agonists. Platelets also reduced elastase secretion in unstimulated cultures and in response to low-dose TLR stimulation. Conversely, platelet co-culture increased neutrophil phagocytosis in unstimulated cultures and in response to low-dose Pam3CSK4 and FSL-1. Platelets also increased IL-8 secretion in response to low-dose LPS. Conclusion: Platelets are complex immunomodulators that can attenuate some, and simultaneously augment other, neutrophil functions. This modulation can occur both in the absence and presence of TLR stimulation. [ABSTRACT FROM AUTHOR]

Various agents including Ca. Piscichlamydia salmonis, Ca. Branchiomonas cysticola, Desmozoon lepeophtherii, Paramoeba perurans and salmon gill poxvirus may be associated with complex gill disease in Atlantic salmon. Co-infections involving two or more of these agents are common and histopathological interpretation of lesions is therefore challenging. In this study, we developed a semi-quantitative scoring system for examination of histopathological gill lesions in sea-farmed Atlantic salmon suffering from gill disease. Following qPCR analysis of gills sampled for Ca. P. salmonis, Ca. B. cysticola, D. lepeophtherii and P. perurans from 22 geographically spread outbreaks, five cases representing different infectious loads and combinations of agents were chosen for histopathological scoring. Twenty-eight histological features were evaluated and potential associations between individual pathological changes and the occurrence of individual agents studied. The inter-observer agreement in interpretation of histological parameters between the three pathologists involved, was calculated to validate robustness of the scoring scheme. Seventeen histological parameters met the criteria for inter-observer agreement analysis and were included in the calculation. The three most frequent findings were identification of subepithelial leukocytes, epithelial cell hyperplasia and mucus cell hyperplasia. While few findings could be specifically related to particular agents, necrosis in hyperplastic lesions, pustules and necrosis of subepithelial cells appeared to be associated with the presence of Ca. B. cysticola. Further, lesion profiles clearly support the previously identified association between P. perurans and pathological changes associated with AGD. Very few pathological changes were observed in the single case in which Ca. P. salmonis was the dominating agent. Some lesions were only very rarely observed e.g. chloride cell necrosis, epithelial cell apoptosis, lamellar deposition of melanin and haemophagocytosis. The scoring scheme developed and applied was robust and sensitive. A less extensive scheme for routine diagnostic use is proposed. [ABSTRACT FROM AUTHOR]

Background: The Pregnane X Receptor (PXR) is a principal signal transducer in mucosal responses to xenobiotic stress. It is well-recognized that inflammatory bowel disease is accompanied by xenobiotic stress, but the importance of the PXR in limiting inflammatory responses in inflammatory bowel disease remains obscure at best. Methods: We stimulate a total of 106 colonic biopsies from 19 Crohn’s disease patients with active disease, 36 colonic biopsies from 8 control patients, colonic organoids and various cell culture models (either proficient or genetically deficient with respect to PXR) in vitro with the PXR ligand rifampicin or vehicle. Effects on NF-κB activity are assessed by measuring interleukin-8 (IL-8) and interleukin-1ß (IL-1ß) mRNA levels by qPCR and in cell culture models by NF-κB reporter-driven luciferase activity and Western blot for signal transduction elements. Results: We observe a strict inverse correlation between colonic epithelial PXR levels and NF-κB target gene expression in colonic biopsies from Crohn’s disease patients. PXR, activated by rifampicin, is rate-limiting for mucosal NF-κB activation in IBD. The correlation between colonic epithelial PXR levels and NF-κB target gene expression was also observed in intestinal organoids system. Furthermore, in preclinical in vitro models of intestinal inflammation, including intestinal organoids, genetic inactivation of PXR unleashes NF-κB-dependent signal transduction whereas conversely NF-κB signaling reduces levels of PXR expression. Conclusions: Our data indicate that the PXR is a major and clinically relevant antagonist of NF-κB activity in the intestinal epithelial compartment during inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Background: Patients with cirrhosis and acute myocardial infarction (AMI) present dilemma whether dual antiplatelet therapy (DAPT) should be used. Methods: Electronic medical records between 2001–2013 were retrieved from Taiwan National Health Insurance Research Database. Patients were excluded for missing information, age <20 years old, history of AMI, liver transplant, autoimmune disease, coagulopathy, taking DAPT 3 months before index date, follow-up <3 months, anticoagulation user, without DAPT, and events of myocardial infarction (MI), ischemic stroke, major bleeding, and heart failure within 3-month of enrollment. Primary outcomes were 1-year all-cause mortality, recurrent MI, major bleeding, and gastrointestinal bleeding. Results: A total of 150,887 patients with AMI retrieved. After exclusion criteria and propensity score-matching, 914 cirrhotic and 3,656 non-cirrhotic patients with AMI on DAPT were studied. During 1-year follow-up, there was significantly increased mortality in cirrhotic patients compared to non-cirrhotic patients (HR = 1.49, 95% CI = 1.28–1.74). There was significantly decreased recurrent MI in cirrhotic patients compared to non-cirrhotic patients (subdistribution HR [SHR] = 0.71, 95% CI = 0.54–0.92). However, non-significantly increased major bleeding (SHR = 1.23, 95% CI = 0.87–1.73) and significantly increased gastrointestinal bleeding (SHR = 1.49, 95% CI = 1.31–1.70). Conclusions: In cirrhotic patients with AMI, DAPT offers benefit with decreased recurrent MI at the expense of increased gastrointestinal bleeding. [ABSTRACT FROM AUTHOR]

Objective: In clinical prediction/diagnostic rules aimed at early detection of critically ill patients, the respiratory rate plays an important role. We investigated the accuracy and interobserver-agreement of respiratory rate measurements by healthcare professionals, and the potential effect of incorrect measurements on the scores of 4 common clinical prediction/diagnostic rules: Systemic Inflammatory Response Syndrome (SIRS) criteria, quick Sepsis-related Organ Failure Assessment (qSOFA), National Early Warning Score (NEWS), and Modified Early Warning Score (MEWS). Methods: Using an online questionnaire, we showed 5 videos with a healthy volunteer, breathing at a fixed (true) rate (13–28 breaths/minute). Respondents measured the respiratory rate, and categorized it as low, normal, or high. We analysed how accurate the measurements were using descriptive statistics, and calculated interobserver-agreement using the intraclass correlation coefficient (ICC), and agreement between measurements and categorical judgments using Cohen’s Kappa. Finally, we analysed how often incorrect measurements led to under/overestimation in the selected clinical rules. Results: In total, 448 healthcare professionals participated. Median measurements were slightly higher (1-3/min) than the true respiratory rate, and 78.2% of measurements were within 4/min of the true rate. ICC was moderate (0.64, 95% CI 0.39–0.94). When comparing the measured respiratory rates with the categorical judgments, 14.5% were inconsistent. Incorrect measurements influenced the 4 rules in 8.8% (SIRS) to 37.1% (NEWS). Both underestimation (4.5–7.1%) and overestimation (3.9–32.2%) occurred. Conclusions: The accuracy and interobserver-agreement of respiratory rate measurements by healthcare professionals are suboptimal. This leads to both over- and underestimation of scores of four clinical prediction/diagnostic rules. The clinically most important effect could be a delay in diagnosis and treatment of (critically) ill patients. [ABSTRACT FROM AUTHOR]

The purpose of this study was to produce two statistical survival models in those with cirrhosis utilising only routine parameters, including non-liver-related clinical factors that influence survival. The first model identified and utilised factors impacting short-term survival to 90-days post incident diagnosis, and a further model characterised factors that impacted survival following this acute phase. Data were from the Clinical Practice Research Datalink linked with Hospital Episode Statistics. Incident cases in patients ≥18 years were identified between 1998 and 2014. Patients that had prior history of cancer or had received liver transplants prior were excluded. Model-1 used a logistic regression model to predict mortality. Model-2 used data from those patients who survived 90 days, and used an extension of the Cox regression model, adjusting for time-dependent covariables. At 90 days, 23% of patients had died. Overall median survival was 3.7 years. Model-1: numerous predictors, prior comorbidities and decompensating events were incorporated. All comorbidities contributed to increased odds of death, with renal disease having the largest adjusted odds ratio (OR = 3.35, 95%CI 2.97–3.77). Model-2: covariables included cumulative admissions for liver disease-related events and admissions for infections. Significant covariates were renal disease (adjusted hazard ratio (HR = 2.89, 2.47–3.38)), elevated bilirubin levels (aHR = 1.38, 1.26–1.51) and low sodium levels (aHR = 2.26, 1.84–2.78). An internal validation demonstrated reliability of both models. In conclusion: two survival models that included parameters commonly recorded in routine clinical practice were generated that reliably forecast the risk of death in patients with cirrhosis: in the acute, post diagnosis phase, and following this critical, 90 day phase. This has implications for practice and helps better forecast the risk of mortality from cirrhosis using routinely recorded parameters without inputs from specialists. [ABSTRACT FROM AUTHOR]

Intracranial germinoma sometimes present as bifocal germinoma, and whether bifocal germinoma should be treated as a synchronous or disseminated disease remains unclear. This study aimed to determine the optimal treatment modality for bifocal germinoma. Patients with bifocal germinoma who received radiotherapy (RT) from March 1990 to August 2017 were included for analysis. A total of 21 patients were included. The median follow-up period was 76.2 months (range, 6.2–305.4 months). There were 17 patients who received cranio-spinal irradiation (CSI) with local RT; 3, whole ventricular RT (WVRT) with local RT; and 1, local RT only. Three recurrences occurred (1 patient each among those who underwent CSI, WVRT, and local RT). Recurrence in the patient who received CSI and who received WVRT occurred in the right thalamus and right frontal convexity, respectively. Meanwhile, the patient who received local RT showed not only a recurred lesion in the hypothalamus, but also cerebrospinal fluid seeding. For this patient, salvage CSI was performed and complete response was achieved after treatment. However, after 9 years and 6 months, he was diagnosed with glioblastoma and expired. As for toxicity, although 17 patients showed decrease in complete blood count levels during treatment, all patients recovered soon after treatment completion. Our findings suggest that bifocal germinoma may be considered as a disseminated disease when considering the patterns of failure according to RT fields. In addition, patients who received CSI showed low acute toxicity rates. However, further studies are necessary to confirm these findings. [ABSTRACT FROM AUTHOR]

Trauma and hemorrhagic shock can lead to acute traumatic coagulopathy (ATC) that is not fully reversed by prehospital resuscitation as simulated with a limited volume of fresh whole blood (FWB) in a rat model. Tranexamic Acid (TXA) is used as an anti-fibrinolytic agent to reduce surgical bleeding if administered prior to or during surgery, and to improve survival in trauma if given early after trauma. It is not clear from the existing clinical literature whether TXA has the same mechanism of action in both settings. This study sought to explore the molecular mechanisms of TXA activity in trauma and determine whether administration of TXA as a supplement to FWB resuscitation could attenuate the established ATC in a rat model simulating prehospital resuscitation of polytrauma and hemorrhagic shock. In a parallel in-vitro study, the effects on clotting assays of adding plasmin at varying doses along with either simultaneous addition of TXA or pre-incubation with TXA were measured, and the results suggested that maximum anti-fibrinolytic effect of TXA on plasmin-induced fibrinolysis required pre-incubation of TXA and plasmin prior to clot initiation. In the rat model, ATC was induced by polytrauma followed by 40% hemorrhage. One hour after trauma, the rats were resuscitated with FWB collected from donor rats. Vehicle or TXA (10mg/kg) was given as bolus either before trauma (TXA-BT), or 45min after trauma prior to resuscitation (TXA-AT). The TXA-BT group was included to contrast the coagulation effects of TXA when used as it is in elective surgery vs. what is actually feasible in real trauma patients (TXA-AT group). A single dose of TXA prior to trauma significantly delayed the onset of ATC from 30min to 120min after trauma as measured by a rise in prothrombin time (PT). The plasma d-dimer as well as plasminogen/fibrinogen ratio in traumatized liver of TXA-BT were significantly lower as compared to vehicle and TXA-AT. Wet/dry weight ratio and leukocytes infiltration of lungs were significantly decreased only if TXA was administrated later, prior to resuscitation (TXA-AT). In conclusion: Limited prehospital trauma resuscitation that includes FWB and TXA may not correct established systemic ATC, but rather may improve overall outcomes of resuscitation by attenuation of acute lung injury. By contrast, TXA given prior to trauma reduced levels of fibrinolysis at the site of tissue injury and circulatory d-dimer, and delayed development of coagulopathy independent of reduction of fibrinogen levels following trauma. These findings highlight the importance of early administration of TXA in trauma, and suggest that further optimization of dosing protocols in trauma to exploit TXA’s various sites and modes of action may further improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background & aims: Previous studies from western countries have reported that active hepatocellular carcinoma (HCC) was associated with direct-acting antiviral (DAA) treatment failure. We sought to examine this issue in an Asian cohort. Methods: A retrospective cohort study was conducted on hepatitis C virus (HCV)-infected patients with advanced fibrosis who were treated with DAAs at our hospital between January 2017 and June 2018. Results: We treated 1021 HCV-infected patients during this period. A total of 976 of those patients were enrolled in a per-protocol analysis, including 556 (57.2%) who had genotype 1b infections, and 314 (32.3%) who had genotype 2 infections. The mean age of all 976 patients was 65.5 years, and 44.5% were male. 781 of the patients had no HCC, 172 had inactive HCC, and 23 had active HCC. Non-sustained virologic response (SVR) was noted in 10 (1.3%) patients without HCC, 5 (2.9%) patients with inactive HCC, and 4 (13.0%) patients with active HCC. After adjustment for confounders, active HCC (versus inactive HCC and non-HCC) was associated with non-SVR (adjusted odds ratio [AOR] = 24.5 (95% confidence interval [CI] = 4.4–136.9), P<0.001). Next, we excluded the 23 patients with active HCC from the multivariate analysis. After adjustment for confounders, inactive HCC (versus non-HCC) was not associated with non-SVR (AOR = 3.1 (95% CI = 0.94–9.95), P = 0.06). Conclusion: Active HCC was associated with non-SVR, while inactive HCC was not. We thus suggest the deferral of DAA treatment until after the complete radiological response of HCCs to treatment. [ABSTRACT FROM AUTHOR]

Cognitive impairments are a common consequence of traumatic brain injury (TBI). The hippocampus is a subcortical structure that plays a key role in the formation of declarative memories and is highly vulnerable to TBI. The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in the hippocampus and reduced expression and function of this receptor are linked with cognitive impairments in Alzheimer’s disease and schizophrenia. Positive allosteric modulation of α7 nAChRs with AVL-3288 enhances receptor currents and improves cognitive functioning in naïve animals and healthy human subjects. Therefore, we hypothesized that targeting the α7 nAChR with the positive allosteric modulator AVL-3288 would enhance cognitive functioning in the chronic recovery period of TBI. To test this hypothesis, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury or sham surgery. At 3 months after recovery, animals were treated with vehicle or AVL-3288 at 30 min prior to cue and contextual fear conditioning and the water maze task. Treatment of TBI animals with AVL-3288 rescued learning and memory deficits in water maze retention and working memory. AVL-3288 treatment also improved cue and contextual fear memory when tested at 24 hr and 1 month after training, when TBI animals were treated acutely just during fear conditioning at 3 months post-TBI. Hippocampal atrophy but not cortical atrophy was reduced with AVL-3288 treatment in the chronic recovery phase of TBI. AVL-3288 application to acute hippocampal slices from animals at 3 months after TBI rescued basal synaptic transmission deficits and long-term potentiation (LTP) in area CA1. Our results demonstrate that AVL-3288 improves hippocampal synaptic plasticity, and learning and memory performance after TBI in the chronic recovery period. Enhancing cholinergic transmission through positive allosteric modulation of the α7 nAChR may be a novel therapeutic to improve cognition after TBI. [ABSTRACT FROM AUTHOR]

Background: Linezolid has shown strong antimicrobial activity against multidrug-resistant (MDR)/rifampin-resistant strains of Mycobacterium tuberculosis. Linezolid achieves clinical efficacy mainly through area under the concentration time curve/minimum inhibitory concentration ratio in the infected lesion site. Previous studies mainly focused on the relationship between linezolid concentrations in the blood and infected bone tissue when the blood drug concentration reached the peak 2 h after administration. However, we do not know whether linezolid can maintain the same bone/plasma ratio in infected bone tissue when the blood concentration reaches the trough level. Therefore, this study aimed to evaluate the penetrability of linezolid into bone tissue 24 h after administration in patients with MDR spinal tuberculosis (TB). Methods: Nine MDR spinal TB patients, who received a treatment regimen including linezolid and underwent surgery, were enrolled prospectively from April 2017 to March 2019. Blood and diseased bone tissue specimens were collected simultaneously during operations 24 h after taking 600 mg of linezolid orally. Linezolid concentrations in plasma and diseased bone tissue specimens were determined by high-performance liquid chromatography–tandem mass spectrometry. Results: Following a 600 mg oral administration of linezolid 24 h before surgery, median concentrations of linezolid in plasma and diseased bone tissue for the 9 patients were 1.98 mg/L (range 0.30–3.44 mg/L) and 0.60 mg/L (range 0.18–2.13 mg/L), respectively, at resection time. The median diseased bone/plasma linezolid concentration ratio was 0.48 (range 0.30–0.67). Pearson’s correlation analysis showed that linezolid concentrations in the plasma were positively related to those in diseased bone tissue (r = 0.949, p < 0.001). Conclusions: After 24 h of medication, linezolid still had good penetrability into diseased bone tissue in patients with MDR spinal TB. [ABSTRACT FROM AUTHOR]

Background: Diabetes is the most common comorbidity of necrotizing fasciitis (NF), but the effect of stress-induced hyperglycemia (SIH) on diabetic patients with NF has never been investigated. The aim of this study was to assess whether SIH, as determined by the glycemic gap between admission glucose levels and A1C-derived average glucose levels, predicts adverse outcomes in diabetic patients hospitalized with NF. Methods: We retrospectively reviewed the glycemic gap and clinical outcomes in 252 diabetic patients hospitalized due to NF from 2011 to 2018 in a single medical center in Taiwan. A receiver operating characteristic (ROC) curve was used to analyze the optimal cutoff values for predicting adverse outcomes. Univariate and multivariate logistic regression analyses were employed to identify significant predictors of adverse outcomes. Results: In total, 194 diabetic NF patients were enrolled. Compared with patients without adverse outcomes, patients with adverse outcomes had significantly higher glycemic gaps, Acute Physiology and Chronic Health Evaluation (APACHE) II scores and C-reactive protein (CRP) levels; lower albumin and hemoglobin levels; greater incidence of limb loss; and longer hospital and intensive care unit stays. The glycemic gap positively correlates with the laboratory risk indicator for NF scores, APACHE II scores and CRP levels. A glycemic gap of 146 mg/dL was the optimal cutoff value for predicting adverse outcomes using the ROC curve. Compared with patients with glycemic gaps ≤146 mg/dL, those with glycemic gaps >146 mg/dL had higher APACHE II scores and incidence rates of adverse outcomes, especially bacteremia and acute kidney injury. Multivariate analysis revealed that a glycemic gap >146 mg/dL and APACHE II score >15 were independent predictors of adverse outcomes, while the presence of hyperglycemia at admission was not. Conclusions: An elevated glycemic gap was significantly independently associated with adverse outcomes in diabetic NF patients. Further prospective studies are warranted to validate the role of the glycemic gap in NF patients with diabetes. [ABSTRACT FROM AUTHOR]

Introduction: The earliest changes in the brain due to Alzheimer’s disease are associated with the neural networks related to memory function. We investigated changes in functional and structural connectivity among regions that support memory function in prodromal Alzheimer’s disease, i.e., during the mild cognitive impairment (MCI) stage. Methods: Twenty-three older healthy controls and 25 adults with MCI underwent multimodal MRI scanning. Limbic white matter tracts–the fornix, parahippocampal cingulum, retrosplenial cingulum, subgenual cingulum and uncinate fasciculus–were reconstructed in ExploreDTI using constrained spherical deconvolution-based tractography. Using a network-of-interest approach, resting-state functional connectivity time-series correlations among sub-parcellations of the default mode and limbic networks, the hippocampus and the thalamus were calculated in Conn. Analysis: Controlling for age, education, and gender between group linear regressions of five diffusion-weighted measures and of resting state connectivity measures were performed per hemisphere. FDR-corrections were performed within each class of measures. Correlations of within-network Fisher Z-transformed correlation coefficients and the mean diffusivity per tract were performed. Whole-brain graph theory measures of cluster coefficient and average path length were inspecting using the resting state data. Results & conclusion: MCI-related changes in white matter structure were found in the fornix, left parahippocampal cingulum, left retrosplenial cingulum and left subgenual cingulum. Functional connectivity decreases were observed in the MCI group within the DMN-a sub-network, between the hippocampus and sub-areas -a and -c of the DMN, between DMN-c and DMN-a, and, in the right hemisphere only between DMN-c and both the thalamus and limbic-a. No relationships between white matter tract ‘integrity’ (mean diffusivity) and within sub-network functional connectivity were found. Graph theory revealed that changes in the MCI group was mostly restricted to diminished between-neighbour connections of the hippocampi and of nodes within DMN-a and DMN-b. [ABSTRACT FROM AUTHOR]

The development of ICU-acquired sodium disturbances is not fully understood. Alterations in non-osmotic skin sodium storage, hypothetically inflammation-driven, could play a role. To investigate this in critically ill patients we conducted a patient-control study with skin punch biopsies in patients with sepsis (n = 15), after coronary artery bypass grafting (CABG, n = 15) and undergoing total hip arthroplasty (THA-controls, n = 15) respectively, together representing a range in severity of systemic inflammation. Biopsies were taken within 24 hours (sepsis) and within 2 hours (CABG) after ICU-admission, and prior to arthroplasty. Biopsies were analysed for sodium content. In addition immunostainings and quantitative real time PCR were performed. The primary aim of this study was to detect possible differences in amounts of cutaneous sodium. The secondary aims were to quantify inflammation and lymphangiogenesis with concomitant markers. The highest amounts of both water and sodium were found in patients with sepsis, with slightly lower values after CABG and the lowest amounts in THA-controls. Correlation between water and sodium was 0.5 (p<0.01). In skin biopsies in all groups comparable amounts of macrophages, T-cells and lymph vessels were found. In all groups comparable expression of inflammation markers were found. However, higher mRNA transcript expression levels of markers of lymphangiogenesis were found in patients with sepsis and after CABG. The conjoint accumulation of water and sodium points towards oedema formation. However, the correlation coefficient of 0.5 leaves room for alternative explanations, including non-osmotic sodium storage. No signs of dermal inflammation were found, but upregulation of markers of lymphangiogenesis could indicate future lymphangiogenesis. [ABSTRACT FROM AUTHOR]

Background: Malaria in pregnancy is associated with adverse birth outcomes. However, the underlying mechanisms remain poorly understood. Tight regulation of angiogenic, metabolic, and inflammatory pathways are essential for healthy pregnancies. We hypothesized that malaria disrupts these pathways leading to preterm birth (PTB).Methods and Findings: We conducted a secondary analysis of a randomized trial of malaria prevention in pregnancy conducted in Malawi from July 21, 2011, to March 18, 2013. We longitudinally assessed circulating mediators of angiogenic, metabolic, and inflammatory pathways during pregnancy in a cohort of HIV-negative women (n = 1,628), with a median age of 21 years [18, 25], and 562 (35%) were primigravid. Pregnancies were ultrasound dated, and samples were analyzed at 13 to 23 weeks (Visit 1), 28 to 33 weeks (Visit 2), and/or 34 to 36 weeks (Visit 3). Malaria prevalence was high; 70% (n = 1,138) had PCR-positive Plasmodium falciparum infection at least once over the course of pregnancy and/or positive placental histology. The risk of delivering preterm in the entire cohort was 20% (n = 304/1506). Women with malaria before 24 weeks gestation had a higher risk of PTB (24% versus 18%, p = 0.005; adjusted relative risk [aRR] 1.30, 95% confidence interval [CI] 1.04-1.63, p = 0.021); and those who were malaria positive only before week 24 had an even greater risk of PTB (28% versus 17%, p = 0.02; with an aRR of 1.67, 95% CI 1.20-2.30, p = 0.002). Using linear mixed-effects modeling, malaria before 24 weeks gestation was associated with altered kinetics of inflammatory (C-Reactive Protein [CRP], Chitinase 3-like protein-1 [CHI3L1], Interleukin 18 Binding Protein [IL-18BP], soluble Tumor Necrosis Factor receptor II [sTNFRII], soluble Intercellular Adhesion Molecule-1 [sICAM-1]), angiogenic (soluble Endoglin [sEng]), and metabolic mediators (Leptin, Angiopoietin-like 3 [Angptl3]) over the course of pregnancy (χ2 > 13.0, p ≤ 0.001 for each). Limitations include being underpowered to assess the impact on nonviable births, being unable to assess women who had not received any antimalarials, and, because of the exposure to antimalarials in the second trimester, there were limited numbers of malaria infections late in pregnancy.Conclusions: Current interventions for the prevention of malaria in pregnancy are initiated at the first antenatal visit, usually in the second trimester. In this study, we found that many women are already malaria-infected by their first visit. Malaria infection before 24 weeks gestation was associated with dysregulation of essential regulators of angiogenesis, metabolism, and inflammation and an increased risk of PTB. Preventing malaria earlier in pregnancy may reduce placental dysfunction and thereby improve birth outcomes in malaria-endemic settings. [ABSTRACT FROM AUTHOR]

Background: COPD is a common HIV comorbidity, and HIV-infected individuals have a higher incidence and earlier onset of COPD compared to HIV-uninfected individuals. While the pathogenesis of HIV-associated COPD is largely unknown, chronic inflammation may contribute. Four pneumoproteins known to be markers of lung injury and inflammation have been associated with COPD in HIV-uninfected individuals: PARC/CCL-18, SP-D, CC-16, and sRAGE. Objective: To determine whether these pneumoproteins are also associated with pulmonary function and COPD Assessment Test (CAT) scores in HIV-infected individuals. Methods: Associations between plasma pneumoprotein levels and pulmonary function were determined in a cross-sectional study of otherwise healthy HIV-infected individuals enrolled between September 2016 and June 2017. Covariates included HIV-associated (antiretroviral therapy, CD4 count, and viral load) and COPD-associated (smoking and BMI) covariates. Results: Among 65 participants, 78.5% were male, 50.8% had undetectable viral load, and 76.9% were ever-smokers. Mean post-bronchodilator FEV1/FVC was 0.71, and mean DLco%predicted was 61%. Higher PARC/CCL-18 was associated with lower DLco%predicted and higher CAT score. Higher CC-16 was associated with lower DLco%predicted and lower FVC%predicted. Conclusions: This exploratory analysis is the first to characterize associations between these four pneumoproteins and pulmonary function in an HIV-infected cohort. Our findings suggest the pathogenesis of HIV-associated COPD may differ from that of non-HIV-associated COPD due to HIV-specific inflammatory changes affecting DLco. PARC/CCL-18 is associated with structural and functional pulmonary abnormalities and may be an important COPD biomarker candidate in HIV infection. Our study is a preliminary step toward finding clinically relevant COPD biomarkers in high-risk populations. [ABSTRACT FROM AUTHOR]

Background: Approximately 40,000 newborns die each year in Tanzania. Regional differences in outcome are common. Reviewing current local data, as well as defining potential causal pathways leading to death are urgently needed, before targeted interventions can be implemented Objective: To describe the clinical characteristics and potential causal pathways contributing to newborn death and determine the presumed causes of newborn mortality within seven days, in a rural hospital setting. Methods: Prospective observational study of admitted newborns born October 2014–July 2017. Information about labour/delivery and newborn management/care were recorded on data collection forms. Causes of deaths were predominantly based on clinical diagnosis. Results: 671 were admitted to a neonatal area. Reasons included prematurity n = 213 (32%), respiratory issues n = 209 (31%), meconium stained amniotic fluid with respiratory issues n = 115 (17%) and observation for < 24 hours n = 97 (14%). Death occurred in 124 infants. Presumed causes were birth asphyxia (BA) n = 59 (48%), prematurity n = 19 (15%), presumed sepsis n = 19 (15%), meconium aspiration syndrome (MAS) n = 13 (10%) and congenital abnormalities n = 14 (11%). More newborns who died versus survivors had oxygen saturation <60% on admission (37/113 vs 32/258; p≤0.001) respectively. Moderate hypothermia on admission was common i.e. deaths 35.1 (34.6–36.0) vs survivors 35.5 (35.0–36.0)°C (p≤0.001). Term newborns who died versus survivors were fourfold more likely to have received positive pressure ventilation after birth i.e. 4.57 (1.22–17.03) (p<0.02). Conclusion: Intrapartum-related complications (BA, MAS), prematurity, and presumed sepsis were the leading causes of death. Intrapartum hypoxia, prematurity and attendant complications and presumed sepsis, are major pathways leading to death. Severe hypoxia and hypothermia upon admission are additional contributing factors. Strategies to identify fetuses at risk during labour e.g. improved fetal heart rate monitoring, coupled with timely interventions, and implementation of WHO interventions for preterm newborns, may reduce mortality in this low resource setting. [ABSTRACT FROM AUTHOR]