The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020.

Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non-pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression-free survival and tumor response were summarized in meta-analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33-4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72-0.79, I2  = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000-2005; 41% in 2016-2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement.

Effect of different decellularization protocols on reendothelialization with human cells for a perfused renal bioscaffold of the rat.

BACKGROUND: Scaffolds for tissue engineering can be received by whole organ decellularization while maintaining the site-specific extracellular matrix and the vascular tree. One among other decellularization techniques is the perfusion-based method using specific agents e.g. SDS for the elimination of cellular components. While SDS can disrupt the composition of the extracellular matrix and impair the adherence and growth of site-specific cells there are indications that xenogeneic cell types may benefit from protein denaturation by using higher detergent concentrations. The aim of this work is to investigate the effect of two different SDS-concentrations (i.e. 0.66% and 3%) on the ability of human endothelial cells to adhere and proliferate in an acellular rat kidney scaffold. MATERIAL AND METHODS: Acellular rat kidney scaffold was obtained by perfusion-based decellularization through the renal artery using a standardized protocol including SDS at concentrations of 0.66% or 3%. Subsequently cell seeding was performed with human immortalized endothelial cells EA.hy 926 via the renal artery. Recellularized kidneys were harvested after five days of pressure-controlled dynamic culture followed sectioning, histochemical and immunohistochemical staining as well as semiquantitative analysis. RESULTS: Efficacy of decellularization was verified by absence of cellular components as well as preservation of ultrastructure and adhesive proteins of the extracellular matrix. In semiquantitative analysis of recellularization, cell count after five days of dynamic culture more than doubled when using the gentle decellularization protocol with a concentration of SDS at 0.66% compared to 3%. Detectable cells maintained their endothelial phenotype and presented proliferative behavior while only a negligible fraction underwent apoptosis. CONCLUSION: Recellularization of acellular kidney scaffold with endothelial cells EA.hy 926 seeded through the renal artery benefits from gentle decellularization procedure. Because of that, decellularization with a SDS concentration at 0.66% should be preferred in further studies and coculture experiments.

Reduced heart rate variability in people with type 1 diabetes and elevated diabetes distress: Results from the longitudinal observational DIA-LINK1 study.

AIMS: People with type 1 diabetes have a higher risk for cardiovascular disease (CVD). Reduced heart rate variability (HRV) is a clinical marker for CVD. In this observational study using continuous HRV measurement across 26 days, we investigated whether psychological stressors (diabetes distress, depressive symptoms) and glycaemic parameters (hypo- and hyperglycaemic exposure, glycaemic variability and HbA1c ) are associated with lower HRV in people with type 1 diabetes. METHODS: Data from the non-interventional prospective DIA-LINK1 study were analysed. At baseline, depressive symptoms and diabetes distress were assessed. Glucose values and HRV were recorded daily for 26 days using continuous glucose monitoring (CGM) and a wrist-worn health tracker respectively. Multilevel modelling with participant as nesting factor was used to analyse associations between day-to-day HRV and diabetes distress, depressive symptoms and CGM-derived parameters. RESULTS: Data from 149 participants were analysed (age: 38.3 ± 13.1 years, HbA1c : 8.6 ± 1.9%). Participants with elevated diabetes distress had a significantly lower HRV across the 26 days compared to participants without elevated distress (ß = -0.28; p = 0.004). Elevated depressive symptoms were not significantly associated with HRV (ß = -0.18; p = 0.074). Higher daily exposure to hyperglycaemia (ß = -0.44; p = 0.044), higher average exposure to hypoglycaemia (ß = -0.18; p = 0.042) and higher HbA1c (ß = -0.20; p = 0.018) were associated with reduced HRV across the 26 days. Sensitivity analysis with HRV averaged across all days corroborated these results. CONCLUSIONS: Diabetes distress is a clinically meaningful psychosocial stressor that could play a role in the cardiovascular health of people with type 1 diabetes. These findings highlight the need for integrated psychosocial care in diabetes management.

The short- and long-term outcome after the surgical management of common bile duct stones in a tertiary referral hospital.

BACKGROUND: The removal of common bile duct stones by endoscopic retrograde cholangiopancreatography (ERCP) shows excellent results with low complication rates and is therefore considered a gold standard. However, in case of stones non-removable by ERCP, surgical extraction is needed. The surgical approach is still controversial and clinical guidelines are missing. This study aims to analyze the outcomes of patients treated with choledochotomy or hepaticojejunostomy for common bile duct stones. METHODS: All patients who underwent choledochotomy or hepaticojejunostomy for common bile duct stones at a tertiary referral hospital over 11 years were included. The analyzed data contains basic demographics, diagnostics, surgical parameters, length of hospitalization, and morbidity and mortality. RESULTS: Over the study period, 4375 patients underwent cholecystectomy, and 655 received an ERCP with stone extraction, with 48 of these patients receiving subsequent surgical treatment. ERCP was attempted in 23/30 (77%) of the choledochotomy patients pre/intraoperatively and 11/18 (56%) in hepaticojejunostomy patients. The 30-day major complication rate (Clavien-Dindo > II) was 1/30 (3%) in the choledochotomy group and 2/18 (11%) in the hepaticojejunostomy group. Complications after 30 days occurred in 3/30 (10%) patients and 2/18 (11%), respectively, and no mortality occurred. CONCLUSION: ERCP should still be considered the gold standard, although due to low short- and long-term morbidity rates, choledochotomy and hepaticojejunostomy represent effective surgical solutions for common bile duct stones.

Structural analysis of the intrinsically disordered splicing factor Spp2 and its binding to the DEAH-box ATPase Prp2.

The spliceosome consists of five small RNAs and more than 100 proteins. Almost 50% of the human spliceosomal proteins were predicted to be intrinsically disordered or to contain disordered regions, among them the G-patch protein Spp2. The G-patch region of Spp2 binds to the DEAH-box ATPase Prp2, and both proteins together are essential for promoting the transition from the Bact to the catalytically active B* spliceosome. Here we show by circular dichroism and nuclear magnetic resonance (NMR) spectroscopy that Spp2 is intrinsically disordered in solution. Crystal structures of a complex consisting of Prp2-ADP and the G-patch domain of Spp2 demonstrate that the G-patch gains a defined fold when bound to Prp2. While the N-terminal region of the G-patch always folds into an α-helix in five different crystal structures, the C-terminal part is able to adopt two alternative conformations. NMR studies further revealed that the N-terminal part of the Spp2 G-patch, which is the most conserved region in different G-patch proteins, transiently samples helical conformations, possibly facilitating a conformational selection binding mechanism. The structural analysis unveils the role of conserved residues of the G-patch in the dynamic interaction mode of Spp2 with Prp2, which is vital to maintain the binding during the Prp2 domain movements needed for RNA translocation.

Coordination of glucose monitoring, self-care behaviour and mental health: achieving precision monitoring in diabetes.

Monitoring of glucose plays an essential role in the management of diabetes. However, to fully understand and meaningfully interpret glucose levels, additional information on context is necessary. Important contextual factors include data on behaviours such as eating, exercise, medication-taking and sleep, as well as data on mental health aspects such as stress, affect, diabetes distress and depressive symptoms. This narrative review provides an overview of the current state and future directions of precision monitoring in diabetes. Precision monitoring of glucose has made great progress over the last 5 years with the emergence of continuous glucose monitoring (CGM), automated analysis of new glucose variables and visualisation of CGM data via the ambulatory glucose profile. Interestingly, there has been little progress in the identification of subgroups of people with diabetes based on their glycaemic profile. The integration of behavioural and mental health data could enrich such identification of subgroups to stimulate precision medicine. There are a handful of studies that have used innovative methodology such as ecological momentary assessment to monitor behaviour and mental health in people's everyday life. These studies indicate the importance of the interplay between behaviour, mental health and glucose. However, automated integration and intelligent interpretation of these data sources are currently not available. Automated integration of behaviour, mental health and glucose could lead to the identification of certain subgroups that, for example, show a strong association between mental health and glucose in contrast to subgroups that show independence of mental health and glucose. This could inform precision diagnostics and precision therapeutics. We identified just-in-time adaptive interventions as a potential means by which precision monitoring could lead to precision therapeutics. Just-in-time adaptive interventions consist of micro-interventions that are triggered in people's everyday lives when a certain problem is identified using monitored behaviour, mental health and glucose variables. Thus, these micro-interventions are responsive to real-life circumstances and are adaptive to the specific needs of an individual with diabetes. We conclude that, with current developments in big data analysis, there is a huge potential for precision monitoring in diabetes.

The bidirectional longitudinal association between depressive symptoms and HbA1c : A systematic review and meta-analysis.

AIM: To investigate whether there is a bidirectional longitudinal association of depression with HbA1c . METHODS: We conducted a systematic literature search in PubMed, PsycINFO, CINAHL and EMBASE for observational, longitudinal studies published from January 2000 to September 2020, assessing the association between depression and HbA1c in adults. We assessed study quality with the Newcastle-Ottawa-Scale. Pooled effect estimates were reported as partial correlation coefficients (rp ) or odds ratios (OR). RESULTS: We retrieved 1642 studies; 26 studies were included in the systematic review and eleven in the meta-analysis. Most studies (16/26) focused on type 2 diabetes. Study quality was rated as good (n = 19), fair (n = 2) and poor (n = 5). Of the meta-analysed studies, six investigated the longitudinal association between self-reported depressive symptoms and HbA1c and five the reverse longitudinal association, with a combined sample size of n = 48,793 and a mean follow-up of 2 years. Higher levels of baseline depressive symptoms were associated with subsequent higher levels of HbA1c (partial r = 0.07; [95% CI 0.03, 0.12]; I2 38%). Higher baseline HbA1c values were also associated with 18% increased risk of (probable) depression (OR = 1.18; [95% CI 1.12,1.25]; I2 0.0%). CONCLUSIONS: Our findings support a bidirectional longitudinal association between depressive symptoms and HbA1c . However, the observed effect sizes were small and future research in large-scale longitudinal studies is needed to confirm this association. Future studies should investigate the role of type of diabetes and depression, diabetes distress and diabetes self-management behaviours. Our results may have clinical implications, as depressive symptoms and HbA1c levels could be targeted concurrently in the prevention and treatment of diabetes and depression. REGISTRATION: PROSPERO ID CRD42019147551.

Evaluation of a Stepped Care Approach to Manage Depression and Diabetes Distress in Patients with Type 1 Diabetes and Type 2 Diabetes: Results of a Randomized Controlled Trial (ECCE HOMO Study).

INTRODUCTION: Depression is a common and serious complication of diabetes. Treatment approaches addressing the specific demands of affected patients are scarce. OBJECTIVE: The aim of this work was to test whether a stepped care approach for patients with diabetes and depression and/or diabetes distress yields greater depression reduction than treatment-as-usual. METHODS: Two-hundred and sixty patients with diabetes and elevated depressive symptoms (CES-D ≥16) and/or elevated diabetes distress (PAID ≥40) were randomized to stepped care for depression or diabetes treatment-as-usual. The primary outcome was the rate of meaningful depression reduction at the 12-month follow-up according to the HAMD (score <9 or reduction by ≥50%). Secondary outcomes were changes in depression scores (HAMD/CES-D), diabetes distress (PAID), diabetes acceptance (AADQ), well-being (WHO-5), quality of life (EQ-5D/SF-36), self-care behavior (SDSCA/DSMQ), HbA1c, and biomarkers of inflammation. RESULTS: One-hundred and thirty-one individuals were assigned to stepped care and 129 to treatment-as-usual. Overall, 15.4% were lost to follow-up. Meaningful depression reduction was observed in 80.2 versus 51.2% in stepped care versus treatment-as-usual (p < 0.001, intention-to-treat analysis). Of the secondary measures, the HAMD (∆ -3.2, p < 0.001), WHO-5 (∆ 1.5, p = 0.007), and AADQ (∆ -1.0, p = 0.008) displayed significant treatment effects, while effects on CES-D (∆ -2.3, p = 0.065), PAID (∆ -3.5, p = 0.109), and SDSCA (∆ 0.20, p = 0.081) were not significantly different. Both groups showed comparable changes in EQ-5D/SF-36, DSMQ, HbA1c, and biomarkers of inflammation (all p ≥ 0.19). CONCLUSIONS: The stepped care approach improved depression, well-being, and acceptance. The results support that increasing treatment intensity on demand is effective and can help provide more optimal treatment. The inclusion of diabetes-specific interventions may be beneficial for patients with diabetes and elevated depression.

Excellent clinical and radiological outcomes after both open flake refixation and autologous chondrocyte implantation following acute patella dislocation and concomitant flake fractures.

PURPOSE: To investigate clinical and magnetic resonance (MR) imaging results of patients undergoing patella stabilization with either open flake refixation (oFR) or autologous chondrocyte implantation (ACI) and concomitant soft tissue patella stabilization after sustaining primary, acute patella dislocation with confirmed chondral and/or osteochondral flake fractures. It was hypothesized that refixation will lead to better results than ACI at mid-term follow-up. METHODS: A retrospective chart review was conducted to identify all patients undergoing oFR or ACI after sustaining (osteo-)chondral flake fractures and concomitant soft tissue patella stabilization following primary, acute patella dislocation between 01/2012 and 09/2018 at the author's institution. Patients were excluded if they were aged < 14 years or > 30 and had previous knee surgeries at the index knee. Clinical outcomes were assessed using the Tegner activity score, Kujala score, subjective IKDC score, and the KOOS score at a minimum follow-up of 24 months postoperatively. MR images were assessed using the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) 2.0 knee score. Thirty patients were included in the study, with 16 patients assorted to the oFR group and 14 patients to the ACI group (Follow-up 81%). RESULTS: Demographic data did not show significant group differences (oFR: 6 females, 10 males; age 26.9 ± 5.6 years, FU: 57 months (27-97 months); ACI: 9 females, 5 males; age 25.5 ± 4.9 years, FU: 51 months (29-91 months); n.s.). Defect location was similar in both groups (oFR: 12 × patella/4 × lateral femoral condyle; ACI: 12/2; n.s.). Both groups showed excellent clinical outcomes, with no statistically significant difference between both the groups (oFR group vs. ACI group: Tegner: 5.1 ± 1.8 vs. 5.1 ± 1.4; Kujala: 86.1 ± 12.6 vs. 84.9 ± 9.1; IKDC: 83.8 ± 15.0 vs. 83.6 ± 11.3; KOOS: 83.3 ± 14.0 vs. 83.6 ± 12.0; n.s.). One patient in each group suffered a patella re-dislocation and needed revision surgery. The MOCART 2.0 score showed good results for the oFR group (68.2 ± 11.1) and the ACI group (61.1 ± 16.9) while no significant differences were noted between both the groups. The inter-rater reliability was excellent (0.847). CONCLUSION: Open refixation of (osteo-)chondral fragments in patients after sustaining acute patella dislocation with (osteo)-chondral flake fractures led to good clinical and radiological results at a minimum follow of 24 months, showing that it is a good surgical option in the treatment algorithm. However, if open refixation is not possible, ACI may be an excellent fallback option in these younger patients with equally good clinical and radiological outcomes, but requiring a second minimally invasive surgery. LEVEL OF EVIDENCE: III.

Autologous chondrocyte implantation combined with anterior cruciate ligament reconstruction: similar short-term results in comparison with isolated cartilage repair in ligament intact joints.

PURPOSE: Both acute ruptures of the anterior cruciate ligament (ACL) as well as chronic ACL insufficiency show a high association with focal cartilage defects of the knee. However, the results after combined ACL reconstruction and cartilage repair are not well investigated. The aim of the present study was to investigate the short-term outcomes after autologous chondrocyte implantation (ACI) in combination with ACL reconstruction and to compare the results with patients who underwent isolated ACI in ligament intact knees. METHODS: All patients who were registered in the German Cartilage Registry with ACI for focal cartilage defects in the knee joint in combination with ACL reconstruction and who completed the 24 month follow-up were included in the study group. A matched-pair procedure according to gender, defect location, defect size, and age was used to create a control group of patients with isolated ACI in ACL intact joints. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and the numeric analog scale for pain (NAS) were used to assess the preoperative state as well as the clinical outcomes 12 and 24 months after surgery. RESULTS: A total of 34 patients were included in both the study group (age mean 33.3 ± SD 8.8 years) and the control group (33.6 ± 8.4 years) with a median defect size of 466 (25%-75% IQR 375-600) mm2 and 425 (IQR 375-600) mm2, respectively. In comparison with the preoperative state (median 67, IQR 52-75), the study group showed a significant increase of the total KOOS after 12 months (78, IQR 70-86; p = 0.014) and after 24 months (81, IQR 70-84; p = 0.001). The NAS for pain did not change significantly in the postoperative course. In comparison with the control group there was no significant difference for the total KOOS neither preoperative (control group median 67, IQR 52-73) nor at any postoperative time point (12 months: 82, IQR 67-93; 24 months: 81, IQR 71-91). CONCLUSION: The clinical short-term outcomes after ACI at the knee joint in combination with ACL reconstruction are good and similar to the results after isolated ACI in ligament intact knees. LEVEL OF EVIDENCE: III.

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

Associations of Time in Range and Other Continuous Glucose Monitoring-Derived Metrics With Well-Being and Patient-Reported Outcomes: Overview and Trends.

Time in glucose ranges is increasingly relevant for research and clinical practice. Whereas the clinical validity of these metrics has been demonstrated with regard to long-term complications, their associations with patient-reported outcomes such as well-being, diabetes distress, and fear of hypoglycemia remain an open research question. This article reviews existing evidence on links between times in glycemic ranges and patient-reported outcomes. It also describes a novel research approach of using ecological momentary assessment to analyze on a more granular level in real time possible associations of these parameters of glycemic control and patient-reported outcomes. Such an approach could further our understanding of how glucose and patient-reported outcomes may be interconnected.

Suspension button constructs restore posterior knee laxity in solid tibial avulsion of the posterior cruciate ligament.

PURPOSE: Dislocated tibial avulsions of the posterior cruciate ligament (PCL) require surgical intervention. Several arthroscopic strategies are options to fix the fragment and restore posterior laxity, including two types of suspension button devices: adjustable (self-locking) and rigid knotted systems. Our hypothesis was that a rigid knotted button construct has superior biomechanical properties regarding laxity restoration compared with an adjustable system. Both techniques were compared with standard screw fixation and the native PCL. METHODS: Sixty porcine knees were dissected. The constructs were tested for elongation, stiffness, yield force, load to failure force, and failure mode in a material testing machine. Group N (native, intact PCL) was used as a control group. In group DB (Dogbone™), TR (Tightrope™), and S (screw), a standardized block osteotomy with the osteotomized fragment attached to the PCL was set. The DB and TR groups simulated using a suspension button system with either a rigid knotted (DB) or adjustable system (TR). These groups were compared to a screw technique (S) simulating antegrade screw fixation from posterior. RESULTS: Comparing the different techniques (DB, TR, S), no significant elongation was detected; all techniques achieved a sufficient posterior laxity restoration. Significant elongation in the DB and TR group was detected compared with the native PCL (N). In contrast, screw fixation did not lead to significant elongation. The stiffness, yield load, and load to failure force did not differ significantly between the techniques. None of the techniques reached the same level of yield load and load to failure force as the intact state. CONCLUSION: Arthroscopic suspension button techniques sufficiently restore the posterior laxity and gain a comparable construct strength as an open antegrade screw fixation.

Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis.

Importance: Convalescent plasma is a proposed treatment for COVID-19. Objective: To assess clinical outcomes with convalescent plasma treatment vs placebo or standard of care in peer-reviewed and preprint publications or press releases of randomized clinical trials (RCTs). Data Sources: PubMed, the Cochrane COVID-19 trial registry, and the Living Overview of Evidence platform were searched until January 29, 2021. Study Selection: The RCTs selected compared any type of convalescent plasma vs placebo or standard of care for patients with confirmed or suspected COVID-19 in any treatment setting. Data Extraction and Synthesis: Two reviewers independently extracted data on relevant clinical outcomes, trial characteristics, and patient characteristics and used the Cochrane Risk of Bias Assessment Tool. The primary analysis included peer-reviewed publications of RCTs only, whereas the secondary analysis included all publicly available RCT data (peer-reviewed publications, preprints, and press releases). Inverse variance-weighted meta-analyses were conducted to summarize the treatment effects. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation. Main Outcomes and Measures: All-cause mortality, length of hospital stay, clinical improvement, clinical deterioration, mechanical ventilation use, and serious adverse events. Results: A total of 1060 patients from 4 peer-reviewed RCTs and 10 722 patients from 6 other publicly available RCTs were included. The summary risk ratio (RR) for all-cause mortality with convalescent plasma in the 4 peer-reviewed RCTs was 0.93 (95% CI, 0.63 to 1.38), the absolute risk difference was -1.21% (95% CI, -5.29% to 2.88%), and there was low certainty of the evidence due to imprecision. Across all 10 RCTs, the summary RR was 1.02 (95% CI, 0.92 to 1.12) and there was moderate certainty of the evidence due to inclusion of unpublished data. Among the peer-reviewed RCTs, the summary hazard ratio was 1.17 (95% CI, 0.07 to 20.34) for length of hospital stay, the summary RR was 0.76 (95% CI, 0.20 to 2.87) for mechanical ventilation use (the absolute risk difference for mechanical ventilation use was -2.56% [95% CI, -13.16% to 8.05%]), and there was low certainty of the evidence due to imprecision for both outcomes. Limited data on clinical improvement, clinical deterioration, and serious adverse events showed no significant differences. Conclusions and Relevance: Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes. The certainty of the evidence was low to moderate for all-cause mortality and low for other outcomes.

Promising clinical and magnetic resonance imaging results after internal bracing of acute posterior cruciate ligament lesions in multiple injured knees.

PURPOSE: The purpose of this study was to evaluate the clinical and radiological outcomes of acute posterior cruciate ligament (PCL) lesions in multiple injured knees that were surgically treated with internal bracing. METHODS: Acute complete PCL lesions in multiple injured knees with subsequent internal-bracing treatment within 21 days between 2014 and 2016 were eligible for inclusion. At final follow-up, patients were assessed with Tegner, Lysholm, and IKDC scores. PCL stability and healing were verified with KT-2000, stress radiography and magnetic resonance imaging (MRI). RESULTS: Fourteen patients [mean age 37.4 (± 17.8; SD) years] were evaluated after a mean follow-up of 19.9 (± 7.7; SD) months. Thirteen patients suffered complete lesions of the PCL with concomitant ligamentous injuries (Schenck I: six cases, Schenck III M: five cases, Schenck IV N: one case, Schenck V: one case). Median Tegner, mean Lysholm and mean IKDC scores at follow-up were 4 (2-7; interquartile range), 69.1 (± 16.6; SD) and 68.9 (± 18.1; SD) respectively. Posterior translation averaged 5.8 (± 2.2; SD) mm with the KT 2000 and stress radiography showed a mean posterior tibial translation of 5.5 (± 4.1; SD) mm in the side to side comparison. MRI showed adequate PCL healing. CONCLUSIONS: Internal bracing as treatment for acute PCL ruptures in multiple injured knees showed adequate restoration of posterior tibial translation in a single-centre study including 14 cases. LEVEL OF EVIDENCE: IV.

PrgB promotes aggregation, biofilm formation, and conjugation through DNA binding and compaction.

Gram-positive bacteria deploy type IV secretion systems (T4SSs) to facilitate horizontal gene transfer. The T4SSs of Gram-positive bacteria rely on surface adhesins as opposed to conjugative pili to facilitate mating. Enterococcus faecalis PrgB is a surface adhesin that promotes mating pair formation and robust biofilm development in an extracellular DNA (eDNA) dependent manner. Here, we report the structure of the adhesin domain of PrgB. The adhesin domain binds and compacts DNA in vitro. In vivo PrgB deleted of its adhesin domain does not support cellular aggregation, biofilm development and conjugative DNA transfer. PrgB also binds lipoteichoic acid (LTA), which competes with DNA binding. We propose that PrgB binding and compaction of eDNA facilitates cell aggregation and plays an important role in establishment of early biofilms in mono- or polyspecies settings. Within these biofilms, PrgB mediates formation and stabilization of direct cell-cell contacts through alternative binding of cell-bound LTA, which in turn promotes establishment of productive mating junctions and efficient intra- or inter-species T4SS-mediated gene transfer.

Rituximab in primary central nervous system lymphoma-A systematic review and meta-analysis.

The CD-20 antibody rituximab is a standard component of treatment of non-Hodgkin B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). Primary DLBCL of the central nervous system, also called primary central nervous system lymphoma (PCNSL), is a DLBCL confined to the central nervous system. There has been debate whether intravenous rituximab accumulates sufficiently in the central nervous system to exert an effect. In this systematic review, we assess the benefits and harms of rituximab in the treatment of immunocompetent patients with PCNSL. By searching MEDLINE, CENTRAL, and ClincialTrials.gov up to March 2019, we identified randomized controlled trials (RCTs) investigating the effect of rituximab in patients with PCNSL. We extracted study characteristics and results, assessed risk of bias, performed trial-level random-effects meta-analyses, and graded the certainty of evidence. The protocol was registered with PROSPERO (CRD42019121965). Main outcomes were overall survival (time to death), progression-free survival (time to progression or death), quality of life, grades 3 and 4 toxicity, and treatment-related mortality. We included two RCTs with a total of 343 participants. Overall survival was not statistically significantly improved (HR 0.76; 95% CI, 0.52-1.12; low certainty), with 187 fewer to 39 more deaths after 2 years in 1000 treated patients. Low certainty of evidence indicated that rituximab improved progression-free survival (HR 0.65; 95% CI, 0.45-0.95), which translated into 137 fewer progressions or deaths after 2 years in 1000 treated patients (231 to 18 fewer). None of the RCTs provided data on quality of life. We found no evidence that rituximab increased grades 3 and 4 toxicity or treatment-related mortality (RR 0.53; 95% CI, 0.20-1.37; low certainty). Overall, the available evidence suggests with low certainty that rituximab in combination with methotrexate-based chemotherapy may improve progression-free survival in immunocompetent patients with newly diagnosed PCNSL, the pooled effect estimates did not show evidence for improvement of overall survival.

Intramedullary Cortical Button Repair for Distal Biceps Tendon Rupture: A Single-Center Experience.

PURPOSE: The aim of this retrospective study was to evaluate the clinical outcome and complication rate of intramedullary cortical button repair for distal biceps tendon rupture (partial and complete tears). METHODS: Between 2010 and 2014, a total of 28 patients with an acute distal biceps tendon rupture underwent intramedullary cortical button repair. Twenty-four patients (mean age, 49 years) with a mean follow-up of 28 months were included in the study. Twenty patients were examined clinically and by maximum isometric strength testing in flexion (at 90°) and supination of both arms. Twenty-four patients completed functional scores including the Mayo Elbow Performance Score (MEPS), the Andrews-Carson-Score (ACS) and the shortened Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire. Furthermore, follow-up radiographs of 24 patients were analyzed. RESULTS: Compared with the contralateral elbow, the active range of motion (ROM) was the same. The mean strength for flexion was 100.8% ± 14% and for supination 93.1% ± 22% compared with the uninjured side. The mean MEPS for all patients was 95.6 ± 8.2, the mean ACS 194.2 ± 9.4 and the QuickDASH 3.8 ± 7.6. Heterotopic ossification (HO) was seen on radiographs in 46% of patients, but was symptomatic in only 1 patient. One patient suffered a tendon rerupture, and 1 asymptomatic button migration was seen in the follow-up. CONCLUSIONS: Intramedullary cortical button repair provides good results with respect to strength, ROM, and functional outcomes. Because the posterior cortex is not violated, the risk of iatrogenic posterior interosseous nerve injury is minimized. However, the patient should be warned of a high prevalence of postoperative HO. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Improving results in rat fracture models: enhancing the efficacy of biomechanical testing by a modification of the experimental setup.

BACKGROUND: Animal fracture models, primarily performed in rats, are crucial to investigate normal and pathological bone healing. However, results of biomechanical testing representing a major outcome measure show high standard deviations often precluding statistical significance. Therefore, the aim of our study was a systematical examination of biomechanical characteristics of rat femurs during three-point bending. Furthermore, we tried to reduce variation of results by individually adapting the span of bearing and loading areas to the bone's length. METHODS: We examined 40 paired femurs of male Wistar-rats by DXA (BMD and BMC of the whole femur) and pQCT-scans at the levels of bearing and loading areas of the subsequent biomechanical three-point bending test. Individual adjustment of bearing and loading bars was done respecting the length of each specimen. Subgroups of light (< 400 g, n = 22) and heavy (> 400 g, n = 18) animals were formed and analysed separately. We furthermore compared the results of the individualised bending-setting to 20 femurs tested with a fix span of 15 mm. RESULTS: Femurs showed a length range of 34 to 46 mm. The failure loads ranged from 116 to 251 N (mean 175.4 ± 45.2 N; heavy animals mean 221 ± 18.9 N; light animals mean 138.1 ± 16.4 N) and stiffness ranged from 185 N/mm to 426 N/mm (mean 315.6 ± 63 N/mm; heavy animals mean 358.1 ± 34.64 N/mm; light animals mean 280.8 ± 59.85 N/mm). The correlation of densitometric techniques and failure loads was high (DXA R2 = 0.89 and pQCT R2 = 0.88). In comparison to femurs tested with a fix span, individual adaptation of biomechanical testing homogenized our data significantly. Most notably, the standard deviation of failure loads (221 ± 18.95 N individualized setting vs. 205.5 ± 30.36 N fixed) and stiffness (358.1 ± 34.64 N/mm individualized setting vs. 498.5 ± 104.8 N/mm fixed) was reduced by at least one third. CONCLUSIONS: Total variation observed in any trait reflects biological and methodological variation. Precision of the method hence affects the statistical power of the study. By simply adapting the setting of the biomechanical testing, interindividual variation could be reduced, which improves the precision of the method significantly.