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We report a subtype of immune‐mediated encephalitis associated with COVID‐19, which closely mimics acute‐onset sporadic Creutzfeldt–Jakob disease. A 64‐year‐old man presented with confusion, aphasia, myoclonus, and a silent interstitial pneumonia. He tested positive for SARS‐CoV‐2. Cognition and myoclonus rapidly deteriorated, EEG evolved to generalized periodic discharges and brain MRI showed multiple cortical DWI hyperintensities. CSF analysis was normal, except for a positive 14‐3‐3 protein. RT‐QuIC analysis was negative. High levels of pro‐inflammatory cytokines were present in the CSF and serum. Treatment with steroids and intravenous immunoglobulins produced EEG and clinical improvement, with a good neurological outcome at a 6‐month follow‐up.

Zusammenfassung. Ein 50-jähriger Patient wurde zur weiteren Abklärung einer progredienten, chronischen Diarrhö mit Gewichtsverlust und therapierefraktärer Hypokaliämie zugewiesen. Nach den Abklärungen konnte als Ursache der Diarrhö ein neuroendokriner Tumor des Pankreas (VIPom) festgestellt und mittels erfolgreicher Pankreaslinksresektion und vorübergehender medikamentöser Behandlung mit Octreotid behandelt werden. Wichtig bei der Abklärung einer chronischen Diarrhö ist ein strukturiertes Vorgehen, insbesondere mit ausführlicher Anamnese sowie klinischen Untersuchungen, Labordiagnostik und Bildgebung.

Background Patient-derived airway cells differentiated at Air Liquid Interface (ALI) are valuable models for Cystic fibrosis (CF) precision therapy. Different culture expansion methods have been established to extend expansion capacity of airway basal cells, while retaining functional airway epithelium physiology. Considerable variation in response to CFTR modulators is observed in cultures even within the same CFTR genotype and despite the use of similar ALI culture techniques. We aimed to address culture expansion method impact on differentiation. Methods Nasal epithelial brushings from 14 individuals (CF=9; non-CF=5) were collected, then equally divided and expanded under conditional reprogramming culture (CRC) and feeder-serum-free “dual-SMAD inhibition” (SMADi) methods. Expanded cells from each culture were differentiated with proprietary PneumaCult™-ALI media. Morphology (Immunofluorescence), global proteomics (LC-MS/MS) and function (barrier integrity, cilia motility, and ion transport) were compared in CRCALI and SMADiALI under basal and CFTR corrector treated (VX-809) conditions. Results No significant difference in the structural morphology or baseline global proteomics profile were observed. Barrier integrity and cilia motility were significantly different, despite no difference in cell junction morphology or cilia abundance. Epithelial Sodium Channels and Calcium-activated Chloride Channel activity did not differ but CFTR mediated chloride currents were significantly reduced in SMADiALI compare to their CRCALI counterparts. Conclusion Alteration of cellular physiological function in vitro were more prominent than structural and differentiation potential in airway ALI. Since initial expansion culture conditions significantly influence CFTR activity, this could lead to false conclusions if data from different labs are compared against each other without specific reference ranges.

Purpose We aimed to identify job accommodations that help persons with physical disabilities maintain or return to work and explore the barriers and facilitators that influence the provision and reception of job accommodations. Methods We conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review was registered in PROSPERO (CRD42019129645). The search strategy incorporated keywords describing physical disabilities, employer-approved job accommodations, and employment retention or return to work approaches. We searched MEDLINE, the Cochrane Library, Embase, CINAHL, PsycINFO, Web of Science, and ProQuest Theses and dissertations. Reviewers independently selected studies for inclusion. We used Hawker et al.'s method to assess study quality. Results We identified 2203 articles, of which 52 met inclusion criteria, developed a table of job accommodations commonly used by persons with physical disabilities, summarized the percentages of job accommodations used by persons with disabilities, synthesized evidence of the effectiveness of job accommodations, and identified the factors that influence job accommodation use. The most frequently reported accommodations were as follows: modification of job responsibilities, change of workplace policy, supportive personnel provision, flexible scheduling, and assistive technology. We summarized four types of facilitators and barriers that affect job accommodation use: employee-related factors, accommodation-related factors, job-related factors, and social workplace-related factors. Conclusion The absence of randomized controlled trials and prevalence of cross-sectional surveys provides inconclusive evidence regarding the effectiveness of specific job accommodations for people with particular functional limitations. Our system of categorizing job accommodations provides a guide to investigators seeking to evaluate the effectiveness of job accommodations using experimental methods.

A febre amarela e uma doenca infecciosa causada pelo virus do genero Flavivirus , transmitido pelo mosquito Aedes aegypti e que tem a vacina oferecida pelo Sistema Unico de Saude como principal meio para a prevencao da doenca. Este trabalho teve como objetivo verificar a epidemiologia da febre amarela na regiao Sul do pais de 2007 a 2019, a partir dos dados disponibilizados pelo Ministerio da Saude, definindo a territorializacao e as caracteristicas referente a presenca da doenca. Os dados foram apresentados em graficos, de acordo com a estatistica descritiva. A caracterizacao mostrou 31 casos, predominio de transmissao autoctone (74%), na area urbana (80%), em individuos da raca branca (99%) e do sexo masculino (71%), em idade produtiva de 29 a 59 anos (80,7%), com escolaridade superior a 4a serie do ensino fundamental (32,2%) e que tiveram o diagnostico prioritariamente laboratorial (87%). As medidas adotadas pelo Ministerio da Saude, em conjunto com as Secretarias Estaduais e Municipais de Saude, para o controle da febre amarela na regiao Sul apos a expansao da area de circulacao do virus observada em 2018 permitiram o controle da disseminacao da doenca em 2019. No entanto, de janeiro a abril de 2020 ja foram registrados novos 13 casos e com dois obitos, todos no estado de Santa Catarina. Isto indica a necessidade de medidas de controle da febre amarela no estado, aliada ao controle da pandemia de coronavirus da sindrome respiratoria aguda grave 2 (SARS-CoV-2) que acontece neste momento.

The delivery of diagnostic laboratory services has undergone significant change in recent years. Specifically, clinical microbiology laboratories are being asked to become more efficient and to utilize health care dollars more effectively while still providing the highest level of care for patients and meeting the needs of health care providers. In some cases, this has led to the need to centralize and consolidate the clinical microbiology laboratory. Here, we discuss the key points to consider surrounding centralization and consolidation of microbiology services during these uncertain times, many of which we have encountered ourselves. We present a methodical approach to assess the factors associated with consolidation, including topics related to management of the microbiology laboratory and ensuring that quality patient care stays at the center of the decision-making process, all while maintaining efficiency and compliance with regulatory guidelines.

Background Group B Streptococcus (GBS) remains a significant cause of neonatal infection, but the maternal risk factors for GBS colonization remain poorly defined. We hypothesized that there may be an association between antibiotic exposure during pregnancy and GBS colonization and/or the presence of inducible clindamycin resistance (iCLI-R) in GBS isolates from GBS-colonized pregnant women. Methods A retrospective cohort study was performed at Louisiana State University Health Sciences Center – Shreveport including demographic and clinical data from 1513 pregnant women who were screened for GBS between July 1, 2009 and December 31, 2010. Results Among 526 (34.8%) women who screened positive for GBS, 124 (23.6%) carried GBS strains with iCLI-R (GBS-iCLI-R). While antibiotic exposure, race, sexually-transmitted infection (STI) in pregnancy, GBS colonization in prior pregnancy and BMI were identified as risk factors for GBS colonization in univariate analyses, the only independent risk factors for GBS colonization were African–American race (AOR = 2.142; 95% CI = 2.092–3.861) and STI during pregnancy (AOR = 1.309; 95% CI = 1.035–1.653). Independent risk factors for GBS-iCLI-R among women colonized with GBS were non-African–American race (AOR = 2.13; 95% CI = 1.20–3.78) and younger age (AOR = 0.94; 95% CI = 0.91–0.98). Among GBS-colonized women with an STI in the current pregnancy, the only independent risk factor for iCLI-R was Chlamydia trachomatis infection (AOR = 4.31; 95% CI = 1.78–10.41). Conclusions This study identified novel associations for GBS colonization and colonization with GBS-iCLI-R. Prospective studies will improve our understanding of the epidemiology of GBS colonization during pregnancy and the role of antibiotic exposure in alterations of the maternal microbiome.

Eine 34-jahrige Patientin stellte sich mit einer 1,5 cm durchmessenden medianen zervikalen Raumforderung vor. Nebenbefundlich zeigte sich noch eine zweite zystische Raumforderung im Level 2 linksseitig. Nach kompletter Exstirpation ergab die histopathologische Aufarbeitung die Diagnose eines dystopen papillaren Schilddrusenkarzinoms. Wir fuhrten die totale Thyreoidektomie mit Neck-Dissection beidseits durch. Postoperativ kam es zu einem transienten Hypoparathyreoidismus. Das Hauptpraparat zeigte 4 intraparenchymatos gelegene Nebenschilddrusen. Anschliesend wurde eine Radiojodtherapie eingeleitet.

Zusammenfassung Anamnese und klinischer Befund Ein 58-jähriger Mann stellte sich mit therapierefraktärer Hypokaliämie und rascher Gewichtszunahme vor. Klinisch bestanden hypertensive Blutdruckwerte, eine stammbetonte Adipositas und ausgeprägte Beinödeme. Untersuchungen und Diagnose Die Laboruntersuchungen ergaben eine hypokaliämische metabolische Alkalose bei ACTH-abhängigem Hyperkortisolismus. Die Thorax-Abdomen-CT zeigte eine pulmonale Raumforderung und eine Raumforderung der rechten Nebenniere. Bioptisch wurde die Diagnose eines ACTH-produzierenden kleinzelligen Lungenkarzinoms gestellt. Therapie und Verlauf Unter Therapie mit Ketoconazol und Chemotherapie war der Tumor größenregredient, der Hyperkortisolismus konnte kontrolliert werden. Die Raumforderung der rechten Nebenniere war im Verlauf größenkonstant, sodass wir von einem inzidentellen Nebennierenadenom ausgingen. Folgerung Die Diagnose des paraneoplastischen Cushing-Syndroms kann eine Herausforderung sein, da klassische Cushing-Stigmata aufgrund des raschen Auftretens fehlen können. Bei neu aufgetretener, therapierefraktärer Hypokaliämie, metabolischer Alkalose und arterieller Hypertonie sollte man daher nicht zuletzt an Hyperkortisolismus denken.

This longitudinal study was designed to examine how science, technology, engineering, and mathematics (STEM) project-based learning (PBL) affected the success of high school women in comparison with high school men in mathematics and science, with English performance as a control. We analysed the four-year performance, course-taking, and retention of high school students (n = 186) in these three subjects in a school where STEM PBL was enacted. Students’ Texas state-mandated high-stakes test scores were collected. A repeated measures MANOVA was used for analysing changes in performance after infusing STEM PBL activities into their classes. The results indicated that there was a statistically significant change in scores for both men and women in mathematics and science; however, the attrition for women was much less than for men. We included implications for how to escalate women's performance and retention in STEM-based areas.

Diabetic patients are at higher risk of developing infectious diseases and severe complications, compared to the general population. Almost no data is available in the literature on influenza immunization in people with type 1 diabetes mellitus (T1DM). As part of a broader project on immunization in diabetic patients, we conducted a cross-sectional study to: (i) report on seasonal influenza coverage rates in T1DM patients, (ii) explore knowledge, attitudes, and practices (KAPs) towards seasonal influenza in this population, and (iii) identify factors associated with vaccine uptake, including the role of family doctors and diabetologists. A survey was administered to 251 T1DM patients attending the Diabetes Clinic at San Raffaele Research Hospital in Milan, Italy and individual-level coverage data were retrieved from immunization registries. Self-reported seasonal influenza immunization coverage was 36%, which decreased to 21.7% when considering regional immunization registries, far below coverage target of 75%. More than a third (36.2%) of T1DM patients were classified as pro-vaccine, 30.7% as hesitant, 17.9% as uninformed, and 15.1% as anti-vaccine. Diabetologists resulted to be the most trusted source of information on vaccines’ benefits and risks (85.3%) and should be more actively involved in preventive interventions. Our study highlights the importance of developing tailored vaccination campaigns for people with diabetes, including hospital-based programs involving diabetes specialists.

Measurements of cilia function (beat frequency, pattern) have been established as diagnostic tools for respiratory diseases such as primary ciliary dyskinesia. However, the wider application of these techniques is limited by the extreme susceptibility of ciliary function to changes in environmental factors e.g., temperature, humidity, and pH. In the airway of patients with Cystic Fibrosis (CF), mucus accumulation impedes cilia beating. Cilia function has been investigated in primary airway cell models as an indicator of CF Transmembrane conductance Regulator (CFTR) channel activity. However, considerable patient-to-patient variability in cilia beating frequency has been found in response to CFTR-modulating drugs, even for patients with the same CFTR mutations. Furthermore, the impact of dysfunctional CFTR-regulated chloride secretion on ciliary function is poorly understood. There is currently no comprehensive protocol demonstrating sample preparation of in vitro airway models, image acquisition, and analysis of Cilia Beat Frequency (CBF). Standardized culture conditions and image acquisition performed in an environmentally controlled condition would enable consistent, reproducible quantification of CBF between individuals and in response to CFTR-modulating drugs. This protocol describes the quantification of CBF in three different airway epithelial cell model systems: 1) native epithelial sheets, 2) air-liquid interface models imaged on permeable support inserts, and 3) extracellular matrix-embedded three-dimensional organoids. The latter two replicate in vivo lung physiology, with beating cilia and production of mucus. The ciliary function is captured using a high-speed video camera in an environment-controlled chamber. Custom-built scripts are used for the analysis of CBF. Translation of CBF measurements to the clinic is envisioned to be an important clinical tool for predicting response to CFTR-modulating drugs on a per-patient basis.

Background Healthcare workers (HCW) adherence to hand hygiene (HH) is the most effective infection prevention and control (IPC) measure to fight healthcare-associated infections (HAI) and is a crucial component for standard precautions, especially in a pandemic context. As suggested by the WHO and Joint Commission Network Project, evaluating adherence to HH is essential to identify deficiencies and promote improvement interventions. Methods San Raffaele Hospital in Milan, Italy, adopted internal audits to measure HCWs' adherence to HH according to WHO Guidelines. Public health (PH) residents were enrolled as auditors. They were trained with WHO technical manual for observers and handovers among residents. WHO observation form was used for collection. Process index was HH adherence, stratified by profession, unit, opportunity and indication. Results 8 PH medical residents carried out observations from January 2018 to December 2019. 434 HCWs were observed in 26 hospital units (191 nurses, 148 physicians, 83 healthcare assistants and 11 other professionals). Global adherence was 53%, calculated on 1,969 opportunities, and 2,221 indications observed, followed by 932 hands rubbing and 110 handwashing. Most observations involved nurses (adherence of 53%) and physicians (54%). Global adherence was generally higher in medicine, specialist surgery and intensive-care units while lower in general surgery and rehabilitation units. Indications with the highest adherence were “after body fluid exposure risk” (69%) and “after touching a patient” (64%). The lowest adherence (44%) was observed for “before clean/aseptic procedure” indication. The belief that gloves use may replace HH might partially explain the data. Conclusions Global HH adherence was in line with significant published data and was far better than 2016 data but slightly lower than observations in 2018 when the program started. We believe 2020 HH compliance could have changed due to HCW involvement in IPC against COVID-19. Key messages Hand hygiene (HH) audits represent a crucial tool of clinical governance and risk management: auditors’ training, monthly and annual reports, and feedbacks allowed to structure a virtuous process. If HH audits aim to improve practice we should understand when HH is most beneficial, assessing quality, improving performances through achievable targets using reproducible methods and technologies.

Background:A subdural hematoma is defined as clot formation in the subdural space after vessel rupture or brain parenchyma damage. Several demographic and tomographic factors were associated to poor prognosis, although some debate according to their specific roles still remains.Methods:Retrospective cohort study of comatose patients admitted to a single-institution, tertiary hospital center, between the years 2013 and 2019 with traumatic acute subdural hematoma requiring surgical evacuation were studied. Demographic and tomographic data were obtained from medical records. Univariate and multivariate statistical analysis were performed, using a value ofP< 0.05 for significance.Results:Seventy-seven patients were selected using the criteria and a total of 37 (48%) head CT exams were evaluated. The overall mortality was 57.1% and achieved 100% at ≥75-years-old subgroup. Univariate analysis only found young age as a good prognosis factor (P= 0.002). Gender (P= 0.784), abnormal pupillary response (P= 0.643), midline shift (P= 0.874), clot thickness (P= 0.206), compressed basal cisterns (P= 0.643), hematoma side (P= 0.879), and subarachnoid hemorrhage (P= 0.510) showed no association. Multivariate analysis showed no statistically significant association between covariates.Conclusion:Traumatic acute subdural hematoma is a life-threatening condition. Younger age was the only positive prognostic factor identified. More research is necessary to establish age as a rule-out criterion to surgical indication.

Repurposing of the existing medications has become the mainstream focus of anti-COVID-19 drug discovery as it offers rapid and cost-effective solutions for therapeutic development. However, there is still a great deal to enhance efficacy of repurposing therapeutic options through combination therapy, in which promising drugs with varying mechanisms of action are administered together. Nonetheless, our ability to identify and validate effective combinations is limited due to the huge number of possible drug pairs. Yet, there is no available resource which can systematically guide to identify or choose the effective individual drugs or best possible synergistic drug combinations for the treatment of SARS-CoV-2 infection. To address this resource gap, we developed a web-based platform that displays the network-based mechanism of action of drug combinations, thus simultaneously giving a visual of the cellular interactome involved in the mode of action of the chosen drugs. The platform allows the freedom to choose two or more drug combinations and provides the options to investigate network-based efficacy of drug combinations and understand the similarity score, primary indications, and contraindications of using these drugs combinations. In a nutshell, the platform (accessible via: http://vafaeelab.com/COVID19_repositioning.html) is of the first of its type which provides a systematic approach for pre-clinical investigation of combination therapy for treating COVID-19 on the fingertips of the clinicians or researchers.

Background: Most residents do not have a defined program for simulation training in video surgery in Brazil. The training takes place for the most part in vivo or in short courses. The goal of this article is to describe and evaluate a set of exercises using low-cost materials, created by the residents themselves, to enable basic skills training in video surgery. Materials and Methods: Seven exercises were elaborated aiming to simulate main maneuvers performed in video surgery. The residents were guided by a written and video description showing the execution of the exercises, performed the exercises, and answered a questionnaire. After 3 weeks of free training, the residents performed the exercises and answered the questionnaire again. Results: Seven residents started the study; however, 6 completed the two steps. Among the participants, 83% received in vivo video surgery training, and only 2 (33%) received some supervised simulation training in minimally invasive surgery before this time. All participants considered the set of seven exercises representative of the actual skills in video surgery. There was no difficulty in acquiring the materials or in assembling them to carry out the training. All the participants had a shorter training time than initially proposed, on average 1 day/week for 20 minutes. Conclusions: A simple set of exercises can be elaborated by the residents themselves and make feasible the simulated training in video surgery even without the availability of sophisticated and expensive materials. The presence of a tutor and the scheduling of exclusive training seem necessary for more satisfactory results.

Real-time PCR are often used for the diagnosis and monitoring of Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections in susceptible populations. In this context, we evaluated the analytical performances of the Abbott RealTime CMV/EBV maxCycle protocol automated on the m2000 platform (Abbott). It was compared to our routinely-used procedure consisting of a NucleoMag® DNA extraction automated on a STARlet platform followed by manually processed CMV and EBV quantitative real-time PCR (Diagenode). In this study, we showed that both EBV assays exhibited a similar sensitivity but with a better precision for the EBV Abbott RealTime assay. For the CMV performances, the Abbott assay was more sensitive and more precise than our routine method. The use of WHO International Standards also indicated a slight underestimation of the viral loads (-0.25 log10 IU/mL and -0.21 log10 IU/mL for CMV and EBV assays respectively) while these were rather overestimated with the Starlet/Diagenode method (0.48 log10 IU/mL and 0.19 log10 IU/mL for CMV and EBV assays respectively). These trends were confirmed using relevant whole-blood clinical samples and external quality controls. The workflows were also compared and we highlighted a significant technician hands-on time reduction (-63%) using the Abbott CMV/EBV maxCycle automated protocol.

Background Available methods to quantify regional dynamic thoracic function in thoracic insufficiency syndrome (TIS) are limited. Purpose To evaluate the use of quantitative dynamic MRI to depict changes in regional dynamic thoracic function before and after surgical correction of TIS. Materials and Methods Images from free-breathing dynamic MRI in pediatric patients with TIS (July 2009-August 2015) were retrospectively evaluated before and after surgical correction by using vertical expandable prosthetic titanium rib (VEPTR). Eleven volumetric parameters were derived from lung, chest wall, and diaphragm segmentations, and parameter changes before versus after operation were correlated with changes in clinical parameters. Paired analysis from Student t test on MRI parameters and clinical parameters was performed to detect if changes (from preoperative to postoperative condition) were statistically significant. Results Left and right lung volumes at end inspiration and end expiration increased substantially after operation in pediatric patients with thoracic insufficiency syndrome, especially right lung volume with 22.9% and 26.3% volume increase at end expiration (P = .001) and end inspiration (P = .002), respectively. The average lung tidal volumes increased after operation for TIS; there was a 43.8% and 55.3% increase for left lung tidal volume and right lung tidal volume (P < .001 for both), respectively. However, clinical parameters did not show significant changes from pre- to posttreatment states. Thoracic and lumbar Cobb angle were poor predictors of MRI tidal volumes (chest wall, diaphragm, and left and right separately), but assisted ventilation rating and forced vital capacity showed moderate correlations with tidal volumes (chest wall, diaphragm, and left and right separately). Conclusion Vertical expandable prosthetic titanium rib operation was associated with postoperative increases in all components of tidal volume (left and right chest wall and diaphragm, and left and right lung tidal volumes) measured at MRI. Clinical parameters did not demonstrate improvements in postoperative tidal volumes. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Paltiel in this issue.

Background Hibernation is a physiological state exploited by many animals exposed to prolonged adverse environmental conditions associated with winter. Large changes in metabolism and cellular function occur, with many stress response pathways modulated to tolerate physiological challenges that might otherwise be lethal. Many studies have sought to elucidate the molecular mechanisms of mammalian hibernation, but detailed analyses are lacking in reptiles. Here we examine gene expression in the Australian central bearded dragon (Pogona vitticeps) using mRNA-seq and label-free quantitative mass spectrometry in matched brain, heart and skeletal muscle samples from animals at late hibernation, 2 days post-arousal and 2 months post-arousal. Results We identified differentially expressed genes in all tissues between hibernation and post-arousal time points; with 4264 differentially expressed genes in brain, 5340 differentially expressed genes in heart, and 5587 differentially expressed genes in skeletal muscle. Furthermore, we identified 2482 differentially expressed genes across all tissues. Proteomic analysis identified 743 proteins (58 differentially expressed) in brain, 535 (57 differentially expressed) in heart, and 337 (36 differentially expressed) in skeletal muscle. Tissue-specific analyses revealed enrichment of protective mechanisms in all tissues, including neuroprotective pathways in brain, cardiac hypertrophic processes in heart, and atrophy protective pathways in skeletal muscle. In all tissues stress response pathways were induced during hibernation, as well as evidence for gene expression regulation at transcription, translation and post-translation. Conclusions These results reveal critical stress response pathways and protective mechanisms that allow for maintenance of both tissue-specific function, and survival during hibernation in the central bearded dragon. Furthermore, we provide evidence for multiple levels of gene expression regulation during hibernation, particularly enrichment of miRNA-mediated translational repression machinery; a process that would allow for rapid and energy efficient reactivation of translation from mature mRNA molecules at arousal. This study is the first molecular investigation of its kind in a hibernating reptile, and identifies strategies not yet observed in other hibernators to cope stress associated with this remarkable state of metabolic depression. Electronic supplementary material The online version of this article (10.1186/s12864-019-5750-x) contains supplementary material, which is available to authorized users.

Background The syndrome of the trephined was described in 1939 by Grant and Norcross and is defined as a progressive neurological deterioration after craniectomy. Commonly, it is associated with sinking of the skin near the bone-free area. The symptoms and signs improve after cranioplasty. This report intends to describe an uncommon case of a patient who presented to the hospital with the syndrome of the trephined and was temporarily treated with a plastered helmet. Case description 45-year old male was submitted to a decompressive craniectomy due to severe traumatic brain injury. After one month, he was diagnosed with the syndrome of the trephined. Once he was in sepsis, cranioplasty could not be done. An alternative treatment was proposed and the patient improved in both clinical and radiological cenarios. Conclusion The external cranioplasty made with plastered helmet proved to be an effective technique that can be safely applied to patients with the syndrome of the trephined who cannot be promptly treated with surgery.

Objective To compare the accuracy of computer versus physician predictions of hospitalization and to explore the potential synergies of hybrid physician–computer models. Materials and Methods A single-center prospective observational study in a tertiary pediatric hospital in Boston, Massachusetts, United States. Nine emergency department (ED) attending physicians participated in the study. Physicians predicted the likelihood of admission for patients in the ED whose hospitalization disposition had not yet been decided. In parallel, a random-forest computer model was developed to predict hospitalizations from the ED, based on data available within the first hour of the ED encounter. The model was tested on the same cohort of patients evaluated by the participating physicians. Results 198 pediatric patients were considered for inclusion. Six patients were excluded due to incomplete or erroneous physician forms. Of the 192 included patients, 54 (28%) were admitted and 138 (72%) were discharged. The positive predictive value for the prediction of admission was 66% for the clinicians, 73% for the computer model, and 86% for a hybrid model combining the two. To predict admission, physicians relied more heavily on the clinical appearance of the patient, while the computer model relied more heavily on technical data-driven features, such as the rate of prior admissions or distance traveled to hospital. Discussion Computer-generated predictions of patient disposition were more accurate than clinician-generated predictions. A hybrid prediction model improved accuracy over both individual predictions, highlighting the complementary and synergistic effects of both approaches. Conclusion The integration of computer and clinician predictions can yield improved predictive performance.

A 60-year-old man presented to our hospital because of febrile neutropenia due to chemotherapy for his metastasized colon cancer. During hospital stay, polyuria and polydipsia were noted. He reported that his thirst had become increasingly intolerable over the last weeks. Diabetes mellitus was diagnosed. Polyuria and polydipsia persisted despite euglycemia under insulin treatment. Because of thirst and high urine volumes during the night, diabetes insipidus was suspected. Endocrinological work up revealed complete panhypopituitarism with impairment of all anterior and posterior axes. After substitution with hydrocortisone, levothyroxine and desmopressin symptoms resolved. MRI of the brain revealed one round, contrast enhancing lesion in the pituitary stalk and one in the pineal gland. Because of extensive extracerebral metastasis and poor performance status, the patient opted for radiation therapy only. He died 2.5 months later due to non-cerebral manifestations of his cancer before cerebral radiotherapy could be initiated.

Age-dependent differences in the clinical response to SARS-CoV-2 infection is well-documented1–3 however the underlying molecular mechanisms involved are poorly understood. We infected fully differentiated human nasal epithelium cultures derived from healthy children (1-12 years old), young adults (26-34 years old) and older adults (56-62 years old) with SARS-COV-2 to identify age-related cell-intrinsic differences that may influence viral entry, replication and host defence response. We integrated imaging, transcriptomics, proteomics and biochemical assays revealing age-related changes in transcriptional regulation that impact viral replication, effectiveness of host responses and therapeutic drug targets. Viral load was lowest in infected older adult cultures despite the highest expression of SARS-CoV-2 entry and detection factors. We showed this was likely due to lower expression of hijacked host machinery essential for viral replication. Unlike the nasal epithelium of young adults and children, global host response and induction of the interferon signalling was profoundly impaired in older adults, which preferentially expressed proinflammatory cytokines mirroring the “cytokine storm” seen in severe COVID-194,5. In silico screening of our virus-host-drug network identified drug classes with higher efficacy in older adults. Collectively, our data suggests that cellular alterations that occur during ageing impact the ability for the host nasal epithelium to respond to SARS-CoV-2 infection which could guide future therapeutic strategies.

The aim of this study was the identification of specific proteomic profiles, related to a restored cystic fibrosis transmembrane conductance regulator (CFTR) activity in cystic fibrosis (CF) leukocytes before and after ex vivo treatment with the potentiator VX770. We used leukocytes, isolated from CF patients carrying residual function mutations and eligible for Ivacaftor therapy, and performed CFTR activity together with proteomic analyses through micro-LC–MS. Bioinformatic analyses of the results obtained revealed the downregulation of proteins belonging to the leukocyte transendothelial migration and regulation of actin cytoskeleton pathways when CFTR activity was rescued by VX770 treatment. In particular, we focused our attention on matrix metalloproteinase 9 (MMP9), because the high expression of this protease potentially contributes to parenchyma lung destruction and dysfunction in CF. Thus, the downregulation of MMP9 could represent one of the possible positive effects of VX770 in decreasing the disease progression, and a potential biomarker for the prediction of the efficacy of therapies targeting the defect of Cl− transport in CF.

Digitalisation offers great potential to improve vaccine uptake, supporting the need for effective life-course immunisation services. We conducted semi-structured in-depth interviews with public health experts from 10 Western European countries (Germany, Greece, Italy, Luxembourg, Malta, the Netherlands, Norway, Poland, Portugal, and the United Kingdom) to assess the current level of digitalisation in immunisation programmes and retrieve data on interventions and best practices. Interviews were performed using an ad hoc questionnaire, piloted on a sample of national experts. We report a mixed level of digital technologies deployment within vaccination services across Europe: Some countries are currently developing eHealth strategies, while others have already put in place robust programmes. Institutional websites, educational videos, and electronic immunisation records are the most frequently adopted digital tools. Webinars and dashboards represent valuable resources to train and support healthcare professionals in immunisation services organisation. Text messages, email-based communication, and smartphone apps use is scattered across Europe. The main reported barrier to the implementation of digital-based programmes is the lack of resources and shared standards. Our study offers a comprehensive picture of the European context and shows the need for robust collaboration between states and international institutions to share best practices and inform the planning of digital intervention models with the aim of countering vaccine hesitancy and increasing vaccine uptake.

An effective monotherapy to target the complex and multifactorial pathology of SARS-CoV-2 infection poses a challenge to drug repositioning, which can be improved by combination therapy. We developed an online network pharmacology-based drug repositioning platform, COVID-CDR (http://vafaeelab.com/COVID19repositioning.html), that enables a visual and quantitative investigation of the interplay between the drug primary targets and the SARS-CoV-2-host interactome in the human protein-protein interaction network. COVID-CDR prioritizes drug combinations with potential to act synergistically through different, yet potentially complementary pathways. It provides the options for understanding multi-evidence drug-pair similarity scores along with several other relevant information on individual drugs or drug pairs. Overall, COVID-CDR is the first-of-its-kind online platform that provides a systematic approach for pre-clinical in silico investigation of combination therapies for treating COVID-19 at the fingertips of the clinicians and researchers.

OBJECTIVES: To compare the performance and test characteristics of an automated sepsis screening tool with that of a manual sepsis screen in patients presenting to a pediatric emergency department (ED). METHODS: We conducted a retrospective cohort study of encounters in a pediatric ED over a 2-year period. The automated sepsis screening algorithm replaced the manual sepsis screen 1 year into the study. A positive case was defined as development of severe sepsis or septic shock within 24 hours of disposition from the ED. We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and positive and negative likelihood ratios with 95% confidence intervals (CIs) for each. RESULTS: There were 122 221 ED encounters during the study period and 273 cases of severe sepsis. During year 1 of the study, the manual screen was performed in 8910 of 61 026 (14.6%) encounters, resulting in the following test characteristics: sensitivity of 64.6% (95% CI 54.2%–74.1%), specificity of 91.1% (95% CI 90.5%–91.7%), PPV of 7.3% (95% CI 6.3%–8.5%), and NPV of 99.6% (95% CI 99.5%–99.7%). During year 2 of the study, the automated screen was performed in 100% of 61 195 encounters, resulting in the following test characteristics: sensitivity of 84.6% (95% CI 77.4%–90.2%), specificity of 95.1% (95% CI 94.9%–95.2%), PPV of 3.7% (95% CI 3.4%–4%), and NPV of 99.9% (95% CI 99.9%–100%). CONCLUSIONS: An automated sepsis screening algorithm had higher sensitivity and specificity than a widely used manual sepsis screen and was performed on 100% of patients in the ED, ensuring continuous sepsis surveillance throughout the ED stay.

Systemic glutathione deficiency, inflammation, and oxidative stress are hallmarks of cystic fibrosis (CF), an inherited disease that causes persistent lung infections and severe damage to the respiratory system and many of the body organs. Improvements to current antioxidant therapeutic strategies are needed. The dietary supplement, &gamma, glutamylcysteine (GGC), which is the immediate precursor to glutathione, rapidly boosts cellular glutathione levels following a single dose in healthy individuals. Efficacy of GGC against oxidative stress induced by Pseudomonas aeruginosa, which is a common and chronic pathogen infecting lungs of CF patients, remains unassessed. Primary mucocilliary differentiated airway (bronchial and/or nasal) epithelial cells were created from four individuals with CF. Airway oxidative stress and inflammation was induced by P. aeruginosa lipopolysaccharide (LPS). Parameters including global proteomics alterations, cell redox state (glutathione, oxidative stress), pro-inflammatory mediators (IL-8, IDO-1), and cellular health (membrane integrity, stress granule formation, cell metabolic viability) were assayed under six experimental conditions: (1) Mock, (2) LPS-challenged (3) therapeutic, (4) prophylactic (5) therapeutic and prophylactic and (6) GGC alone. Proteomic analysis identified perturbation of several pathways related to cellular respiration and stress responses upon LPS challenge. Most of these were resolved when cells were treated with GGC. While GGC did not resolve LPS-induced IL-8 and IDO-1 activity, it effectively attenuated LPS-induced oxidative stress and stress granule formation, while significantly increasing total intracellular glutathione levels, metabolic viability and improving epithelial cell barrier integrity. Both therapeutic and prophylactic treatments were successful. Together, these findings indicate that GGC has therapeutic potential for treatment and prevention of oxidative stress-related damage to airways in cystic fibrosis.

Introduction Over the last two decades, the outcomes of patients with multiple myeloma (MM), a malignant plasma cells dyscrasia, have dramatically improved. The development and the introduction of the immunomodulatory drugs (IMiDs) which include thalidomide, lenalidomide, and pomalidomide, have contributed significantly to these improvements. Evidence acquisition The IMiDs have been shown a multitude of mechanisms of action, including antiangiogenic, cytotoxic and immunomodulatory. The more recent discoveries that the IMiDs bind to cereblon and thus regulate the ubiquitination of key transcription factors including IKZF1 and IKZF3, have provided new insight about their activities. Evidence synthesis The IMIDs are widely used in the treatment of the different setting of MM patients and particularly lenalidomide represents the backbone in the therapy of newly diagnosed transplant eligible and transplant ineligible patients, in the maintenance setting post-transplant and in the relapsed/refractory setting, while pomalidomide is currently utilized in the relapsed/refractory setting. Conclusions Here the mechanisms of action, the clinical efficacy and the management of side effects are reviewed as well as the new classes of cereblon E3 ligase modulator (CELMoD) and their promising clinical data are described.

To determine if implementation of an automated sepsis screening algorithm with low positive predictive value led to inappropriate resource utilization in emergency department (ED) patients as evidenced by an increased proportion of children with false-positive sepsis screens receiving intravenous (IV) antibiotics.Retrospective cohort study comparing children18 years of age presenting to an ED who triggered a false-positive sepsis alert during 2 different 5-month time periods: a silent alert period when alerts were generated but not visible to clinicians and an active alert period when alerts were visible. Primary outcome was the proportion of patients who received IV antibiotics. Secondary outcomes included proportion receiving IV fluid boluses, proportion admitted to the hospital, and ED length of stay (LOS).Of 1457 patients, 1277 triggered a false-positive sepsis alert in the silent and active alert periods, respectively. In multivariable models, there were no changes in the proportion administered IV antibiotics (27.0% vs 27.6%, aOR 1.1 [0.9,1.3]) or IV fluid boluses (29.7% vs 29.1%, aOR 1.0 [0.8,1.2]). Differences in ED LOS and proportion admitted to the hospital were not significant when controlling for similar changes seen across all ED encounters.An automated sepsis screening algorithm did not lead to changes in the proportion receiving IV antibiotics or IV fluid boluses, department LOS, or the proportion admitted to the hospital for patients with false-positive sepsis alerts.

Changing collective behaviour and supporting non-pharmaceutical interventions is an important component in mitigating virus transmission during a pandemic. In a large international collaboration (Study 1, N = 49,968 across 67 countries), we investigated self-reported factors that associated with people reported adopting public health behaviours (e.g., spatial distancing and stricter hygiene) and endorsed public policy interventions (e.g., closing bars and restaurants) during the early stage of the pandemic (April-May 2020). Respondents who reported identifying more strongly with their nation consistently reported greater engagement in public health behaviours and support for public health policies. Results were similar for representative and non-representative national samples. Study 2 (N = 42 countries) conceptually replicated the central finding using aggregate indices of national identity (obtained using the World Values Survey) and a measure of actual behaviour change during the pandemic (obtained from Google mobility reports). Higher levels of national identification prior to the pandemic predicted lower mobility during the early stage of the pandemic (r = -.40). We discuss the potential implications of links between national identity, leadership, and public health for managing COVID-19 and future pandemics.