ReLink strategy in diagnosed-but-untreated hepatitis C-positive patients in Germany: report from a single center.

OBJECTIVE: The ReLink project aims to reintegrate diagnosed-but-untreated hepatitis-C-positive patients into medical care and initiate a therapy. MATERIAL/METHODS: A retrospective search within the practice management system of a single center in Germany identified among 1965 hepatitis-C-positive patients 100 untreated patients with available contact details and meeting all inclusion criteria. Patients were contacted by 2 contact rounds. RESULTS: Out of 100 patients, 64% were male. Most patients (81%) were aged between 30 and 59 years. The patients belonged to high-risk groups for hepatitis C virus infections or had other comorbidities. The majority of patients injected drugs (21%) and/or were currently or had been on substitution therapy (44%); alcohol addiction was also frequent (21%). Out of 25 patients who agreed to an appointment, 10 patients (40%) started therapy and 5 additional patients (20%) agreed to therapy but were not yet able to start or had not yet made a decision. One­third of patients who agreed to an appointment did not show up. CONCLUSIONS: Diagnosed-but-untreated patients are an important subgroup of hepatitis-C-positive patients; their recall to the clinic for direct-acting antiviral therapy is possible. However, inaccurate contact information, unresponsiveness to outreach, and further reluctance to attend doctor appointments limited the overall impact of this program. Regular review of the patients' contact details may facilitate both follow-up and recall.

Clinical characteristics of monkeypox virus infections among men with and without HIV: A large outbreak cohort in Germany.

BACKGROUND: Since May 2022, increasing numbers of monkeypox virus (MPXV) infections have been reported from across Europe and North America. Studies, mainly from Africa, have suggested a higher risk for severe MPXV cases in people living with HIV. METHODS: This was a retrospective study of all confirmed MPXV infections observed in the participating centres since 19 May 2022. We conducted a chart review to evaluate clinical characteristics, comorbidities, and coinfections, including HIV, viral hepatitis, and sexually transmitted infections (STIs). RESULTS: By 30 June 2022, a total of 546 MPXV infections were reported from 42 German centres. All patients were men who have sex with men (MSM), of whom 256 (46.9%) were living with HIV, mostly with a preserved immune system and with viral suppression. In total, 232 (42.5%) MSM were also taking HIV pre-exposure prophylaxis (PrEP) and 58 (10.6%) MSM had no known HIV infection or PrEP use. The median age was 39 years (range 20-67), and comorbidities were rare. However, 52.4% and 29.4% of all patients had been diagnosed with at least one STI within the last 6 months or within the last 4 weeks, respectively. The most frequent localizations of MPXV infection were genital (49.9%) and anal (47.9%), whereas fever (53.2%) and lymphadenopathy (42.6%) were the most frequent general symptoms. The hospitalization rate was low (4.0%), and no fatal course was observed. The clinical picture showed no apparent differences between MSM with or without HIV. CONCLUSIONS: In this preliminary cohort analysis from a current large outbreak among MSM in Germany, the clinical picture of MPXV infection did not differ between MSM with and without HIV infection. Severe courses were rare and hospitalization rates were low. However, most patients were relatively healthy, and only a few people living with HIV were viremic or severely immunosuppressed.

The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: A systematic review and a pooled multicentre individual-patient meta-analysis.

BACKGROUND: Delay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as 'test-and-treat' policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM. METHODS AND FINDINGS: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case-control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle-Ottawa scale, and all studies were ranked as 'Good', scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07-1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92-4.06; p < 0.001) for a delay of 2-3 days and 5.46 (95% CI: 3.49-8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24-4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70-9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify. CONCLUSIONS: Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment.

Nutritional status and disease severity in children acutely presenting to a primary health clinic in rural Gambia.

BACKGROUND: Accurate and timely data on the health of a population are key for evidence-based decision making at both the policy and programmatic level. In many low-income settings, such data are unavailable or outdated. Using an electronic medical records system, we determined the association between nutritional status and severe illness and mortality among young children presenting to a rural primary health care facility in the Gambia. METHODS: Clinical data collected over five years (2010-2014) on children aged under 60 months making acute visits to a primary health care clinic in the rural Gambian district of Kiang West were retrospectively extracted from the medical records system. Generalised estimating equation models were used to investigate associations between nutritional status and illness severity, accounting for repeat visits, gender, age and access to transport to the clinic. The Population Attributable Fraction (PAF) was used to determine the proportion of severe illness likely attributable to different grades of malnutrition. RESULTS: 3839/5021 (77%) children under 60 months of age living in Kiang West presented acutely to the clinic at least once, yielding 21,278 visits (47% girls, median age 20.2 months (Interquartile Range (IQR) 23.92 months)) and 26,001 diagnoses, 86% being infectious diseases. Severe illness was seen in 4.5% of visits (961/21,278). Wasting was associated with an increased risk of severe illness in a dose-dependent manner, ('WHZ < -1' adjusted Odds Ratio (aOR) 1.68, 95% CI:1.43-1.98, p < 0.001, 'WHZ <-2 and ≥-3' aOR 2.78, 95% CI:2.31-3.36, p < 0.001 and 'WHZ < -3' aOR 7.82, 95% CI:6.40-9.55, p < 0.001) the PAF for wasting (WHZ < -2) was 0.21 (95% CI: 0.18-0.24). Stunting, even in the most severe form (HAZ < -3), was not significantly associated with severe illness (aOR 1.19 95% CI:0.94-1.51) but was associated with a significantly increased risk of death (aOR 6.04 95% CI:1.94-18.78). CONCLUSION: In this population-based cohort of young children in rural Gambia, wasting was associated with disease severity in a dose-dependent manner. Further research is needed into strategies to identify and reach these children with effective interventions to improve their nutritional status.

The Human Immune Response to Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) is an important etiological agent of respiratory infections, particularly in children. Much information regarding the immune response to RSV comes from animal models and in vitro studies. Here, we provide a comprehensive description of the human immune response to RSV infection, based on a systematic literature review of research on infected humans. There is an initial strong neutrophil response to RSV infection in humans, which is positively correlated with disease severity and mediated by interleukin-8 (IL-8). Dendritic cells migrate to the lungs as the primary antigen-presenting cell. An initial systemic T-cell lymphopenia is followed by a pulmonary CD8+ T-cell response, mediating viral clearance. Humoral immunity to reinfection is incomplete, but RSV IgG and IgA are protective. B-cell-stimulating factors derived from airway epithelium play a major role in protective antibody generation. Gamma interferon (IFN-γ) has a strongly protective role, and a Th2-biased response may be deleterious. Other cytokines (particularly IL-17A), chemokines (particularly CCL-5 and CCL-3), and local innate immune factors (including cathelicidins and IFN-λ) contribute to pathogenesis. In summary, neutrophilic inflammation is incriminated as a harmful response, whereas CD8+ T cells and IFN-γ have protective roles. These may represent important therapeutic targets to modulate the immunopathogenesis of RSV infection.

Impact of fortified versus unfortified lipid-based supplements on morbidity and nutritional status: A randomised double-blind placebo-controlled trial in ill Gambian children.

BACKGROUND: Multiple micronutrients (MMN) are commonly prescribed in pediatric primary healthcare in sub-Saharan Africa to improve nutritional status and appetite without evidence for their effectiveness or international clinical guidelines. Community-wide MMN supplementation has shown limited and heterogeneous impact on growth and morbidity. Short-term ready-to-use therapeutic foods in acutely sick children in a hospital setting also had limited efficacy regarding subsequent growth. The effectiveness of MMN in improving morbidity or growth in sick children presenting for primary care has not been assessed. METHODS AND FINDINGS: We undertook a double-blind randomised controlled trial of small-quantity lipid-based nutrient supplements (SQ-LNS) fortified with 23 micronutrients in children aged 6 months (mo) to 5 years (y) presenting with an illness at a rural primary healthcare centre in The Gambia. Primary outcomes were repeat clinic presentations and growth over 24 wk. Participants were randomly assigned to receive 1 of 3 interventions: (1) supplementation with micronutrient-fortified SQ-LNS for 12 wk (MMN-12), (2) supplementation with micronutrient-fortified SQ-LNS for 6 wk followed by unfortified SQ-LNS for 6 wk (MMN-6), or (3) supplementation with unfortified SQ-LNS for 12 wk (MMN-0) to be consumed in daily portions. Treatment masking used 16 letters per 6-wk block in the randomisation process. Blinded intention-to-treat analysis based on a prespecified statistical analysis plan included all participants eligible and correctly enrolled. Between December 2009 and June 2011, 1,101 children (age 6-60 mo, mean 25.5 mo) were enrolled, and 1,085 were assessed (MMN-0 = 361, MMN-6 = 362, MMN-12 = 362). MMN supplementation was associated with a small increase in height-for-age z-scores 24 wk after recruitment (effect size for MMN groups combined: 0.084 SD/24 wk, 95% CI: 0.005, 0.168; p = 0.037; equivalent to 2-5 mm depending on age). No significant difference in frequency of morbidity measured by the number of visits to the clinic within 24 wk follow-up was detected with 0.09 presentations per wk for all groups (MMN-0 versus MMN-6: adjusted incidence rate ratio [IRR] 1.03, 95% CI: 0.92, 1.16; MMN-0 versus MMN-12: 1.05, 95% CI: 0.93, 1.18). In post hoc analysis, clinic visits significantly increased by 43% over the first 3 wk of fortified versus unfortified SQ-LNS (adjusted IRR 1.43; 95% CI: 1.07, 1.92; p = 0.016), with respiratory presentations increasing by 52% with fortified SQ-LNS (adjusted IRR 1.52; 95% CI: 1.01, 2.30; p = 0.046). The number of severe adverse events during supplementation were similar between groups (MMN-0 = 20 [1 death]; MMN-6 = 21 [1 death]; MMN-12 = 20 [0 death]). No participant withdrew due to adverse effects. Study limitations included the lack of supervision of daily supplementation. CONCLUSION: Prescribing micronutrient-fortified SQ-LNS to ill children presenting for primary care in rural Gambia had a very small effect on linear growth and did not reduce morbidity compared to unfortified SQ-LNS. An early increase in repeat visits indicates a need for the establishment of evidence-based guidelines and caution with systematic prescribing of MMN. Future research should be directed at understanding the mechanisms behind the lack of effect of MMN supplementation on morbidity measures and limited effect on growth. TRIAL REGISTRATION: ISRCTN 73571031.

Whole genome sequencing enhances molecular diagnosis of primary ciliary dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a genetic disorder affecting motile cilia. Most cases are inherited recessively, due to variants in >50 genes that result in abnormal or absent motile cilia. This leads to chronic upper and lower airway disease, subfertility, and laterality defects. Given overlapping clinical features and genetic heterogeneity, diagnosis can be difficult and often occurs late. Of those tested an estimated 30% of genetically screened PCD patients still lack a molecular diagnosis. A molecular diagnosis allows for appropriate clinical management including prediction of phenotypic features correlated to genotype. Here, we aimed to identify how readily a genetic diagnosis could be made using whole genome sequencing (WGS) to facilitate identification of pathogenic variants in known genes as well as novel PCD candidate genes. METHODS: WGS was used to screen for pathogenic variants in eight patients with PCD. RESULTS: 7/8 cases had homozygous or biallelic variants in DNAH5, DNAAF4 or DNAH11 classified as pathogenic or likely pathogenic. Three identified variants were deletions, ranging from 3 to 13 kb, for which WGS identified precise breakpoints, permitting confirmation by Sanger sequencing. WGS yielded identification of a de novo variant in a novel PCD gene TUBB4B. CONCLUSION: Here, WGS uplifted genetic diagnosis of PCD by identifying structural variants and novel modes of inheritance in new candidate genes. WGS could be an important component of the PCD diagnostic toolkit, increasing molecular diagnostic yield from current (70%) levels, and enhancing our understanding of fundamental biology of motile cilia and variants in the noncoding genome.

Validation of the Emergency Department-Paediatric Early Warning Score (ED-PEWS) for use in low- and middle-income countries: A multicentre observational study.

Early recognition of children at risk of serious illness is essential in preventing morbidity and mortality, particularly in low- and middle-income countries (LMICs). This study aimed to validate the Emergency Department-Paediatric Early Warning Score (ED-PEWS) for use in acute care settings in LMICs. This observational study is based on previously collected clinical data from consecutive children attending four diverse settings in LMICs. Inclusion criteria and study periods (2010-2021) varied. We simulated the ED-PEWS, consisting of patient age, consciousness, work of breathing, respiratory rate, oxygen saturation, heart rate, and capillary refill time, based on the first available parameters. Discrimination was assessed by the area under the curve (AUC), sensitivity and specificity (previously defined cut-offs < 6 and ≥ 15). The outcome measure was for each setting a composite marker of high urgency. 41,917 visits from Gambia rural, 501 visits from Gambia urban, 2,608 visits from Suriname, and 1,682 visits from Tanzania were included. The proportion of high urgency was variable (range 4.6% to 24.9%). Performance ranged from AUC 0.80 (95%CI 0.70-0.89) in Gambia urban to 0.62 (95%CI 0.55-0.67) in Tanzania. The low-urgency cut-off showed a high sensitivity in all settings ranging from 0.83 (95%CI 0.81-0.84) to 1.00 (95%CI 0.97-1.00). The high-urgency cut-off showed a specificity ranging from 0.71 (95%CI 0.66-0.75) to 0.97 (95%CI 0.97-0.97). The ED-PEWS has a moderate to good performance for the recognition of high urgency children in these LMIC settings. The performance appears to have potential in improving the identification of high urgency children in LMICs.

Biomechanical evaluation of a posterior non-fusion instrumentation of the lumbar spine.

PURPOSE: Numerous posterior non-fusion systems have been developed within the past decade to resolve the disadvantages of rigid instrumentations and preserve spinal motion. The aim of this study was to investigate the effect of a new dynamic stabilization device, to measure the screw anchorage after flexibility testing and compare it with data reported in the literature. METHODS: Six human lumbar spine motion segments (L2-5) were loaded in a spine tester with pure moments of 7.5 Nm in lateral bending, flexion/extension and axial rotation. Specimens were tested intact, after instrumentation of the intact segment, after destabilization by a nucleotomy and after instrumentation of the destabilised segment with the new non-fusion device (Elaspine). After flexibility testing all screws were subjected to a pull-out test. RESULTS: Instrumentation of the intact segment significantly reduced the RoM (p < 0.002) in flexion, extension and lateral bending to 49.7, 44.6 and 53% of the intact state, respectively. In axial rotation, the instrumentation resulted in a non-significant RoM reduction to 95% of the intact state. Compared to the intact segment, instrumentation of the destabilized segment significantly (p < 0.05) reduced the RoM to 69.8, 62.3 and 79.1% in flexion, extension and lateral bending, respectively. In axial rotation, the instrumented segment showed a significantly higher RoM than the intact segment (137.6% of the intact state (p < 0.01)). The pull-out test showed a maximum pull-out force of 855.1 N (±334) with a displacement of 6.1 mm (±2.8) at maximum pull-out force. CONCLUSIONS: The effect of the investigated motion preservation device on the RoM of treated segments is in the range of other devices reported in the literature. Compared to the most implanted and investigated device, the Dynesys, the Elaspine has a less pronounced motion restricting effect in lateral bending and flexion/extension, while being less effective in limiting axial rotation. The pull-out force of the pedicle screws demonstrated anchorage comparable to other screw designs reported in the literature.

Biomechanical analysis of a new expandable vertebral body replacement combined with a new polyaxial antero-lateral plate and/or pedicle screws and rods.

PURPOSE: Restoration of the anterior spinal profile and regular load-bearing is the main goal treating anterior spinal defects in case of fracture. Over the past years, development and clinical usage of cages for vertebral body replacement have increased rapidly. For an enhanced stabilization of rotationally unstable fractures, additional antero-lateral implants are common. The purpose of this study was the evaluation of the biomechanical behaviour of a recently modified, in situ distractible vertebral body replacement (VBR) combined with a newly developed antero-lateral polyaxial plate and/or pedicle screws and rods using a full corpectomy model as fracture simulation. METHODS: Twelve human spinal specimens (Th12-L4) were tested in a six-degree-of-freedom spine tester applying pure moments of 7.5 Nm to evaluate the stiffness of three different test instrumentations using a total corpectomy L2 model: (1) VBR+antero-lateral plate; (2) VBR, antero-lateral plate+pedicle screws and rods and (3) VBR+pedicle screws and rods. RESULTS: In the presented total corpectomy defect model, only the combined antero-posterior instrumentation (VBR, antero-lateral plate+pedicle screws and rods) could achieve higher stiffness in all three-movement planes than the intact specimen. In axial rotation, neither isolated anterior instrumentation (VBR+antero-lateral plate) nor isolated posterior instrumentation (VBR+pedicle screws and rods) could stabilize the total corpectomy compared to the intact state. CONCLUSIONS: For rotationally unstable vertebral body fractures, only combined antero-posterior instrumentation could significantly decrease the range of motion (ROM) in all motion planes compared to the intact state.

An environment for sustainable research software in Germany and beyond: current state, open challenges, and call for action.

Research software has become a central asset in academic research. It optimizes existing and enables new research methods, implements and embeds research knowledge, and constitutes an essential research product in itself. Research software must be sustainable in order to understand, replicate, reproduce, and build upon existing research or conduct new research effectively. In other words, software must be available, discoverable, usable, and adaptable to new needs, both now and in the future. Research software therefore requires an environment that supports sustainability. Hence, a change is needed in the way research software development and maintenance are currently motivated, incentivized, funded, structurally and infrastructurally supported, and legally treated. Failing to do so will threaten the quality and validity of research. In this paper, we identify challenges for research software sustainability in Germany and beyond, in terms of motivation, selection, research software engineering personnel, funding, infrastructure, and legal aspects. Besides researchers, we specifically address political and academic decision-makers to increase awareness of the importance and needs of sustainable research software practices. In particular, we recommend strategies and measures to create an environment for sustainable research software, with the ultimate goal to ensure that software-driven research is valid, reproducible and sustainable, and that software is recognized as a first class citizen in research. This paper is the outcome of two workshops run in Germany in 2019, at deRSE19 - the first International Conference of Research Software Engineers in Germany - and a dedicated DFG-supported follow-up workshop in Berlin.

Modeling Crop Genetic Resources Phenotyping Information Systems.

Documentation of phenotype information is a priority need in biodiversity, crop modeling, breeding, ecology, and evolution research, for association studies, gene discovery, retrospective statistical analysis and data mining, QTL re-mapping, choosing cultivars, and planning crosses. Lack of access to phenotype information is still seen as a limiting factor for the use of plant genetic resources. Phenotype data are complex. Information on the context, under which they were collected, is indispensable, and the domain is continuously evolving. This study describes comprehensive data and object models supporting web interfaces for multi-site field phenotyping and data acquisition, which have been developed for Central Crop Databases within the European Cooperative Programme for Plant Genetic Resources over the years and which can be used as blueprints for phenotyping information systems. We start from the hypothesis, that entity relationship and object models useful for software development can picture domain expertise, similar as domain ontologies, and encourage a discussion of scientific information systems on modeling level. Starting from information requirements for statistical analysis, meta-analysis, and knowledge discovery, models are discussed in consideration of several standardization and modeling approaches including crop ontologies. Following an object-oriented modeling approach, we keep data and object models close together and to domain concepts. This will make database and software design better understandable and usable for domain experts and support a modular use of software artifacts to be shared across various domains of expertise. Classes and entities represent domain concepts with attributes naturally assigned to them. Field experiments with randomized plots, as typically used in the evaluation of plant genetic resources and in plant breeding, are in the focus. Phenotype observations, which can be listed as raw or aggregated data, are linked to explanatory metadata describing experimental treatments and agronomic interventions, observed traits and observation methodology, field plan and plot design, and the experiment site as a geographical entity. Based on clearly defined types, potential links to information systems in other domains (e.g., geographic information systems) can be better identified. Work flows are shown as web applications for the generation of field plans, field books, templates, upload of spreadsheet data, and images.

The respiratory microbiome and respiratory infections.

Despite advances over the past ten years lower respiratory tract infections still comprise around a fifth of all deaths worldwide in children under five years of age with the majority in low- and middle-income countries. Known risk factors for severe respiratory infections and poor chronic respiratory health do not fully explain why some children become sick and others do not. The respiratory tract hosts bacteria that can cause respiratory infections but also normal commensal bacteria. Together, this microbial population is called the microbiome. The composition of the respiratory microbiome in the first few months of life is likely influenced by external factors such as environment, mode of delivery and infant feeding practices, which are also associated with susceptibility to respiratory infections and wheezing illness/asthma. Recently, multiple studies have shown that respiratory microbiota profiles early in life are associated with an increased risk and frequency of subsequent respiratory infections, disease severity and occurrence of wheeze in later childhood. Early interactions between infectious agents such as viruses and the respiratory microbiome have shown to modulate host immune responses potentially affecting the course of the disease and future respiratory health. Deeper understanding of these interactions will help the development of new therapeutic agents or preventive measures that may modify respiratory health outcomes and help us to stratify at risk populations to better target our current interventional approaches.

A Case of "Abnormally Abnormal" Hypoxic Ventilatory Responses: A Novel NPARM PHOX 2B Gene Mutation.

ABSTRACT: Congenital central hypoventilation syndrome (CCHS) is a rare disorder associated with dysregulation of the autonomic ventilatory response to hypoxia and hypercarbia usually caused by polyalanine repeat expansion mutations in the PHOX 2B gene. Non-polyalanine repeat mutations (NPARM) represent approximately 10% of cases, and usually require continuous ventilation during sleep, although our knowledge of disease progression is limited. Here we present a case with a novel NPARM CCHS mutation associated with a premature stop codon for the PHOX 2B protein. Despite the type of the mutation, patient management with supplementary oxygen has been sufficient. Experience from our case may help when counseling parents.