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Abstract Background The aim of the study was to investigate functional impairment and its relationship to illness severity in a sample of patients with a diagnosis of mood or anxiety disorder during inpatient treatment and 1 year after discharge. Methods Two hundred thirty-nine inpatients with primary diagnoses of mood or anxiety disorders were assessed at baseline and at follow-up by a range of validated instruments. Mini-ICF-APP was used for the assessment of functional impairment, BDI-II for the assessment of clinical symptoms and remission. Sample characteristics and measures of impairment at baseline and at follow-up were analysed descriptively. Symptomatically remitted and non-remitted patients were compared with regard to capacity limitations. Results Initially, the sample showed considerable impairment in many capacities, particularly endurance, spontaneous activities, structuring of tasks, competency and flexibility. After 1 year, all capacities significantly improved. The level of impairment was correlated with employment status and severity of clinical symptoms. About 50% of the patients remitted in clinical symptomatology. Retrospectively, the remitted and the unremitted did not differ in functional impairment at baseline but there were considerable differences at follow-up. Conclusions Mini-ICF-APP is a useful instrument to monitor functional status and change in psychiatric samples, complementing the usual focus on symptom reduction.

A prospective observational study comparing mechanical power density (MP normalized to dynamic compliance) with traditional spontaneous breathing indexes (e.g., predicted body weight normalized tidal volume [VT/PBW], rapid shallow breathing index [RSBI], or the integrative weaning index [IWI]) for predicting prolonged weaning failure in 140 tracheotomized patients. We assessed the diagnostic accuracy of these indexes at the start and end of the weaning procedure using ROC curve analysis, expressed as the area under the receiver operating characteristic curve (AUROC). Weaning failure occurred in 41 out of 140 patients (29%), demonstrating significantly higher MP density (6156 cmH 2 O 2 /min [4402-7910] vs. 3004 cmH 2 O 2 /min [2153-3917], P < 0.01), lower spontaneous VT/PBW (5.8 mL*kg -1 [4.8-6.8] vs. 6.6 mL*kg -1 [5.7-7.9], P < 0.01) higher RSBI (68 min -1 *L -1 [44-91] vs. 55 min -1 *L -1 [41-76], P < 0.01) and lower IWI (41 L 2 /cmH 2 O*%*min*10 -3 [25-72] vs. 71 L 2 /cmH 2 O*%*min*10 -3 [50-106], P < 0.01) and at the end of weaning. MP density was more accurate at predicting weaning failures (AUROC 0.91 [95%CI 0.84-0.95]) than VT/PBW (0.67 [0.58-0.74]), RSBI (0.62 [0.53-0.70]), or IWI (0.73 [0.65-0.80]), and may help clinicians in identifying patients at high risk for long-term ventilator dependency., (© 2024. The Author(s).)

Objectives: T cell immunity is key for the control of viral infections including SARS-CoV-2, in particular with regard to immune memory and protection against arising genetic variants., Methods: We recently evaluated a peptide-based SARS-CoV-2 T cell activator termed CoVac-1 in a first-in-human trial in healthy adults. Here, we report on long-term safety and efficacy data of CoVac-1 until month 12., Results: CoVac-1 is well tolerated without long-term immune-related side effects and induces long-lasting anti-viral T cell responses in 100% of study participants, with potent expandability of clusters of differentiation (CD4 + ) and CD8 + T cells targeting multiple different CoVac-1 T cell epitopes. T cell responses were associated with stronger injection site reaction. Beyond induction of T cell immunity, 89% of subjects developed CoVac-1-specific immunoglobulin G antibodies which associated with the intensity of the T cell response, indicating that CoVac-1-specific CD4 + T cells support the induction of B-cell responses. Vaccination with approved COVID-19 vaccines boosted CoVac-1-specific T cell responses. Overall, a low SARS-CoV-2 infection rate (8.3%) was observed., Conclusion: Together, a single application of CoVac-1 elicits long-lived and broad SARS-CoV-2-specific T cell immunity, which further supports the current evaluation of our T cell activator in patients with congenital or acquired B-cell defects., Competing Interests: Declarations of Competing Interest JSH, HRS, H-GR, and JSW are listed as inventors on a patent (EP 20 169 047.6) related to the SARS-CoV-2 T cell epitopes included in CoVac-1. H-GR and K-HW are listed as inventors on a patent related to the adjuvant XS15 included in CoVac-1 (DE102016005550.2). The other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

T-cell immunity is central for control of COVID-19, particularly in patients incapable of mounting antibody responses. CoVac-1 is a peptide-based T-cell activator composed of SARS-CoV-2 epitopes with documented favorable safety profile and efficacy in terms of SARS-CoV-2-specific T-cell response. We here report a Phase I/II open-label trial (NCT04954469) in 54 patients with congenital or acquired B-cell deficiency receiving one subcutaneous CoVac-1 dose. Immunogenicity in terms of CoVac-1-induced T-cell responses and safety are the primary and secondary endpoints, respectively. No serious or grade 4 CoVac-1-related adverse events have been observed. Expected local granuloma formation has been observed in 94% of study subjects, whereas systemic reactogenicity has been mild or absent. SARS-CoV-2-specific T-cell responses have been induced in 86% of patients and are directed to multiple CoVac-1 peptides, not affected by any current Omicron variants and mediated by multifunctional T-helper 1 CD4 + T cells. CoVac-1-induced T-cell responses have exceeded those directed to the spike protein after mRNA-based vaccination of B-cell deficient patients and immunocompetent COVID-19 convalescents with and without seroconversion. Overall, our data show that CoVac-1 induces broad and potent T-cell responses in patients with B-cell/antibody deficiency with a favorable safety profile, which warrants advancement to pivotal Phase III safety and efficacy evaluation. ClinicalTrials.gov identifier NCT04954469., (© 2023. Springer Nature Limited.)

Background: The ability to walk is an important indicator of general health and mobility deficits have wide-ranging economic implications. We undertook a systematic review to elucidate the impact of walking parameters on health care costs.  METHODS: Publications reporting on associations between health care costs and walking parameters were identified by a systematic literature search in MEDLINE, Embase, and manual reference screening, following the PRISMA reporting guidelines. First, titles and abstracts were screened by two independent reviewers followed by a review of the full articles if they met the inclusion criteria. Costs were converted to US-Dollars with inflation adjustment for 2021. A narrative synthesis was performed.  RESULTS: Ten studies conducted between 2001 and 2021 fulfilled the inclusion criteria. Assessment of walking ability was carried out via patient reported outcomes, performance tests, or using wearable digital devices. Walking more than one hour per day, a faster walking speed and the ability to walk without impairments are associated with significant lower health care costs. A higher number of steps per day is associated with significant lower costs in two simulation studies, while in the study using a digital device, taking more than 10,000 steps per day is not significantly associated with lower direct costs. The heterogeneity of mobility assessments and of economic analyses both precluded a quantitative synthesis., Conclusion: Cross-sectional and observational studies from this systematic review suggest a significant association of better walking performance with lower health care costs. Future health economic research and health technology assessments should use quantifiable mobility outcomes when evaluating new drugs or non-pharmacological interventions., (© 2022. The Author(s).)

Background and study aims  Indeterminate biliary strictures represent a major challenge in clinical diagnostics. Diagnostic yield of radiological, endoscopic imaging and histopathological diagnosis is insufficient. The cryobiopsy technique is a new method for tissue extraction already used in different clinical settings. The aim of this ex vivo clinical study was to investigate feasibility and tissue quality of cryobiopsy in the bile duct. Patients and methods  We included 14 patients who underwent pancreaticoduodenectomy. Bile duct samples were taken with either a new prototype cryoprobe or one of two forceps types. Results were analyzed for general feasibility, specimen size, histological assessability as well as representativity of retrieved tissue. Results  Feasibility of cholangioscopic forceps was poor compared to gastric biopsy forceps or cryobiopsy. Significantly larger tissue samples were obtained with cryobiopsy (5.6 ± 4.5 mm 2 ) compared to gastric biopsy forceps (3.3 ± 5.1 mm 2 , P  = 0.006). Furthermore, cryobiopsy was superior in histological assessment quality ( P  = 0.02) and concerning representativity ( P  = 0.03). Conclusions  Cryobiopsy in the bile duct is feasible and the quality of the obtained tissue is high. Further investigation of bile duct cryobiopsy in vivo is warranted., Competing Interests: Competing interests The co-authors Walter Linzenbold and Markus Enderle are employees of ERBE Elektromedizin GmbH, Tuebingen, Germany. Cryoprobes were provided by ERBE Elektromedizin GmbH, Tuebingen, Germany. All other authors have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Mobility is defined as the ability to independently move around the environment and is a key contributor to quality of life, especially in older age. The aim of this study was to evaluate the use of mobility as a decisive outcome for the marketing authorisation of drugs by the European Medicines Agency (EMA)., Methods: Fifteen therapeutic areas which commonly lead to relevant mobility impairments and alter the quantity and/or the quality of walking were selected: two systemic neurological diseases, four conditions primarily affecting exercise capacity, seven musculoskeletal diseases and two conditions representing sensory impairments. European Public Assessment Reports (EPARs) published by the EMA until September 2020 were examined for mobility endpoints included in their 'main studies'. Clinical study registries and primary scientific publications for these studies were also reviewed., Results: Four hundred and eighty-four EPARs yielded 186 relevant documents with 402 'main studies'. The EPARs reported 153 primary and 584 secondary endpoints which considered mobility; 70 different assessment tools (38 patient-reported outcomes, 13 clinician-reported outcomes, 8 performance outcomes and 13 composite endpoints) were used. Only 15.7% of those tools distinctly informed on patients' mobility status. Out of 402, 105 (26.1%) of the 'main studies' did not have any mobility assessment. Furthermore, none of these studies included a digital mobility outcome., Conclusions: For conditions with a high impact on mobility, mobility assessment was given little consideration in the marketing authorisation of drugs by the EMA. Where mobility impairment was considered to be a relevant outcome, questionnaires or composite scores susceptible to reporting biases were predominantly used., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Aims: Older patients in particular suffer from adverse drug reactions (ADR) when presenting in the emergency department. We aimed to characterise the phenotype of those ADRs, to be able to recognise an ADR in older patients., Methods: Cases of ADRs in emergency departments collected within the multicentre prospective observational study (ADRED) were analysed (n = 2215). We analysed ADR-associated diagnoses, symptoms and their risk profiles. We present frequencies and odds ratios (OR) with 95% confidence intervals for adults (18-64 years) compared to older adults (≥65 years; young-old 65-79, old-old ≥80 years) and regression coefficients (B) for each year of age., Results: Most prominent differences were seen for drug-associated confusion, dehydration, and bradycardia (OR 6.70 [1.59-28.27], B .054; OR 6.02 [2.41-15.03], B .081, and 4.82 [2.21-10.54], B .040), more likely seen in older adults. Bleedings were reported in all age groups, but gastrointestinal bleedings occurred with more than doubled chance in older adults (OR 2.46 [1.77-3.41], B .030), likewise did other bleedings such as haemorrhage from respiratory passages (OR 2.89 [1.37-6.11], B.036). Falls were more likely in older adults (OR 2.84 [1.77-4.53], B .030), while dizziness was frequent in both age groups., Conclusion: Our data point to differences in symptoms of ADRs between adults and older individuals, with dangerous drug-associated phenomena in the older adult such as bleedings or falls. Physicians should consider drug-associated origins of symptoms in older adults with an increased risk for serious health problems., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose: Adverse drug reactions (ADR) account for 5 to 7% of emergency department (ED) consultations. We aimed to assess medication risk profiles for ADRs leading to ED visits., Methods: We analysed medication intake and patient demographics in a prospective multi-centre observational study collecting ADR cases in four large EDs in Germany. Odds ratios (OR) were calculated to relate drug classes taken to those suspicious for an ADR after a causality assessment., Results: A total of 2215 cases of ED visits due to ADRs were collected. The median age of the cohort was 73 years; in median, six co-morbidities and an intake of seven drugs were documented. Antineoplastic/immunomodulating agents had the highest OR for being suspected for an ADR (OR 20.45, 95% CI 14.54-28.77), followed by antithrombotics (OR 2.94, 95% CI 2.49-3.47), antibiotics (OR 2.65, 95% CI 1.78-3.95), systemic glucocorticoids (OR 2.43, 95% CI 1.54-3.82) and drugs affecting the central nervous system (CNS), such as antipsychotics (OR 2.36, 95% CI 1.46-3.81), antidepressants (OR 2.10, 95% CI 1.57-2.83), antiparkinsonian medication (OR 2.11, 95% CI 1.15-3.84), opioids (OR 1.79, 95% CI 1.26-2.54) and non-opioid analgesics (OR 1.32, 95% CI 1.01-1.72)., Conclusions: Patients experiencing ADRs leading to ED visits are commonly old, multi-morbid and multi-medicated. CNS drugs may be more relevant than prior expected. With calculating ORs, we could replicate involvement of antineoplastic agents, antithrombotics, antibiotics, systemic glucocorticoids and non-opioid analgesics as frequently suspected for ADRs in EDs., Trial Registration: DRKS-ID: DRKS00008979.

Background: Although there is evidence that the CYP3A4*22 variant should be considered in tacrolimus dosing in renal transplantation, its impact beyond tacrolimus dose requirements remains controversial. Methods: In a cohort of 121 kidney transplant recipients, we analyzed the CYP3A4*1B , CYP3A4*22 , and CYP3A5*3 alleles and the ABCB1 variants 1236C>T , 2677G>T/A , and 3435C>T for their impact on exposure and dose requirement. Relevant clinical outcome measures such as acute rejection within the first year after transplantation, delayed graft function, and renal function at discharge (estimated glomerular filtration rate) were evaluated. Results: Extensive metabolizer (n = 17, CYP3A4*1/*1 carriers with at least one CYP3A5*1 allele) showed significantly higher tacrolimus dose requirement (P = 0.004) compared with both intermediate metabolizer (IM, n = 93, CYP3A5*3/*3 plus CYP3A4*1/*1 or CYP3A4*22 carriers plus one CYP3A5*1 allele), and poor metabolizer (n = 11, CYP3A4*22 allele in combination with CYP3A5*3/*3) after onset of therapy. Significantly higher dose requirement was observed in CYP3A5 expressers (P = 0.046) compared with non-expressers again at onset of therapy. Using the log additive genetic model, the area under the curve for the total observation period up to 16 days was significantly associated with the CYP3A5*3 genotype (P = 3.34 × 10 -4 ) as well as with the IM or extensive metabolizer phenotype (P = 1.54 × 10 -4 ), even after adjustment for multiple testing. Heterozygous carriers for CYP3A4*22 showed significantly higher areas under the curve than the CYP3A4*1/*1 genotype in the second week post-transplantation (adjusted P = 0.016). Regarding clinical outcomes, acute rejection was significantly associated with human leukocyte antigen mismatch (≥3 alleles; OR = 12.14, 95% CI 1.76, 525.21, P = 0.019 after correction for multiple testing). Graft recipients from deceased donors showed higher incidende of delayed graft function (OR 7.15, 95% CI 2.23, 30.46, adjusted P = 0.0008) and a lower estimated glomerular filtration rate at discharge (P = 0.0001). Tested CYP3A4 or CYP3A5 variants did not show any effects on clinical outcome parameters. ABCB1 variants did neither impact on pharmacokinetics nor on clinical endpoints. Conclusion: At our transplantation center, both CYP3A5*3 and, to a lesser extent, CYP3A4*22 affect tacrolimus pharmacokinetics early after onset of therapy with consequences for steady-state treatment in routine clinical practice., (Copyright © 2019 Abdel-Kahaar, Winter, Tremmel, Schaeffeler, Olbricht, Wieland, Schwab, Shipkova and Jaeger.)

Purpose: Severe hematotoxicity in patients with thiopurine therapy has been associated with genetic polymorphisms in the thiopurine S-methyltransferase (TPMT). While TPMT genetic testing is clinically implemented for dose individualization, alterations in the nudix hydrolase 15 (NUDT15) emerged as independent determinant of thiopurine-related hematotoxicity. Because data for European patients are limited, we investigated the relevance of NUDT15 in Europeans., Methods: Additionally to TPMT phenotyping/genotyping, we performed in-depth Sanger sequencing analyses of NUDT15 coding region in 107 European patients who developed severe thiopurine-related hematotoxicity as extreme phenotype. Moreover, genotyping for NUDT15 variants in 689 acute lymphoblastic leukemia (ALL) patients was performed., Results: As expected TPMT was the main cause of severe hematotoxicity in 31% of patients, who were either TPMT deficient (10%) or heterozygous carriers of TPMT variants (21%). By comparison, NUDT15 genetic polymorphism was identified in 14 (13%) patients including one novel variant (p.Met1Ile). Six percent of patients with severe toxicity carried variants in both TPMT and NUDT15. Among patients who developed toxicity within 3 months of treatment, 13% were found to be carriers of NUDT15 variants., Conclusion: Taken together, NUDT15 and TPMT genetics explain ~50% of severe thiopurine-related hematotoxicity, providing a compelling rationale for additional preemptive testing of NUDT15 genetics not only in Asians, but also in Europeans.

Background: Ulcerative proctitis may often be managed with topical salicylates or steroids alone, but in some patients, symptoms are persistent and severe. We analyzed the efficacy of tacrolimus suppositories in patients who had proven refractory to combined topical and systemic treatment., Methods: In this retrospective analysis, ulcerative colitis activity index (CAI), side effects, co-medication and drug levels were assessed in 43 patients with distal ulcerative colitis who received suppositories containing 2 mg of tacrolimus b.i.d. as add-on medication., Results: A total of 23 patients with ulcerative proctitis presented to follow-up within ≤50 days (mean 27.0 days) after suppositories were started. A decrease in CAI (from 8.0 to 5.5 points) was observed and 52.3% reached clinical remission (CAI ≤4). In total, 43 patients were available for analysis, of whom 9 had inflammation of the sigmoid colon as well. For the entire cohort, the median treatment duration was 76 days; 60% were in remission on the last documented visit. Serum measurements revealed a substantial tacrolimus level with a mean of 5.5 ng/mL. We observed one case of mild reversible acute kidney injury., Conclusions: In ulcerative proctitis, adding tacrolimus suppositories can be an effective and safe option when topical mesalazine, corticoid formulations and concomitant oral or parenteral medications have failed.

Intestinal fibrosis is thought to be a consequence of excessive tissue repair, and constitutes a common problem in patients with Crohn's disease (CD). While fibrosis seems to require inflammation as a prerequisite it is unclear whether the severity or persistence of inflammation influences the degree of fibrosis. Our aim was to investigate the role of sustained inflammation in fibrogenesis. For the initiation of fibrosis in vivo the models of Il10 -/- spontaneous colitis, dextran sodium sulfate (DSS)-induced chronic colitis and heterotopic transplantation were used. In Il10 -/- mice, we determined a positive correlation between expression of pro-inflammatory factors (Il1β, Tnf, Ifnγ, Mcp1 and Il6). We also found a positive correlation between the expression of pro-fibrotic factors (Col3a1 Col1a1, Tgfβ and αSma). In contrast, no significant correlation was determined between the expression of pro-inflammatory Tnf and pro-fibrotic αSma, Col1a1, Col3a1, collagen layer thickness and the hydroxyproline (HYP) content. Results from the DSS-induced chronic colitis model confirmed this finding. In the transplantation model for intestinal fibrosis a pronounced increase in Mcp1, inos and Il6 in Il10 -/- as compared to WT grafts was observed, indicating more severe inflammation in Il10 -/- grafts. However, the increase of collagen over time was virtually identical in both Il10 -/- and WT grafts. Severity of inflammation during onset of fibrogenesis did not correlate with collagen deposition. Although inflammation might be a pre-requisite for the initiation of fibrosis our data suggest that it has a minor impact on the progression of fibrosis. Our results suggest that development of fibrosis and inflammation may be disconnected. This may be important for explaining the inefficacy of anti-inflammatory treatments agents in most cases of fibrotic inflammatory bowel diseases (IBD).

A recent randomized study of whipworm Trichuris suis ova (TSO) in ileal Crohn's disease failed to demonstrate a clinical benefit compared to placebo after 12 weeks. Nonetheless, it has recently been shown that the spontaneous small intestinal inflammatory changes in Nod2 -/- (Nucleotide-binding oligomerization domain 2) mice could be substantially ameliorated when these mice were colonized by Trichuris muris. Those and complementary epidemiologic findings in humans lead to the hypothesis that helminths may be advantageous only in patients carrying defective NOD2 variants. Thus, 207 participants of the TSO trial were retrospectively genotyped for six functional NOD2 genetic variants to evaluate whether the treatment outcome differed in patients carrying NOD2 variants. We observed no significant association of the NOD2 variants or their haplotypes with clinical outcome after TSO treatment.

Human β-defensin 1 (hBD-1) is an antimicrobial peptide expressed by epithelia and hematopoietic cells. We demonstrated recently that hBD-1 shows activity against enteric commensals and Candida species only after its disulfide bonds have been reduced by thioredoxin (TRX) or a reducing environment. Here we show that besides TRX, glutaredoxin (GRX) is also able to reduce hBD-1, although with far less efficacy. Moreover, living intestinal and lymphoid cells can effectively catalyze reduction of extracellular hBD-1. By chemical inhibition of the TRX system or specific knockdown of TRX, we demonstrate that cell-mediated reduction is largely dependent on TRX. Quantitative PCR in intestinal tissues of healthy controls and inflammatory bowel disease patients revealed altered expression of some, although not all, redox enzymes, especially in ulcerative colitis. Reduced hBD-1 and TRX localize to extracellular colonic mucus, suggesting that secreted or membrane-bound TRX converts hBD-1 to a potent antimicrobial peptide in vivo.

The human intestinal tract is highly colonized by a vast number of microorganisms. Despite this permanent challenge, infections remain rare, due to a very effective barrier defense system. Essential effectors of this system are antimicrobial peptides and proteins (AMPs), which are secreted by intestinal epithelial and lymphoid cells, balance the gut microbial community, and prevent the translocation of microorganisms. Several antimicrobial proteins have already been identified in the gut. Nonetheless, we hypothesized that additional AMPs are yet to be discovered in this setting. Using biological screening based on antimicrobial function, here we identified competent antibacterial activity of high-mobility-group box 2 (HMGB2) against Escherichia coli. By recombinant expression, we confirmed this biologically new antimicrobial activity against different commensal and pathogenic bacteria. In addition, we demonstrated that the two DNA-binding domains (HMG boxes A and B) are crucial for the antibiotic function. We detected HMGB2 in several gastrointestinal tissues by mRNA analysis and immunohistochemical staining. In addition to the nuclei, we also observed HMGB2 in the cytoplasm of intestinal epithelial cells. Furthermore, HMGB2 was detectable in vitro in the supernatants of two different cell types, supporting an extracellular function. HMGB2 expression was not changed in inflammatory bowel disease but was detected in certain stool samples of patients, whereas it was absent from control individuals. Taken together, we characterized HMGB2 as an antimicrobial protein in intestinal tissue, complementing the diverse repertoire of gut mucosal defense molecules.