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Abstract Background Children with non-ambulatory cerebral palsy (CP) frequently develop progressive neuromuscular scoliosis and require surgical intervention. Due to their comorbidities, they are at high risk for developing peri- and post-operative complications. The objectives of this study were to compare stepwise and LASSO variable selection techniques for consistency in identifying predictors when modelling these post-operative complications and to identify potential predictors of respiratory complications and infections following spine surgery among children with CP. Methods In this retrospective cohort study, a large administrative claims database was queried to identify children who met the following criteria: 1) ≤ 25 years old, 2) diagnosis of CP, 3) underwent surgery during the study period, 4) had ≥ 12-months pre-operative, and 5) ≥ 3-months post-operative continuous health plan enrollment. Outcome measures included the development of a post-operative respiratory complication (e.g., pneumonia, aspiration pneumonia, atelectasis, pleural effusion, pneumothorax, pulmonary edema) or an infection (e.g., surgical site infection, urinary tract infection, meningitis, peritonitis, sepsis, or septicemia) within 3 months of surgery. Codes were used to identify CP, surgical procedures, medical comorbidities and the development of post-operative respiratory complications and infections. Two approaches to variable selection, stepwise and LASSO, were compared to determine which potential predictors of respiratory complications and infection development would be identified using each approach. Results The sample included 220 children. During the 3-month follow-up, 21.8% (n = 48) developed a respiratory complication and 12.7% (n = 28) developed an infection. The prevalence of 11 variables including age, sex and 9 comorbidities were initially considered to be potential predictors based on the intended outcome of interest. Model discrimination utilizing LASSO for variable selection was slightly improved over the stepwise regression approach. LASSO resulted in retention of additional comorbidities that may have meaningful associations to consider for future studies, including gastrointestinal issues, bladder dysfunction, epilepsy, anemia and coagulation deficiency. Conclusions Potential predictors of the development of post-operative complications were identified in this study and while identified predictors were similar using stepwise and LASSO regression approaches, model discrimination was slightly improved with LASSO. Findings will be used to inform future research processes determining which variables to consider for developing risk prediction models.

The AMMA (African Monsoon Multidisciplinary Analysis) program is dedicated to providing a better understanding of the West African monsoon and its influence on the physical, chemical and biological environment regionally and globally, as well as relating variability of this monsoon system to issues of health, water resources, food security and demography for West African nations. Within this framework, an intensive field campaign took place during the summer of 2006 to better document specific processes and weather systems at various key stages of this monsoon season. This campaign was embedded within a longer observation period that documented the annual cycle of surface and atmospheric conditions between 2005 and 2007. The present paper provides a large and regional scale overview of the 2006 summer monsoon season, that includes consideration of of the convective activity, mean atmospheric circulation and synoptic/intraseasonal weather systems, oceanic and land surface conditions, continental hydrology, dust concentration and ozone distribution. The 2006 African summer monsoon was a near-normal rainy season except for a large-scale rainfall excess north of 15° N. This monsoon season was also characterized by a 10-day delayed onset compared to climatology, with convection becoming developed only after 10 July. This onset delay impacted the continental hydrology, soil moisture and vegetation dynamics as well as dust emission. More details of some less-well-known atmospheric features in the African monsoon at intraseasonal and synoptic scales are provided in order to promote future research in these areas.

Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome associated with cutaneous metastatic melanoma in which patients develop vision deficits that include reduced night vision, poor contrast sensitivity, and photopsia. MAR is caused by autoantibodies targeting TRPM1, an ion channel found in melanocytes and retinal ON-bipolar cells (ON-BCs). The visual symptoms arise when TRPM1 autoantibodies enter ON-BCs and block the function of TRPM1, thus detection of TRPM1 autoantibodies in patient serum is a key criterion in diagnosing MAR. Electroretinograms are used to measure the impact of TRPM1 autoantibodies on ON-BC function and represent another important diagnostic tool for MAR. To date, MAR case reports have included one or both diagnostic components, but only for a single time point in the course of a patient’s disease. Here, we report a case of MAR supported by longitudinal analysis of serum autoantibody detection, visual function, ocular inflammation, vascular integrity, and response to slow-release intraocular corticosteroids. Integrating these data with the patient’s oncological and ophthalmological records reveals novel insights regarding MAR pathogenesis, progression, and treatment, which may inform new research and expand our collective understanding of the disease. In brief, we find TRPM1 autoantibodies can disrupt vision even when serum levels are barely detectable by western blot and immunohistochemistry; intraocular dexamethasone treatment alleviates MAR visual symptoms despite high levels of circulating TRPM1 autoantibodies, implicating antibody access to the retina as a key factor in MAR pathogenesis. Elevated inflammatory cytokine levels in the patient’s eyes may be responsible for the observed damage to the blood-retinal barrier and subsequent entry of autoantibodies into the retina.

Background:. The coronavirus disease 2019 (COVID-19) pandemic caused disruptions to pediatric surgical care. Although surgical capacity has returned to the prepandemic state, barriers to surgical access may still exist for children who are medically underserved. We assessed pediatric plastic and oral and maxillofacial surgical volumes by sociodemographic characteristics before and during the COVID-19 pandemic. Methods:. A 72-month retrospective cohort analysis of 10,681 pediatric plastic and oral and maxillofacial procedures between 2016 and 2021 was conducted. Multivariable logistic regression and interrupted time series analyses were used to analyze surgical volume trends by sociodemographic groups and Child Opportunity Index (COI). Results:. Compared with prepandemic, patients undergoing procedures were more likely to be older than 18 years (P < 0.001) and Hispanic/Latino (adjusted odds ratio 1.38; 95% confidence interval, 1.14–1.68; P < 0.01). Surgical volume trends among patients from the lowest COI levels were lower than where they were estimated to have been if the pandemic did not occur (P = 0.040). Patients who spoke a primary language other than English or Spanish (P = 0.02) and patients with the lowest COI levels (P = 0.04) continued to have unrecovered surgical volumes. Conclusions:. There were differences in the sociodemographic case-mix of patients undergoing plastic and oral and maxillofacial surgical procedures before and during the pandemic, and surgical volumes did not recover at the same rate for all patients. Further research can determine why certain sociodemographic groups and patients with low COI levels had decreased surgical access compared with prepandemic trends, and develop interventions focused on equitable pediatric surgical access.

Snakebite envenoming is a neglected tropical disease that causes as many as 1.8 million envenomings and 140,000 deaths annually. To address treatment limitations that exist with current antivenoms, the search for small molecule drug-based inhibitors that can be administered as early interventions has recently gained traction. Snake venoms are complex mixtures of proteins, peptides and small molecules and their composition varies substantially between and within snake species. The phospholipases A2 (PLA2) are one of the main pathogenic toxin classes found in medically important viper and elapid snake venoms, yet varespladib, a drug originally developed for the treatment of acute coronary syndrome, remains the only PLA2 inhibitor shown to effectively neutralise venom toxicity in vitro and in vivo, resulting in an extremely limited drug portfolio. Here, we describe a high-throughput drug screen to identify novel PLA2 inhibitors for repurposing as snakebite treatments. We present method optimisation of a 384-well plate, colorimetric, high-throughput screening assay that allowed for a throughput of ∼2,800 drugs per day, and report on the screening of a ∼3,500 post-phase I repurposed drug library against the venom of the Russell’s viper, Daboia russelii. We further explore the broad-spectrum inhibitory potential and efficacy of the resulting top hits against a range of medically important snake venoms and demonstrate the utility of our method in determining drug EC50s. Collectively, our findings support the future application of this method to fully explore the chemical space to discover novel PLA2-inhibiting drugs of value for preventing severe pathology caused by snakebite envenoming.

Snakebite envenoming results in ∼100,000 deaths per year, with close to four times as many victims left with life-long sequelae. Current antivenom therapies have several limitations including high cost, variable cross-snake species efficacy and a requirement for intravenous administration in a clinical setting. Next-generation snakebite therapies are being widely investigated with the aim to improve cost, efficacy, and safety. In recent years several small molecule drugs have shown considerable promise for snakebite indication, with oral bioavailability particularly promising for community delivery rapidly after a snakebite. However, only two such drugs have entered clinical development for snakebite. To offset the risk of attrition during clinical trials and to better explore the chemical space for small molecule venom toxin inhibitors, here we describe the first high throughput drug screen against snake venom metalloproteinases (SVMPs)—a pathogenic toxin family responsible for causing haemorrhage and coagulopathy. Following validation of a 384-well fluorescent enzymatic assay, we screened a repurposed drug library of 3,547 compounds against five geographically distinct and toxin variable snake venoms. Our drug screen resulted in the identification of 14 compounds with pan-species inhibitory activity. Following secondary potency testing, four SVMP inhibitors were identified with nanomolar EC50s comparable to the previously identified matrix metalloproteinase inhibitor marimastat and superior to the metal chelator dimercaprol, doubling the current global portfolio of SVMP inhibitors. Following analysis of their chemical structure and ADME properties, two hit-to-lead compounds were identified. These clear starting points for the initiation of medicinal chemistry campaigns provide the basis for the first ever designer snakebite specific small molecules.

Abstract Objective To describe inpatient resource use in the 2 years following infantile epileptic spasms syndrome (IESS) diagnosis, examine the association between clinical/demographic variables and incidence of readmission, and identify risk factors/reasons for frequent readmissions. Methods Retrospective cohort analysis of readmissions (scheduled/unscheduled) within the first 2 years following IESS diagnosis, details of readmissions (number/time between rehospitalizations, and length of stay), demographic/clinical variables, and reasons for readmissions were collected. Negative binomial regression analysis evaluated associations between incidence of readmissions (both scheduled/unscheduled and unscheduled alone) and demographic/clinical factors. Logistic regression assessed the risk of having recurrent readmissions (≥5 readmissions). Results Among 93 (60% males) new‐onset IESS patients, there were 394 readmissions (56% scheduled and 44% unscheduled) within 2‐years following IESS diagnosis. Mean length of stay was 3.5 days (SD: 5.9). Readmissions occurred in 82 patients (88%) and 37 (40%) experienced ≥5 readmissions. On multivariate regression analysis, readmissions were increased with use of multiple first‐line treatments for IESS (P = 0.006), technology assistance (P ≤ 0.001), and multispecialty care (P = 0.01); seizure freedom (P = 0.015) and known etiology (P = 0.011) lowered the incidence of readmissions. Examining unscheduled readmissions separately, increased readmissions occurred with public insurance (P = 0.013), technology use (P ≤ 0.0.001), and multispecialty care (P = 0.013); seizure freedom decreased unscheduled readmissions (P = 0.006). Technology assistance (G‐tube, NG tube, VP shunt, and tracheostomy use) increased the odds (P = 0.007) for recurrent readmissions. Reasons for readmissions included EEG monitoring (protocol driven for verification of IESS remission/characterization of events/EEG surveillance/presurgical monitoring) (51%), acute medical issues (21%), and seizure exacerbation (15%). Protocol‐driven readmissions declined an estimated 52% following protocol modification during the study. Significance In the 2 years following IESS diagnosis, there is substantial inpatient resource use with nearly 40% experiencing ≥5 readmissions (mostly epilepsy related). Since readmissions are increased by intrinsic patient characteristics such as medical complexity (technology use and multispecialty care) or epilepsy‐related issues, the preventability of readmissions is uncertain, except for protocol‐driven ones.

Background: Spitzoid morphology in familial melanoma has been associated with germline variants in POT1, a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid differentiation. Objective: To assess if familial melanoma cases associated with germline variants in TMG (POT1, ACD, TERF2IP, and TERT) commonly exhibit spitzoid morphology. Methods: In this case series, melanomas were classified as having spitzoid morphology if at least 3 of 4 dermatopathologists reported this finding in ≥25% of tumor cells. Logistic regression was used to calculate odds ratios (OR) of spitzoid morphology compared to familial melanomas from unmatched noncarriers that were previously reviewed by a National Cancer Institute dermatopathologist. Results: Spitzoid morphology was observed in 77% (23 of 30), 75% (3 of 4), 50% (2 of 4), and 50% (1 of 2) of melanomas from individuals with germline variants in POT1, TERF2IP, ACD, and TERT, respectively. Compared to noncarriers (n = 139 melanomas), POT1 carriers (OR = 225.1, 95% confidence interval: 51.7-980.5; P

Since the 1940s, when maritime archaeology was established, the systematic excavation of submerged wrecks began to be refined. Systematic excavations led to the recovery of a vast array of organic and inorganic artefacts, including human and non-human bones and teeth. In order to preserve the materials recovered from the sea, the discipline of maritime conservation rapidly expanded and dealt with unique issues, including, but not limited to, marine salts’ encrustation of archaeological artefacts. Bone and teeth are organic artefacts which provide crucial information about natural and social environments of the past. When recovered from marine settings, they are often friable and require conservation processes and consolidation treatments, e.g., to prevent shrinkage during drying. However, conservation processes and consolidants can interfere with pathological, traumatic and taphonomical evidence associated with bone and teeth, and can bias sample preparation and analysis through mechanical action and chemical composition. The aim of this paper, in which a few examples of interference are listed, is to highlight the need of accurately documenting any type of conservation process and/or consolidation treatment that has been performed on bone and teeth stored in archaeological collections. This becomes essential when samples are selected for study, especially if this includes destructive analysis, and will assist in clarifying any conflicting results, leading to reliable interpretations.

Les divers procédés de filtration, phénomènes uniquement physiques et mécaniques, sont ia gravité, la pression, le vide et la force centrifuge. La filtration par gravité s'applique aux eaux de consommation courante, la filtration sous pression et sous vide est utilisée pour les liquides conte¬ nant très peu de matières en suspension jusqu'aux suspensions contenant 50 p. 100 de matières solides. La force centrifuge est utilisée pour la clarification des liquides contenant des teneurs supérieures de matières solides.

Antimalarials targeting the ubiquinol-oxidation (Qo) site of the Plasmodium falciparum bc1 complex, such as atovaquone, have become less effective due to the rapid emergence of resistance linked to point mutations in the Qo site. Recent findings showed a series of 2-aryl quinolones mediate inhibitions of this complex by binding to the ubiquinone-reduction (Qi) site, which offers a potential advantage in circumventing drug resistance. Since it is essential to understand how 2-aryl quinolone lead compounds bind within the Qi site, here we describe the co-crystallization and structure elucidation of the bovine cytochrome bc1 complex with three different antimalarial 4(1H)-quinolone sub-types, including two 2-aryl quinolone derivatives and a 3-aryl quinolone analogue for comparison. Currently, no structural information is available for Plasmodial cytochrome bc1. Our crystallographic studies have enabled comparison of an in-silico homology docking model of P. falciparum with the mammalian’s equivalent, enabling an examination of how binding compares for the 2- versus 3-aryl analogues. Based on crystallographic and computational modeling, key differences in human and P. falciparum Qi sites have been mapped that provide new insights that can be exploited for the development of next-generation antimalarials with greater selective inhibitory activity against the parasite bc1 with improved antimalarial properties.

OBJECTIVES: To identify children at risk for in-hospital mortality following tracheotomy. DESIGN: Retrospective cohort study. SETTING: 25 746 876 US hospitalisations for children within the Kids'' Inpatient Database 1997, 2000, 2003 and 2006. PARTICIPANTS: 18 806 hospitalisations of children ages 0–18 years undergoing tracheotomy, identified from ICD-9-CM tracheotomy procedure codes. MAIN OUTCOME MEASURE: Mortality during the initial hospitalisation when tracheotomy was performed in relation to patient demographic and clinical characteristics (neuromuscular impairment (NI), chronic lung disease, upper airway anomaly, prematurity, congenital heart disease, upper airway infection and trauma) identified with ICD-9-CM codes. RESULTS: Between 1997 and 2006, mortality following tracheotomy ranged from 7.7% to 8.5%. In each year, higher mortality was observed in children undergoing tracheotomy who were aged <1 year compared with children aged 1–4 years (mortality range: 10.2–13.1% vs 1.1–4.2%); in children with congenital heart disease, compared with children without congenital heart disease (13.1–18.7% vs 6.2–7.1%) and in children with prematurity, compared with children who were not premature (13.0–19.4% vs 6.8–7.3%). Lower mortality was observed in children with an upper airway anomaly compared with children without an upper airway anomaly (1.5–5.1% vs 9.1–10.3%). In 2006, the highest mortality (40.0%) was observed in premature children with NI and congenital heart disease, who did not have an upper airway anomaly. CONCLUSIONS: Congenital heart disease, prematurity, the absence of an upper airway anomaly and age <1 year were characteristics associated with higher mortality in children following tracheotomy. These findings may assist provider communication with children and families regarding early prognosis following tracheotomy. [ABSTRACT FROM AUTHOR]

Abstract. Based on hints of Tschebychev, a continued fraction is described which gives an effective algorithm for calculating the torsion, if finite, of divisors D − D− on a hyperelliptic curve of genus ≥2, where D is an effective divisor of degree 2 and D− denotes the image of D under the hyperelliptic involution. The difficulties involved in extending the algorithm to divisors of degree ≥3 are briefly discussed. [ABSTRACT FROM AUTHOR]

{Cubic reciprocity is used to derive primality tests analogous to the Lucas-Lehmer test for integers of the form $A.3^n \pm 1$. The test for $A.3^n-1$ is a minor improvement on a test derived by Williams by other means; the test for $A.3^n+1$ seems to be new.} [ABSTRACT FROM AUTHOR]

Alkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of active enzyme homogentisate 1,2-dioxygenase (HGD). The primary consequence of HGD deficiency is increased circulating homogentisic acid (HGA), the main agent in the pathology of AKU disease. Here we report the first metabolomic analysis of AKU homozygous Hgd knockout (Hgd−/−) mice to model the wider metabolic effects of Hgd deletion and the implication for AKU in humans. Untargeted metabolic profiling was performed on urine from Hgd−/− AKU (n = 15) and Hgd+/− non-AKU control (n = 14) mice by liquid chromatography high-resolution time-of-flight mass spectrometry (Experiment 1). The metabolites showing alteration in Hgd−/− were further investigated in AKU mice (n = 18) and patients from the UK National AKU Centre (n = 25) at baseline and after treatment with the HGA-lowering agent nitisinone (Experiment 2). A metabolic flux experiment was carried out after administration of 13C-labelled HGA to Hgd−/−(n = 4) and Hgd+/−(n = 4) mice (Experiment 3) to confirm direct association with HGA. Hgd−/− mice showed the expected increase in HGA, together with unexpected alterations in tyrosine, purine and TCA-cycle pathways. Metabolites with the greatest abundance increases in Hgd−/− were HGA and previously unreported sulfate and glucuronide HGA conjugates, these were decreased in mice and patients on nitisinone and shown to be products from HGA by the 13C-labelled HGA tracer. Our findings reveal that increased HGA in AKU undergoes further metabolism by mainly phase II biotransformations. The data advance our understanding of overall tyrosine metabolism, demonstrating how specific metabolic conditions can elucidate hitherto undiscovered pathways in biochemistry and metabolism.