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Background: While the effectiveness of patient-reported outcome measures (PROMs) as an intervention to impact patient pathways has been established for cancer care, it is unknown for other indications. We assessed the cost-effectiveness of a PROM-based monitoring and alert intervention for early detection of critical recovery paths following hip and knee replacement., Methods and Findings: The cost-effectiveness analysis (CEA) is based on a multicentre randomised controlled trial encompassing 3,697 patients with hip replacement and 3,110 patients with knee replacement enrolled from 2019 to 2020 in 9 German hospitals. The analysis was conducted with a subset of 546 hip and 492 knee replacement cases with longitudinal cost data from 24 statutory health insurances. Patients were randomised 1:1 to a PROM-based remote monitoring and alert intervention or to a standard care group. All patients were assessed at 12-months post-surgery via digitally collected PROMs. Patients within the intervention group were additionally assessed at 1-, 3-, and 6-months post-surgery to be contacted in case of critical recovery paths. For the effect evaluation, a PROM-based composite measure (PRO-CM) was developed, combining changes across various PROMs in a single index ranging from 0 to 100. The PRO-CM included 6 PROMs focused on quality of life and various aspects of physical and mental health. The primary outcome was the incremental cost-effectiveness ratio (ICER). The intervention group showed incremental outcomes of 2.54 units PRO-CM (95% confidence interval (CI) [0.93, 4.14]; p = 0.002) for patients with hip and 0.87 (95% CI [-0.94, 2.67]; p = 0.347) for patients with knee replacement. Within the 12-months post-surgery period the intervention group had less costs of 376.43€ (95% CI [-639.74, -113.12]; p = 0.005) in patients with hip, and 375.50€ (95% CI [-767.40, 16.39]; p = 0.060) in patients with knee replacement, revealing a dominant ICER for both procedures. However, it remains unclear which step of the multistage intervention contributes most to the positive effect., Conclusions: The intervention significantly improved patient outcomes at lower costs in patients with hip replacements when compared with standard care. Further it showed a nonsignificant cost reduction in knee replacement patients. This reinforces the notion that PROMs can be utilised as a cost-effective instrument for remote monitoring in standard care settings., Trial Registration: Registration: German Register for Clinical Studies (DRKS) under DRKS00019916., Competing Interests: The project was funded by the Innovation Fund of the of Joint Federal Committee Germany (01NVF18016). Project funding was paid to the consortium institutions and covered the employment positions of LS, VS, LW, BL and CP. CP reports a salaried position with MedTech company Stryker that is separate and independent from his university research employment and position. FC reports an employment relation with Heartbeat Medical Solutions GmBH. GM reports receiving royalties or contracts, grants, consulting fees, payments for lectures and leadership in other boards, all outside the submitted work. RB reports being member of the government commission on modern and needs-based hospital care, outside the submitted work. DS reports receiving payments for lectures from Zimmer Biomet outside the submitted work. All other authors declare no competing interests., (Copyright: © 2024 Schöner et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: As patient-reported outcomes (PROs) gain prominence in hip and knee arthroplasty (HA and KA), studies indicate PRO variations between genders. Research on the specific health domains particularly impacted is lacking. Hence, we aim to quantify the gender health gap in PROs for HA/KA patients, differentiating between general health, health-related quality of life (HrQoL), physical functioning, pain, fatigue, and depression., Methods: The study included 3,693 HA patients (1,627 men, 2,066 women) and 3,110 KA patients (1,430 men, 1,680 women) receiving surgery between 2020 to 2021 in nine German hospitals, followed up until March 2022. Questionnaires used were: EQ-VAS, EQ-5D-5L, HOOS-PS, KOOS-PS, PROMIS-F-SF, PROMIS-D-SF, and a joint-specific numeric pain scale. PROs at admission, discharge, 12-months post-surgery, and the change from admission to 12-months (PRO-improvement) were compared by gender, tested for differences, and assessed using multivariate linear regressions. To enable comparability, PROs were transformed into z-scores (standard deviations from the mean)., Results: Observed differences between genders were small in all health domains and differences reduced over time. Men reported significantly better health versus women pre-HA (KA), with a difference of 0.252 (0.224) standard deviations from the mean for pain, 0.353 (0.243) for fatigue (PROMIS-F-SF), 0.327 (0.310) for depression (PROMIS-D-SF), 0.336 (0.273) for functionality (H/KOOS-PS), 0.177 (0.186) for general health (EQ-VAS) and 0.266 (0.196) for HrQoL (EQ-5D-5L). At discharge, the gender health gap reduced and even disappeared for some health dimensions since women improved in health to a greater extent than men. No gender health gap was observed in most PRO-improvements and at month 12., Conclusions: Men experiencing slightly better health than women in all health dimensions before surgery while experiencing similar health benefits 12-months post-surgery, might be an indicator of men receiving surgery inappropriately early, women unnecessarily late or both. As studies often investigate the PRO-improvement, they miss pre-surgery gender differences, which could be an important target for improvement initiatives in patient-centric care. Moreover, future research on cutoffs for meaningful between-group PRO differences per measurement time would aid the interpretation of gender health disparities., Trial Registration: German Register for Clinical Trials, DRKS00019916, 26 November 2019., (© 2024. The Author(s).)

Background: Toxic shock syndrome toxin-1 (TSST-1) is a superantigen produced by Staphylococcus aureus that causes the life-threatening toxic shock syndrome. The development of a safe and immunogenic vaccine against TSST-1 remains an unmet medical need. We investigated the safety, tolerability and immunogenicity of a recombinant TSST-1 variant vaccine (rTSST-1v) after 1-3 injections in healthy volunteers., Methods: In this randomised, double-blind, adjuvant-controlled, parallel-group, phase 2 trial, healthy adults aged 18-64 were randomly allocated to undergo 1-3 injections of either 10 or 100 μg rTSST-1v or Al(OH) 3 . The primary endpoint was safety and tolerability of rTSST-1v in the intention-to-treat population. The per-protocol population was used for the immunogenicity analysis. The trial is registered with EudraCT#: 2015-003714-24; ClinicalTrials.gov#: NCT02814708., Findings: Between April and November 2017,140 subjects were enrolled and 126 completed the trial. rTSST-1v showed a good safety and tolerability profile. A total of 855 systemic adverse events occurred, 280 of which were suspected related adverse events, without dose dependency. Two participants were discontinued early because of allergic reactions. Seroconversion occurred in >81% of subjects within 3 months of the first immunisation which was sustained until 18 months after the third immunisation in over 70% of subjects in the pooled low-dose group and in over 85% in the pooled high-dose group., Interpretation: rTSST-1v in cumulative doses of up to 300 μg was safe, well-tolerated and highly immunogenic. Two immunisations with 100 μg rTSST-1v provided the most persistent immune response and may be evaluated in future trials., Funding: Biomedizinische Forschung & Bio-Produkte AG funded this study., Competing Interests: GG, CS, CF, MMS, NB, UD, AT, and BJ declare no competing interests. Martha M. Eibl was the owner of Biomedizinische Forschung & Bio-Produkte AG. DH, LS, NM, and AR are employees of the study funder Biomedizinische Forschung & Bio-Produkte AG, a biotechnology company engaged in the development of BioMed rTSST-1v., (© 2024 Published by Elsevier Ltd.)

Importance: Although remote patient-reported outcome measure (PROM) monitoring has shown promising results in cancer care, there is a lack of research on PROM monitoring in orthopedics., Objective: To determine whether PROM monitoring can improve health outcomes for patients with joint replacement compared with the standard of care., Design, Setting, and Participants: A 2-group, patient-level randomized clinical trial (PROMoting Quality) across 9 German hospitals recruited patients aged 18 years or older with primary hip or knee replacement from October 1, 2019, to December 31, 2020, with follow-up until March 31, 2022., Interventions: Intervention and control groups received the standard of care and PROMs at hospital admission, discharge, and 12 months after surgery. In addition, the intervention group received PROMs at 1, 3, and 6 months after surgery. Based on prespecified PROM score thresholds, at these times, an automated alert signaled critical recovery paths to hospital study nurses. On notification, study nurses contacted patients and referred them to their physicians if necessary., Main Outcomes and Measures: The prespecified outcomes were the mean change in PROM scores (European Quality of Life 5-Dimension 5-Level version [EQ-5D-5L; range, -0.661 to 1.0, with higher values indicating higher levels of health-related quality of life (HRQOL)], European Quality of Life Visual Analogue Scale [EQ-VAS; range, 0-100, with higher values indicating higher levels of HRQOL], Hip Disability and Osteoarthritis Outcome Score-Physical Function Shortform [HOOS-PS; range, 0-100, with lower values indicating lower physical impairment] or Knee Injury and Osteoarthritis Outcome Score-Physical Function Shortform [KOOS-PS; range, 0-100, with lower values indicating lower physical impairment], Patient-Reported Outcomes Measurement Information System [PROMIS]-fatigue [range, 33.7-75.8, with lower values indicating lower levels of fatigue], and PROMIS-depression [range, 41-79.4, with lower values indicating lower levels of depression]) from baseline to 12 months after surgery. Analysis was on an intention-to-treat basis., Results: The study included 3697 patients with hip replacement (mean [SD] age, 65.8 [10.6] years; 2065 women [55.9%]) and 3110 patients with knee replacement (mean [SD] age, 66.0 [9.2] years; 1669 women [53.7%]). Exploratory analyses showed significantly better health outcomes in the intervention group on all PROMs except the EQ-5D-5L among patients with hip replacement, with a 2.10-point increase on the EQ-VAS in the intervention group compared with the control group (HOOS-PS, -1.86 points; PROMIS-fatigue, -0.69 points; PROMIS-depression, -0.57 points). Patients in the intervention group with knee replacement had a 1.24-point increase on the EQ-VAS, as well as significantly better scores on the KOOS-PS (-0.99 points) and PROMIS-fatigue (-0.84 points) compared with the control group. Mixed-effect models showed a significant difference in improvement on the EQ-VAS (hip replacement: effect estimate [EE], 1.66 [95% CI, 0.58-2.74]; knee replacement: EE, 1.71 [95% CI, 0.53-2.90]) and PROMIS-fatigue (hip replacement: EE, -0.65 [95% CI, -1.12 to -0.18]; knee replacement: EE, -0.71 [95% CI, -1.23 to -0.20]). The PROMIS-depression score was significantly reduced in the hip replacement group (EE, -0.60 [95% CI, -1.01 to -0.18])., Conclusions and Relevance: In this randomized clinical trial, the PROM-based monitoring intervention led to a small improvement in HRQOL and fatigue among patients with hip or knee replacement, as well as in depression among patients with hip replacement., Trial Registration: Deutsches Register Klinischer Studien ID: DRKS00019916.

Ice nucleation (IN) active bacteria such as Pseudomonas syringae promote the growth of ice crystals more effectively than any material known. Using the specialized ice nucleation protein (INP) InaZ, P. syringae-the well studied epiphytic plant pathogen-attacks plants by frost damage and, likewise fascinating, drives ice nucleation within clouds when airborne in the atmosphere by linkage to the Earth's water cycle. While ice nucleation proteins play a tremendous role for life on the planet, the molecular details of their activity on the bacterial membrane surface are largely unknown. Bacterial ghosts (BGs) derived from Escherichia coli can be used as simplified model systems to study the mode of action of InaZ. In this work, the authors used BGs to study the role of InaZ localization on the luminal side of the bacterial inner membrane. Naturally, P. syringae INPs are displayed on the surface of the outer membrane; so in contrast, the authors engineered an N-terminal truncated form of inaZ lacking the transport sequence for anchoring of InaZ on the outer membrane. This construct was fused to N- and C-terminal inner membrane anchors and expressed in Escherichia coli C41. The IN activity of the corresponding living recombinant E. coli catalyzing interfacial ice formation of supercooled water at high subzero temperatures was tested by a droplet-freezing assay and surface spectroscopy. The median freezing temperature (T 50 ) of the parental living E. coli C41 cells without INP was detected at -20.1 °C and with inner membrane anchored INPs at a T 50 value between -7 and -9 °C, demonstrating that the induction of IN from the inside of the bacterium by inner membrane anchored INPs facing the luminal inner membrane side is very similar to IN induced by bacterial INPs located at the outer membrane. Bacterial ghosts derived from these different constructs showed first droplet freezing values between -6 and -8 °C, whereas E. coli C41 BGs alone without carrying inner membrane anchored INPs exhibit a T 50 of -18.9 °C. Sum frequency generation spectroscopy showed structural ordered water at the BG/water interface, which increased close to the water melting point. Together, this indicates that the more efficient IN of INP-BGs compared to their living parental strains can be explained by the free access of inner membrane anchored INP constructs to ultrapure water filling the inner space of the BGs.

In a concept study the ability to induce heterogeneous ice formation by Bacterial Ghosts (BGs) from Escherichia coli carrying ice nucleation protein InaZ from Pseudomonas syringae in their outer membrane was investigated by a droplet-freezing assay of ultra-pure water. As determined by the median freezing temperature and cumulative ice nucleation spectra it could be demonstrated that both the living recombinant E. coli and their corresponding BGs functionally display InaZ on their surface. Under the production conditions chosen both samples belong to type II ice-nucleation particles inducing ice formation at a temperature range of between -5.6 °C and -6.7 °C, respectively. One advantage for the application of such BGs over their living recombinant mother bacteria is that they are non-living native cell envelopes retaining the biophysical properties of ice nucleation and do no longer represent genetically modified organisms (GMOs).

In this study, we describe the construction of the first genetically modified mutant of a halovirus infecting haloalkaliphilic Archaea By random choice, we targeted ORF79, a currently uncharacterized viral gene of the haloalkaliphilic virus ϕCh1. We used a polyethylene glycol (PEG)-mediated transformation method to deliver a disruption cassette into a lysogenic strain of the haloalkaliphilic archaeon Natrialba magadii bearing ϕCh1 as a provirus. This approach yielded mutant virus particles carrying a disrupted version of ORF79. Disruption of ORF79 did not influence morphology of the mature virions. The mutant virus was able to infect cured strains of N. magadii , resulting in a lysogenic, ORF79-disrupted strain. Analysis of this strain carrying the mutant virus revealed a repressor function of ORF79. In the absence of gp79, onset of lysis and expression of viral proteins occurred prematurely compared to their timing in the wild-type strain. Constitutive expression of ORF79 in a cured strain of N. magadii reduced the plating efficiency of ϕCh1 by seven orders of magnitude. Overexpression of ORF79 in a lysogenic strain of N. magadii resulted in an inhibition of lysis and total absence of viral proteins as well as viral progeny. In further experiments, gp79 directly regulated the expression of the tail fiber protein ORF34 but did not influence the methyltransferase gene ORF94. Further, we describe the establishment of an inducible promoter for in vivo studies in N. magadii IMPORTANCE Genetic analyses of haloalkaliphilic Archaea or haloviruses are only rarely reported. Therefore, only little insight into the in vivo roles of proteins and their functions has been gained so far. We used a reverse genetics approach to identify the function of a yet undescribed gene of ϕCh1. We provide evidence that gp79, a currently unknown protein of ϕCh1, acts as a repressor protein of the viral life cycle, affecting the transition from the lysogenic to the lytic state of the virus. Thus, repressor genes in other haloviruses could be identified by sequence homologies to gp79 in the future. Moreover, we describe the use of an inducible promoter of N. magadii Our work provides valuable tools for the identification of other unknown viral genes by our approach as well as for functional studies of proteins by inducible expression., (Copyright © 2017 American Society for Microbiology.)