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Large language models (LLMs) continue to exhibit noteworthy capabilities across a spectrum of areas, including emerging proficiencies across the health care continuum. Successful LLM implementation and adoption depend on digital readiness, modern infrastructure, a trained workforce, privacy, and an ethical regulatory landscape. These factors can vary significantly across health care ecosystems, dictating the choice of a particular LLM implementation pathway. This perspective discusses 3 LLM implementation pathways—training from scratch pathway (TSP), fine-tuned pathway (FTP), and out-of-the-box pathway (OBP)—as potential onboarding points for health systems while facilitating equitable adoption. The choice of a particular pathway is governed by needs as well as affordability. Therefore, the risks, benefits, and economics of these pathways across 4 major cloud service providers (Amazon, Microsoft, Google, and Oracle) are presented. While cost comparisons, such as on-demand and spot pricing across the cloud service providers for the 3 pathways, are presented for completeness, the usefulness of managed services and cloud enterprise tools is elucidated. Managed services can complement the traditional workforce and expertise, while enterprise tools, such as federated learning, can overcome sample size challenges when implementing LLMs using health care data. Of the 3 pathways, TSP is expected to be the most resource-intensive regarding infrastructure and workforce while providing maximum customization, enhanced transparency, and performance. Because TSP trains the LLM using enterprise health care data, it is expected to harness the digital signatures of the population served by the health care system with the potential to impact outcomes. The use of pretrained models in FTP is a limitation. It may impact its performance because the training data used in the pretrained model may have hidden bias and may not necessarily be health care–related. However, FTP provides a balance between customization, cost, and performance. While OBP can be rapidly deployed, it provides minimal customization and transparency without guaranteeing long-term availability. OBP may also present challenges in interfacing seamlessly with downstream applications in health care settings with variations in pricing and use over time. Lack of customization in OBP can significantly limit its ability to impact outcomes. Finally, potential applications of LLMs in health care, including conversational artificial intelligence, chatbots, summarization, and machine translation, are highlighted. While the 3 implementation pathways discussed in this perspective have the potential to facilitate equitable adoption and democratization of LLMs, transitions between them may be necessary as the needs of health systems evolve. Understanding the economics and trade-offs of these onboarding pathways can guide their strategic adoption and demonstrate value while impacting health care outcomes favorably.

Purpose: Many youth with medical conditions also have co-occurring mental health concerns. Limited attention has been given to the mental health transition needs of these youth. We explore bringing transition readiness assessment into the mental health care of youth with co-occurring disorders. Design and Methods: Mental health transition readiness was assessed in transition-aged youth seen in a hospital-based specialty mental health clinic for youth with co-occurring medical and mental health conditions. Patients and/or parents reported on their awareness of transition policies and experiences. Clinicians formally assessed youth mental health transition readiness using the TRXANSITION Index. Results: Only 46.53 % of families knew about the clinic’s transition policy. Less than 1/3 reported their provider ever mentioning transition and only 6.93 % knew the deadline for transfer to adult care. Few patients had a transition goal in their treatment plan, even when required by the payor. By assessing transition readiness, clinicians were able to identify deficits in need of remediation in 95 % of patients. Transition readiness was highest in the following domains of the TRXANSITION Index: Ongoing support (85.15 %), Adherence (78.38 %), and Trade/School (71.29 %). Transition readiness was lowest in New Providers (30.94 %), Rx/Medications (37.99 %), and Insurance (42.57 %). Few knew when their current health insurance coverage would end (10.89 %) or how to get health insurance coverage when they became an adult (11.88 %). Mental health transition readiness and medical condition transition readiness did not differ in a sub-sample of youth with available data, t(14) = −1.33, p =.20. Conclusion: Mental health transition readiness is suboptimal in youth with co-occurring mental health and medical conditions. Findings point to specific targets for future intervention to improve patient mental health transition readiness and patient/family awareness of transition practices.

Randomized controlled trials (RCTs) are an increasingly common research design for evaluating the effectiveness of community college (CC) interventions. However, when planning an RCT evaluation of a CC intervention, there is limited empirical information about what sized effects an intervention might reasonably achieve, which can lead to under- or over-powered studies. Relatedly, when interpreting results from an evaluation of a CC intervention, there is limited empirical information to contextualize the magnitude of an effect estimate relative to what sized effects have been observed in past evaluations. We provide empirical benchmarks to help with the planning and interpretation of community college evaluations. To do so, we present findings across well-executed RCTs of 39 CC interventions that are part of a unique dataset known as The Higher Education Randomized Controlled Trials (THE-RCT). The analyses include 21,163–65,604 students (depending on outcome and semester) enrolled in 44 institutions. Outcomes include enrollment, credits earned, and credential attainment. Effect size distributions are presented by outcome and semester. For example, across the interventions examined, the mean effect on cumulative credits earned after three semesters is 1.14 credits. Effects around 0.16 credits are at the 25th percentile of the distribution. Effects around 1.69 credits are at the 75th percentile of the distribution. This work begins to provide empirical benchmarks for planning and interpreting effects of CC evaluations. A public database with effect sizes is available to researchers (https://www.mdrc.org/the-rct-empirical-benchmarks).

Abstract Background During the Syrian civil war, patients were initially treated on-site in Syria and later transferred to medical centers in Israel. Relevant details concerning the exact nature of injury and medical/surgical care received in Syria were unavailable to clinicians in Israel. Many of these patients required abdominal re-exploration for obvious or suspected problems related to their injury. Our aim is to present our approach to abdominal trauma patients who survived initial on-site surgery and needed subsequent abdominal re-exploration abroad, in our medical center. Methods Clinical data from all medical records were retrospectively analyzed. Each patient underwent total body computerized tomography on arrival, revealing diverse multi-organ trauma. We divided the patient population who had abdominal trauma into 4 sub-groups according to the location in which abdominal surgical intervention was performed (abdominal surgery performed only in Syria, surgery in Syria and subsequent re-laparotomy in Israel, abdominal surgery only in Israel, and management of patients without abdominal surgical intervention). We focused on missed injuries and post-operative complications in the re-laparotomy sub-group. Results By July 2018, 1331 trauma patients had been admitted to our hospital, of whom 236 had suffered abdominal trauma. Life-saving abdominal intervention was performed in 138 patients in Syria before arrival to our medical center. A total of 79 patients underwent abdominal surgery in Israel, of whom 46 (33%) required re-laparotomy. The absence of any communication between the surgical teams across the border markedly affected our medical approach. Indications for re-exploration included severe peritoneal inflammation, neglected or overlooked abdominal foreign bodies, hemodynamic instability and intestinal fistula. Mortality occurred in 37/236 patients, with severe abdominal trauma as the main cause of fatality in 10 of them (4.2%), usually following urgent re-laparotomy. Conclusions Lack of information about the circumstances of injury in an environment of catastrophe in Syria at the time and the absence of professional communication between the surgical teams across the border markedly dictated our medical approach. Our concerns were that some patients looked deceptively stable while others had potentially hidden injuries. We had no information on who had had definitive versus damage control surgery in Syria. The fact that re-operation was not performed by the same team responsible for initial abdominal intervention also posed major diagnostic challenges and warranted increased clinical suspicion and a change in our standard medical approach.

Preterm infants bypass the crucial in utero period of brain development and are at increased risk of malnutrition. We aimed to determine if their nutritional status is associated with brain tissue volumes at term equivalent age (TEA), applying recently published malnutrition guidelines for preterm infants. We performed a single center retrospective chart review of 198 infants < 30 weeks’ gestation between 2018 and 2021. We primarily analyzed the relationship between the manually obtained neonatal MR-based brain tissue volumes with the maximum weight and length z-score. Significant positive linear associations between brain tissue volumes at TEA and weight and length z-scores were found (p < 0.05). Recommended nutrient intake for preterm infants is not routinely achieved despite efforts to optimize nutrition. Neonatal MR-based brain tissue volumes of preterm infants could serve as objective, quantitative and reproducible surrogate parameters of early brain development. Nutrition is a modifiable factor affecting neurodevelopment and these results could perhaps be used as reference data for future timely nutritional interventions to promote optimal brain volume.

Abstract Background Enterobacter cloacae complex is a group of common opportunistic pathogens on neonatal intensive care units. Active microbiological screening to guide empirical antimicrobial treatment or to detect transmission events is recommended in high-risk preterm neonates. A rise in colonization with E. cloacae complex was observed in a German perinatal centre. The aim of this study was to evaluate the performance of different typing techniques using whole genome sequencing (WGS) as a reference. Methods Enterobacter cloacae complex isolates from clinical and screening specimens with an epidemiological link to the neonatal intensive care units were further assessed. Identification and antibiotic susceptibility testing was performed by a combination of VITEK2 (bioMérieux) and MALDI-TOF (Bruker Daltonics), followed by RAPD/rep-PCR and PFGE (XbaI). Retrospectively, all isolates were analyzed by Fourier-transform infrared (FTIR) spectroscopy (IR Biotyper, Bruker Daltonics). Whole genome sequencing with SNP-based clustering was used as the reference method. Furthermore, resistome analysis, sequence type and species identification were derived from the WGS data. Transmission analysis was based on epidemiological and typing data. Results Between September 2017 and March 2018 32 mostly preterm neonates were found to be colonized with E. cloacae complex and 32 isolates from 24 patients were available for further typing. RAPD/rep-PCR and PFGE showed good concordance with WGS whereas FTIR displayed mediocre results [adjusted rand index (ARI) = 0.436]. A polyclonal increase and two dominant and overlapping clonal clusters of two different E. hormaechei subspecies were detected. Overall, four different species were identified. Genotyping confirmed third-generation cephalosporin resistance development in isolates of the same patient. During the six-month period several infection prevention interventions were performed and no E. cloacae complex isolates were observed during the following months. Conclusions Interpretation of the microbiological results alone to detect transmission events is often challenging and bacterial typing is of utmost importance to implement targeted infection control measures in an epidemic occurrence of E. cloacae complex. WGS is the most discriminatory method. However, traditional methods such as PFGE or RAPD/rep-PCR can provide reliable and quicker results in many settings. Furthermore, research is needed to quickly identify E. cloacae complex to the species level in the microbiological laboratory.

Summary: Background: Infants born extremely preterm (

Purpose: Few examples of hospital-wide transition programs have been presented in the literature and to date, we have no data on the clinical and financial operations of such services. Design and methods: A transition clinic, guided by Got Transition’s Six Core Elements, was created for youth with moderate-to-high medical and psychosocial complexity (per Bob’s Levels of Social Support scale). The clinic visit and transition readiness assessment (UNC TRxANSITION Index) were billed fee-for-service or under a bundled payment managed care model. We present data on patient characteristics, clinic operations, finances, and patient/parent satisfaction (online survey) in the clinic’s first year of operation (March 2021-February 2022). Results: In Year 1, the clinic completed 115 appointments (113 unique patients). Most patients were older adolescents/young adults (M = 19.7 ± 1.8 years) and nearly half were Latinx. Patients presented with several complex medical needs including coordination of care across multiple subspecialties, high health care utilization, decision-making determinations, behavioral and mental health concerns, and resource needs. Implementation of the Six Core elements was high (range 99.1%−100%). The average billed per patient was $498 (in 2021–2022 USD). Considering paid and unpaid office visits, we collected an average of 31.6 cents on the dollar. Almost 80% of office visit claims and 21.9–33.3% of transition readiness assessments were paid by insurers. Patient/parent satisfaction was high, with over 90% of families reporting that they learned something, knew one thing they could do to improve transition readiness, and were able to get their questions asked and answered. Conclusions: Transition clinics may never be fully self-sustainable given low collection rates and inability to capture extra charge codes related to chronic care management and transitional care. However, our collection rate was on-par with the collection rate for our hospital’s subspecialty clinics and we show it is possible to receive some funding from insurers.

Abstract Background This study aims to show the long-time stability of straight and tilted implants loaded immediately with a provisional resin bridge followed by a definitive prosthodontic rehabilitation in edentulous jaws despite difficult hygiene conditions postoperatively. Results This study included the participation of 23 patients and the restoration of 170 dental implants in 32 edentulous jaws. Patient data was analyzed from the start of treatment with a minimum follow-up period of 6 years in order to determine long-term implant success rates. However, the age of patients at time of surgery significantly affected the BOP to the detriment of younger patients (median 62 years old). Conclusion Although there was a higher risk of implant failure due to general disease, all the implants in this study survived successfully. As a replacement for a complete dental arch, the reduced number of implants in combination with the avoidance of augmentations reduces treatment costs. The immediate fixed prosthetic restoration of edentulous jaws thus represents a reliable therapeutic alternative to a two- to three-stage procedure. Optimized aftercare including professional teeth cleaning (PTC) (at least twice a year) can minimize the anamnestic effect of smoking, diabetes mellitus, and osteoporosis on BOP and possible bone loss.

Abstract Background Various methods exist for statistical inference about a prevalence that consider misclassifications due to an imperfect diagnostic test. However, traditional methods are known to suffer from truncation of the prevalence estimate and the confidence intervals constructed around the point estimate, as well as from under-performance of the confidence intervals’ coverage. Methods In this study, we used simulated data sets to validate a Bayesian prevalence estimation method and compare its performance to frequentist methods, i.e. the Rogan-Gladen estimate for prevalence, RGE, in combination with several methods of confidence interval construction. Our performance measures are (i) error distribution of the point estimate against the simulated true prevalence and (ii) coverage and length of the confidence interval, or credible interval in the case of the Bayesian method. Results Across all data sets, the Bayesian point estimate and the RGE produced similar error distributions with slight advantages of the former over the latter. In addition, the Bayesian estimate did not suffer from the RGE’s truncation problem at zero or unity. With respect to coverage performance of the confidence and credible intervals, all of the traditional frequentist methods exhibited strong under-coverage, whereas the Bayesian credible interval as well as a newly developed frequentist method by Lang and Reiczigel performed as desired, with the Bayesian method having a very slight advantage in terms of interval length. Conclusion The Bayesian prevalence estimation method should be prefered over traditional frequentist methods. An acceptable alternative is to combine the Rogan-Gladen point estimate with the Lang-Reiczigel confidence interval.

Nontuberculous mycobacteria (NTM) are an emerging cause of infections, including chronic lymphadenitis in children. To identify risk factors for NTM lymphadenitis, particularly complicated disease, we collected epidemiologic, clinical, and microbiological data on 138 cases of NTM lymphadenitis in children across 13 centers in Germany and Austria. We assessed lifestyle factors but did not identify specific risk behaviors. We noted that more cases of NTM lymphadenitis occurred during cold months than during warm months. Moreover, we noted female sex and age

Abstract Background Motor and cognitive deficits and consequently mobility problems are common in geriatric patients. The currently available methods for diagnosis and for the evaluation of treatment in this vulnerable cohort are limited. The aims of the ComOn (COgnitive and Motor interactions in the Older populatioN) study are (i) to define quantitative markers with clinical relevance for motor and cognitive deficits, (ii) to investigate the interaction between both motor and cognitive deficits and (iii) to assess health status as well as treatment outcome of 1000 geriatric inpatients in hospitals of Kiel (Germany), Brescia (Italy), Porto (Portugal), Curitiba (Brazil) and Bochum (Germany). Methods This is a prospective, explorative observational multi-center study. In addition to the comprehensive geriatric assessment, quantitative measures of reduced mobility and motor and cognitive deficits are performed before and after a two week’s inpatient stay. Components of the assessment are mobile technology-based assessments of gait, balance and transfer performance, neuropsychological tests, frailty, sarcopenia, autonomic dysfunction and sensation, and questionnaires to assess behavioral deficits, activities of daily living, quality of life, fear of falling and dysphagia. Structural MRI and an unsupervised 24/7 home assessment of mobility are performed in a subgroup of participants. The study will also investigate the minimal clinically relevant change of the investigated parameters. Discussion This study will help form a better understanding of symptoms and their complex interactions and treatment effects in a large geriatric cohort.

Background: The extent to which children and adolescents contribute to SARS-CoV-2 transmission remains not fully understood. Novel high-capacity testing methods may provide real-time epidemiological data in educational settings helping to establish a rational approach to prevent and minimize SARS-CoV-2 transmission. We investigated whether pooling of samples for SARS-CoV-2 detection by RT-qPCR is a sensitive and feasible high-capacity diagnostic strategy for surveillance of SARS-CoV-2 infections in schools. Methods: In this study, students and school staff of 14 educational facilities in Germany were tested sequentially between November 9 and December 23, 2020, two or three times per week for at least three consecutive weeks. Participants were randomized for evaluation of two different age adjusted swab sampling methods (oropharyngeal swabs or buccal swabs compared to saliva swabs using a ‘lolli method’). Swabs were collected and pooled for SARS-CoV-2 RT-qPCR. Individuals of positive pooled tests were retested by RT-qPCR the same or the following day. Positive individuals were quarantined while the SARS-CoV-2 negative individuals remained in class with continued pooled RT-qPCR surveillance. The study is registered with the German Clinical Trials register (registration number: DRKS00023911). Findings: 5,537 individuals were eligible and 3970 participants were enroled and included in the analysis. In students, a total of 21,978 swabs were taken and combined in 2218 pooled RT-qPCR tests. We detected 41 positive pooled tests (1·8%) leading to 36 SARS-CoV-2 cases among students which could be identified by individual re-testing. The cumulative 3-week incidence for primary schools was 564/100,000 (6/1064, additionally 1 infection detected in week 4) and 1249/100,000 (29/2322) for secondary schools. In secondary schools, there was no difference in the number of SARS-CoV-2 positive students identified from pooled oropharyngeal swabs compared to those identified from pooled saliva samples (lolli method) (14 vs. 15 cases; 1·3% vs. 1·3%; OR 1.1; 95%-CI 0·5–2·5). A single secondary school accounted for 17 of 36 cases (47%) indicating a high burden of asymptomatic prevalent SARS-CoV-2 cases in the respective school and community. Interpretation: In educational settings, SARS-CoV-2 screening by RT-qPCR-based pooled testing with easily obtainable saliva samples is a feasible method to detect incident cases and observe transmission dynamics. Funding: Federal Ministry of education and research (BMBF; Project B-FAST in “NaFoUniMedCovid19”; registration number: 01KX2021).

The objective of this paper is to show how topic modeling and concept mapping can be used to conduct a literature review in a new domain. The paper makes two contributions. First, it uses topic modeling to map out the literature in the new domain. Topic modeling provides an alternative to manual clustering of articles and allows the identification of non-obvious connections between ideas expressed in a collection of articles. Second, it identifies the underlying concepts in the new domain and their relationships by creating a concept map from the extracted topics . As a case study, the paper reviews the recent literature in the intersection of managed security services and small businesses. In particular, it identifies elements of the managed security services concept as it applies to small businesses. The audience of the paper includes anyone who is exploring a new domain by reviewing the literature, and in particular, students, researchers, and members of industrial R&D projects.

Objective: Two-Thumb(TT) technique provides superior quality chest compressions compared with Two-Finger(TF) in an instrumented infant manikin. Whether this translates to differences in blood flow, such as carotid arterial blood flow(CABF), has not been evaluated. We hypothesized that TT-CPR generates higher CABF and Coronary Perfusion Pressure(CPP) compared with TF-CPR in a neonatal swine cardiac arrest model. Methods: Twelve anesthetized & ventilated piglets were randomized after 3 min of untreated VF to receive either TT-CPR or TF-CPR by PALS certified rescuers delivering a compression rate of 100/min. The primary outcome, CABF, was measured using an ultrasound transonic flow probe placed on the left carotid artery. CPP was calculated and end-tidal CO2(ETCO2) was measured during CPR. Data(mean ± SD) were analyzed and p-value ≤0.05 was considered statistically significant. Results: Carotid artery blood flow (% of baseline) was higher in TT-CPR (66.2 ± 35.4%) than in the TF-CPR (27.5 ± 10.6%) group, p = 0.013. Mean CPP (mm Hg) during three minutes of chest compression for TT-CPR was 12.5 ± 15.8 vs. 6.5 ± 6.7 in TF-CPR, p = 0.41 and ETCO2 (mm Hg) was 29.0 ± 7.4 in TT-CPR vs. 20.7 ± 5.8 in TF-CPR group, p = 0.055. Conclusion: TT-CPR achieved more than twice the CABF compared with TF-CPR in a piglet cardiac arrest model. Although CPP and ETCO2 were higher during TT-CPR, these parameters did not reach statistical significance. This study provides direct evidence of increased blood flow in infant swine using TT-CPR and further supports that TT chest compression is the preferred method for CPR in infants.

Abstract Background Pediatric oncology patients have high rates of hospital readmission but there is a dearth of research into risk factors for unplanned 30‐day readmissions among this high‐risk population. Aim In this study, we built a statistical model to provide insight into risk factors of unplanned readmissions in this pediatric oncology. Methods We retrieved 32 667 encounters from 10 418 pediatric patients with a neoplastic condition from 16 hospitals in the Cerner Health Facts Database and built a mixed‐effects model with patients nested within hospitals for inference on 75% of the data and reserved the remaining as an independent test dataset. Results The mixed‐effects model indicated that patients with acute lymphoid leukemia (in relapse), neuroblastoma, rhabdomyosarcoma, or bone/cartilage cancer have increased odds of readmission. The number of cancer medications taken by the patient and the administration of chemotherapy were associated with increased odds of readmission for all cancer types. Wilms Tumor had a significant interaction with administration of chemotherapy, indicating that the risk due to chemotherapy is exacerbated in patients with Wilms Tumor. A second two‐way interaction between recent history of chemotherapy treatment and infections was associated with increased odds of readmission. The area under the receiver operator characteristic curve (and corresponding 95% confidence interval) of the mixed‐effects model was 0.714 (0.702, 0.725) on the independent test dataset. Conclusion Readmission risk in oncology is modified by the specific type of cancer, current and past administration of chemotherapy, and increased health care utilization. Oncology‐specific models can provide decision support where model built on other or mixed population has failed.

Schistosomiasis is a neglected tropical disease caused by blood flukes of the genus Schistosoma. In silico screenings of compounds for the identification of novel anti-parasitic drug candidates have received considerable attention in recent years, including the screening of natural compounds. For the first time, we investigated molecules from insects, a rather neglected source in drug discovery, in an in silico screening approach to find novel antischistosomal compounds. Based on the Dictionary of Natural Products (DNP), we created a library of 1327 insect compounds suitable for molecular docking. A structure-based virtual screening against the crystal structure of a known druggable target in Schistosoma mansoni, the thioredoxin glutathione reductase (SmTGR), was performed. The top ten compounds predominantly originated from beetles and were predicted to interact particularly with amino acids in the doorstop pocket of SmTGR. For one compound from a jewel beetle, buprestin H, we tested and confirmed antischistosomal activity against adult and juvenile parasites in vitro. At concentrations with anti-parasitic activity, we could also exclude any unspecific cytotoxic activity against human HepG2 cells. This study highlights the potential of insect molecules for the identification of novel antischistosomal compounds. Our library of insect-derived molecules could serve not only as basis for future in silico screenings against additional target proteins of schistosomes, but also of other parasites.

Recent DNA-based studies have shown that the built environment is surprisingly rich in fungi. These indoor fungi – whether transient visitors or more persistent residents – may hold clues to the rising levels of human allergies and other medical and building-related health problems observed globally. The taxonomic identity of these fungi is crucial in such pursuits. Molecular identification of the built mycobiome is no trivial undertaking, however, given the large number of unidentified, misidentified, and technically compromised fungal sequences in public sequence databases. In addition, the sequence metadata required to make informed taxonomic decisions – such as country and host/substrate of collection – are often lacking even from reference and ex-type sequences. Here we report on a taxonomic annotation workshop (April 10–11, 2017) organized at the James Hutton Institute/University of Aberdeen (UK) to facilitate reproducible studies of the built mycobiome. The 32 participants went through public fungal ITS barcode sequences related to the built mycobiome for taxonomic and nomenclatural correctness, technical quality, and metadata availability. A total of 19,508 changes – including 4,783 name changes, 14,121 metadata annotations, and the removal of 99 technically compromised sequences – were implemented in the UNITE database for molecular identification of fungi (https://unite.ut.ee/) and shared with a range of other databases and downstream resources. Among the genera that saw the largest number of changes were Penicillium, Talaromyces, Cladosporium, Acremonium, and Alternaria, all of them of significant importance in both culture-based and culture-independent surveys of the built environment.

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

In this study, the attachment of microcapsules on the membrane surface and its influence on the flow field for a cross-flow membrane setup are investigated. The microcapsules were placed on the top layer of the membrane. The overall purpose of this modification was the prevention of membrane biofouling. Therefore, in a first step, the influence of such a combination on the fluid flow was investigated using computational fluid dynamics (CFD). Here, different properties, which are discussed as indicators for biofouling in the literature, were considered. In parallel, different fixation strategies for the microcapsules were experimentally tested. Two different methods to add the microcapsules were identified and further investigated. In the first method, the microcapsules are glued to the membrane surface, whereas in the second method, the microcapsules are added during the membrane fabrication. The different membrane modifications were studied and compared using CFD. Therefore, virtual geometries mimicking the real ones were created. An idealized virtual geometry was added to the comparison. Results from the simulation were fed back to the experiments to optimize the combined membrane. For the presented setup, it is shown that the glued configuration provides a lower transmembrane pressure than the configuration where microcapsules are added during fabrication.

BackgroundPsychological distress is common in patients with cardiovascular disease and negatively impacts outcome.HypothesisPsychological distress is high in acute high risk cardiac patients eligible for a WCD, and associated with low quality of life. Distress is aggravated by WCD.MethodsConsecutive patients eligible for a WCD were included in the prospective, multicenter "Cologne Registry of External Defibrillator" registry. Quality of life (Short Form-12), depressive symptoms (Beck-Depression Inventory II) and anxiety (State Trait Anxiety Inventory) were assessed at enrollment and 6-weeks, and associations with WCD prescription were analyzed.Results123 patients (mean [SD] age 59 [± 14] years, 75% male) were included, 85 (69%) of whom received a WCD. At enrollment 21% showed clinically significant depressive symptoms and 52% anxiety symptoms, respectively. At 6 weeks, depressive and anxious symptoms significantly decreased to 7% and 25%, respectively. Depressive symptoms at enrollment and changes at 6 weeks showed significant associations with health-related quality of life, whereas anxious symptoms did not. There was a trend for better improvement of depression scores in patients with WCD (mean [SD] change in score points: -4.1 [6.1] vs -1.8 [3.9]; p = 0.09), whereas change of the anxiousness score was not different (-4.6 [9.5]) vs -3.7 [9.1], p = 0.68).ConclusionIn patients eligible for a WCD, depressive and anxiety symptoms were initially common and depressive symptoms showed a strong association with reduced health-related quality of life contributing to their clinical relevance. WCD recipients showed at least similar improvement of depression and anxiety at 6 weeks when compared to non recipients.

Bacteria of the genus Campylobacter are an important cause of human illness worldwide. Campylobacter infections are expressed as gastroenteritis and can lead to severe sequelae like reactive arthritis, Guillain-Barré syndrome, irritable bowel syndrome and inflammatory bowel disease. In Germany, Campylobacter-associated gastroenteritis cases are notifiable but there is no reporting obligation for the sequelaes and the disease burden is clearly underestimated. The aim of our study was to quantify reliably the current disease burden of all Campylobacter spp.-associated diseases for Germany with the method of disability-adjusted life years (DALYs). DALYs combine mortality and morbidity in a single summary measure, whereby one DALY represents the loss of one year in full health. For acute gastroenteritis, we estimated 967 DALYs of which only 484 DALYs were detected within the reporting system. Overall, we estimated that 8811 DALYs were caused by the campylobacter-related diseases known so far. 98% of the DALYs were associated with morbidity and 2% with mortality. Mortality was caused by the health outcomes Gastroenteritis and Guillain-Barré syndrome exclusively.

This study aimed to estimate the disease burden of methylmercury for children born in Germany in the year 2014. Humans are mainly exposed to methylmercury when they eat fish or seafood. Prenatal methylmercury exposure is associated with IQ loss. To quantify this disease burden, we used Monte Carlo simulation to estimate the incidence of mild and severe mental retardation in children born to mothers who consume fish based on empirical data. Subsequently, we calculated the disease burden with the disability-adjusted life years (DALY)-method. DALYs combine mortality and morbidity in one measure and quantify the gap between an ideal situation, where the entire population experiences the standard life expectancy without disease and disability, and the actual situation. Thus, one DALY corresponds to the loss of one year of life in good health. The methylmercury-induced burden of disease for the German birth cohort 2014 was an average of 14,186 DALY (95% CI 12,915-15,440 DALY). A large majority of the DALYs was attributed to morbidity as compared to mortality. Of the total disease burden, 98% were attributed to mild mental retardation, which only leads to morbidity. The remaining disease burden was a result of severe mental retardation with equal proportions of premature death and morbidity.

Mashups enable end-users to "mix and match" data and services available on the web to create applications. Their creation is supported by a complex ecosystem of i) data providers who offer open APIs to users, ii) users who combine APIs into mashups, and iii) platforms, such as the ProgrammableWeb or Mashape, that facilitate the construction and publication of mashups. In this article, we argue that the evolution of the mashup ecosystem can be explained in terms of ecosystem niches anchored around hub or keystone APIs. The members of a niche are focused on an area of specialization (e.g., mapping applications) and contribute their knowledge to the value proposition of the ecosystem as a whole. To demonstrate the formation of niches in the mashup ecosystem, we model groups of related mashups as species, and we reconstruct the evolution of mashup species through phylogenetic analysis.

Open source software has evolved from being an effort driven by a collective of volunteers to become an integral part of commercial software. Constant demands for new features besides maintaining product quality made companies seek open source as an answer for these demands. These growing demands brought with them control of quality, architecture, contribution management, and community management. This article explores the governance strategies adopted by open source software projects to manage the quality of complements (such as plug-ins that extend a platform's functionality) developed by community members outside the core team. The outcomes of the research contribute to our understanding of the strategies followed by different open source platform owners (the open source project initiators) to manage external innovation in the case of platform extensions in two areas: i) governance models and ii) regulatory tools.

The field of technology entrepreneurship is in its infancy when compared to other fields such as economics and management. Articles on technology entrepreneurship have been published in at least 62 journals, of which only 18 contribute to technology innovation management or entrepreneurship. Less than a handful of these 62 journals are considered to be "good" journals and none can claim a leadership position in technology entrepreneurship. The purpose of this article is to provide an overview of the 20 journal articles published in the February, March, April, and May 2012 issues of the Technology Innovation Management Review (TIM Review).

User frustrations are an excellent source of new product ideas. Starting with this observation, this article describes an approach that entrepreneurs can use to discover business opportunities. Opportunity discovery starts with a problem that the user has, but may not be able to articulate. User-centered design techniques can help elicit those latent needs. The entrepreneur should then try to understand how users are solving their problem today, before proposing a solution that draws on the unique skills and technical capabilities available to the entrepreneur. Finally, an in-depth understanding of the user allows the entrepreneur to hone in on the points of difference and resonance that are the foundation of a strong customer value proposition.

Where software product development occurs is shifting from single companies to groups or collectives of companies. In this article, we retrace the evolution of how software product development is organized and then offer insights into the economic motivation for collectives, which will be relevant to companies considering joining a software product development collective. Building on the literature on software product line economics, we identify three factors affecting the economics of collectives (level of contribution, number of members, and diversity of use), and develop a model that links those factors to three economic outcomes (time, quality, and cost). This model can be used by potential members when deciding whether or not to join a collective.

Molecular diversity surveys have demonstrated that aquatic fungi are highly diverse, and that they play fundamental ecological roles in aquatic systems. Unfortunately, comparative studies of aquatic fungal communities are few and far between, due to the scarcity of adequate datasets. We combined all publicly available fungal 18S ribosomal RNA (rRNA) gene sequences with new sequence data from a marine fungi culture collection. We further enriched this dataset by adding validated contextual data. Specifically, we included data on the habitat type of the samples assigning fungal taxa to ten different habitat categories. This dataset has been created with the intention to serve as a valuable reference dataset for aquatic fungi including a phylogenetic reference tree. The combined data enabled us to infer fungal community patterns in aquatic systems. Pairwise habitat comparisons showed significant phylogenetic differences, indicating that habitat strongly affects fungal community structure. Fungal taxonomic composition differed considerably even on phylum and class level. Freshwater fungal assemblage was most different from all other habitat types and was dominated by basal fungal lineages. For most communities, phylogenetic signals indicated clustering of sequences suggesting that environmental factors were the main drivers of fungal community structure, rather than species competition. Thus, the diversification process of aquatic fungi must be highly clade specific in some cases.The combined data enabled us to infer fungal community patterns in aquatic systems. Pairwise habitat comparisons showed significant phylogenetic differences, indicating that habitat strongly affects fungal community structure. Fungal taxonomic composition differed considerably even on phylum and class level. Freshwater fungal assemblage was most different from all other habitat types and was dominated by basal fungal lineages. For most communities, phylogenetic signals indicated clustering of sequences suggesting that environmental factors were the main drivers of fungal community structure, rather than species competition. Thus, the diversification process of aquatic fungi must be highly clade specific in some cases.

Entorrhiza is a small fungal genus comprising 14 species that all cause galls on roots of Cyperaceae and Juncaceae. Although this genus was established 130 years ago, crucial questions on the phylogenetic relationships and biology of this enigmatic taxon are still unanswered. In order to infer a robust hypothesis about the phylogenetic position of Entorrhiza and to evaluate evolutionary trends, multiple gene sequences and morphological characteristics of Entorrhiza were analyzed and compared with respective findings in Fungi. In our comprehensive five-gene analyses Entorrhiza appeared as a highly supported monophyletic lineage representing the sister group to the rest of the Dikarya, a phylogenetic placement that received but moderate maximum likelihood and maximum parsimony bootstrap support. An alternative maximum likelihood tree with the constraint that Entorrhiza forms a monophyletic group with Basidiomycota could not be rejected. According to the first phylogenetic hypothesis, the teliospore tetrads of Entorrhiza represent the prototype of the dikaryan meiosporangium. The alternative hypothesis is supported by similarities in septal pore structure, cell wall and spindle pole bodies. Based on the isolated phylogenetic position of Entorrhiza and its peculiar combination of features related to ultrastructure and reproduction mode, we propose a new phylum Entorrhizomycota, for the genus Entorrhiza, which represents an apparently widespread group of inconspicuous fungi.

Bird song plays an important role in the establishment and maintenance of prezygotic reproductive barriers. When two closely related species come into secondary contact, song convergence caused by acquisition of heterospecific songs into the birds' repertoires is often observed. The proximate mechanisms responsible for such mixed singing, and its effect on the speciation process, are poorly understood. We used a combination of genetic and bioacoustic analyses to test whether mixed singing observed in the secondary contact zone of two passerine birds, the Thrush Nightingale (Luscinia luscinia) and the Common Nightingale (L. megarhynchos), is caused by introgressive hybridization. We analysed song recordings of both species from allopatric and sympatric populations together with genotype data from one mitochondrial and seven nuclear loci. Semi-automated comparisons of our recordings with an extensive catalogue of Common Nightingale song types confirmed that most of the analysed sympatric Thrush Nightingale males were 'mixed singers' that use heterospecific song types in their repertoires. None of these 'mixed singers' possessed any alleles introgressed from the Common Nightingale, suggesting that they were not backcross hybrids. We also analysed songs of five individuals with intermediate phenotype, which were identified as F1 hybrids between the Thrush Nightingale female and the Common Nightingale male by genetic analysis. Songs of three of these hybrids corresponded to the paternal species (Common Nightingale) but the remaining two sung a mixed song. Our results suggest that although hybridization might increase the tendency for learning songs from both parental species, interspecific cultural transmission is the major proximate mechanism explaining the occurrence of mixed singers among the sympatric Thrush Nightingales. We also provide evidence that mixed singing does not substantially increase the rate of interspecific hybridization and discuss the possible adaptive value of this phenomenon in nightingales.

Unilateral hand clenching increases neuronal activity in the frontal lobe of the contralateral hemisphere. Such hand clenching is also associated with increased experiencing of a given hemisphere's "mode of processing." Together, these findings suggest that unilateral hand clenching can be used to test hypotheses concerning the specializations of the cerebral hemispheres during memory encoding and retrieval. We investigated this possibility by testing effects of unilateral hand clenching on episodic memory. The hemispheric Encoding/Retrieval Asymmetry (HERA) model proposes left prefrontal regions are associated with encoding, and right prefrontal regions with retrieval, of episodic memories. It was hypothesized that right hand clenching (left hemisphere activation) pre-encoding, and left hand clenching (right hemisphere activation) pre-recall, would result in superior memory. Results supported the HERA model. Also supported was that simple unilateral hand clenching can be used as a means by which the functional specializations of the cerebral hemispheres can be investigated in intact humans.

Differences in individual male birds' singing may serve as honest indicators of male quality in male-male competition and female mate choice. This has been shown e.g. for overall song output and repertoire size in many bird species. More recently, differences in structural song characteristics such as the performance of physically challenging song components were analysed in this regard. Here we show that buzz elements in the song of nightingales (Luscinia megarhynchos) hold the potential to serve as indicators of male quality and may therefore serve a communicative function. Buzzes were produced with considerable differences between males. The body weight of the males was correlated with one measure of these buzzes, namely the repetition rate of the buzz subunits, and individuals with larger repertoires sang buzzes at higher subunit-rates. A model of buzz performance constraints suggested that buzzes were sung with different proficiencies. In playback experiments, female nightingales showed more active behaviour when hearing buzz songs. The results support the idea that performance differences in the acoustic fine structure of song components are used in the communication of a large repertoire species such as the nightingale.

Inconspicuous basidiomycetes from the order Sebacinales are known to be involved in a puzzling variety of mutualistic plant-fungal symbioses (mycorrhizae), which presumably involve transport of mineral nutrients. Recently a few members of this fungal order not fitting this definition and commonly referred to as 'endophytes' have raised considerable interest by their ability to enhance plant growth and to increase resistance of their host plants against abiotic stress factors and fungal pathogens. Using DNA-based detection and electron microscopy, we show that Sebacinales are not only extremely versatile in their mycorrhizal associations, but are also almost universally present as symptomless endophytes. They occurred in field specimens of bryophytes, pteridophytes and all families of herbaceous angiosperms we investigated, including liverworts, wheat, maize, and the non-mycorrhizal model plant Arabidopsis thaliana. They were present in all habitats we studied on four continents. We even detected these fungi in herbarium specimens originating from pioneering field trips to North Africa in the 1830s/40s. No geographical or host patterns were detected. Our data suggest that the multitude of mycorrhizal interactions in Sebacinales may have arisen from an ancestral endophytic habit by specialization. Considering their proven beneficial influence on plant growth and their ubiquity, endophytic Sebacinales may be a previously unrecognized universal hidden force in plant ecosystems.