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Christine de la Loge,1 Fatoumata Fofana,2 Paul Williams,1 Sarah Rusch,3 Marita Stevens,4 Jane Scott5 1Patient-Centered Outcomes, Mapi (an ICON Plc. company), Lyon, France; 2Patient-Centered Outcomes, Mapi (an ICON Plc. company), Leiden, the Netherlands; 3Statistical Decisions and Sciences, Janssen Biostatistics Research & Development, Beerse, B-2340, Belgium; 4Global Clinical Development Infectious Diseases, Janssen Research & Development, Beerse, B-2340, Belgium; 5Janssen Global Services LLC, High Wycombe, UKCorrespondence: Christine de la Loge Tel +33 7 85 61 78 59Email cdelaloge@outlook.frPurpose: PRESORS ClinRO completed by clinicians and ObsRO completed by caregivers were developed to characterize the clinical course of respiratory syncytial virus (RSV) infection. This study describes preliminary analysis of PRESORS’ measurement properties using clinical trial data.Patients and Methods: PRESORS ClinRO and ObsRO data were collected in a 28-day randomized, double-blind, Phase 1b trial of JNJ-53718678 or placebo in infants and children ≤ 24 months of age treated for RSV infection in hospitals. PRESORS data were scored and key psychometric properties of scores were evaluated, including ability to discriminate between known groups and to detect change over time. Time to resolution of RSV signs was explored using two responder definitions.Results: Daily completion rates for PRESORS ClinRO and ObsRO were high for the 44 children in the study (median: 100% and 93%, respectively). Large floor effects were observed at baseline for signs of severe RSV infection that were either absent (cyanosis, fever, apnea) or rarely reported (reduced urination/dehydration, vomiting). Implausible ObsRO ratings suggested some caregivers could not accurately measure heart rate. Known-group validity was confirmed: children in poor health based on baseline ClinRO had mean baseline composite scores that were significantly worse for both ObsRO (p=0.001) and ClinRO (p< 0.001) compared to those with better overall health. ObsRO (p=0.009) and ClinRO (p< 0.001) composite scores were responsive to change in overall health status from baseline to Day 3. Mean scores for RSV sign dimensions decreased rapidly from baseline to Day 7 except for coughing and sleep ratings by caregivers. Time to recovery varied greatly depending on definitions used.Conclusion: PRESORS ClinRO and ObsRO can inform endpoints and enable monitoring the clinical course of RSV in pediatric trials. Improved alignment between ClinRO and ObsRO and revisions ensuring caregivers can assess all signs will be addressed in revised PRESORS.Keywords: psychometric validation, clinician-reported outcomes, observer-reported outcomes, pediatrics, respiratory syncytial virus

Summary: Background: Chronic wounds, a common morbidity in recessive dystrophic epidermolysis bullosa (RDEB), lack definitive therapies. Objectives: To assess allogeneic epidermal skin grafts in terms of wound healing and durability over time. Methods: In a prospective, open‐label clinical trial for postallogeneic haematopoietic cell transplantation (post‐alloHCT) patients with RDEB, up to nine chronic wounds per patient were grafted over 1 year. Epidermal grafts measuring 5 cm2 were obtained from related alloHCT donors in the outpatient setting using the CELLUTOMETM Epidermal Harvesting System. Wounds were photographed and symptom inventories completed at baseline and 6, 12 and 52 weeks after grafting. The trial was registered at ClinicalTrials.gov (NCT02670837). Results: Between August 2016 and January 2019, eight patients with RDEB received a total of 35 epidermal allografts at a median of 1157 days (range 548–2884) post‐alloHCT. The median (interquartile range) percentage reductions in wound surface area were 75% (52–94), 95% (72–100) and 100% (97–100) at 6, 12 and 52 weeks postgraft, respectively, each significantly reduced from baseline (P < 0·001). Donor harvest sites healed quickly without scarring. Biopsy evaluation at 1 year of an epidermal allograft site revealed wildtype type VII collagen (immunofluorescence), anchoring fibrils (electron microscopy), and full‐thickness skin whole‐DNA donor chimerism of 42% (compared with 16% in concurrently biopsied native skin). This strategy subsequently supported release of RDEB pseudosyndactyly. Conclusions: The immune tolerance established by alloHCT supports successful adoptive transfer of donor epidermal grafts. Persistence of donor grafts in a single patient beyond 1 year and observed migration of donor‐grafted cells into adjacent wound suggest that epidermal allografts include nonterminally differentiated cells and/or trigger recruitment of donor bone‐marrow‐derived cells to mediate wound healing. What is already known about this topic?Chronic nonhealing wounds cause great morbidity in patients with recessive dystrophic epidermolysis bullosa (RDEB) including pain, itch and loss of local barrier/thermoregulatory skin function, and serve as a nidus for infection and squamous cell carcinoma development.The standard of care for chronic RDEB wounds is supportive, with local cleansing, emollient and dressing application.Skin grafts from healthy allogeneic (nonself) donors provide only transient benefit as genetic differences drive immune rejection of transplanted tissue. What does this study add?Successful allogeneic haematopoietic cell transplantation establishes immune tolerance for secondary tissue grafts from the same donor, herein demonstrated with skin grafts.Persistence of epidermal allografts beyond the keratinocyte lifespan and outgrowth into the adjacent wound suggest inclusion of nonterminally differentiated cells in the graft.Epidermal allografting can be completed in a minimally invasive manner in the outpatient setting, with tolerability to the donor allowing for repeat sessions over time. Linked Comment: Bauer. Br J Dermatol 2021; 184:1002–1003. [ABSTRACT FROM AUTHOR]

Abstract Background Severe malaria has been attributed to the expression of a restricted subset of the var multi-gene family, which encodes for Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 mediates cytoadherence and sequestration of infected erythrocytes into the post-capillary venules of vital organs such as the brain, lung or placenta. var genes are highly diverse and can be classified in three major groups (ups A, B and C) and two intermediate groups (B/A and B/C) based on the genomic location, gene orientation and upstream sequences. The genetic diversity of expressed var genes in relation to severity of disease in Tanzanian children was analysed. Methods Children with defined severe (SM) and asymptomatic malaria (AM) were recruited. Full-length var mRNA was isolated and reversed transcribed into var cDNA. Subsequently, the DBL and N-terminal domains, and up-stream sequences were PCR amplified, cloned and sequenced. Sequences derived from SM and AM isolates were compared and analysed. Results The analysis confirmed that the var family is highly diverse in natural Plasmodium falciparum populations. Sequence diversity of amplified var DBL-1α and upstream regions showed minimal overlap among isolates, implying that the var gene repertoire is vast and most probably indefinite in endemic areas. var DBL-1α sequences from AM isolates were more diverse with more singletons found (pvar DBL-1α sequences from SM patients were rare and restricted suggesting that certain PfEMP1 variants might induce severe disease. Conclusions The genetic sequence diversity of var genes of P. falciparum isolates from Tanzanian children is large and its relationship to disease severity has been studied. Observed differences suggest that different var genes might have fundamentally different roles in the host-parasite interaction. Further research is required to examine clear disease-associations of var gene subsets in different geographical settings. The importance of very strict clinical definitions and appropriate large control groups needs to be emphasized for future studies on disease associations of PfEMP1.

Introduction: Interprofessional collaboration in healthcare involves diverse professionals working together to address complex patient needs. Interprofessional training wards offer workplace-based interprofessional education in real healthcare settings, fostering collaborative learning among students. While their educational value is widely recognized, debates persist regarding their cost-effectiveness due to limited research. This study assesses the cost efficiency of the interprofessional training ward Regensburg (A-STAR) within the Department of Internal Medicine I at the University Hospital Regensburg, compared to conventional wards., Methods: From October 2019 to December 2022, 7,244 patient cases were assigned to A-STAR or conventional wards by case managers, with a comprehensive analysis of all associated revenues and costs., Results: A-STAR treated 1,482 patients, whereas conventional wards treated 5,752 patients, with more males and younger patients at A-STAR. A-STAR achieved higher profit per case (€1,508.74) attributed to increased revenues and reduced material costs. It generated an average of €1,366.54 more Diagnosis Related Groups (DRG) revenue per case annually than conventional wards, due to greater medical complexity reflected in a higher case-mix index (CMI: 2.4 vs. 2.2). The increased case complexity led to longer patient stays (9.0 vs. 8.1 days) and fewer cases treated annually at A-STAR (27.4 cases/year vs. 37.8 cases/year). The higher CMI did not result in a higher proportion of patients requiring isolation. A-STAR exhibited a higher capacity utilization rate (87.1% vs. 83.9%). Personnel costs per case at A-STAR were initially elevated due to enhanced observation by the senior physician but were gradually mitigated by expanding A-STAR's bed capacity. Material costs were consistently lower on a per-case basis at A-STAR (€1512.02 vs. €1577.12), particularly in terms of medication expenses, indicating more resource-efficient operations. From the A-STAR graduates, 18 individuals were recruited for permanent positions as doctors or nurses over 2 years., Conclusion: A-STAR demonstrates economic efficiency and stability even during the COVID-19 pandemic. The substantial personnel acquisition is likely influenced by high levels of satisfaction with education and work and is economically relevant in medical staff shortages. These findings provide a compelling rationale for the broader implementation of interprofessional training wards, establishing them as vital platforms for nurturing future professionals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Schlosser-Hupf, Aichner, Meier, Albaladejo-Fuertes, Mahnke, Ruttmann, Rusch, Michels, Mehrl, Kunst, Schmid and Müller.)

Neutrophils are critical immune cells in severe coronavirus disease 2019 (COVID-19). S100 calcium-binding protein A12 (S100A12) is highly expressed in neutrophils during acute inflammation. The aim of this study was to evaluate serum S100A12 levels as a diagnostic and prognostic tool in COVID-19. Serum samples of patients with moderate and severe COVID-19 were collected during 2020 to 2024. Enzyme-linked immunosorbent assay was used to measure serum S100A12 levels in 63 patients with moderate COVID-19, 60 patients with severe disease and 33 healthy controls. Serum S100A12 levels were elevated in moderate COVID-19 compared to controls and were even higher in severe cases. In moderate disease, serum S100A12 levels positively correlated with immune cell counts. While C-reactive protein and procalcitonin are established inflammation markers, they did not correlate with serum S100A12 levels in either patient cohort. Patients with severe COVID-19 and vancomycin-resistant enterococcus (VRE) infection had increased S100A12 levels. Elevated S100A12 levels were also observed in patients with herpes simplex reactivation. Fungal superinfections did not alter S100A12 levels. These data show that serum S100A12 increases in moderate and severe COVID-19 and is further elevated by VRE bloodstream infection and herpes simplex reactivation. Therefore, S100A12 may serve as a novel biomarker for severe COVID-19 and an early diagnostic indicator for bacterial and viral infections.

Background: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in children aged ≤ 5 years and adults aged ≥ 60 years worldwide. Despite this, RSV-specific therapeutic options are limited. Rilematovir is an investigational, orally administered inhibitor of RSV fusion protein-mediated viral entry., Objective: To establish the antiviral activity, clinical outcomes, safety, and tolerability of rilematovir (low or high dose) in children aged ≥ 28 days and ≤ 3 years with RSV disease., Methods: CROCuS was a multicenter, international, double-blind, placebo-controlled, randomized, adaptive phase II study, wherein children aged ≥ 28 days and ≤ 3 years with confirmed RSV infection who were either hospitalized (Cohort 1) or treated as outpatients (Cohort 2) were randomized (1:1:1) to receive rilematovir (low or high dose) or placebo. Study treatment was administered daily as an oral suspension from days 1 to 7, with dosing based on weight and age groups. The primary objective was to establish antiviral activity of rilematovir by evaluating the area under the plasma concentration-time curve of RSV viral load in nasal secretions from baseline through day 5. Severity and duration of RSV signs and symptoms and the safety and tolerability of rilematovir were also assessed through day 28 (± 3)., Results: In total, 246 patients were randomized, treated, and included in the safety analysis population (Cohort 1: 147; Cohort 2: 99). Of these, 231 were included in the intent-to-treat-infected analysis population (Cohort 1: 138; Cohort 2: 93). In both cohorts, demographics were generally similar across treatment groups. In both cohorts combined, the difference (95% confidence interval) in the mean area under the plasma concentration-time curve of RSV RNA viral load through day 5 was - 1.25 (- 2.672, 0.164) and - 1.23 (- 2.679, 0.227) log 10 copies∙days/mL for the rilematovir low-dose group and the rilematovir high-dose group, respectively, when compared with placebo. The estimated Kaplan-Meier median (95% confidence interval) time to resolution of key RSV symptoms in the rilematovir low-dose, rilematovir high-dose, and placebo groups of Cohort 1 was 6.01 (4.24, 7.25), 5.82 (4.03, 8.18), and 7.05 (5.34, 8.97) days, respectively; in Cohort 2, estimates were 6.45 (4.81, 9.70), 6.26 (5.41, 7.84), and 5.85 (3.90, 8.27) days, respectively. A similar incidence of adverse events was reported in patients treated with rilematovir and placebo in Cohort 1 (rilematovir: 61.9%; placebo: 58.0%) and Cohort 2 (rilematovir: 50.8%; placebo: 47.1%), with most reported as grade 1 or 2 and none leading to study discontinuation. The study was terminated prematurely, as the sponsor made a non-safety-related strategic decision to discontinue rilematovir development prior to full recruitment of Cohort 2., Conclusions: Data from the combined cohort suggest that rilematovir has a small but favorable antiviral effect of indeterminate clinical relevance compared with placebo, as well as a favorable safety profile. Safe and effective therapeutic options for RSV in infants and young children remain an unmet need., Clinical Trial Registration: EudraCT Number: 2016-003642-93; ClinicalTrials.gov Identifier: NCT03656510. First posted date: 4 September, 2018., (© 2024. The Author(s).)

Introduction: Interprofessional teamwork is pivotal in modern healthcare, prompting the establishment of interprofessional training wards since 1996. While these wards serve as hubs for optimizing healthcare professional collaboration and communication, research into patient outcomes remains notably sparse and geographically limited, predominantly examining patient satisfaction and sparingly exploring other metrics like mortality or self-discharge rates. This study seeks to bridge this gap, comparing patient outcomes in interprofessional training wards and conventional wards under the hypothesis that the former offers no disadvantage to patient outcomes., Materials and Methods: We explored patient outcomes within an interprofessional student ward called A-STAR at a University Hospital from October 2019 to December 2022. Engaging with patients discharged between May 2021 and April 2022, we utilized digital and paper-based anonymous questionnaires, catering to patient preference, to gather pertinent data., Results: Analysis of outcomes for 1,482 A-STAR (interprofessional student ward) and 5,752 conventional ward patients revealed noteworthy findings. A-STAR patients tended to be younger (59 vs. 61 years, p  < 0.01) and more frequently male (73.5% vs. 70.4%, p  = 0.025). Vital clinical outcomes, such as discharges against medical advice, complication-driven readmissions, and ICU transfers, were statistically similar between groups, as were mortality rates (1.2% vs. 1.3%, p  = 0.468). A-STAR demonstrated high patient satisfaction, underscored by positive reflections on team competence, ward atmosphere, and responsiveness to concerns, emphasizing the value placed on interprofessional collaboration. Patient narratives commended team kindness, lucid explanations, and proactive involvement., Discussion: This data collectively underscores the safety and reliability of patient care within training wards, affirming that patients can trust the care provided in these settings. Patients on the interprofessional ward demonstrated high satisfaction levels: 96.7% appreciated the atmosphere and conduct of ward rounds. In comparison, 98.3% were satisfied with the discussion and information about their treatment during their hospital stay., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Schlosser-Hupf, Aichner, Meier, Albaladejo-Fuertes, Ruttmann, Rusch, Michels, Mehrl, Kunst, Schmid and Müller.)

Background: Patient registries are an important tool for networking medical caregivers and research, especially in the field of rare diseases. Individuals afflicted by multi-organ autoimmune diseases typically suffer from inflammation of multiple organs., Project: GAIN (German genetic multi-organ Auto-Immunity Network) is the German network for research and therapy optimisation for individuals with congenital multi-organ autoimmune diseases. As a sub-project of the network, the registry systematically collects data from this patient group and makes it available for research purposes., Results: A data set was developed and made available for the GAIN Registry that can map the complex clinical status of persons with multi-organ autoimmune diseases. Data from 486 individuals have been documented to date., Conclusions: The GAIN register allows for a very comprehensive documentation that clearly goes beyond previous approaches, e.g. by linking it to biosamples collected in the consortium. The planned inclusion of patients in the documentation, e.g. of data on quality of life, opens up a new field., Competing Interests: Conflicts of interest The authors declare that there is no conflict of interest., (© Robert Koch Institute. All rights reserved unless explicitly granted.)

Background: Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking., Objectives: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS., Methods: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs., Results: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS., Conclusions: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Objectives: To assess the antiviral effect, clinical outcomes, and safety of the respiratory syncytial virus (RSV) fusion inhibitor rilematovir in non-hospitalized RSV-infected adults., Methods: This phase 2a, double-blind, multicentre study randomly assigned RSV-positive adult outpatients ≤5 days from symptom onset 1:1:1 to receive rilematovir 500 mg, 80 mg, or placebo once-daily for 7 days. Antiviral effect was assessed by RSV RNA viral load (VL), measured by quantitative RT-PCR, and Kaplan-Meier (KM) estimates of time to undetectable VL. Clinical course was assessed by KM estimates of median time to resolution of key RSV symptoms assessed through patient-reported outcomes., Results: RSV-positive patients (n = 72) were randomly assigned; 66 had confirmed RSV infection and received rilematovir 500 mg (n = 23), 80 mg (n = 21) or placebo (n = 22). Differences versus placebo in mean RSV RNA VL area under the curve (90% CI) through days 3, 5 and 8, respectively, were 0.09 (-0.837; 1.011), -0.10 (-2.171; 1.963), and -1.03 (-4.746; 2.682) log 10 copies.day/mL for rilematovir 500 mg, and 1.25 (0.291; 2.204), 2.53 (0.430; 4.634), and 3.85 (0.097; 7.599) log 10 copies.day/mL for rilematovir 80 mg. KM estimates of median (90% CI) time-to-first confirmed undetectable VL were 5.9 (3.85; 6.90), 8.0 (6.86; 12.80) and 7.0 (6.62; 10.88) days and 5.7 (2.93; 7.01), 8.1 (6.74; 12.80) and 7.9 (6.62; 11.74) days in patients with symptom onset ≤3 days, for rilematovir 500 mg, 80 mg, and placebo, respectively. KM estimates of median (90% CI) time to resolution of key RSV symptoms were 7.1 (5.03; 11.43), 7.6 (5.93; 8.32), and 9.6 (5.95; 14.00) days for rilematovir 500 mg, 80 mg, and placebo, respectively; and in patients with symptom onset ≤3 days, median 8.0, 7.6, and 11.8 days, respectively., Discussion: Rilematovir use, initiated early, suggests a potential clinical benefit in RSV-infected adults, with data supporting development of RSV therapeutic options., Trial Registration: This study is registered with clinicaltrials.gov (NCT03379675)., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Patient registries are a very important and essential tool for investigating rare diseases, as most physicians only see a limited number of cases during their career. Diseases of multi-organ autoimmunity and autoinflammation are especially challenging, as they are characterized by diverse clinical phenotypes and highly variable expressivity. The GAIN consortium (German multi-organ Auto Immunity Network) developed a dataset addressing these challenges. ICD-11, HPO, and ATC codes were incorporated to document various clinical manifestations and medications with a defined terminology. The GAIN dataset comprises detailed information on genetics, phenotypes, medication, and laboratory values. Between November 2019 and July 2022, twelve centers from Europe have registered 419 patients with multi-organ autoimmunity or autoinflammation. The median age at onset of symptoms was 13 years (IQR 3-28) and the median delay from onset to diagnosis was 5 years (IQR 1-14). Of 354 (84.5%) patients who were genetically tested, 248 (59.2%) had a defined monogenetic cause. For 87 (20.8%) patients, no mutation was found and for 19 (4.5%), the result was pending. The most common gene affected was NFkB1 (48, 11.5%), and the second common was CTLA4 (40, 9.5%), both genetic patient groups being fostered by specific research projects within GAIN. The GAIN registry may serve as a valuable resource for research in the inborn error of immunity community by providing a platform for etiological and diagnostic research projects, as well as observational trials on treatment options., (© 2023. The Author(s).)

With the implementation of the new MDR 2017/745 by the European Parliament, more robust clinical and pre-clinical data will be required due to a more stringent approval process. The EFORT Implant and Patient Safety Initiative WG1 'Introduction of Innovation', combined knowledge of orthopaedic surgeons, research institutes, orthopaedic device manufacturers, patient representatives and regulatory authorities to develop a comprehensive set of recommendations for the introduction of innovations in joint arthroplasty within the boundaries of MDR 2017/745. Recommendations have been developed to address key questions about pre-clinical and clinical requirements for the introduction of new implants and implant-related instrumentation with the participation of a steering group, invited by the EFORT Board in dialogue with representatives from European National Societies and Speciality Societies. Different degrees of novelty and innovation were described and agreed on in relation to when surgeons can start, using implants and implant-related instrumentation routinely. Before any clinical phase of a new implant, following the pre-market clinical investigation or the equivalent device PMCF pathway, it is a common understanding that all appropriate pre-clinical testing (regulatory mandatory and evident state of the art) - which has to be considered for a specific device - has been successfully completed. Once manufacturers receive the CE mark for a medical device, it can be used in patients routinely when a clinical investigation has been conducted to demonstrate the conformity of devices according to MDR Article 62 or full equivalence for the technical, biological and clinical characteristics has been demonstrated (MDR, Annex XIV, Part A, 3.) and a PMCF study has been initiated.

The objectives of the 1st EFORT European Consensus on 'Medical and Scientific Research Requirements for the Clinical Introduction of Artificial Joint Arthroplasty Devices' were foremost to focus on patient safety by establishing performance requirements for medical devices. The 1st EFORT European Consensus applied an a priori-defined, modified Delphi methodology to produce unbiased, high-quality recommendation statements, confirmed by consensus voting of a European expert panel. Intended key outcomes are practical guidelines justified by the current stage of knowledge and based on a broad European Expert Consensus, to maintain innovation and optimisation of orthopaedic devices within the boundaries of MDR 2017/745. Twenty-one main research areas of relevance were defined relying on input from the EFORT IPSI WG1 'Introduction of Innovation' recommendations and a related survey. A modified Delphi approach with a preparatory literature review and work in small groups were used to prepare answers to the research questions in the form of 32 draft Consensus statements. A Consensus Conference in a hybrid format, on-site in the Carl Gustav Carus University of Dresden was organised to further refine the draft statements and define consensus within the complete group of participants by final voting, intended to further quantify expert opinion knowledge. The modified Delphi approach provides practical guidelines for hands-on orientation for orthopaedic surgeons, research institutes and laboratories, orthopaedic device manufacturers, patient representatives, Notified Bodies, National Institutes and authorities. For the first time, initiated by the EFORT IPSI (WG1 'Introduction of Innovation'), knowledge of all related stakeholders was combined in the 1st EFORT European Consensus to develop guidelines and result in a comprehensive set of recommendations.

Storms represent a major disturbance factor in forest ecosystems, but the effects of windthrows on soil organic carbon (SOC) stocks are poorly quantified. Here, we assessed the SOC stocks of windthrown forests at 19 sites across Switzerland spanning an elevation gradient from 420 to 1550 m, encompassing a strong climatic gradient. Results show that the effect size of disturbance on SOC stocks increases with the size of the initial SOC stocks. The largest windthrow-induced SOC losses of up to 29 t C ha -1 occurred in high-elevation forests with a harsh climate developing thick organic layers. In contrast, SOC stocks of low-elevation forests with thin organic layers were hardly affected. A mineralization study further revealed high elevation forests to store higher amounts of easily mineralizable C in thick organic layers that got lost following windthrow. These findings are supported by a meta-analysis of available windthrow studies, showing an increase of storm-induced SOC losses with the size of the initial SOC stocks. Modelling simulations further indicate longer-lasting SOC losses and a slower recovery of SOC stocks after windthrow at high compared to low elevations, due to a slower regeneration of mountain forests and associated lower C inputs into soils in a harsh climate. Upscaling the experimental findings/observed patterns by linking them to a data base of Swiss forest soils shows a total SOC loss of ∼0.4 Mt. C for the whole forested area of Switzerland after two major storm events, counteracting the forest net carbon sink of decades. Our study provides strong evidence that the vulnerability of SOC stocks to windthrow is particularly high in forests featuring thick and slowly forming organic layers, such as mountain soils. Thus, the risk of losing SOC to more frequent windthrows in mountain forests strongly limits their potential to mitigate climate change., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Early total knee arthroplasty failures continue to surface in the literature. Cementation technique and implant design are two of the most important scenarios that can affect implant survivorship. Our objectives were to develop a more suitable preclinical test to evaluate the endurance of the implant-cement-bone interface under anterior shear and internal-external (I/E) torsional shear testing condition in a biomechanical sawbones., Methods: Implants tested included the AS VEGA System PS and the AS Columbus CR/PS (Aesculap AG, Germany), with zirconium nitride (ZrN) coating. Tibial implants were evaluated under anterior shear and I/E torsional shear conditions with 6 samples in 4 test groups. For the evaluation of the I/E torsional shear endurance behavior, a test setup was created allowing for clinically relevant I/E rotation with simultaneous high axial/tibio-femoral load. The test was performed with an I/E displacement of ±17.2°, for 1 million cycles with an axial preload of 3,000 N., Results: After the anterior shear test an implant-cement-bone fixation strength for the AS VEGA System tibial tray of 2,674 ± 754 N and for the AS Columbus CR/PS tibial tray of 2,177 ± 429 N was determined (P = .191). After I/E rotational shear testing an implant-cement-bone fixation strength for the AS VEGA System PS tray of 2,561 ± 519 N and for the AS Columbus CR/PS tray of 2,824 ± 515 N was resulted (P = .39)., Conclusion: Both methods had varying degrees of failure modes from debonding to failure of the sawbones foam. These two intense biomechanical loading tests are more strenuous and more representative of clinical activity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations., Objective: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts., Methods: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered., Results: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years., Conclusions: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

α-Thalassemia (α-thal) is caused by DNA deletions or point mutations in the genes coding for the α-globin chains and can lead to hemolytic anemia in its carriers. If only one of the four α genes is affected, the mutation is mostly discovered by chance, as the carriers are asymptomatic. Hb Évora ( HBA2 : c.106T>C) is an Hb variant that leads to such an α-thal trait (α T α/αα) and thus, to mild microcytic hypochromic anemia. The mutation was first reported in 2001 and named Hb Évora in 2007 (based on the geographic origin of one of the studied families). It was found in four unrelated families originating from Portugal and the Philippines. We now report the discovery of Hb Évora not only in a proband with no known ancestors from either country, but also on an unexpected allele. Subsequently, her close relatives were studied, revealing the same mutation in her brother. No clear correlation between phenotype and genotype was observed.

Background: This phase 1b study evaluated the pharmacokinetics, safety, and antiviral effects of the respiratory syncytial virus (RSV)-specific fusion inhibitor JNJ-53718678 (JNJ-8678) in hospitalized RSV-infected patients aged > 1 to ≤24 months., Methods: Patients categorized by age (cohort 1: ≥6 to ≤24 months; cohort 2: ≥3 to < 6 months; cohort 3: > 1 to < 3 months) were randomized to oral JNJ-8678 or placebo once daily for 7 days. Dose increases followed data review committee recommendations (cohort 1: 2/6/8/9 mg/kg; cohort 2: 1.5/4.5/6 mg/kg; cohort 3: 1/3/5 mg/kg). Cohort 1 included a 9 mg/kg dose, as target exposures were not reached at lower doses. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modeling. Safety was assessed by adverse events (AEs), laboratory tests, and electrocardiograms. To assess antiviral effects, RSV RNA viral load from nasal swabs was quantified over time using reverse-transcription quantitative polymerase chain reaction., Results: Patients received JNJ-8678 (n = 37) or placebo (n = 7). Pharmacokinetic parameters were similar at the highest doses for cohorts 1-3 (area under the plasma concentration-time curve from time of administration up to 24 hours postdosing at day 7: 35 840, 34 980, and 39 627 ng × hour/mL, respectively). Two grade 3 AEs were reported (both bronchiolitis; 1 JNJ-8678, 1 placebo), reported as serious AEs; all other AEs were grade 1 or 2. Two additional serious AEs were reported (rhinitis [JNJ-8678]; pneumonia [placebo]). No deaths, grade 4 AEs, or AEs leading to discontinuation were reported. Median RSV viral load change from baseline in JNJ-8678 vs placebo by day 3 was -1.98 vs -0.32 log10 copies/mL., Conclusions: In RSV-infected infants, JNJ-8678 was well tolerated. Target exposures were reached and antiviral activity was observed., Clinical Trials Registration: NCT02593851., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The German Network on Primary Immunodeficiency Diseases (PID-NET) utilizes the European Society for Immunodeficiencies (ESID) registry as a platform for collecting data. In the context of PID-NET data, we show how registries based on custom software can be made interoperable for better collaborative access to precollected data. The Open Source Registry System for Rare Diseases (Open-Source-Registersystem für Seltene Erkrankungen [OSSE], in German) provides patient organizations, physicians, scientists, and other parties with open source software for the creation of patient registries. In addition, the necessary interoperability between different registries based on the OSSE, as well as existing registries, is supported, which allows those registries to be confederated at both the national and international levels., Objective: Data from the PID-NET registry should be made available in an interoperable manner without losing data sovereignty by extending the existing custom software of the registry using the OSSE registry framework., Methods: This paper describes the following: (1) the installation and configuration of the OSSE bridgehead, (2) an approach using a free toolchain to set up the required interfaces to connect a registry with the OSSE bridgehead, and (3) the decentralized search, which allows the formulation of inquiries that are sent to a selected set of registries of interest., Results: PID-NET uses the established and highly customized ESID registry software. By setting up a so-called OSSE bridgehead, PID-NET data are made interoperable according to a federated approach, and centrally formulated inquiries for data can be received. As the first registry to use the OSSE bridgehead, the authors introduce an approach using a free toolchain to efficiently implement and maintain the required interfaces. Finally, to test and demonstrate the system, two inquiries are realized using the graphical query builder. By establishing and interconnecting an OSSE bridgehead with the underlying ESID registry, confederated queries for data can be received and, if desired, the inquirer can be contacted to further discuss any requirements for cooperation., Conclusions: The OSSE offers an infrastructure that provides the possibility of more collaborative and transparent research. The decentralized search functionality includes registries into one search application while still maintaining data sovereignty. The OSSE bridgehead enables any registry software to be integrated into the OSSE network. The proposed toolchain to set up the required interfaces consists of freely available software components that are well documented. The use of the decentralized search is uncomplicated to use and offers a well-structured, yet still improvable, graphical user interface to formulate queries., (©Raphael Scheible, Dennis Kadioglu, Stephan Ehl, Marco Blum, Martin Boeker, Michael Folz, Bodo Grimbacher, Jens Göbel, Christoph Klein, Alexandra Nieters, Stephan Rusch, Gerhard Kindle, Holger Storf. Originally published in JMIR Medical Informatics (http://medinform.jmir.org), 07.10.2020.)

Introduction: The study objective was to characterize the excretion and metabolic profile of the respiratory syncytial virus fusion protein inhibitor, JNJ-53718678. Prior animal and in vitro studies suggested three main elimination pathways: N-glucuronidation to M8; CYP(3A4) metabolism leading to circulating metabolites M5, M12, M19 and M37; and JNJ-53718678 biliary excretion. To gain insight into the relative contribution of JNJ-53718678 and M8 biliary excretion, duodenal fluid sampling was incorporated into this mass balance study., Methods: A single oral dose of 500 mg 14 C-JNJ-53718678 was administered to six healthy male subjects. Four hours after study drug intake, gallbladder contraction was stimulated and duodenal fluid samples were collected. JNJ-53718678, its key circulating metabolites and total radioactivity (TR) were quantified in plasma, feces, urine and duodenal fluid. Safety was monitored throughout., Results: JNJ-53718678 and M12 represented 47.4% and 17.8%, respectively, of TR area under the curve (AUC) ∞ in plasma. M37 (9.6%), M19 (5.2%), M5 (4.3%) and M8 (1.4%) were minor metabolites; 70.6% of TR was recovered in feces and 19.9% in urine. Duodenal fluid concentrations (% of TR) were highest for JNJ-53718678 (11.6%) followed by M8 (10.4%), M5 (5.9%) and M12 (1.1%). In feces, 10-16% of TR was JNJ-53718678, 5-8% M5, < 1% M12 and < 1% M8. N-glucuronidation to M8 and direct biliary excretion of JNJ-53718678 represented 7% and 8% of drug clearance, respectively. JNJ-53718678 was safe and well tolerated., Conclusions: JNJ-53718678 is primarily eliminated through CYP3A4-mediated metabolism. By integrating duodenal sampling, N-glucuronidation was confirmed as another metabolic pathway despite the low amount of M8 excreted in urine and feces., Trial Registration: Eudract no. 2016-002664-14.

Summary: Primary Immunodeficiencies (PIDs) belong to the group of rare diseases. The European Society for Immunodeficiencies (ESID) operates an international research database application for continuous long-term documentation of patient data. The system is a web application which runs in a standard browser. Therefore, the system is easy to access from any location. Technically, the system is based on Gails backed by MariaDB with high standard security features to comply with the demands of a modern research platform., Availability and Implementation: The ESID Online Database is accessible via the official website: https://esid.org/Working-Parties/Registry-Working-Party/ESID-Registry. A demo system is available via: https://cci-esid-reg-demo-app.uniklinik-freiburg.de/EERS with user demouser and password Demo-2019., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

Patient registries are instrumental for clinical research in rare diseases. They help to achieve a sufficient sample size for epidemiological and clinical research and to assess the feasibility of clinical trials. The European Society for Immunodeficiencies (ESID) registry currently comprises information on more than 25,000 patients with inborn errors of immunity (IEI). The prerequisite of a patient to be included into the ESID registry is an IEI either defined by a defect in a gene included in the disease classification of the international union of immunological societies, or verified by applying clinical criteria. Because a relevant number of patients, including those with common variable immunodeficiency (CVID), representing the largest group of patients in the registry, remain without a genetic diagnosis, consensus on classification of these patients is mandatory. Here, we present clinical criteria for a large number of IEI that were designed in expert panels with an external review. They were implemented for novel entries and verification of existing data sets from 2014, yielding a substantial refinement. For instance, 8% of adults and 27% of children with CVID (176 of 1704 patients) were reclassified to 22 different immunodeficiencies, illustrating progress in genetics, but also the previous lack of standardized disease definitions. Importantly, apart from registry purposes, the clinical criteria are also helpful to support treatment decisions in the absence of a genetic diagnosis or in patients with variants of unknown significance., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Methods to diagnose malaria are of paramount interest to eradicate the disease. Current methods have severe limitations, as they are either costly or not sensitive enough to detect low levels of parasitemia. Here we report an ultrasensitive, yet low-resource chemical assay for the detection and quantification of hemozoin, a biomarker of all Plasmodium species. Solubilized hemozoin catalyzes the atom transfer radical polymerization of N-isopropylacrylamide above the lower critical solution temperature of poly(N-isopropylacrylamide). The solution becomes turbid, which can be observed by naked eye and quantified by UV-visible spectroscopy. The rate of turbidity increase is proportional to the concentration of hemozoin, with a detection limit of 0.85 ng mL -1 . Malaria parasites in human blood can be detected down to 10 infected red blood cells μL -1 . The assay could potentially be applied as a point-of-care test. The signal-amplification of an analyte by biocatalytic precipitation polymerization represents a powerful approach in biosensing.

Accurate and affordable rapid diagnostic tests (RDTs) are indispensable but often lacking for many infectious diseases. Specifically, there is a lack of highly sensitive malaria RDTs that can detect low antigen concentration at the onset of infection. Here, we present a strategy to improve the sensitivity of malaria RDTs by using capillary-driven microfluidic chips and combining sandwich immunoassays with electroless silver staining. We used 5 μm fluorescent beads functionalized with capture antibodies (cAbs). These beads are self-assembled by capillary action in recessed "bead lanes", which cross the main flow path of chips microfabricated in Si and SU-8. The binding of analytes to detection antibodies (dAbs) and secondary antibodies (2 nd Abs) conjugated to gold nanoparticles (NPs) allows the formation of a silver film on the beads. Such silver film masks the fluorescent core of the bead inversely proportional to the concentration of antigen in a sample. We illustrate this method using the recombinant malaria antigen Plasmodium falciparum histidine-rich-protein 2 (rPfHRP2) spiked in human serum. This antigen was a recombinant HRP2 protein expressed in Escherichia coli, which is also the standard reference material. The limit of detection (LOD) of our immunoassay was found to be less than 6 ng mL -1 of rPfHRP2 within 20 min, which is approaching the desired sensitivity needed in the Target Product Profile (TPP) for malaria elimination settings. The concept presented here is flexible and may also be utilized for implementing fluorescence immunoassays for the parallel detection of biomarkers on capillary-driven microfluidic chips.

Background: P27A is an unstructured 104mer synthetic peptide from Plasmodium falciparum trophozoite exported protein 1 (TEX1), the target of human antibodies inhibiting parasite growth. The present project aimed at evaluating the safety and immunogenicity of P27A peptide vaccine in malaria-nonexposed European and malaria-exposed African adults., Methods: This study was designed as a staggered, fast-track, randomized, antigen and adjuvant dose-finding, multicenter phase 1a/1b trial, conducted in Switzerland and Tanzania. P27A antigen (10 or 50 μg), adjuvanted with Alhydrogel or glucopyranosil lipid adjuvant stable emulsion (GLA-SE; 2.5 or 5 μg), or control rabies vaccine (Verorab) were administered intramuscularly to 16 malaria-nonexposed and 40 malaria-exposed subjects on days 0, 28, and 56. Local and systemic adverse events (AEs) as well as humoral and cellular immune responses were assessed after each injection and during the 34-week follow-up., Results: Most AEs were mild to moderate and resolved completely within 48 hours. Systemic AEs were more frequent in the formulation with alum as compared to GLA-SE, whereas local AEs were more frequent after GLA-SE. No serious AEs occurred. Supported by a mixed Th1/Th2 cell-mediated immunity, P27A induced a marked specific antibody response able to recognize TEX1 in infected erythrocytes and to inhibit parasite growth through an antibody-dependent cellular inhibition mechanism. Incidence of AEs and antibody responses were significantly lower in malaria-exposed Tanzanian subjects than in nonexposed European subjects., Conclusions: The candidate vaccine P27A was safe and induced a particularly robust immunogenic response in combination with GLA-SE. This formulation should be considered for future efficacy trials., Clinical Trials Registration: NCT01949909, PACTR201310000683408.

Background: Respiratory syncytial virus (RSV) disease has no effective treatment. JNJ-53718678 is a fusion inhibitor with selective activity against RSV., Methods: After confirmation of RSV infection or 5 days after inoculation with RSV, participants (n = 69) were randomized to JNJ-53718678 75 mg (n = 15), 200 mg (n = 17), 500 mg (n = 18), or placebo (n = 17) orally once daily for 7 days. Antiviral effects were evaluated by assessing RSV RNA viral load (VL) area under the curve (AUC) from baseline (before the first dose) until discharge, time-to-peak VL, duration of viral shedding, clinical symptoms, and quantity of nasal secretions., Results: Mean VL AUC was lower for individuals treated with different doses of JNJ-53718678 versus placebo (203.8-253.8 vs 432.8 log10 PFUe.hour/mL). Also, mean peak VL, time to peak VL, duration of viral shedding, mean overall symptom score, and nasal secretion weight were lower in each JNJ-53718678-treated group versus placebo. No clear exposure-response relationship was observed. Three participants discontinued due to treatment-emergent adverse events of grade 2 and 1 electrocardiogram change (JNJ-53718678 75 mg and 200 mg, respectively) and grade 2 urticaria (placebo)., Conclusions: JNJ-53718678 at all 3 doses substantially reduced VL and clinical disease severity, thus establishing clinical proof of concept and the compound's potential as a novel RSV treatment., Clinical Trials Registration: ClinicalTrials.gov: NCT02387606; EudraCT number: 2014-005041-41.

Point-of-care (POC) diagnostics are critically needed for the detection of infectious diseases, particularly in remote settings where accurate and appropriate diagnosis can save lives. However, it is difficult to implement immunoassays, and specifically immunoassays relying on signal amplification using silver staining, into POC diagnostic devices. Effective immobilization of antibodies in such devices is another challenge. Here, we present strategies for immobilizing capture antibodies (cAbs) in capillary-driven microfluidic chips and implementing a gold-catalyzed silver staining reaction. We illustrate these strategies using a species/anti-species immunoassay and the capillary assembly of fluorescent microbeads functionalized with cAbs in "bead lanes", which are engraved in microfluidic chips. The microfluidic chips are fabricated in silicon (Si) and sealed with a dry film resist. Rabbit IgG antibodies in samples are captured on the beads and bound by detection antibodies (dAbs) conjugated to gold nanoparticles. The gold nanoparticles catalyze the formation of a metallic film of silver, which attenuates fluorescence from the beads in an analyte-concentration dependent manner. The performance of these immunoassays was found comparable to that of assays performed in 96 well microtiter plates using "classical" enzyme-linked immunosorbent assay (ELISA). The proof-of-concept method developed here can detect 24.6 ng mL -1 of rabbit IgG antibodies in PBS within 20 min, in comparison to 17.1 ng mL -1 of the same antibodies using a ~140-min-long ELISA protocol. Furthermore, the concept presented here is flexible and necessitate volumes of samples and reagents in the range of just a few microliters.

Background: PrEP-001 Nasal Powder, a proprietary formulation of polyriboinosinic and polyribocytidylic acid effectively elicits a cellular innate immune response in nasal epithelium. The aim of these 2 studies was to investigate the safety and efficacy of PrEP-001 prophylaxis against rhinovirus (HRV-A16) and influenza-A (H3N2-IAV)., Methods: Healthy subjects randomly received 2 doses of PrEP-001 or placebo, 48 and 24 h pre-challenge with 10 TCID 50 of HRV-A16 (Study 1) or H3N2-IAV (Study 2)., Results: In Study 1, PrEP-001 reduced median total symptom score from 38.5 to 4.5 (p = 0.004), median symptom duration from 6.0 to 1.7 days and median mucus production from 15 g to 3 g. The percentage of subjects classified as ill was reduced 3-fold (placebo 73%, PrEP-001 23%, p = 0.002). In Study 2, PrEP-001 reduced median total symptom score from 8.0 to 4.1 (p = 0.021), median symptom duration from 4.6 to 3.7 days and median mucus production from 3.6 g to 1.5 g. The percentage of subjects classified as ill was reduced 2-fold (placebo 48%, PrEP-001 24%, p = 0.064). PrEP-001 reduced peak viral shedding in both studies, as assessed by qRT-PCR of nasal lavage. Seroconversion rates were comparable between placebo and PrEP-001 (Study 1: 77% [both arms]; Study 2: placebo 73%, PrEP-001 80%). PrEP-001 was well-tolerated, with no clinically significant adverse events., Conclusions: PrEP-001 reduced the number of individuals with clinical illness and attenuated severity and duration of HRV-A16 and H3N2-IAV infections without compromising seroconversion, and was well-tolerated. This supports further evaluation of PrEP-001 as a potential pan-viral prophylaxis for upper respiratory tract infections., Clinical Trial Registration: Study 1, HRV-A16 study: EudraCT Number 2012-005579-14 (study conducted before ClinicalTrials.gov registration required). Study 2, H3N2-IAV study: EudraCT Number 2015-002895-26 and ClinicalTrials.gov: NCT03220048., (Copyright © 2018. Published by Elsevier B.V.)

Background: Primary antibody deficiencies (PADs) are the most frequent primary immunodeficiencies in human subjects. The genetic causes of PADs are largely unknown. Sec61 translocon alpha 1 subunit (SEC61A1) is the major subunit of the Sec61 complex, which is the main polypeptide-conducting channel in the endoplasmic reticulum membrane. SEC61A1 is a target gene of spliced X-box binding protein 1 and strongly induced during plasma cell (PC) differentiation., Objective: We identified a novel genetic defect and studied its pathologic mechanism in 11 patients from 2 unrelated families with PADs., Methods: Whole-exome and targeted sequencing were conducted to identify novel genetic mutations. Functional studies were carried out ex vivo in primary cells of patients and in vitro in different cell lines to assess the effect of SEC61A1 mutations on B-cell differentiation and survival., Results: We investigated 2 families with patients with hypogammaglobulinemia, severe recurrent respiratory tract infections, and normal peripheral B- and T-cell subpopulations. On in vitro stimulation, B cells showed an intrinsic deficiency to develop into PCs. Genetic analysis and targeted sequencing identified novel heterozygous missense (c.254T>A, p.V85D) and nonsense (c.1325G>T, p.E381*) mutations in SEC61A1, segregating with the disease phenotype. SEC61A1-V85D was deficient in cotranslational protein translocation, and it disturbed the cellular calcium homeostasis in HeLa cells. Moreover, SEC61A1-V85D triggered the terminal unfolded protein response in multiple myeloma cell lines., Conclusion: We describe a monogenic defect leading to a specific PC deficiency in human subjects, expanding our knowledge about the pathogenesis of antibody deficiencies., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2-3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.

Background: JNJ-53718678 is a potent small-molecule inhibitor of the F-glycoprotein-mediated complex membrane fusion process of the respiratory syncytial virus. Here, we report the pharmacokinetics, the population pharmacokinetic modeling, and the safety and tolerability of JNJ-53718678 from the first-in-human, double-blind, randomized, placebo-controlled phase I study., Methods: Healthy subjects were randomized (6:3) into five single-dose groups (25-1000 mg) or three multiple-dose groups [250 mg every 24 h (q24h), 500 mg q24h, 250 mg every 12 h; fed conditions for 8 days] to receive JNJ-53718678 or placebo. Blood and urine samples were collected at several timepoints up to 72 h after intake of JNJ-53718678 and analyzed using validated liquid chromatography-mass spectrometry methods. A population pharmacokinetic model was developed and validated., Results: Peak plasma concentrations of JNJ-53718678 increased with increasing single (159 ± 54.9 to 6702 ± 1733 ng/mL) and multiple (on day 8, 1528 ± 256 to 2655 ± 591 ng/mL) doses. Steady-state conditions were reached on day 2 of the 8-day dosing regimen. Less than 4% of JNJ-53718678 was excreted in urine across all dose groups. Mean exposure of JNJ-53718678 was 7% lower in the fed state compared with the fasted state at the same dose. A two-compartment model with first-order absorption with parallel linear and non-linear elimination best described the pharmacokinetics of JNJ-53718678. No covariate effects were observed., Conclusions: A population pharmacokinetic model that describes the concentration data well with good precision of all parameter estimates was developed and validated. JNJ-53718678 was well tolerated at all single and multiple doses studied.