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Objective: The true case fatality rate (CFR) of a disease outbreak can only be ascertained after all cases and deaths have been tabulated at the end of the epidemic. We define a metric, the interim case fatality rate (ICFR) which is the incremental change in the ratio of cases to deaths. To examine longitudinal changes in the ICFR of the COVID-19 pandemic and to evaluate the likelihood that the ICFR can predict the final CFR., Methods: Publicly available databases were used to gather data on the number of cases and deaths in Europe and the United States (USA). These data were gathered over the period from Mar.1, 2020 to Aug. 15, 2021, on four regions of the USA and four regions of Europe on a bi-weekly basis. Statistical methods were utilized to evaluate changes over the final month of the study (July 15, 2021 to August 15, 2021). Stability of the ICFR was based on acceptance of the null hypothesis that no significant difference (p>0.05) was observed over that period., Results: In all regions studied, the early months of the pandemic were marked by very high ICFRs. By late 2020, these began to stabilize at levels well below 5%. During the final month of the study, only one (Northeast USA) of the eight regions evaluated showed a statistically significant difference in ICFR. Mean ICFR projections, based on weighted values of cases are 1.8% (95% CI: 1.2% to 2.3%) for the USA and 2.1% (95% CI: 1.5% 2.7% for Europe., Conclusion: After an early peak, very little change was observed in the ICFR, and by summer 2021, the rates had stabilized. Weighted ICFR for all regions may well reflect the final ICFR., (© 2022 by the Association of Clinical Scientists, Inc.)

Recognition and response to non self is essential to development and survival of all organisms. It can occur between individuals of the same species or between different organisms. Fungi are established models for conspecific non self recognition in the form of vegetative incompatibility (VI), a genetically controlled process initiating a programmed cell death (PCD) leading to the rejection of a fusion cell between genetically different isolates of the same species. In Podospora anserina VI is controlled by members of the hnwd gene family encoding for proteins analogous to NOD Like Receptors (NLR) immune receptors in eukaryotes. It was hypothesized that the hnwd controlled VI reaction was derived from the fungal innate immune response. Here we analyze the P. anserina transcriptional responses to two bacterial species, Serratia fonticola to which P. anserina survives and S. marcescens to which P. anserina succumbs, and compare these to the transcriptional response induced under VI conditions. Transcriptional responses to both bacteria largely overlap, however the number of genes regulated and magnitude of regulation is more important when P. anserina survives. Transcriptional responses to bacteria also overlap with the VI reaction for both up or down regulated gene sets. Genes up regulated tend to be clustered in the genome, and display limited phylogenetic distribution. In all three responses we observed genes related to autophagy to be up-regulated. Autophagy contributes to the fungal survival in all three conditions. Genes encoding for secondary metabolites and histidine kinase signaling are also up regulated in all three conditions. Transcriptional responses also display differences. Genes involved in response to oxidative stress, or encoding small secreted proteins are essentially expressed in response to bacteria, while genes encoding NLR proteins are expressed during VI. Most functions encoded in response to bacteria favor survival of the fungus while most functions up regulated during VI would lead to cell death. These differences are discussed in the frame of a multilayered response to non self in fungi.

Objective: To study the impact of methicillin-resistant Staphylococcus aureus (MRSA) surveillance on the incidence of MRSA-related bloodstream infection (BSI) in neonatal intensive care unit (NICU) and to evaluate cost-effectiveness of MRSA surveillance., Study Design: MRSA surveillance policy was introduced in our NICU in April 2008. Pre-MRSA surveillance period (P1, April 2006-March 2008) was compared with the surveillance period (P2, April 2008-April 2010) for MRSA-related BSI (MRSA BSI)., Results: During P1 and P2, 1,576 and 1,512 neonates were enrolled. Of these, 3.8/1,000 and 5.3/1,000 developed MRSA BSI, respectively. During P2, 100% MRSA-related BSI occurred in MRSA-colonized neonates, as compared with zero in noncolonized group (p < 0.0001). Overall, 7 (30%) of the 23 neonates colonized during hospitalization developed MRSA BSI as compared with 1 of the 31 (3%) neonates colonized at admission (p = 0.007). Direct screening cost was $208 per patient. Since 28 neonates had to be screened to detect one colonization, $5,824 estimated per detection, excluding indirect costs., Conclusions: MRSA surveillance may protect non-MRSA colonized neonates from becoming colonized. This is of considerable importance because the acquisition of colonization during hospitalization was associated with a 10-fold increase in risk of developing MRSA BSI. Cost-effectiveness of MRSA surveillance remains debatable and further studies are needed to delineate cost-benefit ratio., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are intracellular receptors that control innate immunity and other biotic interactions in animals and plants. NLRs have been characterized in plant and animal lineages, but in fungi, this gene family has not been systematically described. There is however previous indications of the involvement of NLR-like genes in nonself recognition and programmed cell death in fungi. We have analyzed 198 fungal genomes for the presence of NLRs and have annotated a total of 5,616 NLR candidates. We describe their phylogenetic distribution, domain organization, and evolution. Fungal NLRs are characterized by a great diversity of domain organizations, suggesting frequently occurring combinatorial assortments of different effector, NOD and repeat domains. The repeat domains are of the WD, ANK, and TPR type; no LRR motifs were found. As previously documented for WD-repeat domains of fungal NLRs, TPR, and ANK repeats evolve under positive selection and show highly conserved repeats and repeat length polymorphism, suggesting the possibility of concerted evolution of these repeats. We identify novel effector domains not previously found associated with NLRs, whereas others are related to effector domains of plant or animals NLRs. In particular, we show that the HET domain found in fungal NLRs may be related to Toll/interleukin-1 receptor domains found in animal and plant immune receptors. This description of fungal NLR repertoires reveals both similarities and differences with plant and animals NLR collections, highlights the importance of domain reassortment and repeat evolution and provides a novel entry point to explore the evolution of NLRs in eukaryotes., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Fluconazole prophylaxis is being used efficaciously in the neonatal intensive care unit (NICU) for fungal prophylaxis in very low birth weight and extremely low birth weight (ELBW) neonates. Little is known about the effect of fluconazole prophylaxis on bacterial infections. The purpose of this study was to examine that issue in a subset of ELBW, those weighing ≤900 g at birth. This is a retrospective study conducted in a level III NICU at state-designated children hospital in New Jersey (USA). We examined the data from our records of neonates ≤ 900 g birth weight during the period March 1, 2007-February 28, 2011. Inclusion in the study was all infants ≤ 900 g before (n = 67) and after (n = 81) the institution of fluconazole prophylaxis. Fluconazole prophylaxis was accompanied by a significant decrease in both the rate and number of days of bacterial infections as well as co-infections. We found that the incidence of coagulase-negative Staphylococcus (CONS) decreased from 46.2 to 24.7 % (OR 2.63; 95 % CI 1.31-5.27). Similarly, days of infection also decreased significantly (p < 0.0001). These data suggest that fluconazole prophylaxis may be associated with a reduction in CONS infections in that subset of ELBW neonates.

Background: Simulation in healthcare lacks a dedicated framework and supporting taxonomy for instructional design (ID) to assist educators in creating appropriate simulation learning experiences., Aims: This article aims to fill the identified gap. It provides a conceptual framework for ID of healthcare simulation., Methods: The work is based on published literature and authors' experience with simulation-based education., Results: The framework for ID itself presents four progressive levels describing the educational intervention. Medium is the mode of delivery of instruction. Simulation modality is the broad description of the simulation experience and includes four modalities (computer-based simulation, simulated patient (SP), simulated clinical immersion, and procedural simulation) in addition to mixed, hybrid simulations. Instructional method describes the techniques used for learning. Presentation describes the detailed characteristics of the intervention. The choice of simulation as a learning medium is based on a matrix of simulation relating acuity (severity) to opportunity (frequency) of events, with a corresponding zone of simulation. An accompanying chart assists in the selection of appropriate media and simulation modalities based on learning outcomes., Conclusion: This framework should help educators incorporate simulation in their ID efforts. It also provides a taxonomy to streamline future research and ID efforts in simulation.

Anopheles gambiae mosquitoes are the major vectors of human malaria parasites. However, mosquitoes are not passive hosts for parasites, actively limiting their development in vivo. Our current understanding of the mosquito antiparasitic response is mostly based on the phenotypic analysis of gene knockdowns obtained by RNA interference (RNAi), through the injection or transfection of long dsRNAs in adult mosquitoes or cultured cells, respectively. Recently, RNAi has been extended to silence specifically one allele of a given gene in a heterozygous context, thus allowing to compare the contribution of different alleles to a phenotype in the same genetic background.

The ability of Anopheles gambiae mosquitoes to transmit Plasmodium parasites is highly variable between individuals. However, the genetic basis of this variability has remained unknown. We combined genome-wide mapping and reciprocal allele-specific RNA interference (rasRNAi) to identify the genomic locus that confers resistance to malaria parasites and demonstrated that polymorphisms in a single gene encoding the antiparasitic thioester-containing protein 1 (TEP1) explain a substantial part of the variability in parasite killing. The link between TEP1 alleles and resistance to malaria may offer new tools for controlling malaria transmission. The successful application of rasRNAi in Anopheles suggests that it could also be applied to other organisms where RNAi is feasible to dissect complex phenotypes to the level of individual quantitative trait alleles.

Objective: Increased thyroid-stimulating hormone (TSH) and FT(3) levels are often found in clinically euthyroid obese individuals. Information on thyroid gene expression in human adipose tissue is scarce. The objective of this study was to measure the expression of the TSH receptor (TSHR) and the thyroid hormone receptor (TRalpha1) genes in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in obese individuals and to test the effect of weight loss on these genes., Study Design and Participants: This study is a prospective study involving 107 obese (body mass index (BMI)=46+/-8 kg m(-2), 52 with type 2 diabetes or impaired glucose tolerance) and 12 lean nondiabetic participants. A total of 27 obese patients were restudied 1 year after gastric bypass surgery. Total RNA was extracted from SAT and VAT obtained at baseline from all participants, and from SAT in obese patients post surgery., Results: Circulating TSH and FT(3) levels were 170 and 36%, respectively, higher in obese patients than in controls. In SAT, TSHR and TRalpha1 were reduced in the obese by 67 and 33%, respectively, regardless of glucose tolerance. A similar trend was found in VAT. Post surgery, a BMI decrease of 33% was associated with a decrease in TSH and FT(3) levels and with a 150 and 70% increase in SAT of TSHR and TRalpha1, respectively., Conclusion: In both subcutaneous and visceral fat, the thyroid gene expression (especially TSHR) is reduced in obesity. The reversal of these changes with major weight loss and the reciprocal changes in plasma TSH and FT(3) levels suggest a role for adipocytes in the regulation of TSH and thyroid hormones.

Purpose: To assess the diagnostic value of MR cholangiography (MRC) for detecting common bile duct (CBD) stones in candidates for laparoscopic cholecystectomy (LC)., Material and Methods: A series of 95 selected patients with gallstones and suspected CBD lithiasis (abnormal serum liver tests and/or CBD size > or = 6.5 mm at US) were referred to our institution for MRC, before LC. MRC was performed on a 0.5 T magnet through a non-breath-hold, respiratory-triggered, fat-suppressed, thin-slab, heavily T2-weighted fast spin-echo sequence and through a breath-hold, thick-slab, single-shot T2-weighted sequence in the coronal plane. Axial T1- and T2-weighted sequences were first obtained. Two observers in conference reviewed source images and maximum intensity projections to determine the presence or absence of choledocholithiasis. MR findings were compared with endoscopic retrograde cholangiography and intraoperative cholangiography (IOC); IOC was always performed during LC., Results: CBD calculi (single or multiple) were identified in 41 out of 95 patients (43%). Two false-positive and 4 false-negative cases were found on MRC. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of MRC for choledocholithiasis were 90%, 96%, 94%, 95%, and 93%, respectively., Conclusion: MRC is a highly effective diagnostic modality for evaluation of patients with risk factors for CBD stones prior to LC.

Background and Objectives: In adult acute myeloid leukemia (AML), a variety of clinical and biological parameters have been examined for their potential value in predicting treatment response. Early response to induction therapy could be an important prognostic factor in this disease., Design and Methods: We studied the relationship between reduced blasts in bone marrow aspirate on the 14th day (BMA14th) of induction chemotherapy and treatment outcome in 198 adult AML patients of whom 124 were < 60 years old (group A) and 74 > or = 60 years old (group B). Receiver operating characteristic curve analysis was used to assess the prognostic performance of BMA14th. Using the percentages of blasts of < or = 22% and < or = 15% as criteria for predicting treatment outcome gave the highest accuracy in terms of sensitivity and specificity in groups A and B, respectively., Results: In group A, of 97 patients with a BMA14th < or = 22%, 77 (79%) achieved complete remission (CR), whereas of 27 patients with a BMA14th > 22%, 22 (81%) were non-responders (NR) (p < 0.0001). The test sensitivity and specificity were 93.9% and 71.4%, respectively. In group B, of 27 patients with a BMA14th < or = 15%, 18 (67%) achieved CR, whereas of 47 patients with a BMA14th >15%, 38 (81%) were NR (p = 0.0001). The test sensitivity and specificity were 66.7% and 80.9%, respectively., Interpretation and Conclusions: Our data suggest that BMA14th may be a predictive test for CR, helping to identify NR patients early in their disease. Further studies are needed to establish the practical implications of the results of our study.

To evaluate ultrasound (US) versus conventional plain film radiography (CPF) in the detection of pneumoperitoneum, 30 patients with postsurgical pneumoperitoneum and a control group of 22 patients were studied using US and CPF. Sonograms and radiograms were obtained while patients were supine and in left lateral decubitus. The two orthogonal plain films of the abdomen were acquired with a horizontal X-ray beam. The epigastric region and right hypochondrium were investigated with ultrasonography. Four experienced, blinded radiologists examined 160 sonograms and 104 radiograms. Statistical analysis yielded a sensitivity of 75.7% for radiography versus 86% for ultrasonography, a specificity of 89.2% versus 83.5%, an accuracy of 81.5% versus 85%, a positive predictive value of 90.2% versus 87%, and a negative predictive value of 76.2% versus 83.5%, respectively. US could therefore be considered a reliable alternative imaging technique in the detection of pneumoperitoneum.