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Background and Purpose The cardiovascular risk in Parkinson’s disease (PD) remains uncertain and controversial. Some studies suggest PD patients present an increased risk of cerebrovascular disease. We aimed to study the prevalence of neuroimaging cerebrovascular biomarkers in PD patients compared to controls, using an accurate and complete magnetic resonance (MR) imaging evaluation. Material and Methods Neuroimaging sub-study within a larger cross-sectional case–control study. An enriched subgroup of PD patients (≤10 years since diagnosis) with at least a moderate cardiovascular mortality risk based on a Systematic COronary Risk Evaluation (SCORE) was compared to community-based controls regarding neuroimaging biomarkers. Patients underwent a high-resolution T1-weighted MR imaging sequence at 3.0 T to visualize neuromelanin. A 3D SWI FFE, sagittal 3D T1-weighted, axial FLAIR and diffusion-weighted image sequences were obtained. Results The study included 47 patients, 24 with PD and 23 controls. PD patients presented a reduced area and signal intensity of the substantia nigra and locus coeruleus on neuromelanin-sensitive MR. The median SCORE was 5% in both groups. No significant differences regarding white matter hyperintensities (OR 4.84, 95% CI 0.50, 47.06), lacunes (OR 0.43, 95% CI 0.07, 2.63), microbleeds (OR 0.64, 95% CI 0.13, 3.26), or infarcts (0.95, 95% CI 0.12, 7.41) was found. The frequency of these neuroimaging biomarkers was very low in both groups. Conclusion The present study does not support an increased prevalence of neuroimaging cerebrovascular biomarkers in PD patients.

We aimed to analyze recent infant and neonatal mortality from congenital heart defects (CHD) in Costa Rica, a middle-income country where CHD mortality was above expectations.A descriptive analysis of infant and neonatal mortality rates from CHD (IMR-CHD and NMR-CHD) during 2000-2019 was performed, according to province, sex, specific CHD, and sub-period, using data from the National Institute of Statistics and Censuses. We used joinpoint regression to identify any calendar-year where a significant change in trend occurred; the average annual percent change (AAPC) was determined. Using Poisson regression, marginal means and mortality ratios (MR) for IMR-CHD and NMR-CHD by sub-period (2000-2006-referent-, 2007-2013, 2014-2019) were estimated and compared using Wald's chi-square tests (α ≤ .05).During 2000-2019, CHD accounted for 12% of overall infant mortality. IMR-CHD and NMR-CHD decreased linearly over the study period (AAPC = -3.4; p .01). IMR-CHD decreased by 41%, from 13.6 per 10,000 in 2000-2006 (13.4% of infant mortality) to 8.1 per 10,000 in 2014-2019 (10% of infant mortality) (MR = 0.59; 95% confidence intervals [CI] = 0.52-0.68). NMR-CHD decreased by 38%, from 7.9 per 10,000 in 2000-2006 (11.1% of neonatal mortality) to 4.9 per 10,000 in 2014-2019 (7.9% of infant mortality) (MR = 0.59; 95% CI = 0.52-0.68). Male presented significantly higher NMR-CHD. The main causes of mortality (2014-2019) were total anomalous pulmonary venous connections, hypoplastic left heart syndrome, and double inlet ventricle.IMR-CHD, NMR-CHD, and their proportional contribution to mortality by all causes and by birth defects decreased significantly, demonstrating that all improvements implemented in the last decades have yielded favorable results.

BACKGROUND: In June 2019, the Bolivian Ministry of Health reported a cluster of cases of hemorrhagic fever that started in the municipality of Caranavi and expanded to La Paz. The cause of these cases was unknown. METHODS: We obtained samples for next-generation sequencing and virus isolation. Human and rodent specimens were tested by means of virus-specific real-time quantitative reverse-transcriptase–polymerase-chain-reaction assays, next-generation sequencing, and virus isolation. RESULTS: Nine cases of hemorrhagic fever were identified; four of the patients with this illness died. The etiologic agent was identified as Mammarenavirus Chapare mammarenavirus, or Chapare virus (CHAPV), which causes Chapare hemorrhagic fever (CHHF). Probable nosocomial transmission among health care workers was identified. Some patients with CHHF had neurologic manifestations, and those who survived had a prolonged recovery period. CHAPV RNA was detected in a variety of human body fluids (including blood; urine; nasopharyngeal, oropharyngeal, and bronchoalveolar-lavage fluid; conjunctiva; and semen) and in specimens obtained from captured small-eared pygmy rice rats (Oligoryzomys microtis). In survivors of CHHF, viral RNA was detected up to 170 days after symptom onset; CHAPV was isolated from a semen sample obtained 86 days after symptom onset. CONCLUSIONS: M. Chapare mammarenavirus was identified as the etiologic agent of CHHF. Both spillover from a zoonotic reservoir and possible person-to-person transmission were identified. This virus was detected in a rodent species, O. microtis. (Funded by the Bolivian Ministry of Health and others.)

This study aimed to determine the ability of axillary ultrasonography to predict the number of lymph nodes with metastases found in sentinel node axillary surgery or axillary lymph node resection in patients recently diagnosed with breast cancer after percutaneous biopsy.This prospective study included patients diagnosed with invasive breast cancer by percutaneous biopsy. Axillary lymph nodes were classified at ultrasound examination as suspicious or not suspicious, and the number of suspicious nodes was compared with the number classified as suspicious in the surgical specimen.We included 142 patients, 4 of whom had bilateral cancer; 133 of the 146 tumors were clinically classified as T1-T2 N0. The median number of suspicious lymph nodes at ultrasound was 2 (1-6), and the median number of suspicious lymph nodes in the surgical biopsy specimen was 1 (1-16); the difference was not significant (p = 0.1). The correlation between the number of positive lymph nodes on axillary ultrasound and the number of metastatic lymph nodes in the surgical specimen was 72.7% p = 0.0002 and the concordance was 79% (95%CI 62.4%-95.6%) p = 0.0001. For diagnosing high axillary tumor load (≥3 metastatic lymph nodes) versus low axillary tumor load (3 metastatic lymph nodes), axillary ultrasound had 86.6% sensitivity, 83.3% specificity, 92% PPV, and 71.4% NPV.Our results show that preoperative axillary ultrasound can differentiate between low and high tumor load and can be used as a tool to select the type of treatment. These results need to be confirmed in randomized multicenter studies.

Background During the first wave of the COVID-19 pandemic, shortages of ventilators and ICU beds overwhelmed health-care systems. Whether early tracheostomy reduces the duration of mechanical ventilation and ICU stay is controversial. Research Question Can failure-free day outcomes focused on ICU resources help to decide the optimal timing of tracheostomy in overburdened health-care systems during viral epidemics? Study Design and Methods This retrospective cohort study included consecutive patients with COVID-19 pneumonia who had undergone tracheostomy in 15 Spanish ICUs during the surge, when ICU occupancy modified clinician criteria to perform tracheostomy in Patients with COVID-19. We compared ventilator-free days at 28 and 60 days and ICU- and hospital bed-free days at 28 and 60 days in propensity score-matched cohorts who underwent tracheostomy at different timings (≤ 7 days, 8-10 days, and 11-14 days after intubation). Results Of 1,939 patients admitted with COVID-19 pneumonia, 682 (35.2%) underwent tracheostomy, 382 (56%) within 14 days. Earlier tracheostomy was associated with more ventilator-free days at 28 days (≤ 7 days vs > 7 days [116 patients included in the analysis]: median, 9 days [interquartile range (IQR), 0-15 days] vs 3 days [IQR, 0-7 days]; difference between groups, 4.5 days; 95% CI, 2.3-6.7 days; 8-10 days vs > 10 days [222 patients analyzed]: 6 days [IQR, 0-10 days] vs 0 days [IQR, 0-6 days]; difference, 3.1 days; 95% CI, 1.7-4.5 days; 11-14 days vs > 14 days [318 patients analyzed]: 4 days [IQR, 0-9 days] vs 0 days [IQR, 0-2 days]; difference, 3 days; 95% CI, 2.1-3.9 days). Except hospital bed-free days at 28 days, all other end points were better with early tracheostomy. Interpretation Optimal timing of tracheostomy may improve patient outcomes and may alleviate ICU capacity strain during the COVID-19 pandemic without increasing mortality. Tracheostomy within the first work on a ventilator in particular may improve ICU availability.

Background. Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease. Low vitamin D levels have been reported to be a risk factor for MS, and genetic variances could be implicated. The aim of this study was to evaluate the association of MS with rs10766197 polymorphism of CYP2R1 gene and rs10877012 polymorphism of CYP27B1 gene. The second aim was to analyse whether these polymorphisms are associated with the severity of the progression of MS. Material and Methods. In a case-control study, we included 116 MS patients and 226 controls, all of whom were Mexican Mestizo. MS was diagnosed by McDonald criteria (2017). A complete neurological evaluation was performed to evaluate the severity of disease progression. Serum 25-hydroxyvitamin D [25(OH) vitamin D] levels were measured by ELISA. Single nucleotide polymorphisms rs10766197 of CYP2R1 gene and rs10877012 SNP of CYP27B1 gene were genotyped by real-time PCR. Results. Serum 25(OH) vitamin D levels were lower in MS patients than in controls ( p = 0.009 ). No differences were observed between serum 25(OH) vitamin D levels of MS patients with severe progression compared to low progression ( p = 0.88 ). A higher frequency of the A allele of CYP2R1 rs10766197 was observed between MS patients and controls ( p = 0.05 ). No differences were observed in the frequency of T allele of CYP27B1 rs10877012 ( p = 0.65 ). In subanalysis, patients with GA + AA genotypes of CYP2R1 rs10766197 had an increased risk of MS compared to controls ( p = 0.03 ). No increased risk was observed in GT + TT genotypes of CYP27B1 rs10877012 ( p = 0.63 ). No differences were observed in allele frequencies of either polymorphism between patients with severe vs. low disease progression. Conclusion. Lower serum 25(OH) vitamin D levels were observed in MS patients than in controls, although these levels were not associated with disease progression. Carriers of GA + AA genotypes of CYP2R1 rs10766197 had an increased risk of MS. None of these polymorphisms was associated with severe progression of MS.

Background: Respiratory failure in severe coronavirus disease 2019 (COVID-19) is associated with a severe inflammatory response. Acetylcholine (ACh) reduces systemic inflammation in experimental bacterial and viral infections. Pyridostigmine increases the half-life of endogenous ACh, potentially reducing systemic inflammation. We aimed to determine if pyridostigmine decreases a composite outcome of invasive mechanical ventilation (IMV) and death in adult patients with severe COVID-19. Methods: We performed a double-blinded, placebo-controlled, phase 2/3 randomized controlled trial of oral pyridostigmine (60 mg/day) or placebo as add-on therapy in adult patients admitted due to confirmed severe COVID-19 not requiring IMV at enrollment. The primary outcome was a composite of IMV or death by day 28. Secondary outcomes included reduction of inflammatory markers and circulating cytokines, and 90-day mortality. Adverse events (AEs) related to study treatment were documented and described. Results: We recruited 188 participants (94 per group); 112 (59.6%) were men; the median (IQR) age was 52 (44–64) years. The study was terminated early due to a significant reduction in the primary outcome in the treatment arm and increased difficulty with recruitment. The primary outcome occurred in 22 (23.4%) participants in the placebo group vs. 11 (11.7%) in the pyridostigmine group (hazard ratio, 0.47, 95% confidence interval 0.24–0.9; P = 0.03). This effect was driven by a reduction in mortality (19 vs. 8 deaths, respectively). Conclusion: Our data indicate that adding pyridostigmine to standard care reduces mortality among patients hospitalized for severe COVID-19.

PURPOSE A nationwide lockdown was enforced in Brazil starting in March 2020 because of the COVID-19 pandemic when cancer screening activities were reduced. In this study, we evaluated the impact of the COVID-19 pandemic on breast cancer (BC) diagnosis. METHODS We extracted data from the medical records of patients age older than 18 years who were diagnosed with BC and started treatment or follow-up in private oncology institutions in Brazil between 2018 and 2021. The primary objective was to compare the stage distribution during the COVID-19 pandemic (2020-2021) with a historical prepandemic control cohort (2018-2019). Early BC was defined as stage I-II and advanced disease as stage IV. RESULTS We collected data for 11,753 patients with an initial diagnosis of BC, with 6,493 patients in the pandemic (2020-2021) and 5,260 patients in the prepandemic period (2018-2019). We observed a lower prevalence of early-stage BC (63.6% v 68.4%) and a higher prevalence of advanced-stage BC (16.9 v 12.7%), after the onset of the pandemic (both P < .01). This pattern was similar for both estrogen receptor–positive/human epidermal growth factor receptor 2–negative and human epidermal growth factor receptor 2–positive tumors: significantly decreased in the early stage from 69% to 67% and 68% to 58%, respectively, and a considerable increase in advanced-stage disease from 13% to 15% and 13% to 20%, respectively. For triple-negative BC, there was a significantly higher percentage of patients with advanced-stage disease during the pandemic (17% v 11%). Overall, age 50 years or older and postmenopausal status were associated with a greater risk of advanced stage at diagnosis during the pandemic period. CONCLUSION We observed a substantial increase in the number of cases of advanced-stage BC in Brazil during the COVID-19 pandemic.

Disruption of circadian oscillations has a wide-ranging impact on health, with the potential to induce the development of clock-related diseases. Small-molecule modulators of the circadian clock (SMMCC) target core or noncore clock proteins, modulating physiological effects as a consequence of agonist, inverse agonist, or antagonist interference. These pharmacological modulators are usually identified using chemical screening of large libraries of active compounds. However, target-based screens, chemical optimization, and circadian crystallography have recently assisted in the identification of these compounds. In this review, we focus on established and novel SMMCCs targeting both core and noncore clock proteins, identifying their circadian targets, detailed circadian effects, and specific physiological effects. In addition, we discuss their therapeutic potential for the treatment of diverse clock-related disorders (such as metabolic-associated disorders, autoimmune diseases, mood disorders, and cancer) and as chronotherapeutics. Future perspectives are also considered, such as clinical trials, and potential safety hazards, including those in the absence of clinical trials.

To present updated information on odontogenic keratocyst (OKC) classification, etiology, genetic and molecular alterations, epidemiology, clinical presentation, radiographic characteristics, histological and immune histochemical features, differential diagnosis, treatment, and controversies, as well as a literature review of case frequencies in different countries.Studies were selected using the key words 'odontogenic keratocyst,' 'odontogenic cysts,' 'odontogenic keratocyst and clinical study'. Full-text papers were reviewed on the basis of the inclusion and exclusion criteria. The literature search aimed to find articles that would show the frequency of OKC, dentigerous cyst, radicular cyst, and other cysts.OKC presents local aggression and high recurrence; therefore, a better understanding of its clinical characteristics and the genetic and molecular factors involved in this peculiar and controversial lesion is required. It is always essential to discuss treatment alternatives. Although OKC is an entity with a high recurrence, aggressive treatment is not advisable in all cases because factors such as commitment to anatomical structures and possible complications should be considered. However, periodic radiographic controls are advised.To reduce the high number of present cases worldwide, it is important to improve knowledge on this pathology so that accurate diagnoses can be achieved and appropriate treatment can be provided. OKC presents local aggression and high recurrence; therefore, a better understanding is needed of the clinical characteristics and genetic and molecular factors involved in OKC. Furthermore, it is always essential to discuss treatment alternatives.

BACKGROUND: The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied. METHODS: We conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone–bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone–bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses. RESULTS: A total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone–bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone–bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone–bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P

SLC5A7 encodes the presynaptic sodium-dependant high-affinity choline transporter 1 (CHT), which uptakes choline to the presynaptic nerve terminal following the breakdown of acetylcholine by the acetylcholinesterase within the synaptic cleft. We report 5 patients from three consanguineous families with congenital myasthenic syndrome type 20 caused by novel mutations in SLC5A7. The individuals from family 1 and 2 were homozygous for c.320G>A; (p.Arg107His) and c.886G>A (p.Ala296Thr), respectively, and their phenotype was characterised by recurrent apnoeic attacks early after birth and learning and speech difficulties in childhood. Individuals from family 3 were homozygous for c.1240T>A (p.Tyr414Asn) and suffered from more severe central and peripheral manifestations with lack of spontaneous movements and respiratory drive and overall minimal response to external stimuli. All individuals tested showed neurophysiological defects compatible with impaired neuromuscular transmission. Combined treatment with cholinesterase inhibitors and β2-adrenergic agonists was beneficial in patients from family 1 and 2. Affected individuals from family 3 died from complications directly related to their underlying genetic condition. This report provides three novel pathogenic variants in SLC5A7 and highlights the variability in the clinical phenotype, severity and prognosis of this syndrome.

A new coronavirus outbreak emerged on the 31st of December 2019 in Wuhan, China, causing commotion among the medical community and the rest of the world. This new species of coronavirus has been termed 2019-nCoV and has caused a considerable number of cases of infection and deaths in China and, to a growing degree, beyond China, becoming a worldwide public health emergency. 2019-nCoV has high homology to other pathogenic coronaviruses, such as those originating from bat-related zoonosis (SARS-CoV), which caused approximately 646 deaths in China at the start of the decade. The mortality rate for 2019-nCoV is not as high (approximately 2-3%), but its rapid propagation has resulted in the activation of protocols to stop its spread. This pathogen has the potential to become a pandemic. It is therefore vital to follow the personal care recommendations issued by the World Health Organization.

Summary Background & aims Obesity is a major cause of non-alcoholic fatty liver disease (NAFLD). NAFLD is an epidemic affecting nearly 34% of the adult population in the US. As a chronic inflammatory disease, NAFLD influences the immune system by dysregulating T-cell activity. Remedies for the adverse effects on the immune system are urgently needed. We studied Theaphenon E (TE), a standardized formulation of green tea extract, on the adverse effects of NAFLD in C57BL/6J mice fed a high fat diet (HFD). Methods Mice received HFD, low fat diet (LFD) or HFD+2% TE for 35 weeks. Hepatic lipid accumulation, cell proliferation, apoptosis and CD4+T lymphocytes were measured throughout the bioassay. The hepatic composition of fatty acids was determined. The effects of epigallocatechin gallate (EGCG) metabolites on lipid accumulation in mouse and primary human liver cells were studied. Results Unlike mice receiving HFD, mice on HFD+2% TE maintained normal liver to body weight ratios with low levels of alanine and aspartate aminotransferase (ALT and AST). Hepatic lipid accumulation was observed in HFD mice, accompanied by increased proliferation, reduced apoptosis and loss of CD4+ T lymphocytes. TE significantly inhibited lipid accumulation, decreased proliferation, induced apoptosis and increased CD4+ T cell survival in HFD mice. It was found that the EGCG metabolite EGC-M3 reduced lipid accumulation in mouse and human hepatocytes. Linoleic acid showed the largest increase (2.5-fold) in livers of mice on a HFD and this increase was significantly suppressed by TE. Conclusions Livers of HFD-fed mice showed lipid accumulation, increased proliferation, reduced apoptosis, elevated linoleic acid and loss of CD4+ T cells. TE effectively ameliorated all of these adverse effects.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the causative agent of coronavirus disease 2019 (COVID-19), may lead to severe systemic inflammatory response, pulmonary damage, and even acute respiratory distress syndrome (ARDS). This in turn may result in respiratory failure and in death. Experimentally, acetylcholine (ACh) modulates the acute inflammatory response, a neuro-immune mechanism known as the inflammatory reflex. Recent clinical evidence suggest that electrical and chemical stimulation of the inflammatory reflex may reduce the burden of inflammation in chronic inflammatory diseases. Pyridostigmine (PDG), an ACh-esterase inhibitor (i-ACh-e), increases the half-life of endogenous ACh, therefore mimicking the inflammatory reflex. This clinical trial is aimed at evaluating if add-on of PDG leads to a decrease of invasive mechanical ventilation and death among patients with severe COVID-19. Methods A parallel-group, multicenter, randomized, double-blinded, placebo-controlled, phase 2/3 clinical trial to test the efficacy of pyridostigmine bromide 60 mg/day P.O. to reduce the need for invasive mechanical ventilation and mortality in hospitalized patients with severe COVID-19. Discussion This study will provide preliminary evidence of whether or not -by decreasing systemic inflammation- add-on PDG can improve clinical outcomes in patients with severe COVID-19. Trial registration ClinicalTrials.gov NCT04343963 (registered on April 14, 2020).

Summary Background Healthcare-associated infections (HCAIs) continue to be a major cause of morbidity and mortality. Many HCAI pathogens, including multidrug-resistant organisms (MDROs), colonize the gastrointestinal tract. Aim To determine the frequency of MDRO carriage in patients who do and do not harbour toxigenic Clostridioides difficile in their stools. Methods Stool specimens received from nine US laboratories were cultured using media selective for C. difficile, Staphylococcus aureus, vancomycin-resistant enterococci (VRE), and carbapenem-resistant Gram-negative organisms (CROs). Specimens and isolates were also tested by polymerase chain reaction (PCR). Bacterial isolates underwent susceptibility testing and genotyping. Findings Among 363 specimens, 175 yielded toxigenic C. difficile isolates spanning 27 PCR ribotypes. C. difficile (TCD+) stools harboured an additional 28 organisms, including six CROs (3.4%), of which two (1.1%) were carbapenemase-producing organisms (CPOs), 19 VRE (10.9%), and three meticillin-resistant S. aureus isolates (MRSA, 1.7 %). Stools that were culture negative for toxigenic C. difficile (TCD–) yielded 26 organisms, including four CROs (2.1%), 20 VRE (10.6), and two MRSA (1.1%). Excluding C. difficile, no significant differences were seen in the rates of the MDROs between TCD+ and TCD– specimens. Conclusion Overall, 15.4% of the TCD+ stools and 11.2% of the TCD– stools carried at least one non-C. difficile MDRO pathogen, indicating that multiple MDROs may be present in the gastrointestinal tracts of patients, including those that harbour C. difficile.

Objectives This study aimed to identify carbapenem-resistant Gram-negative bacteria from clinical specimens of patients in Yola, Nigeria. Methods Routine clinical specimens were screened for the presence of carbapenem-resistant Gram-negative bacteria using chromogenic agar plates. Susceptibility of all presumptive isolates to carbapenems was tested by MIC and disk diffusion methods. Real-time PCR was used to test for the presence of carbapenemase genes. Results Screening of 1741 clinical specimens yielded 119 (6.8%) presumptive carbapenem-resistant Gram-negative bacteria. Antimicrobial susceptibility testing confirmed carbapenem resistance in 105 of these isolates. New Delhi metallo-β-lactamase (blaNDM) gene was detected in 26 isolates and Verona integron-encoded metallo-β-lactamase (blaVIM) gene was detected in four. The mechanism of resistance could not be identified in approximately two thirds of the carbapenem-resistant isolates. Conclusion While blaNDM and blaVIM accounted for 28.6% of the resistance seen, further molecular-based studies are needed to characterise the other mechanisms of carbapenem resistance in these isolates.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with an increased prevalence in Mexico. Although its etiology is unknown, its development can be influenced by environmental factors such as smoking and viral infections. But among the factors influencing susceptibility, it is the genetic factors that predominate, mainly the HLA-DRB1 genes, and specifically the alleles that have the shared epitope (SE). A transversal study was performed, in which 31 patients (28 women and 3 men) with RA, treated at the autoimmunity clinic of the High Specialty Hospital Ciudad Salud in Tapachula, Chiapas, southern México, were enrolled. Clinical, biochemical, and demographic data were analyzed; ESR (erythrocyte sedimentation rate), CRP (C-reactive protein), RF (rheumatoid factor), and ACPA (anticitrullinated peptide antibody) were recorded. All patients had at least one positive RA biological marker. For HLA alleles frequencies comparison, we enrolled ethnically matched healthy controls in a ratio of 3:1 for 25 cases and 4:1 for 6 cases in order to guarantee the balance between groups regarding the mean of age and proportion of gender (males vs females). HLA-DRB1*04 was found to be significantly increased in patients compared with ethnically matched healthy controls (p 0.0007, OR: 2.8, 95% CI 1.5-5.1); contrarily, DRB1*08 showed a protective effect (p 0.005, OR 0.1). This paper confirmed the involvement of HLA genes on risk determination for RA in a population of Mexican Mestizos from Tapachula, Chiapas. Key Points • HLA-DRB1*04 confirms the increased risk of rheumatoid arthritis. • HLA-DRB1*08 showed a more definite protective effect in southern Mexicans mestizos, a population with more Amerindian ancestry.

Hartmann's procedure (HP) is the conventional treatment in patients with complicated diverticulitis. Segmental resection with primary anastomosis (PA) is a treatment alternative for those patients. Our aim was to compare the postoperative results of HP and PA in patients with complicated diverticulitis (Hinchey stage III).A case-control study was conducted on patients operated on for purulent Hinchey stage III diverticulitis, within the time frame of 2000 and 2019.Twenty-seven patients that underwent PA were compared with 27 that underwent HP. The patients that underwent HP had a greater probability of morbidity at 30 days (OR 3.5; 95% CI 1.13-11.25), as well as a greater probability of major complications (OR 10.9; 95% CI 1.26-95.05).The patients that underwent segmental resection and PA presented with lower morbidity rates and higher stoma reversal rates than the patients that underwent HP.

Mesenchymal stromal cells (MSCs) are a multipotent cell population of clinical interest because of their ability to migrate to injury and tumor sites, where they may participate in tissue repair and modulation of immune response. Although the processes regulating MSC function are incompletely understood, it has been shown that stimulation of Toll-like receptors (TLRs) can alter MSC activity. More specifically, it has been reported that human bone marrow-derived MSCs can be "polarized" by TLR priming into contrasting immunomodulatory functions, with opposite (supportive or suppressive) roles in tumor progression and inflammation. Adipose-derived MSCs (ASCs) represent a promising alternative MSC subpopulation for therapeutic development because of their relative ease of isolation and higher abundance compared with their bone marrow-derived counterparts; however, the polarization of ASCs remains unreported.In this study, we evaluated the phenotypic and functional consequences of short-term, low-level stimulation of ASCs with TLR3 and TLR4 agonists.In these assays, we identified transient gene expression changes resembling the reported pro-inflammatory and anti-inflammatory MSC phenotypes. Furthermore, these priming strategies led to changes in the functional properties of ASCs, affecting their ability to migrate and modulate immune-mediated responses to prostate cancer cells in vitro.TLR3 stimulation significantly decreased ASC migration, and TLR4 stimulation increased ASC immune-mediated killing potential against prostate cancer cells.

Significance We report on a single mutation in the α1-subunit M2 helix (p.α1Leu251Arg) of the muscle acetylcholine receptor (AChR) found in a patient with congenital myasthenic syndrome (CMS) that is shown to convert the AChR into chloride conductance at positive potentials. Constriction of the channel pore with partial desolvation and stabilization of the permeating chloride ions by the arginine residues is revealed as the underlying mechanism. This article is of general interest because it describes a mechanism for the transformation of the muscle AChR into an inhibitory channel, and presents a report of charge selectivity conversion in association with a naturally occurring single mutation. Our findings might also give explanation to a pathomechanism in CMS., Charge selectivity forms the basis of cellular excitation or inhibition by Cys-loop ligand-gated ion channels (LGICs), and is essential for physiological receptor function. There are no reports of naturally occurring mutations in LGICs associated with the conversion of charge selectivity. Here, we report on a CHRNA1 mutation (α1Leu251Arg) in a patient with congenital myasthenic syndrome associated with transformation of the muscle acetylcholine receptor (AChR) into an inhibitory channel. Performing patch-clamp experiments, the AChR was found to be converted into chloride conductance at positive potentials, whereas whole-cell currents at negative potentials, although markedly reduced, were still carried by sodium. Umbrella sampling molecular dynamics simulations revealed constriction of the channel pore radius to 2.4 Å as a result of the mutation, which required partial desolvation of the ions in order to permeate the pore. Ion desolvation was associated with an energetic penalty that was compensated for by the favorable electrostatic interaction of the positively charged arginines with chloride. These findings reveal a mechanism for the transformation of the muscle AChR into an inhibitory channel in a clinical context.

Interleukin-37 (IL-37) has recently been recognized as a strong anti-inflammatory cytokine having anti-tumor activity against hepatocellular carcinoma (HCC) in hepatitis B virus (HBV)-infected patients. HCC is a typical inflammation-related cancer, and genetic variations within the IL-37 gene may be associated with the risk of HBV infection. Identification of the allelic patterns that genetically have a high disease risk is essential for the development of preventive diagnostics for HBV-mediated liver disease pathogenesis. In this study, we aimed to investigate the association between single nucleotide polymorphisms (SNPs) within the IL-37 gene and disease sequelae associated with HBV infection. We genotyped ten IL-37 SNPs in 1274 patients infected with HBV and 599 healthy controls from a Saudi Arabian population. Among the selected SNPs, two SNPs (rs2723175 and rs2708973) were strongly associated with HBV infection, and six SNPs (rs2723176, rs2723175, rs2723186, rs364030, rs28947200, rs4392270) were associated with HBV clearance, comparing healthy controls and HBV infected-patients respectively. A suggestive association of rs4849133 was identified with active HBV surface antigen (HBsAg) carrier and HBV-related liver disease progression. In conclusion, our findings suggest that variations at the IL-37 gene may be useful as genetic predictive risk factors for HBV infection and HBV-mediated liver disease progression in the Saudi Arabian population.

Mutations in COL13A1 cause synaptic basal lamina-associated congenital myasthenic syndrome type 19. Rodriguez Cruz et al. describe the clinical and genetic spectrum associated with COL13A1 mutations, and the key clinical features to look out for., Next generation sequencing techniques were recently used to show mutations in COL13A1 cause synaptic basal lamina-associated congenital myasthenic syndrome type 19. Animal studies showed COL13A1, a synaptic extracellular-matrix protein, is involved in the formation and maintenance of the neuromuscular synapse that appears independent of the Agrin-LRP4-MuSK-DOK7 acetylcholine receptor clustering pathway. Here, we report the phenotypic spectrum of 16 patients from 11 kinships harbouring homozygous or heteroallelic mutations in COL13A1. Clinical presentation was mostly at birth with hypotonia and breathing and feeding difficulties often requiring ventilation and artificial feeding. Respiratory crisis related to recurrent apnoeas, sometimes triggered by chest infections, were common early in life but resolved over time. The predominant pattern of muscle weakness included bilateral ptosis (non-fatigable in adulthood), myopathic facies and marked axial weakness, especially of neck flexion, while limb muscles were less involved. Other features included facial dysmorphism, skeletal abnormalities and mild learning difficulties. All patients tested had results consistent with abnormal neuromuscular transmission. Muscle biopsies were within normal limits or showed non-specific changes. Muscle MRI and serum creatine kinase levels were normal. In keeping with COL13A1 mutations affecting both synaptic structure and presynaptic function, treatment with 3,4-diaminopyridine and salbutamol resulted in motor and respiratory function improvement. In non-treated cases, disease severity and muscle strength improved gradually over time and several adults recovered normal muscle strength in the limbs. In summary, patients with COL13A1 mutations present mostly with severe early-onset myasthenic syndrome with feeding and breathing difficulties. Axial weakness is greater than limb weakness. Disease course improves gradually over time, which could be consistent with the less prominent role of COL13A1 once the neuromuscular junction is mature. This report emphasizes the role of collagens at the human muscle endplate and should facilitate the recognition of this disorder, which can benefit from pharmacological treatment.

Natural background radiation to which humans are continuously exposed to come from the primordial radionuclides on the surface of the Earth. Industrial activities which concentrate natural radionuclides usually in residues and waste materials may enhance natural radioactivity on the ground via airborne contamination. In this study, ambient gamma dose rates were measured inside and outside two industrial facilities in Leyte, Philippines, to assess possible contribution of NORM materials in enhancement of natural radiation background in these areas. Ambient gamma dose rates measured at selected sites from Tacloban City to Isabel, Leyte and in nearby areas of Kananga and Ormoc City, Leyte were within the range of the background ambient gamma dose rates measured in the Philippines, ranging from 21 to 124 nSv/h. The workers in the phosphate rock storage and phosphogypsum pond areas in the phosphate fertiliser production plant received the highest annual effective external dose of 0.76 mSv.

Objective To evaluate corpus callosum (CC) size by neurosonography (NSG) in fetuses with an isolated major congenital heart defect (CHD) and explore the association of CC size with the expected pattern of in-utero oxygen supply to the brain. Methods A total of 56 fetuses with postnatally confirmed isolated major CHD and 56 gestational-age-matched controls were included. Fetuses with CHD were stratified into two categories according to the main expected pattern of cerebral arterial oxygen supply: Class A, moderately to severely reduced oxygen supply (left outflow tract obstruction and transposition of the great arteries) and Class B, near normal or mildly impaired oxygenated blood supply to the brain (other CHD). Transvaginal NSG was performed at 32-36 weeks in all fetuses to evaluate CC length, CC total area and areas of CC subdivisions in the midsagittal plane. Results CHD fetuses had a significantly smaller CC area as compared to controls (7.91 +/- 1.30 vs 9.01 +/- 1.44 mm(2); P < 0.001), which was more pronounced in the most posterior part of the CC. There was a significant linear trend for reduced CC total area across the three clinical groups, with CHD Class-A cases showing more prominent changes (controls, 9.01 +/- 1.44 vs CHD Class B, 8.18 +/- 1.21 vs CHD Class A, 7.53 +/- 1.33 mm(2); P < 0.05). Conclusions Fetuses with major CHD had a smaller CC compared with controls, and the difference was more marked in the CHD subgroup with expected poorer brain oxygenation. Sonographic CC size could be a clinically feasible marker of abnormal white matter development in CHD. (c) 2021 International Society of Ultrasound in Obstetrics and Gynecology.

This study characterized the mechanisms of carbapenem resistance in gram-negative bacteria isolated from patients in Yola, Nigeria. Whole genome sequencing (WGS) was performed on 66 isolates previously identified phenotypically as carbapenem-non-susceptible. The patterns of beta-lactamase resistance genes identified were primarily species-specific. However, blaNDM-7 and blaCMY-4 were detected in all Escherichia coli and most Providencia rettgeri isolates; blaNDM-7 was also detected in 1 Enterobacter cloacae. The E. coli and E. cloacae isolates also shared blaOXA-1, while blaOXA-10 was found in all P. rettgeri, one Pseudomonas aeruginosa and 1 E. coli. Except for Stenotrophomonas maltophilia isolates, which only contained blaL1, most species carried multiple beta-lactamase genes, including those encoding extended-spectrum beta-lactamases, AmpC and OXA in addition to a carbapenemase gene. Carbapenemase genes were either class B or class D beta-lactamases. No carbapenemase gene was detected by WGS in 13.6% of isolates.

Alzheimer's disease (AD) is a well-known neurodegenerative disease characterized by the presence of two main hallmarks - Tau hyperphosphorylation and Aβ deposits. Notwithstanding, in the last few years the scientific evidence about the drivers of AD have been changing and nowadays age-related vascular alterations and several cardiovascular risk factors have been shown to trigger the development of AD. In this context, drugs targeting the Renin Angiotensin System (RAS), commonly used for the treatment of hypertension, are evidencing a high potential to delay AD development due to their action on brain RAS. Indeed, the ACE 1/Ang II/AT1R axis is believed to be upregulated in AD and to be responsible for deleterious effects such as increased oxidative stress, neuroinflammation, blood-brain barrier (BBB) hyperpermeability, astrocytes dysfunction and a decrease in cerebral blood flow. In contrast, the alternative axis - ACE 1/Ang II/AT2R; ACE 2/Ang (1-7)/MasR; Ang IV/ AT4R(IRAP) - seems to counterbalance the deleterious effects of the principal axis and to exert beneficial effects on memory and cognition. Accordingly, retrospective studies demonstrate a reduced risk of developing AD among people taking RAS medication as well as several in vitro and in vivo pre-clinical studies as it is herein critically reviewed. In this review, we first revise, at a glance, the pathophysiology of AD focused on its classic hallmarks. Secondly, an overview about the impact of the RAS on the pathophysiology of AD is also provided, focused on their four essential axes ACE 1/Ang II/AT2R; ACE 2/Ang (1-7)/MasR; Ang IV/ AT4R(IRAP) and ACE 1/Ang II/AT1R. Finally, the therapeutic potential of available drugs targeting RAS on AD, namely angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs), is highlighted and data supporting this hope will be presented, from in vitro and in vivo pre-clinical to clinical studies.

Higher total energy expenditure in free living conditions, regardless of any activity, has been strongly associated with a lower risk of mortality in healthy older adults. Also, a good performance in physical and functional tests is a marker of good functional prognosis. However, it is not yet clear what is the association between total energy expenditure and the performance in physical and functional tests. The objective of this study was to verify the association between the total energy expenditure of older adults measured by doubly labelled water and the performance in functional tests. Cross-sectional study. Fifty-six older people were recruited from health services linked to the participating institutions. Socio-demographic, anthropometric and clinical characteristics were assessed through the application of a structured questionnaire. Body composition was evaluated by isotopic dilution of deuterium oxide and functional status was assessed by the gait speed test, 6-minute walk test and handgrip strength. Total energy expenditure (GET) was assessed using the doubly labelled water method and the physical activity profile was verified using an activity monitor based on accelerometery. The results showed that the highest total energy expenditure correlated with the best performance in the gait speed tests (r = 0.266; p = 0.047), 6-minute walk test (r = 0.424; p = 0.001) and maximum handgrip strength (r = 0.478; p = 0.000). Multivariate regression analysis in a model adjusted for sex and fat-free mass revealed an association between total energy expenditure and the 6-minute walk test (β = 1.790; t = 2.080; p = 0.044) and the number of sedentary events (β = 6.389; t = 2.147; p = 0.038). The results of this study suggest that, in clinical practice, older individuals with lower gait speed, worse performance in the 6-minute walk test and lower handgrip strength, may have lower total energy expenditure, being the stimulus for its increase important for the prevention of possible problems related to low energy expenditure.

© 2021 European Academy of Neurology, Background: The relationship between Parkinson's disease (PD) and cardiovascular and cerebrovascular disease is not yet well established. Recent data suggest an increased risk of myocardial infarction and stroke in PD patients. Therefore, we designed a study to assess surrogate markers of cardiovascular and cerebrovascular risk in PD. Methods: We conducted a case-control study comparing PD patients recruited from a Movement Disorders Unit with controls randomly invited from a primary healthcare center. All participants underwent a detailed clinical evaluation, including medical history, physical assessment, carotid ultrasound, blood and urine analysis, and 24-h ambulatory blood pressure monitoring. The primary outcome was the carotid intima-media thickness (CIMT). Results: We included 102 participants in each study arm. No significant difference was found in the CIMT among groups (MD: 0.01, 95% CI: -0.02, 0.04). Carotid plaques were more frequent in PD patients (OR: 1.90, 95% CI: 1.02, 3.55), although the lipid profile was more favorable in this group (LDL MD: -18.75; 95% CI: -10.69, -26.81). Nocturnal systolic blood pressure was significantly higher in PD patients (MD: 4.37, 95% CI: 0.27, 8.47) and more than half of the PD patients were non-dippers or reverse dippers (OR: 1.83, 95% CI: 1.04, 3.20). Conclusion: We did not find a difference in CIMT between PD and controls. A higher frequency of carotid plaques and abnormal dipper profile supports the hypothesis that PD patients are not protected from cardiovascular and cerebrovascular disease., M.A. was awarded a scholarship from Fundação para a Ciência e Tecnologia (SFRH/BD/129700/2017). IMM - UID/BIM/50005/2019, project funded by Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado

The growing prevalence and diversity of carbapenemase producers among carbapenem-resistant Pseudomonas aeruginosa (CRPA) isolates warrants an expansion of detection capabilities. The purpose of this study was to evaluate the performance of the commercially available Xpert Carba-R (Carba-R) and the research-use-only Xpert Carba-R NxG (Carba-R NxG) in a global collection of P. aeruginosa. The challenge set included 123 P. aeruginosa clinical isolates from 12 countries. Isolates were previously categorized via PCR or whole-genome sequencing. Carbapenemase classes tested include VIM, IMP, NDM, SPM, KPC, and GES. Non-carbapenemase (non-CP)-harboring isolates were also tested (negative control). Isolates were tested using the Carba-R NxG and the Carba-R tests per the manufacturer’s instructions. Carba-R NxG testing was completed by Cepheid (Sunnyvale, CA), blinded to genotype. Both assays gave negative results for all non-CP isolates and positive results for all VIM, NDM, and KPC isolates. An improvement in IMP detection among isolates was observed (100% detection by Carba-R NxG versus 58% by Carba-R). All SPM and GES isolates, targets not present in commercially available Carba-R, were positive by Carba-R NxG. Two isolates harbored both VIM and GES, while a third isolate contained VIM and NDM. The Carba-R NxG identified both targets in all 3 isolates, while the Carba-R was negative for both GES-containing isolates. Overall, the Carba-R NxG successfully categorized 100% of isolates tested compared with 68% for its predecessor. The Carba-R NxG will expand the detection spectrum of the current Carba-R assay to include SPM, GES, and expanded IMP variants, increasing the global utility of the test.

Experimental evidence highlights nuclear factor (erythroid-derived 2)-like 2 (Nrf2) as a molecular target in Alzheimer&rsquo, s disease (AD). The well-known effect of electrophilic cysteine-reactive skin allergens on Nrf2-activation led to the hypothesis that these compounds could have a therapeutic role in AD. This was further supported by the neuroprotective activity of the skin allergen dimethyl fumarate (DMF), demonstrated in in vivo models of neurodegenerative diseases. We evaluated the effect of the cysteine-reactive allergens 1,4-phenylenediamine (PPD) and methyl heptine carbonate (MHC) on (1) neuronal redox imbalance and calcium dyshomeostasis using N2a wild-type (N2a-wt) and human APP-overexpressing neuronal cells (wild-type, N2a-APPwt) and (2) on neuroinflammation, using microglia BV-2 cells exposed to LPS (lipopolysaccharide). Phthalic anhydride (PA, mainly lysine-reactive), was used as a negative control. DMF, PPD and MHC increased Hmox1 gene and HMOX1 protein levels in N2a-APPwt cells suggesting Nrf2-dependent antioxidant activity. MHC, but also PA, rescued N2a-APPwt mitochondrial membrane potential and calcium levels in a Nrf2-independent pathway. All the chemicals showed anti-inflammatory activity by decreasing iNOS protein in microglia. This work highlights the potential neuroprotective and anti-inflammatory role of the selected skin allergens in in vitro models of AD, and supports further studies envisaging the validation of the results using in vivo AD models.

Background The treatment capacity for opioid use disorder (OUD) lags far behind the number of patients in need of treatment. Capacity is limited, in part, by the limited number of physicians who offer office based OUD treatment with buprenorphine. Measurement based care (MBC) has been proposed as a means to support primary care physicians in treating OUD. Here, we propose a set of measures and a clinical decision support algorithm to provide MBC for the treatment of OUD. Methods We utilized literature search and expert consensus to identify measures for universal screening and symptom tracking. We used expert consensus to create the clinical decision support algorithm. Results The Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS) tool was selected as the best published measure for universal screening in primary care. No published measure was identified as appropriate for symptom tracking or medication adherence; therefore, we created the OUD Symptom Checklist from the DSM-5 criteria for OUD and the Patient Adherence Questionnaire for Opioid Use Disorder Treatment (PAQ-OUD) to assess medication adherence. We developed and present a clinical decision support algorithm to provide direct guidance regarding treatment interventions during the first 12 weeks of buprenorphine treatment. Conclusion Creation of these tools is the necessary first step for implementation of MBC for the treatment of OUD with buprenorphine in primary care. Further work is needed to test the feasibility and acceptability of these tools. Trial Registration ClinicalTrials.gov; NCT04059016; 16 August 2019; retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT04059016

Background Neuropeptide Y (NPY) is a sympathetic neurotransmitter with effects on the regulation of inflammatory cells. The role of NPY on autoimmune inflammatory diseases such as rheumatoid arthritis (RA) is not completely understood. Therefore, we evaluate if NPY levels are markers of disease activity in RA and if there is a correlation between NPY levels and tumor necrosis factor-alpha (TNF-α), leptin, and interleukin 6 (IL-6) levels. Methods Cross-sectional design, including 108 women with RA. We assessed disease activity by DAS28-ESR (considering active disease a score of ≥2.6). Serum NPY levels and anti-CCP2 antibody, TNF-α, IL-6, and leptin levels were quantified (ELISA). Results Sixty-eight RA had an active disease (RA-active), and 40 were in remission (RA-remission). RA-active patients had higher NPY levels vs. RA-remission (22.8 ± 13.6 vs. 17.8 ± 10.3; p = 0.04). NPY levels correlated with increased TNF-α levels (r = 0.32, p = 0.001). Leptin or IL-6 did not correlate with NPY levels. In the logistic regression analysis, NPY increased the risk of disease activity (OR: 1.04, 95% CI 1.006-1.09, and p = 0.03). Conclusion Higher NPY levels are an independent marker of disease activity in RA. This study encourages the quantification of NPY levels as a surrogate marker for RA-active. Future studies evaluating the role of NPY levels interacting with other proinflammatory cytokines are required.

Cell free protein synthesis has become a powerful method for the high-throughput production of proteins that are difficult to express in living cells. The protein SAP2 of Fasciola hepatica (FhSAP2), which has demonstrated to be both, an excellent vaccine candidate against experimental fascioliasis and a good antigen for serodiagnosis of human chronic fascioliasis, is a typical example of a molecule that is difficult to produce. This is mainly due to its tendency to get over-expressed in inclusion bodies by prokaryotes. FhSAP2 expressed in an Escherichia coli-based expression system is poorly glycosylated, insoluble and often undergoes improper folding leading it to reduced immunogenicity. In this work, FhSAP2 was expressed in vitro using the eukaryote cell free system, TNT T7 Quick coupled transcription / translation, that has been designed for the expression of PCR-generated DNA templates. FhSAP2 was expressed in micro-volumes and purified by an affinity chromatography method, which gave a protein yield of 500μg/ml as determined by Bicinchoninic Acid Assay (BCA) method. Circular dichroism, Western blotting and enzyme-linked immunosorbent assay (ELISA) analysis were used to confirm the secondary structure, purity and integrity of protein. Results demonstrate that FhSAP2 can be expressed in a cell-free system retaining its main conformational and antigenic properties. The protein purified could be used in immunization experiments and immunodiagnostic techniques.

IntroductionThe adaptive changes of the foetal heart in intrauterine growth restriction can persist postnatally. Data regarding its consequences for early circulatory adaptation to extrauterine life are scarce. The aim of this study was to assess cardiac morphometry and function in newborns with late-onset intrauterine growth restriction to test the hypothesis that intrauterine growth restriction causes cardiac shape and functional changes at birth.MethodsA comprehensive echocardiographic study was performed in 25 neonates with intrauterine growth restriction and 25 adequate-for-gestational-age neonates.ResultsCompared with controls, neonates with intrauterine growth restriction had more globular ventricles, lower longitudinal tricuspid annular motion, and higher left stroke volume without differences in the heart rate. Neonates with intrauterine growth restriction also showed subclinical signs of diastolic dysfunction in the tissue Doppler imaging with lower values of early (e′) diastolic annular peak velocities in the septal annulus. Finally, the Tei index in the tricuspid annulus was higher in the intrauterine growth restriction group.ConclusionNeonates with history of intrauterine growth restriction showed cardiac remodelling and signs of systolic and diastolic dysfunction. Overall, there was a significant tendency to worse cardiac function results in the right heart. The adaptation to extrauterine life occurred with more globular hearts, higher stroke volumes but a similar heart rate compared to adequate-for-gestational-age neonates.

Background and purpose: Hereditary transthyretin (hATTR) amyloidosis causes progressive polyneuropathy resulting from transthyretin (TTR) amyloid deposition throughout the body, including the peripheral nerves. The efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, were demonstrated in the pivotal NEURO-TTR study in patients with hATTR polyneuropathy. Here, the long-term efficacy and safety of inotersen are assessed in an ongoing open-label extension (OLE) study. Methods: Patients who completed NEURO-TTR were eligible to enroll in the OLE (NCT02175004). Efficacy assessments included the modified Neuropathy Impairment Score plus seven neurophysiological tests composite score (mNIS + 7), the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN) questionnaire total score and the Short-Form 36 Health Survey (SF-36) Physical Component Summary (PCS) score. Safety and tolerability were also assessed. Results: Overall, 97% (135/139) of patients who completed NEURO-TTR enrolled in the OLE. Patients who received inotersen for 39 cumulative months in NEURO-TTR and the OLE continued to show benefit; patients who switched from placebo to inotersen in the OLE demonstrated improvement or stabilization of neurological disease progression by mNIS + 7, Norfolk QOL-DN and SF-36 PCS. No new safety concerns were identified. There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of inotersen exposure. Conclusion: Inotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Early treatment with inotersen resulted in greater long-term disease stabilization than delayed initiation. Routine platelet and renal safety monitoring were effective; no new safety signals were observed. info:eu-repo/semantics/publishedVersion

In general terms, fetal growth restriction (FGR) is considered the impossibility of achieving the genetically determined potential size. In the vast majority of cases, it is related to uteroplacental insufficiency. Although its origin remains unknown and causes are only known in 30% of cases, it is believed to be related to an interaction of environmental and genetic factors with either a fetal or maternal origin. One hypothesis is that alterations in the gastrointestinal microbiota composition, and thus alteration in the immune response, could play a role in FGR development. We performed an observational, prospective study in a subpopulation affected with FGR to elucidate the implications of this microbiota on the FGR condition. A total of 63 fetuses with FGR diagnosed in the third trimester as defined by the Delphi consensus, and 63 fetuses with fetal growth appropriate for gestational age will be recruited. Obstetric and nutritional information will be registered by means of specific questionnaires. We will collect maternal fecal samples between 30 to 36 weeks, intrapartum samples (maternal feces, maternal and cord blood) and postpartum samples (meconium and new-born feces at 6 weeks of life). Samples will be analyzed in the Department of Biochemistry and Molecular Biology II, Nutrition and Food Technology Institute of the University of Granada (UGR), for the determination of the gastrointestinal microbiota composition and its relationship with inflammatory biomarkers. This study will contribute to a better understanding of the influence of gastrointestinal microbiota and related inflammatory biomarkers in the development of FGR. Trial registration: NCT04047966. Registered August 7, 2019, during the recruitment stage. Retrospectively registered. Ongoing research., Instituto de Salud Calos III, Fondos de Desarrollo Regional Europeos (FEDER) PI17/01215

Despite the implementation of various vaccination programs, hepatitis B virus (HBV) poses a considerable health problem in Saudi Arabia. Insight on HBV evolutionary history in the region is limited. We performed a comprehensive epidemiological and phylogenetic reconstruction based on a large cohort of HBV infected patients. Three hundred and nineteen HBV-infected patients with different clinical manifestations, including inactive and active chronic carriers and patients with cirrhosis and hepatocellular carcinoma (HCC), were enrolled in this study. The full-length large S gene was amplified and sequenced. Phylogenetic analysis was performed to determine the genotype and subgenotypes of the isolates. Phylogenetic tree analysis revealed that genotype D is the most dominant genotype among patients. Moreover, this analysis identified two strains with genotype E isolated from active carriers. Detailed phylogenetic analyses confirmed the presence of four HBV D subgenotypes, D1 (93%, n = 296), D2 (0.02%, n = 5), D3 (0.003%, n = 1), and D4 (0.003%, n = 1). In addition, six genotype D strains were not assigned to any existing HBV D subgenotype. The large S gene of eight strains showed signatures of genotype recombination between the genotypes D and A and between D and E. Several strains harbored medically important point mutations at the protein level. Along with the dominance of the HBV genotype D, isolation of the E genotype and several recombinant strains from patients with Saudi Arabian origin is an essential result for decisions involving therapeutic measures for patients. Development of vaccines and detection of diagnostic escape mutations at antigenic epitopes on the HBsAg will be valuable to public health authorities. Furthermore, the diversity at the nucleotide and amino acid levels and different proportions of dN/dS at the PreS1, PreS2, and HBsAg reveal the selective pressure trend from inactive status towards advanced liver diseases. ispartof: Infection Genetics And Evolution vol:77 ispartof: location:Netherlands status: Published online

ObjectiveTo determine whether an SRC homology 2 domain-containing phosphotyrosine phosphatase 2 (SHP2) inhibitor would increase muscle-specific kinase (MuSK) phosphorylation and override the inhibitory effect of MuSK-antibodies (Abs).MethodsThe effect of the SHP2 inhibitor NSC-87877 on MuSK phosphorylation and AChR clustering was tested in C2C12 myotubes with 31 MuSK-myasthenia gravis (MG) sera and purified MuSK-MG IgG4 preparations.ResultsIn the absence of MuSK-MG Abs, NSC-87877 increased MuSK phosphorylation and the number of AChR clusters in C2C12 myotubes in vitro and in DOK7-overexpressing C2C12 myotubes that form spontaneous AChR clusters. In the presence of MuSK-MG sera, the AChR clusters were reduced, as expected, but NSC-87877 was able to protect or restore the clusters. Two purified MuSK-MG IgG4 preparations inhibited both MuSK phosphorylation and AChR cluster formation, and in both, clusters were restored with NSC-87877.ConclusionsStimulating the agrin-LRP4-MuSK-DOK7 AChR clustering pathway with NSC-87877, or other drugs, could represent a novel therapeutic approach for MuSK-MG and could potentially improve other NMJ disorders with reduced AChR numbers or disrupted NMJs.

BACKGROUND Diet therapies may be recommended for pediatric functional gastrointestinal disorders (FGIDs). However, little is known about the frequency with which diet therapy is recommended in FGIDs. Our aims were to determine and contrast the frequency and types of diet recommendations provided to children with FGIDs by pediatric gastroenterologists (PGIs) versus primary care pediatricians (PCPs). METHODS A retrospective chart review was performed using data from a large, metropolitan children's academic healthcare system to identify subjects meeting Rome IV criteria for functional abdominal pain, functional dyspepsia, irritable-bowel syndrome (IBS), and/or abdominal migraine over a period of 23 months. RESULTS Of 1929 patient charts reviewed, 268 were included for further analyses. Of these, 186 patients (69%) were seen by a PGI and 82 (31%) by a PCP. The most common diagnosis was IBS (49% for PGIs and 71% for PCPs). Diet recommendations were provided to 115 (43%) patients (PGI group: 86 [75%] vs PCP group: 29 [25%]; P < .1). The most frequent recommendations were high fiber (PGI: 15%; PCP: 14%) and low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) diet (PGI: 12%; PCP: 4%). Of those provided with diet recommendations, only 20% (n = 23) received an educational consult by a dietitian. Provision of diet recommendations was not affected by years in practice. CONCLUSION Despite increasing awareness of the role of diet in the treatment of childhood FGIDs, a minority of patients receive diet recommendations in tertiary care or primary care settings. When diet recommendations were given, there was great variability in the guidance provided.

Human ascariasis is a neglected tropical disease of great relevance to public health and is considered the most frequent helminthiasis in poor regions. Accurately diagnosing this parasite has been challenging due to limitations of current diagnostic methods. Immunoglobulin Y (IgY) technology is a very effective alternative for the production of highly specific and profitable antibodies. This study aimed to produce and apply anti-Ascaris suum IgY antibodies in the immunodiagnosis of human ascariasis. Five immunizations comprising total saline extract from A. suum adult life forms were given at 14-day intervals to Gallus gallus domesticus hens of the Isa Brown line. Eggs and blood samples were collected weekly and fortnightly, respectively, to monitor the production of antibodies. The specificity of antibodies was confirmed by dot-blot, kinetic enzyme-linked immunosorbent assay (ELISA), avidity ELISA, immunoblotting and indirect immunofluorescence antibody tests. The application for disease diagnosis was performed through the detection of immune complexes in human serum samples by sandwich ELISA. Peaks of IgY anti-A. suum production occurred at weeks 6 and 8. IgY showed high avidity levels after the second dose of immunization, ranging from 64% to 93%, with a mean avidity index of 78.30%. Purified IgY recognized 12 bands of proteins from A. suum saline extract. Eggs, the uterine portion and cuticles of A. suum female adult are reactive in immunofluorescence. The detection of immune complexes showed diagnostic values of 80% sensitivity and 90% specificity. In conclusion, specific IgY have been shown to be a potential immunodiagnostic tool with promising future applications in human ascariasis.

Objectives: Firstly, to describe the outcome of a series of fetuses with Ebstein’s anomaly (EA) and, secondly, to study the utility of different second-trimester echocardiographic parameters to predict fetal and neonatal mortality. Methods: 39 fetuses with EA diagnosed between 18 and 28 weeks of gestation were included. Fetal echocardiography included the cardiothoracic ratio (CTR); right atrial (RA) area index; displacement of the tricuspid valve (TV); tricuspid regurgitation; pulmonary artery; and ductus arteriosus flow characteristics. Additionally, 2 novel parameters were obtained: the relative RA area ratio (RA area/cardiac area) and the TV displacement index (TVDI, TV displacement distance/longi­tudinal diameter of the left ventricle). Correlation between the echocardiographic variables and the primary outcome of perinatal mortality or survival at 1 year of life was evaluated. Results: From the initial cohort, 8 cases were excluded due to complex congenital heart defects. Termination of pregnancy (TOP) was performed in 15 cases, and fetal death was diagnosed in 3 cases. In the live-born cohort of 13 patients, 4 died in the neonatal period, yielding a perinatal survival rate of 29 and 56%, respectively, after excluding TOP cases. Compared with survivors, nonsurvivors showed a significantly higher CTR (56.7 ± 16.2 vs. 42.6 ± 8.6; p = 0.04), relative RA area ratio (0.39 ± 0.13 vs. 0.25 ± 0.05; p = 0.01), and TVDI (0.62 ± 0.17 vs. 0.44 ± 0.12; p = 0.03) at diagnosis. The best model to predict perinatal mortality was obtained by using a scoring system which included the relative RA area ratio and TVDI (AUC 0.905 [95% CI 0.732–1.000]). Conclusions: Fetuses with a relative RA area ratio ≥0.29 and TVDI ≥0.65 at the second trimester have the highest risk of dying in the perinatal stage.

Background Protein supplement use is common in bodybuilders because protein supplements are thought to increase muscle mass by preventing protein catabolism during exercise routines. Information on the consequences of protein supplement use is scarce and contradictory. Therefore, the identification of a kidney damage marker, such as microalbuminuria, could be transcendent in preventing probable organ compromise in healthy persons. The aim of this study is to determine the presence of microalbuminuria in gym members and whether there is an associated risk with protein supplement use. Methods An analytic, descriptive, cross-sectional study was conducted. It included gym members whose clinical and nutritional histories were taken, identifying protein supplement use. Microalbuminuria was then determined through a random urine sample. Descriptive and inferential statistics were used for the data analysis. The objective was to determine the presence of microalbuminuria in gym members and whether there is an associated risk with protein supplement use. Results A total of 107 gym members, 71 men and 36 women, that met the inclusion criteria of the study were analyzed. Their mean age was 35±13 years, and the prevalence of microalbuminuria was 9.34%. There was active protein supplement use in 58% of the study participants, with a mean consumption duration of 16±22 months. No association with the presence of microalbuminuria was found (P=0.35). Conclusions The prevalence of microalbuminuria in gym members was higher than that of the general healthy population and was not associated with protein supplement use.

BACKGROUND AND PURPOSE: Fetuses with isolated nonsevere ventriculomegaly (INSVM) are at risk of presenting neurodevelopmental delay. However, the currently used clinical parameters are insufficient to select cases with high risk and determine whether subtle changes in brain development are present and might be a risk factor. The aim of this study was to perform a comprehensive evaluation of cortical development in INSVM by magnetic resonance (MR) imaging and assess its association with neonatal neurobehavior. MATERIALS AND METHODS: Thirty-two INSVM fetuses and 29 healthy controls between 26-28 weeks of gestation were evaluated using MR imaging. We compared sulci and fissure depth, cortical maturation grading of specific areas and sulci and volumes of different brain regions obtained from 3D brain reconstruction of cases and controls. Neonatal outcome was assessed by using the Neonatal Behavioral Assessment Scale at a mean of 4 ± 2 weeks after birth. RESULTS: Fetuses with INSVM showed less profound and underdeveloped sulcation, including the Sylvian fissure (mean depth: controls 16.8 ± 1.9 mm, versus INSVM 16.0 ± 1.6 mm; P = .01), and reduced global cortical grading (mean score: controls 42.9 ± 10.2 mm, versus INSVM: 37.8 ± 9.9 mm; P = .01). Fetuses with isolated nonsevere ventriculomegaly showed a mean global increase of gray matter volume (controls, 276.8 ± 46.0 ×10 mm3, versus INSVM 277.5 ± 49.3 ×10 mm3, P = .01), but decreased mean cortical volume in the frontal lobe (left: controls, 53.2 ± 8.8 ×10 mm3, versus INSVM 52.4 ± 5.4 ×10 mm3; P = < .01). Sulcal depth and brain volumes were significantly associated with the Neonatal Behavioral Assessment Scale severity (P = .005, Nagelkerke R2 = 0.732). CONCLUSIONS: INSVM fetuses showed differences in cortical development, including regions far from the lateral ventricles, that are associated with neonatal neurobehavior. These results suggest the possible use of these parameters to identify cases at higher risk of altered neurodevelopment. ispartof: AMERICAN JOURNAL OF NEURORADIOLOGY vol:40 issue:9 pages:1567-1574 ispartof: location:United States status: published

More than 20% of healthcare-associated infections correspond to those at surgical sites, and there is a higher incidence of infections in colorectal surgery due to the associated bacterial load. Surgical wound protectors are designed to prevent contamination and mechanical trauma. Our aim was to demonstrate the usefulness of a circumferential wound retractor/protector for the prevention of surgical site infections (SSIs) in emergency colorectal surgery.Forty-one patients that underwent emergency open surgery at a tertiary care hospital were randomized into 2 groups: 20 cases without the retractor (group A) and 21 cases with the retractor (group B). Subjects were assigned to a group in a 1:1 randomization allocation ratio. The chi-square and Fisher's exact tests were employed for the quantitative variables, and the statistical analysis was performed using the IBM Statistical Package for the Social Sciences software for Mac, version 16.0 (IBM SPSS Inc., Chicago, IL, USA).The SSI rate was 17%. Six group A patients developed SSI versus one group B patient. The use of a circumferential wound retractor/protector was statistically significant for the prevention of surgical wound infections, with a P=.031 and an OR of 8.5. In addition, preoperative blood glucose levels below 200mg/dl provided a 3.2-times higher protective effect, compared with glucose levels above 200mg/dl.In the present prospective randomized pilot study, the use of the circumferential wound retractor/protector significantly decreased the likelihood of SSI in emergency colorectal surgery.

Acetylcholine receptor deficiency is the most common form of the congenital myasthenic syndromes, a heterogeneous collection of genetic disorders of neuromuscular transmission characterized by fatiguable muscle weakness. Most patients with acetylcholine receptor deficiency respond well to acetylcholinesterase inhibitors; however, in some cases the efficacy of acetylcholinesterase inhibitors diminishes over time. Patients with acetylcholine receptor deficiency can also benefit from the addition of a β2-adrenergic receptor agonist to their medication. The working mechanism of β2-adrenergic agonists in myasthenic patients is not fully understood. Here, we report the long-term follow-up for the addition of β2-adrenergic agonists for a cohort of patients with acetylcholine receptor deficiency on anticholinesterase medication that demonstrates a sustained quantitative improvement. Coincidently we used a disease model to mirror the treatment of acetylcholine receptor deficiency, and demonstrate improved muscle fatigue, improved neuromuscular transmission and improved synaptic structure resulting from the addition of the β2-adrenergic agonist salbutamol to the anticholinesterase medication pyridostigmine. Following an initial improvement in muscle fatiguability, a gradual decline in the effect of pyridostigmine was observed in mice treated with pyridostigmine alone (P < 0.001). Combination therapy with pyridostigmine and salbutamol counteracted this decline (P < 0.001). Studies of compound muscle action potential decrement at high nerve stimulation frequencies (P < 0.05) and miniature end-plate potential amplitude analysis (P < 0.01) showed an improvement in mice following combination therapy, compared to pyridostigmine monotherapy. Pyridostigmine alone reduced postsynaptic areas (P < 0.001) and postsynaptic folding (P < 0.01). Combination therapy increased postsynaptic area (P < 0.001) and promoted the formation of postsynaptic junctional folds (P < 0.001), in particular in fast-twitch muscles. In conclusion, we demonstrate for the first time how the improvement seen in patients from adding salbutamol to their medication can be explained in an experimental model of acetylcholine receptor deficiency, the most common form of congenital myasthenic syndrome. Salbutamol enhances neuromuscular junction synaptic structure by counteracting the detrimental effects of long-term acetylcholinesterase inhibitors on the postsynaptic neuromuscular junction. The results have implications for both autoimmune and genetic myasthenias where anticholinesterase medication is a standard treatment.

Mediastinal infantile hemangioma has not been reported so far (as far as we are aware), using accurate diagnostic methods. MRI scans are essential for a correct characterization and assessment of the extension. Moreover, Endothelial cell glucose transporter 1 (GLUT1) isoform protein represents an extremely important diagnostic tool to differentiate Infantile Hemangioma from other vascular neoplasms. With regards to management, surgery appears to be the treatment of choice, although it is important to highlight that it is a rare disease and more studies are needed to establish a proper diagnostic and therapeutic protocol. The prognosis seems to be favorable, with not known cases of recurrence or progression to malignancy.Los hemangiomas infantiles suponen los tumores más comunes en la época de la infancia. Su localización principal se sitúa en la piel, seguida del hígado. Los hemangiomas mediastínicos no han sido descritos hasta la fecha utilizando los métodos diagnósticos actuales adecuados. La resonancia magnética es esencial para una correcta caracterización y evaluación de la extensión. El estudio es histológico siendo el transportador celular de glucosa tipo 1 (GLUT-1) una importantísima herramienta diagnóstica para diferenciar el hemangioma infantil de otras neoplasias vasculares. En lo que al manejo respecta, la cirugía con excisión completa de la masa parece el tratamiento de elección. Es importante resaltar la rareza de esta enfermedad y la necesidad de realizar más estudios para establecer un adecuado protocolo diagnóstico-terapéutico. El pronóstico parece ser favorable, sin constar casos de recurrencia o progresión hacia la malignidad.

Rosuvastatin is a cholesterol-lowering drug that also attenuates the inflammatory process and oxidative stress via the reduction of superoxide anion production. Superoxide anions are metabolized by manganese-dependent superoxide dismutase (MnSOD or SOD2) in the mitochondria. In humans, there is a gene polymorphism where a change of alanine (Ala) to valine (Val) occurs at the 16th amino acid (Ala16Val-SOD2). The VV genotype has been associated with the risk of developing several metabolic diseases, such as hypercholesterolemia. Thus, to further explore this phenomenon, this study investigated the influence of the Val16Ala-SOD2 polymorphism on the lipid profile and inflammatory and fibrinolytic biomarkers of 122 hypercholesterolemic patients undergoing the first pharmacological cholesterol-lowering therapy who were treated with 20 mg rosuvastatin for 120 days. The findings indicate that the VV patients who present a low-efficiency SOD2 enzyme exhibit an attenuated response to rosuvastatin compared with the A-allele patients. The effect of rosuvastatin on inflammatory and fibrinolytic biomarkers was also less intense in the VV patients. These results suggest some pharmacogenetic effects of Val16Ala-SOD2 in hypercholesterolemia treatment.