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Background and objectives The modified Rankin Scale (mRS) is one of the most frequently used outcome measures in trials in patients with an aneurysmal subarachnoid hemorrhage (aSAH). The assessment method of the mRS is often not clearly described in trials, while the method used might influence the mRS score. The aim of this study is to evaluate the inter-method reliability of different assessment methods of the mRS. Methods This is a prospective, randomized, multicenter study with follow-up at 6 weeks and 6 months. Patients aged ≥ 18 years with aSAH were randomized to either a structured interview or a self-assessment of the mRS. Patients were seen by a physician who assigned an mRS score, followed by either the structured interview or the self-assessment. Inter-method reliability was assessed with the quadratic weighted kappa score and percentage of agreement. Assessment of feasibility of the self-assessment was done by a feasibility questionnaire. Results The quadratic weighted kappa was 0.60 between the assessment of the physician and structured interview and 0.56 between assessment of the physician and self-assessment. Percentage agreement was, respectively, 50.8 and 19.6%. The assessment of the mRS through a structured interview and by self-assessment resulted in systematically higher mRS scores than the mRS scored by the physician. Self-assessment of the mRS was proven feasible. Discussion The mRS scores obtained with different assessment methods differ significantly. The agreement between the scores is low, although the reliability between the assessment methods is good. This should be considered when using the mRS in clinical trials. Trial registration www.trialregister.nl; Unique identifier: NL7859.

BACKGROUND: In patients with aneurysmal subarachnoid haemorrhage, short-term antifibrinolytic therapy with tranexamic acid has been shown to reduce the risk of rebleeding. However, whether this treatment improves clinical outcome is unclear. We investigated whether ultra-early, short-term treatment with tranexamic acid improves clinical outcome at 6 months.METHODS: In this multicentre prospective, randomised, controlled, open-label trial with masked outcome assessment, adult patients with spontaneous CT-proven subarachnoid haemorrhage in eight treatment centres and 16 referring hospitals in the Netherlands were randomly assigned to treatment with tranexamic acid in addition to care as usual (tranexamic acid group) or care as usual only (control group). Tranexamic acid was started immediately after diagnosis in the presenting hospital (1 g bolus, followed by continuous infusion of 1 g every 8 h, terminated immediately before aneurysm treatment, or 24 h after start of the medication, whichever came first). The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin Scale, dichotomised into a good (0-3) or poor (4-6) clinical outcome. Both primary and safety analyses were according to intention to treat. This trial is registered at ClinicalTrials.gov, NCT02684812.FINDINGS: Between July 24, 2013, and July 29, 2019, we enrolled 955 patients; 480 patients were randomly assigned to tranexamic acid and 475 patients to the control group. In the intention-to-treat analysis, good clinical outcome was observed in 287 (60%) of 475 patients in the tranexamic acid group, and 300 (64%) of 470 patients in the control group (treatment centre adjusted odds ratio 0·86, 95% CI 0·66-1·12). Rebleeding after randomisation and before aneurysm treatment occurred in 49 (10%) patients in the tranexamic acid and in 66 (14%) patients in the control group (odds ratio 0·71, 95% CI 0·48-1·04). Other serious adverse events were comparable between groups.INTERPRETATION: In patients with CT-proven subarachnoid haemorrhage, presumably caused by a ruptured aneurysm, ultra-early, short-term tranexamic acid treatment did not improve clinical outcome at 6 months, as measured by the modified Rankin Scale.FUNDING: Fonds NutsOhra.

Background The adage is to use the largest anastomotic coupler device (coupler) size possible, since smaller an anastomosis might be more susceptible to thrombosis. It is unclear if this wisdom is supported by data. This study tests the hypothesis that there is no difference in the reported literature in thrombosis rate between different coupler sizes. Methods We searched PubMed, Embase, and the Cochrane Library. After screening 235 studies, we included 11 retrospective case-series. According to the criteria of Newcastle–Ottowa Scale, quality score ranged from 2 to 4 (out of 5) and funnel plots indicated publication bias. We included a total of 5930 coupled anastomoses. We calculated thrombosis rate per coupler diameter with exact confidence intervals (CIs). We regard non-overlapping CIs as a significant difference. Results Nine studies reported no difference in thrombosis rate based on coupler size. Two studies report a potentially greater thrombosis rates in smaller sizes: (1) 2.0 mm 27% (95% CI 17%–40%, 17/62 cases) vs. 3.0 mm 6.3% (95% CI 2.8%–12%, 8/126 cases) and (2) 1.5 mm 6.9% (95% CI 2.8%–14%, 7/101 cases) vs. 3.0 mm group 1.2% (95% CI 0.64%–2.1%, 13/1079). Conclusion There is some evidence that suggests that smaller coupler sizes are associated with greater thrombosis rate, but the current available evidence has limitations. Performing a second anastomosis, in case, the first anastomosis is performed with a coupler size of 1.0, 1.5, or even 2.0 mm, can potentially reduce this rate, however, this remains to be determined.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 β [IL-1β] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy.

Background In some acute care trials, immediate informed consent is not possible, but deferred consent is often considered problematic. We investigated the opinions of patients, proxies, and physicians about deferred consent in an acute stroke trial to gain insight into its acceptability and effects. Methods Paper-based surveys were sent to patients who were randomly assigned in the Ultra-early Tranexamic Acid After Subarachnoid Hemorrhage (ULTRA) trial between 2015 and 2018 in two tertiary referral centers and to physicians of centers who agreed or declined to participate. The primary outcome measure was the proportion of respondents who agreed with deferral of consent in the ULTRA trial. Secondary outcomes included respondents’ preferred consent procedure for the ULTRA trial, the effect of deferred consent on trust in physicians and scientific research, and the willingness to participate in future research. Results Eighty-nine of 135 (66%) patients or proxies and 20 of 30 (67%) physicians completed the survey. Of these, 82 of 89 (92%) patients or proxies and 14 of 20 (70%) physicians agreed with deferral of consent in the ULTRA trial. When asked for their preferred consent procedure for the ULTRA trial, 31 of 89 (35%) patients or proxies indicated deferred consent, 15 of 89 (17%) preferred immediate informed consent, and 32 of 89 (36%) had no preference. None of the patients’ or proxies’ trust in physicians or scientific research had decreased because of the deferred consent procedure. Willingness to participate in future studies remained the same or increased in 84 of 89 (94%) patients or proxies. Conclusions A large majority of the surveyed patients and proxies and a somewhat smaller majority of the surveyed physicians agreed with deferred consent in the ULTRA trial. Deferred consent may enable acute care trials in an acceptable manner without decreasing trust in medicine. Future research should investigate factors facilitating the responsible use of deferred consent, such as in-depth interviews, to study the minority of participants who agreed with deferred consent but still preferred immediate informed consent.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas. Their resection may lead to serious morbidity. Incidence of postoperative motor and sensory deficits is unknown, and reconstruction aimed at restoring such deficits is infrequently carried out. OBJECTIVE: To identify the incidence and risk factors of postoperative morbidity in MPNST as well as the use and outcomes of functional reconstructions in these patients. METHODS: Postoperative function and treatment of MPNSTs diagnosed from 1988 to 2019 in 10 cancer centers was obtained. Two models were constructed evaluating factors independently associated with postoperative motor (

BACKGROUND: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the coronavirus disease 2019 (Covid-19) pandemic. In a phase 1-2 trial involving healthy adults, the NVX-CoV2373 nanoparticle vaccine had an acceptable safety profile and was associated with strong neutralizing-antibody and antigen-specific polyfunctional CD4+ T-cell responses. Evaluation of vaccine efficacy was needed in a setting of ongoing SARS-CoV-2 transmission. METHODS: In this phase 2a-b trial in South Africa, we randomly assigned human immunodeficiency virus (HIV)-negative adults between the ages of 18 and 84 years or medically stable HIV-positive participants between the ages of 18 and 64 years in a 1:1 ratio to receive two doses of either the NVX-CoV2373 vaccine (5 μg of recombinant spike protein with 50 μg of Matrix-M1 adjuvant) or placebo. The primary end points were safety and vaccine efficacy against laboratory-confirmed symptomatic Covid-19 at 7 days or more after the second dose among participants without previous SARS-CoV-2 infection. RESULTS: Of 6324 participants who underwent screening, 4387 received at least one injection of vaccine or placebo. Approximately 30% of the participants were seropositive for SARS-CoV-2 at baseline. Among 2684 baseline seronegative participants (94% HIV-negative and 6% HIV-positive), predominantly mild-to-moderate Covid-19 developed in 15 participants in the vaccine group and in 29 in the placebo group (vaccine efficacy, 49.4%; 95% confidence interval [CI], 6.1 to 72.8). Vaccine efficacy among HIV-negative participants was 60.1% (95% CI, 19.9 to 80.1). Of 41 sequenced isolates, 38 (92.7%) were the B.1.351 variant. Post hoc vaccine efficacy against B.1.351 was 51.0% (95% CI, -0.6 to 76.2) among the HIV-negative participants. Preliminary local and systemic reactogenicity events were more common in the vaccine group; serious adverse events were rare in both groups. CONCLUSIONS: The NVX-CoV2373 vaccine was efficacious in preventing Covid-19, with higher vaccine efficacy observed among HIV-negative participants. Most infections were caused by the B.1.351 variant. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT04533399.).

Woodlands in the Sudanian zone are under different management regimes, including total protection and controlled use mainly for feeding livestock and collecting fuelwood. This study conducted in Sudanian woodlands of Benin, around the Biosphere Reserve of Pendjari (BRP) aimed to: (i) determine the effect of selective stem thinning and branch pruning on the production of standing biomass of the woodlands; and (ii) assess the effectiveness of Sudanian woodlands to meet the fuelwood demand of the local population. Three vegetation units of about 80 m × 80 m each were identified, relatively uniform floristically and structurally, and representing three woodland development stages in Sudanian woodlands. Three random blocks (replications) of 20 m × 20 m each were demarcated within each vegetation unit. Each block was then divided into four treatment plots of 10 m × 10 m each. Treatments were randomly allocated and consisted of i) no thinning (T1), ii) 30% thinning (T2), iii) 60% thinning (T3), and iv) 100% thinning (T4). Standard branch pruning was applied to all remaining stems. The species name, diameter and/or height of the remaining stems ≥ 1 m height were recorded twice during the year period between 2015 and 2016. A semi-structured questionnaire was randomly applied to 150 households to record detailed information on the tree species as well as the quantity of fuelwood used or sold each day. Thinning and pruning had a positive effect on biomass production. The best biomass production (0.88 t/ha/year or 15,028.5 t/year for an area of 16,938.7 ha) was obtained with 60% thinning and pruning. Whatever the treatment, the biomass production did not meet the demand for fuelwood of the local population around the BRP. A deficit between 69.5% (T1) and 64.6% (T3) was observed. The mean per capita fuelwood needs of the households was 1.3 kg/day, and decreased with increasing household size. Extending the experimentation over a longer period (at least ten years), and establishing and using the allometric equations of recorded tree species will improve the estimation of the biomass production of these woodlands.

Background Malignant peripheral nerve sheath tumors (MPNST) carry a dismal prognosis and require early detection and complete resection. However, MPNSTs are prone to sampling errors and biopsies or resections are cumbersome and possibly damaging in benign peripheral nerve sheath tumor (BPNST). This study aimed to systematically review and quantify the diagnostic accuracy of noninvasive tests for distinguishing MPNST from BPNST. Methods Studies on accuracy of MRI, FDG-PET (fluorodeoxyglucose positron emission tomography), and liquid biopsies were identified in PubMed and Embase from 2000 to 2019. Pooled accuracies were calculated using Bayesian bivariate meta-analyses. Individual level-patient data were analyzed for ideal maximum standardized uptake value (SUVmax) threshold on FDG-PET. Results Forty-three studies were selected for qualitative synthesis including data on 1875 patients and 2939 lesions. Thirty-five studies were included for meta-analyses. For MRI, the absence of target sign showed highest sensitivity (0.99, 95% CI: 0.94-1.00); ill-defined margins (0.94, 95% CI: 0.88-0.98); and perilesional edema (0.95, 95% CI: 0.83-1.00) showed highest specificity. For FDG-PET, SUVmax and tumor-to-liver ratio show similar accuracy; sensitivity 0.94, 95% CI: 0.91-0.97 and 0.93, 95% CI: 0.87-0.97, respectively, specificity 0.81, 95% CI: 0.76-0.87 and 0.79, 95% CI: 0.70-0.86, respectively. SUVmax ≥3.5 yielded the best accuracy with a sensitivity of 0.99 (95% CI: 0.93-1.00) and specificity of 0.75 (95% CI: 0.56-0.90). Conclusions Biopsies may be omitted in the presence of a target sign and the absence of ill-defined margins or perilesional edema. Because of diverse radiological characteristics of MPNST, biopsies may still commonly be required. In neurofibromatosis type 1, FDG-PET scans may further reduce biopsies. Ideal SUVmax threshold is ≥3.5.

Aims: Empagliflozin (EMPA) demonstrates cardioprotective effects on diabetic myocardium but its infarct-sparing effects in normoglycemia remain unspecified. We investigated the acute and chronic effect of EMPA on infarct size after ischemia-reperfusion (I/R) injury and the mechanisms of cardioprotection in nondiabetic mice. Results: Chronic oral administration of EMPA (6 weeks) reduced myocardial infarct size after 30 min/2 h I/R (26.5% ± 3.9% vs 45.8% ± 3.3% in the control group, p < 0.01). Body weight, blood pressure, glucose levels, and cardiac function remained unchanged between groups. Acute administration of EMPA 24 or 4 h before I/R did not affect infarct size. Chronic EMPA treatment led to a significant reduction of oxidative stress biomarkers. STAT-3 (signal transducer and activator of transcription 3) was activated by Y(705) phosphorylation at the 10th minute of R, but it remained unchanged at 2 h of R and in the acute administration protocols. Proteomic analysis was employed to investigate signaling intermediates and revealed that chronic EMPA treatment regulates several pathways at reperfusion, including oxidative stress and integrin-related proteins that were further evaluated. Superoxide dismutase and vascular endothelial growth factor were increased throughout reperfusion. EMPA pretreatment (24 h) increased the viability of human microvascular endothelial cells in normoxia and on 3 h hypoxia/1 h reoxygenation and reduced reactive oxygen species production. In EMPA-treated murine hearts, CD31-/VEGFR2-positive endothelial cells and the pSTAT-3(Y705) signal derived from endothelial cells were boosted at early reperfusion. Innovation: Chronic EMPA administration reduces infarct size in healthy mice via the STAT-3 pathway and increases the survival of endothelial cells. Conclusion: Chronic but not acute administration of EMPA reduces infarct size through STAT-3 activation independently of diabetes mellitus.

Background Free tissue transfer is a commonly used procedure to reconstruct defects of the lower extremity. However, measures of postoperative care to promote flap maturity vary greatly. Dangling protocols tend to be highly divergent regarding the start, duration, schedules and monitoring of dangling, as well as the additional use of compression stockings or bandaging. The aim of this systematic review to review and evaluate current literature and to provide recommendations. Methods A systematic literature review was performed in accordance with PRISMA guidelines. Literature databases were searched for relevant articles about early ambulation following lower leg reconstruction. Results A total of 10 articles met the inclusion criteria: 2 randomized controlled trials and 7 case-series and one cohort study. The optimal start, duration and frequency of the dangling and compression procedures remain unclear, and so does the necessity of dangling and compression in general. An early and aggressive dangling procedure can be safely introduced on postoperative day (POD) 3, taking possible comorbidities into consideration. Early initiation might help shorten hospital stay, thereby reducing associated medical costs. Furthermore, compressive wrapping applied to the dangled leg seems to have a positive effect on flap perfusion and patient comfort. Conclusion Based on the current literature, it is suggested that an early and aggressive dangling procedure can safely be started on POD 3. Compression therapy during dangling increases perfusion and venous return of the free flap and increases the comfort of the patient.

INTRODUCTION: Tibial nerve entrapment is highly prevalent in diabetic subjects, resulting in significantly more neuropathic complaints and concomitant sensory disturbances. The study aim was to assess the impact of tarsal tunnel syndrome (TTS) and sensory loss at baseline on incident diabetic foot ulceration (DFU) in diabetic patients, since decompressing the tibial nerve might change the natural history of the disease.METHODS: In this study, 113 subjects with TTS (69 bilateral, 23 left-sided and 21 right-sided) participating in the prospective Rotterdam Diabetic Foot Study were compared to 303 diabetic controls without TTS, regarding incident DFU. Kaplan-Meier analysis and Cox's regression analysis were used to determine the independent hazard of baseline variables for new DFU.RESULTS: The median observation period was 836.5 days (IQR, 459-1077.8). In bilateral TTS, 17.4% (95% CI: 8.4-26.3%) of subjects experienced DFU versus 8.3% (95% CI: 5.1-11.6%) in controls (left or right) during follow-up (p = 0.0036). In left-sided TTS, no subjects versus 6.2% (95% CI: 3.4-9.0%) in controls had DFUs (p = 0.243). Incident ulceration was seen in 14.3% (95% CI: -0.7% to -29.3%) of right-sided TTS subjects versus 4.1% (95% CI: 1.5-6.3%) in controls (p = 0.034). Besides HbA1c, diminished sensation at the hallux independently increased the risk of ulceration, in patients with (HR: 4.692, p = 0.003) and without (HR: 2.307, p = 0.002) prior DFU.DISCUSSION: Elevated sensory thresholds in TTS render diabetic patients at a higher risk for DFU. With effective surgery, TTS is likely to be an amenable factor to potentially prevent diabetic foot disease and thereby reduce amputation risk.LEVEL OF EVIDENCE: II.

BACKGROUND: Rheumatoid arthritis (RA) of the wrist can lead to loss of wrist function and progressive joint destruction if inadequately treated. Arthroscopic synovectomy of the wrist may prove a valuable treatment for local inflammation. OBJECTIVE: The aim of this study was to perform a systematic review evaluating functional outcomes and pain following arthroscopic synovectomy of the wrist in RA patients. METHODS: A systematic review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) guidelines. MEDLINE, EMBASE, The Cochrane Library, Web of Science, and Google Scholar were searched for studies describing pain or functional outcomes following arthroscopic synovectomy of the wrist in RA patients (CRD42021270846). Risk of bias was assessed using the Methodological Index for Non-Randomized Studies. Data collection included patient characteristics, pain scores, wrist function questionnaires, secondary surgery, and complications. RESULTS: Six noncomparative cohort studies were included, with a total of 153 arthroscopic synovectomies. Disease duration of RA ranged from 32 to 89 months, and radiographic progression was mild to moderate. The Methodological Index for Non-Randomized Studies scores ranged from 8 to 10 out of 16. Mean follow-up ranged from 21 to 95 months. Improvements were seen in pooled mean visual analog scale pain score (from 7.7 to 2.2, p < 0.05), pooled mean Modified Mayo Wrist Score (from 43.3 to 70.4, p < 0.05), and the Disability of the Arm, Shoulder, and Hand (from 67.5 to 36.5, p < 0.05). Two complications occurred, and 5 patients required secondary surgery. CONCLUSIONS: There is limited evidence suggesting that arthroscopic synovectomy of the wrist improves wrist function and pain in patients with RA, with few complications. In centers with arthroscopic expertise, it can be considered as a treatment option.

Purpose Vascular inflammation and disturbed metabolism are observed in heart failure and type 2 diabetes mellitus. Glycolytic enzyme hexokinase II (HKII) is upregulated by inflammation. We hypothesized that SGLT2 inhibitors Canagliflozin (Cana), Empagliflozin (Empa) or Dapagliflozin (Dapa) reduces inflammation via HKII in endothelial cells, and that HKII-dependent inflammation is determined by ERK1/2, NF-κB. and/or AMPK activity in lipopolysaccharide (LPS)-stimulated human coronary artery endothelial cells (HCAECs). Methods HCAECs were pre-incubated with 3 μM or 10 μM Cana, 1 μM, 3 μM or 10 μM Empa or 0.5 μM, 3 μM or 10 μM Dapa (16 h) and subjected to 3 h LPS (1 μg/mL). HKII was silenced via siRNA transfection. Interleukin-6 (IL-6) release was measured by ELISA. Protein levels of HK I and II, ERK1/2, AMPK and NF-κB were detected using infra-red western blot. Results LPS increased IL-6 release and ERK1/2 phosphorylation; Cana prevented these pro-inflammatory responses (IL-6: pg/ml, control 46 ± 2, LPS 280 ± 154 p < 0.01 vs. control, LPS + Cana 96 ± 40, p < 0.05 vs. LPS). Cana reduced HKII expression (HKII/GAPDH, control 0.91 ± 0.16, Cana 0.71 ± 0.13 p < 0.05 vs. control, LPS 1.02 ± 0.25, LPS + Cana 0.82 ± 0.24 p < 0.05 vs. LPS). Empa and Dapa were without effect on IL-6 release and HKII expression in the model used. Knockdown of HKII by 37% resulted caused partial loss of Cana-mediated IL-6 reduction (pg/ml, control 35 ± 5, LPS 188 ± 115 p < 0.05 vs. control, LPS + Cana 124 ± 75) and ERK1/2 activation by LPS. In LPS-stimulated HCAECs, Cana, but not Empa or Dapa, activated AMPK. AMPK activator A769662 reduced IL-6 release. Conclusion Cana conveys anti-inflammatory actions in LPS-treated HCAECs through 1) reductions in HKII and ERK1/2 phosphorylation and 2) AMPK activation. These data suggest a novel anti-inflammatory mechanism of Cana through HKII.

PURPOSE: Delayed cerebral ischemia (DCI) remains a contributor to poor outcome following aneurysmal subarachnoid hemorrhage (aSAH). We evaluated cerebral circulation time (CCT) on digital subtraction angiography (DSA) during endovascular treatment (EVT) in WFNS grade I aSAH patients as a predictor of DCI.METHODS: Of 135 consecutive WNFS grade I aSAH patients, 90 were included. Age, gender, time of DSA from ictus ( 72 h), Fisher scale, severe vasospasm, development of DCI, EVD-dependent hydrocephalus, re-bleeding, and procedural complications were recorded. CCT was calculated retrospectively from multiphase DSA. Association with DCI was established through univariate and, subsequently, multivariable logistic regression. An optimal threshold value was identified using ROC curve analysis. Patient groups defined by threshold CCT value, DCI, and, subsequently, time of DSA from ictus were analyzed using χ2 and Fisher's exact test.RESULTS: CCT was the only significant factor in the multivariable logistic regression for the outcome development of DCI (OR/second increase in CCT = 1.46 [95% CI 1.14-1.86, p = .003]). When CCT was dichotomized at 8.5 s, the odds ratio for developing DCI was 7.12 (95% CI 1.93-26.34, p = .003) for CCT > 8.5 s compared with 8.5 s (all patients, p = .001; patients imaged before and after 72 h of ictus, p = .024 and p = .034, respectively).CONCLUSION: A CCT > 8.5 s on DSA during EVT in WFNS grade I aSAH patients is associated with an increased risk of developing DCI and may aid in the management of high-risk patients.

Background: The costs and health effects associated with lower extremity complications in diabetes mellitus are an increasing burden to society. In selected patients, lower extremity nerve decompression is able to reduce symptoms of neuropathy and the concomitant risks of diabetic foot ulcers and amputations. To estimate the health and economic effects of this type of surgery, the cost-effectiveness of this intervention compared to current nonsurgical care was studied. Methods: To estimate the incremental cost-effectiveness of lower extremity nerve decompression over a 10-year period, a Markov model was developed to simulate the onset and progression of diabetic foot disease in patients with diabetes and neuropathy who underwent lower extremity nerve decompression surgery, compared to a group undergoing current nonsurgical care. Mean survival time, health-related quality of life, presence or risk of lower extremity complications, and in-hospital costs were the outcome measures assessed. Data from the Rotterdam Diabetic Foot Study were used as current care, complemented with information from international studies on the epidemiology of diabetic foot disease, resource use, and costs, to feed the model. Results: Lower extremity nerve decompression surgery resulted in improved life expectancy (88,369.5 life-years versus 86,513.6 life-years), gain of quality-adjusted life-years (67,652.5 versus 64,082.3), and reduced incidence of foot complications compared to current care (490 versus 1087). The incremental cost-effectiveness analysis was -euro59,279.6 per quality-adjusted life-year gained, which is below the Dutch critical threshold of less than euro80,000 per quality-adjusted life-year. Conclusions: Decompression surgery of lower extremity nerves improves survival, reduces diabetic foot complications, and is cost saving and cost-effective compared with current care, suggesting considerable socioeconomic benefit for society.

Background Chronic low-grade inflammation, endothelial dysfunction and oxidative stress are major interactive pathways contributing to the pathogenesis of HFpEF. The sodium/glucose cotransporter 2 (SGLT2) inhibitor Empagliflozin (EMPA) inhibits inflammation-induced ROS generation in endothelial cells. EMPA also lowers Na+/H+ exchanger 1 (NHE1) activity and cytoplasmatic Na+ levels ([Na+]c) in cardiomyocytes. Purpose It is unknown how inflammation causes oxidative stress in endothelial cells and how EMPA can mitigate this. Here we examined for human endothelial cells whether 1) inflammatory mediators activate NHE1 activity, 2) increased [Na+]c mediates the inflammation-induced ROS production, and 3) EMPA reduces inflammation-induced ROS through NHE1 inhibition. Methods Human umbilical vein endothelial cells (HUVECs) and human coronary artery endothelial cells (HCAECs) were incubated with vehicle (V), 10ng/mL TNFα, 1μM EMPA or the canonical NHE1 inhibitor 10μM Cariporide. NHE1 activity was measured using the intracellular pH sensitive seminaphtharhodafluor fluorescence, by the pH recovery rate after an ammonium pulse. Intracellular ROS were detected by fluorescent live cell imaging in the presence of 10ng/mL TNFα or under increased Na+ conditions using 100nM ouabain (partial inhibition of the Na+/K+ pump). [Na+]c was measured using the sodium-binding benzofuran isophthalate 1 fluorescent probe. Results TNFα enhanced NHE1 activity in HCAECs (Fig a, in Δ[H+]/sec, V 0.81±0.14, TNFα 1.86±0.35 p Conclusions TNFα induces oxidative stress in EC through NHE1 activation and the consequently increased [Na+]c. EMPA acutely inhibits TNFα-induced ROS generation by inhibiting NHE1 and lowering [Na+]c in human cardiac and non-cardiac endothelial cells. Our data suggest that the previously reported cardiac effects of EMPA on NHE1 and [Na+]c are also present in endothelial cells. Endothelial ion homeostasis may be a valuable target to reduce inflammation-induced ROS generation and can constitute the pathway through which SGLT2 inhibitors offer protection in HFpEF patients, as examined in the EMPEROR-Preserved trial. Funding Acknowledgement Type of funding sources: None. Figure 1

Diabetic patients are at increased risk of developing coronary artery disease and experience worse clinical outcomes following acute myocardial infarction. Novel therapeutic strategies are required to protect the myocardium against the effects of acute ischaemia-reperfusion injury (IRI). These include one or more brief cycles of non-lethal ischaemia and reperfusion prior to the ischaemic event (ischaemic preconditioning [IPC]) or at the onset of reperfusion (ischaemic postconditioning [IPost]) either to the heart or to extracardiac organs (remote ischaemic conditioning [RIC]). Studies suggest that the diabetic heart is resistant to cardioprotective strategies, although clinical evidence is lacking. We overview the available animal models of diabetes, investigating acute myocardial IRI and cardioprotection, experiments investigating the effects of hyperglycaemia on susceptibility to acute myocardial IRI, the response of the diabetic heart to cardioprotective strategies e.g. IPC, IPost and RIC. Finally we highlight the effects of anti-hyperglycaemic agents on susceptibility to acute myocardial IRI and cardioprotection. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.

BACKGROUND: Based on randomized controlled trials (RCTs), clinical guidelines for the treatment of space-occupying hemispheric infarct employ age (≤60 yr) and time elapsed since stroke onset (≤48 h) as decisive criteria whether to perform decompressive craniectomy (DC). However, only few patients in these RCTs underwent DC after 48 h.OBJECTIVE: To study the association between the timing of DC and (un)favorable outcome in patients with space-occupying middle cerebral artery (MCA) infarct undergoing DC.METHODS: We performed a single-center cohort study from 2007 to 2017. Unfavorable outcome at 1 yr was defined as a Glasgow outcome scale 1 to 3. Additionally, we systematically reviewed the literature up to November 2018, including studies reporting on the timing of DC and other predictors of outcome. We performed Firth penalized likelihood and random-effects meta-analysis with odds ratio (OR) on unfavorable outcome.RESULTS: A total of 66 patients were enrolled. A total of 26 (39%) patients achieved favorable and 40 (61%) unfavorable outcomes (13 [20%] died). DC after 48 h since stroke diagnosis did not significantly increase the risk of unfavorable outcome (OR 0.8, 95% CI 0.3-2.3). Also, in the meta-analysis, DC after 48 h of stroke onset was not associated with a higher risk of unfavorable outcome (OR 1.11; 95% CI 0.89-1.38).CONCLUSION: The outcome of DC performed after 48 h in patients with malignant MCA infarct was not worse than the outcome of DC performed within 48 h. Contrary to current guidelines, we, therefore, advocate not to set a restriction of ≤48 h on the time elapsed since stroke onset in the decision whether to perform DC.

Background. Malignant peripheral nerve sheath tumors (MPNSTs) are rare and aggressive soft tissue sarcomas (STS) that, because of their origin, are operated by several surgical subspecialties. This may cause differences in oncologic treatment recommendations based on presentation. This study investigated these differences both within and between subspecialties. Methods. A survey was distributed among several (inter)national surgical societies. Differences within and between subspecialties were analyzed by χ2-tests. Results. In total, 30 surgical oncologists, 30 neurosurgeons, 85 plastic surgeons, and 29 “others” filled out the survey. Annual caseload, tumor sites operated, and fellowship training differed significantly between subspecialties. While most surgeons agreed upon preoperative use of MRI, the use of radiological staging and FDG-PET use differed between subspecialties. Surgical oncologists agreed upon core needle biopsies as an ideal type of biopsy while other subspecialties differed in opinion. On average, 53% of surgeons always consider preservation of function preoperatively, but 42% would never perform less extensive resections for function preservation. Respondents agreed that radiotherapy should be considered in tumor sizes >10 cm, microscopic, and macroscopic positive margins. A preferred sequence of radiotherapy administration differed between subspecialties. There was no consensus on indications and sequence of administration of chemotherapy in localized disease. Conclusion. Surgical oncologists generally agree on preoperative diagnostics; other subspecialties do not. Considering the preservation of function differed among all subspecialties. Surgeons do agree on some indications for radiotherapy, yet the use of chemotherapy in localized MPNSTs lacks consensus. A preferred sequence of multimodal therapy differs between and within surgical subspecialties, but surgical oncologists prefer neoadjuvant radiotherapy.

BackgroundMalignant peripheral nerve sheath tumors (MPNSTs) are rare yet highly aggressive soft tissue sarcomas. Children with neurofibromatosis type 1 (NF1) have a 10% lifetime risk for development of MPNST. Prognosis remains poor and survival seems worse for NF1 patients.MethodsThis narrative review highlights current practices and pitfalls in the management of MPNST in pediatric NF1 patients.ResultsPreoperative diagnostics can be challenging, but PET scans have shown to be useful tools. More recently, functional MRI holds promise as well. Surgery remains the mainstay treatment for these patients, but careful planning is needed to minimize postoperative morbidity. Functional reconstructions can play a role in improving functional status. Radiotherapy can be administered to enhance local control in selected cases, but care should be taken to minimize radiation effects as well as reduce the risk of secondary malignancies. The exact role of chemotherapy has yet to be determined. Reports on the efficacy of chemotherapy vary as some report lower effects in NF1 populations. Promisingly, survival seems to ameliorate in the last few decades and response rates of chemotherapy may increase in NF1 populations when administering it as part of standard of care. However, in metastasized disease, response rates remain poor. New systemic therapies are therefore desperately warranted and multiple trials are currently investigating the role of drugs. Targeted drugs are nevertheless not yet included in first line treatment.ConclusionBoth research and clinical efforts benefit from multidisciplinary approaches with international collaborations in this rare malignancy.

Background: Despite curative intents of treatment in localized malignant peripheral nerve sheath tumours (MPNSTs), prognosis remains poor. This study investigated survival and prognostic factors for overall survival in non-retroperitoneal and retroperitoneal MPNSTs in the Netherlands.Methods: Data were obtained from the Netherlands Cancer Registry and the Dutch Pathology Database. All primary MPNSTs were collected. Paediatric cases (age 5 cm, and deep-seated tumours were independently associated with worse survival. In retroperitoneal MPNSTs, male sex and age of 60+ years were independently associated with worse survival. Survival of R1 and that of R0 resections were similar for any location, whereas R2 resections were associated with worse outcomes. Radiotherapy and chemotherapy administrations were not associated with survival.Conclusion: In localized MPNSTs, risk stratification for survival can be done using several patient-and tumour-specific characteristics. Resectability is the most important predictor for survival in MPNSTs. No difference is present between R1 and R0 resections in both retroperitoneal and non-retroperitoneal MPNSTs. The added value of radiotherapy and chemotherapy is unclear. (C) 2019 The Author(s). Published by Elsevier Ltd.

Patients with subarachnoid hemorrhage (SAH) who are using antiplatelet drugs prior to their hemorrhage, often receive platelet transfusions to reverse antiplatelet effects prior to life-saving surgical interventions. However, little is known about the effect of platelet transfusion on patient outcome in these patients. The aim of this study is to investigate the effect of platelet transfusion on clinical outcome in patients with aneurysmal SAH (aSAH) who use antiplatelet agents. Consecutive adult patients with an aSAH admitted between 2011 and 2015 to the Academic Medical Center (Amsterdam, the Netherlands) were included. Demographic characteristics and in-hospital complications were compared and clinical outcome was assessed after six months. Multivariable logistic regression analysis was performed to correct for confounding variables. A total of 364 patients with an aSAH were included. Thirty-eight (10%) patients underwent platelet transfusion during admission. Patients receiving platelet transfusion had worse clinical outcome (modified Rankin Scale score 4–6) at six months compared to patients without platelet transfusion (65% versus 32%, odds ratio 4.0, 95% confidence interval:1.9–8.1). Multivariable logistic regression analysis showed that platelet transfusion during admission was associated with unfavorable clinical outcome after six months; adjusted for age, treatment modality, modified Fisher and WFNS on admission (adjusted odds ratio 3.3, 95% confidence interval: 1.3–8.4). In this observational study, platelet transfusion was associated with poor clinical outcome at six months after correcting for confounding influences. In aSAH patients who need surgical treatment at low risk of bleeding, the indication for platelet transfusion needs careful weighing of the risk-benefit-balance.

Summary Background Persistent neuropathic pain severely impacts physical functioning and quality of life (QoL). However, optimal surgical management of persistent neuropathic pain remains unclear. Extensive neurolysis with subsequent free muscle flap coverage, a new surgical procedure for neuropathic pain in the upper extremity, can be performed as a final option to establish pain reduction. Methods All consecutive patients who received extensive microsurgical neurolysis with subsequent free muscle flap for persistent neuropathic pain in the upper extremity between 2007 and 2014 were identified. Patient-reported upper extremity function and QoL were assessed using three questionnaires (36-item short-form health survey (SF-36), the disabilities of the arm, shoulder, and head questionnaire, and the Michigan hand outcomes questionnaire). Results: Fifteen patients were identified; 80% had neuropathic pain in the upper extremity due to nerve injury and a median of 3.0 previous surgeries (range 1–6). Sixty-seven percent developed some kind of complication, flap loss occurred in 22%, and all received a new free flap (one failed again). At last follow-up, pre- and postoperative visual analog scale (VAS) scores significantly differed (p = 0.002), and the median VAS at last follow-up was 1.5. Ten patients (67%) responded to the questionnaires after a median follow-up of 5.7 year (range 2.6–7.3 years). Patients on average reported poorer SF-36 "Physical Component Score" (PCS) and "Bodily Pain" compared to Dutch norms. Forty percent of patients reported still having always (very) severe pain. However, 64% had a postoperative decrease of at least 3.0 on VAS. Conclusion Extensive neurolysis with free muscle flap coverage for persistent neuropathic pain in the upper extremity showed a positive effect on pain reduction on short-term follow-up, and also at five-year follow-up. The impact of pain on functional outcomes remained. Nevertheless, 60% of the patients still experience sufficient pain reduction.

Summary Resection of nerves in extremity soft tissue sarcomas (STS) can lead to large functional deficits. Nerve reconstructions are rarely performed and little is known on their outcomes and indications for their use, even though they are essential in restoring sensation in limb salvage procedures. This study investigated current knowledge on functional outcomes and considerations to be taken before performing such reconstructions after sarcoma resection. A systematic search was performed in July 2018 in PubMed and Embase databases according to PRISMA guidelines. Search terms related to “soft tissue sarcoma” and “nerve reconstruction” were used. Studies evaluating functional outcomes after nerve grafting or nerve transfers in extremity STS were included. Qualitative synthesis was performed on all studies. Nineteen studies were included after full-text screening, describing 26 patients. The majority of patients had a nerve reconstruction in the upper extremity (65%). Perioperative radiotherapy was administered in 67% and perioperative chemotherapy in 29% of patients. Nerve grafting was most commonly performed (n = 23) and nerve transfers were performed in six patients. A wide variety of outcome measures were used. Most patients recovered at least some motor function and sensation, but success rates were higher after upper than lower extremity defects. Multimodal treatment did not preclude successful reconstructions. Nerve reconstructions in extremity STS allow the restoration of sensation in limb salvation, even motor nerve function can be restored with satisfactory function. The use of multimodal therapy does not seem to interfere with success. Nerve reconstructions should therefore be considered in STS patients.

Context Turner syndrome (TS) is a genetic condition that is reported to be associated with a prolonged rate-corrected QT (QTc) interval. Objectives To evaluate the prevalence of QTc prolongation in patients with TS, to compare their QTc intervals with healthy controls, and to investigate whether QTc prolongation is associated with a monosomy 45,X karyotype. Method Girls (n = 101) and women (n = 251) with TS visiting our center from 2004–2018 were included in this cross-sectional study. QT intervals of 12-leaded electrocardiograms were measured manually, using Bazett’s and Hodges formulas to correct for heart rate. A QTc interval of >450 ms for girls and >460 ms for women was considered prolonged. Corrected QT (QTc) intervals of patients with TS were compared to the QTc intervals of healthy girls and women from the same age groups derived from the literature. Results In total, 5% of the population with TS had a prolonged QTc interval using Bazett’s formula and 0% using Hodges formula. Mean QTc intervals of these patients were not prolonged compared with the QTc interval of healthy individuals from the literature. Girls showed shorter mean QTc intervals compared with women. We found no association between monosomy 45,X and prolongation of the QTc interval. Conclusions This study shows that the QTc interval in girls and women with TS is not prolonged compared with the general population derived from the literature, using both Bazett’s and Hodges formulas. Furthermore, girls show shorter QTc intervals compared with women, and a monosomy 45,X karyotype is not associated with QTc prolongation.

To identify risk factors for the development of diabetic peripheral neuropathy, systematic searches of PubMed, Embase, Web-of-Science, Cochrane and Google scholar databases were performed to conduct a meta-analysis of prospective studies that quantified major risk factors for diabetic peripheral neuropathy. Two authors independently extracted data for a random-effects meta-analysis. The standardized mean difference (SMD) and 95% CI for continuous data, and an odds ratio (OR) and 95% CI for dichotomous data were calculated. Of 7473 studies retrieved, 16 qualified studies were included. Contributing risk factors for developing diabetic peripheral neuropathy were age (SMD = 0.36; CI, 0.19 to 0.54;P P P P P = 0.03), haemoglobin A1c (SMD = 0.24; CI, 0.16 to 0.32;P P P P P P P = 0.02), hypertension (OR = 1.90; CI, 1.24 to 2.89;P P P P P

Objective Delayed reconstruction of the articular surface of the distal radius after trauma is a difficult problem for hand surgeons, and the common solution is usually partial or total wrist fusion, relieving pain but sacrificing motion. A relative novel reconstructive technique addresses the problem with a free microvascular osteochondral flap, using the 3rd metatarsal (3MT) bone. We investigate the possibility of using the same donor as a graft rather than a free flap. Methods This was a prospective clinical study of patients with isolated lunate facet damage following trauma who underwent surgery to remove the damaged articular surface and in whom the defect was reconstructed with an osteochondral graft from the base of the 3MT. All of the patients were followed-up at specific time intervals, with pre- and postoutcome measures taken, including pain, grip strength, range of motion (ROM), and postoperative radiographs and computed tomography (CT) scans to evaluate graft resorption and union. Only patients with isolated distal radius defects were included. Results The average follow-up period was of 51 months (range: 14–73 months). The results of 7 patients included an average improvement of the pain score in the visual analogue scale (VAS) by 3 points, with an average arc of motion of 135°. In all, there was radiographic evidence of full incorporation of the graft, with no resorption. Donor site morbidity was minimal. Conclusions The current gold standard for distal radius articular surface reconstruction remains a free 3MT osteochondral flap. However, our results using the base of the 3MT as a graft shows promise, and if further follow-up confirms comparable results to the free flap technique, this would mean an easier and equally robust reconstruction without complicated microsurgery. Level of Evidence Therapeutic, Level V case series.

Background Pernkopf's atlas of Anatomy contains anatomical plates with detailed images of the peripheral nerves. Its use is controversial due to the author's association with the "Third Reich" and the potential depiction of victims of the Holocaust. The ethical implications of using this atlas for informing surgical planning have not been assessed. Objective To (1) assess the role of Pernkopf's atlas in nerve surgeons' current practice and (2) determine whether a proposal for its ethical handling may provide possible guidance for use in surgery and surgical education. Methods Members of American Society for Peripheral Nerve and PASSIO Education (video-based learning platform) were surveyed and 182 responses collected. The survey introduced the historical origin of Pernkopf's atlas, and respondents were asked whether they would use the atlas under specific conditions to serve as a recommendation for its ethical handling. An anatomical plate comparison between Netter's and Pernkopf's atlases was performed to compare anatomical accuracy and surgical utility. Results Fifty-nine percent of respondents were aware of Pernkopf's atlas, with 13% currently using it. Aware of the historical facts, 69% were comfortable using the atlas, 15% uncomfortable, and 17% undecided. Additional information on conditions for an ethical approach to the use of the atlas led 76% of those "uncomfortable" and "undecided" to becoming "comfortable" with use. Conclusion While the use of Pernkopf's atlas remains controversial, a proposal detailing conditions for an ethical approach in its use provides new guidance in surgical planning and education.

Purpose Sonlicromanol is a phase IIB clinical stage compound developed for treatment of mitochondrial diseases. Its active component, KH176m, functions as an antioxidant, directly scavenging reactive oxygen species (ROS), and redox activator, boosting the peroxiredoxin-thioredoxin system. Here, we examined KH176m’s potential to protect against acute cardiac ischemia-reperfusion injury (IRI), compare it with the classic antioxidant N-(2-mercaptopropionyl)-glycine (MPG), and determine whether protection depends on duration (severity) of ischemia. Methods Isolated C56Bl/6N mouse hearts were Langendorff-perfused and subjected to short (20 min) or long (30 min) ischemia, followed by reperfusion. During perfusion, hearts were treated with saline, 10 μM KH176m, or 1 mM MPG. Cardiac function, cell death (necrosis), and mitochondrial damage (cytochrome c (CytC) release) were evaluated. In additional series, the effect of KH176m treatment on the irreversible oxidative stress marker 4-hydroxy-2-nonenal (4-HNE), formed during ischemia only, was determined at 30-min reperfusion. Results During baseline conditions, both drugs reduced cardiac performance, with opposing effects on vascular resistance (increased with KH176m, decreased with MPG). For short ischemia, KH176m robustly reduced all cell death parameters: LDH release (0.2 ± 0.2 vs 0.8 ± 0.5 U/min/GWW), infarct size (15 ± 8 vs 31 ± 20%), and CytC release (168.0 ± 151.9 vs 790.8 ± 453.6 ng/min/GWW). Protection by KH176m was associated with decreased cardiac 4-HNE. MPG only reduced CytC release. Following long ischemia, IRI was doubled, and KH176m and MPG now only reduced LDH release. The reduced protection against long ischemia was associated with the inability to reduce cardiac 4-HNE. Conclusion Protection against cardiac IRI by the antioxidant KH176m is critically dependent on duration of ischemia. The data suggest that with longer ischemia, the capacity of KH176m to reduce cardiac oxidative stress is rate-limiting, irreversible ischemic oxidative damage maximally accumulates, and antioxidant protection is strongly diminished.

Background: Cardioprotective strategies against ischemia-reperfusion injury (IRI) that remain effective in the clinical arena need to be developed. Therefore, maintained efficacy of cardioprotective strategies in the presence of drugs routinely used clinically (e.g., opiates, benzodiazepines, P2Y12 antagonist, propofol) need to be identified in preclinical models.Methods: Here, we examined the efficacy of promising cardioprotective compounds [fingolimod (Fingo), empagliflozin (Empa), melatonin (Mela) and nicotinamide riboside (NR)] administered i.v. as bolus before start ischemia. Infarct size as percentage of the area of risk (IS%) was determined following 25 min of left ascending coronary (LAD) ischemia and 2 h of reperfusion in a fentanyl-midazolam anesthetized IRI rat model. Plasma lactate dehydrogenase (LDH) activity at 30 min reperfusion was determined as secondary outcome parameter. Following pilot dose-response experiments of each compound (3 dosages, n = 4–6 animals per dosage), potential cardioprotective drugs at the optimal observed dosage were subsequently tested alone or in combination (n = 6–8 animals per group). The effective treatment was subsequently tested in the presence of a P2Y12 antagonist (cangrelor; n = 6/7) or propofol aesthesia (n = 6 both groups).Results: Pilot studies suggested potential cardioprotective effects for 50 mg/kg NR (p = 0.005) and 500 μg/kg melatonin (p = 0.12), but not for Empa or Fingo. Protection was subsequently tested in a new series of experiments for solvents, NR, Mela and NR+Mela. Results demonstrated that only singular NR was able to reduce IS% (30 ± 14 vs. 60 ± 16%, P = 0.009 vs. control). Mela (63 ± 18%) and NR+Mela (47 ± 15%) were unable to significantly decrease IS%. NR still reduced IS in the presence of cangrelor (51 ± 18 vs. 71 ± 4%, P = 0.016 vs. control), but lost protection in the presence of propofol anesthesia (62 ± 16 vs. 60 ± 14%, P = 0.839 vs. control). LDH activity measurements supported all IS% results.Conclusion: This observational study suggests that NR is a promising cardioprotective agent to target cardiac ischemia-reperfusion injury in clinical conditions employing opioid agonists, benzodiazepines and platelet P2Y12 inhibitors, but not propofol.

Background Literature is inconclusive regarding the association between antiplatelet agents use and outcome after aneurysmal subarachnoid hemorrhage. Aims To investigate the association between clinical outcome and prehemorrhage use in aneurysmal subarachnoid hemorrhage patients as well as the impact of thrombocyte transfusion on rebleed and clinical outcome. Methods Data were collected from prospective databases of two European tertiary reference centers for aneurysmal subarachnoid hemorrhage patients. Patients were divided into “antiplatelet-user” and “non-user” according to the use of acetylsalicylic acid prior to the hemorrhage. Primary outcome was poor clinical outcome at six months (Glasgow Outcome Scale score 1–3). Secondary outcomes were in-hospital mortality and impact of thrombocyte transfusion. Results Of the 1033 patients, 161 (15.6%) were antiplatelet users. The antiplatelet users were older with higher incidence of cardiovascular risk factors. Antiplatelet use was associated with poor outcome and in-hospital mortality. After correction for age, sex, World Federation of Neurosurgical Societies score, infarction and heart disorder, pre-hemorrhage acetylsalicylic acid use was only associated with poor clinical outcome at six months (adjusted OR 1.80, 95% CI 1.08–3.02). Thrombocyte transfusion was not associated with a reduction in rebleed or poor clinical outcome. Conclusion In this multicenter study, the prehemorrhage acetylsalicylic acid use in aneurysmal subarachnoid hemorrhage patients was independently associated with poor clinical outcome at six months. Thrombocyte transfusion was not associated with the rebleed rate or poor clinical outcome at six months.

Background Teenage parenting is recognised as one of the greatest health and social problems in South Africa. Research in South Africa has shown that by the age of 18 years, more than 30% of teens have given birth at least once. Teen mothers may feel disempowered because they are ‘othered’ and consequently, may develop forms of resistance which in most cases may inhibit their ability to parent. Social support is therefore, an imperative intervention for successful teen parenting but this is not clearly understood in South Africa. This study aimed to compare the relationship between parental efficacy and social support systems of single teen mothers across different family forms. Methods A quantitative methodology with a cross-sectional comparative correlation design was conducted with 160 single teen mothers who resided with a family in a low socio-economic community. The participants completed a self-report questionnaire that comprised of the Social Provisions Scale, and the Parenting Sense of Competence scale. Descriptive statistics and Pearson correlation were used to investigate the data. Results A significant positive relationship between social support and parental efficacy was found. When comparing different family forms, single teen mothers’ residing with one parent reported greater levels of parental efficacy and single teen mothers’ residing with two parents, re-counted high levels of social support under the subscales; guide, reliable and nurture. However, when computing for guardian-skip generation, results show that there is no significant relationship between parental efficacy and social support. As well as no correlation across subscales of social support. Conclusion The positive relationships between social support and parental efficacy are important for planning and applying parenting programmes amongst single teen mothers and facilitating awareness regarding the importance of social support and family forms when considering parenting practices.

To assess the relationship between the degree of loss of foot sensation at baseline and incidence of foot ulceration (DFU).Diabetic patients (n = 416) participating in the observational Rotterdam Diabetic Foot (RDF) Study were followed prospectively (median 955.5 days (IQR, 841.5-1121)). Subjects underwent sensory testing of the feet (39-item RDF Study Test Battery) at baseline and were assessed regarding incident DFU. Seven groups of incremental degree of sensory loss were distinguished, according to the RDF-39 sum score. Kaplan-Meier and regression analyses were used to determine the independent hazard of baseline variables for new DFU.40 participants developed DFUs. The mean incident rate of new-onset ulceration from study start was 4.5 (95%CI: 3.3 to 6.1) per 100 person-years, which increased significantly from 0 to 67.70 in the seven groups (p 0.0005). Predictors for DFUs were higher RDF-39 score (aHR: 1.173, p 0.0005) and kidney function (aHR: 1.022, p = 0.016). Prior DFU suggests increased mortality risk.The degree of sensory loss at baseline was associated with progression to DFU during follow-up. Grading the loss of sensation using the RDF Study Test Battery may result in a more precise risk stratification compared to the use of the 10 g monofilament according to current guidelines.

OBJECTIVE In patients presenting within 6 hours after signs and symptoms of suspected subarachnoid hemorrhage (SAH), CSF examination is judged to be no longer necessary if a noncontrast CT (NCCT) scan rules out SAH. In this study, the authors evaluated the performance of NCCT to rule out SAH in patients with positive CSF findings. METHODS Between January 2006 and April 2018, 1657 patients were admitted with a nontraumatic SAH. Of these patients, 1546 had positive SAH findings on the initial NCCT and 111 patients had an NCCT scan that was reported as negative in the acute setting, but with positive CSF examination for subarachnoid blood. Demographic data, World Federation of Neurosurgical Societies grade, and SAH time points (ictus, time of NCCT, and time of lumbar puncture) were collected. All 111 NCCT scans were reevaluated by an experienced neuroradiologist. RESULTS Of the 111 patients with positive CSF findings, SAH was initially missed on NCCT in 25 patients (23%). Reevaluation of 21 patients presenting within 6 hours of symptom onset confirmed NCCT negative findings in 12 (5 aneurysms), an aneurysmal SAH (aSAH) pattern in 8 (7 aneurysms), and a perimesencephalic pattern in 1 patient. Reevaluation of 90 patients presenting after 6 hours confirmed negative NCCT findings in 74 patients (37 aneurysms), aSAH pattern in 10 (4 aneurysms), and a perimesencephalic pattern in 6 (2 aneurysms). CONCLUSIONS CSF examination is still mandatory to rule out SAH as NCCT can fail to show blood, even within 6 hours after symptom onset. In addition, the diagnosis SAH was frequently missed during initial reporting.

BackgroundThe emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the Covid-19 pandemic. Evaluation of Covid-19 vaccine efficacy against SARS-CoV-2 variants is urgently needed to inform vaccine development and use.MethodsIn this phase 2a/b, multicenter, randomized, observer-blinded, placebo-controlled trial in South Africa, healthy human immunodeficiency virus (HIV)-negative adults (18 to 84 years) or medically stable people living with HIV (PLWH) (18 to 84 years) were randomized in a 1:1 ratio to receive two doses, administered 21 days apart, of either NVX-CoV2373 nanoparticle vaccine (5 µg recombinant spike protein with 50 µg Matrix-M1 adjuvant) or placebo. The primary endpoints were safety and vaccine efficacy ≥7 days following the second dose against laboratory-confirmed symptomatic Covid-19 in previously SARS-CoV-2 uninfected participants.ResultsA total of 4387 participants were randomized and dosed at least once, 2199 with NVX-CoV2373 and 2188 with placebo. Approximately 30% of participants were seropositive at baseline. Among 2684 baseline seronegative participants (94% HIV-negative; 6% PLWH), there were 15 and 29 predominantly mild to moderate Covid-19 cases in NVX-CoV2373 and placebo recipients, respectively; vaccine efficacy was 49.4% (95% confidence interval [CI]: 6.1 to 72.8). Efficacy in HIV-negative participants was 60.1% (95% CI: 19.9 to 80.1), and did not differ by baseline serostatus. Of the primary endpoint cases with available whole genome sequencing, 38 (92.7%) of 41 were the B.1.351 variant. Post-hoc vaccine efficacy against B.1.351 was 51.0% (95% CI: - 0.6 to 76.2) in HIV-negative participants. Among placebo recipients, the incidence of symptomatic Covid-19 was similar in baseline seronegative vs baseline seropositive participants during the first 2 months of follow-up (5.3% vs 5.2%). Preliminary local and systemic reactogenicity were primarily mild to moderate and transient, and higher with NVX-CoV2373; serious adverse events were rare in both groups.ConclusionsThe NVX-CoV2373 vaccine was efficacious in preventing Covid-19, which was predominantly mild to moderate and due to the B.1.351 variant, while evidence of prior infection with the presumptive original SARS-CoV-2 did not confer protection against probable B.1.351 disease. (Funded by Novavax, The Bill and Melinda Gates Foundation, and the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04533399)

Contains fulltext : 239064.pdf (Publisher’s version ) (Open Access) BACKGROUND: Proton magnetic resonance spectroscopy ((1) H-MRS) of the human heart is deemed to be a quantitative method to investigate myocardial metabolite content, but thorough validations of in vivo measurements against invasive techniques are lacking. PURPOSE: To determine measurement precision and accuracy for quantifications of myocardial total creatine and triglyceride content with localized (1) H-MRS. STUDY TYPE: Test-retest repeatability and measurement validation study. SUBJECTS: Sixteen volunteers and 22 patients scheduled for open-heart aortic valve replacement or septal myectomy. FIELD STRENGTH/SEQUENCE: Prospectively ECG-triggered respiratory-gated free-breathing single-voxel point-resolved spectroscopy (PRESS) sequence at 3 T. ASSESSMENT: Myocardial total creatine and triglyceride content were quantified relative to the total water content by fitting the (1) H-MR spectra. Precision was assessed with measurement repeatability. Accuracy was assessed by validating in vivo (1) H-MRS measurements against biochemical assays in myocardial tissue from the same subjects. STATISTICAL TESTS: Intrasession and intersession repeatability was assessed using Bland-Altman analyses. Agreement between (1) H-MRS measurements and biochemical assay was tested with regression analyses. RESULTS: The intersession repeatability coefficient for myocardial total creatine content was 41.8% with a mean value of 0.083% ± 0.020% of the total water signal, and 36.7% for myocardial triglyceride content with a mean value of 0.35% ± 0.13% of the total water signal. Ex vivo myocardial total creatine concentrations in tissue samples correlated with the in vivo myocardial total creatine content measured with (1) H-MRS: n = 22, r = 0.44; P

Cardioprotection; Drug development; Infarction Cardioprotección; Desarrollo de fármacos; Infarto Cardioprotecció; Desenvolupament de fàrmacs; Infart Acute myocardial infarction (AMI) and the heart failure (HF) which may follow are among the leading causes of death and disability worldwide. As such, new therapeutic interventions are still needed to protect the heart against acute ischemia/reperfusion injury to reduce myocardial infarct size and prevent the onset of HF in patients presenting with AMI. However, the clinical translation of cardioprotective interventions that have proven to be beneficial in preclinical animal studies, has been challenging. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic in vivo preclinical assessment of the efficacy of promising cardioprotective interventions prior to their clinical evaluation. To address this, we propose an in vivo set of step-by-step criteria for IMproving Preclinical Assessment of Cardioprotective Therapies (‘IMPACT’), for investigators to consider adopting before embarking on clinical studies, the aim of which is to improve the likelihood of translating novel cardioprotective interventions into the clinical setting for patient benefit. This article is based on the work from COST Action EU-CARDIOPROTECTION CA16225 supported by COST (European Cooperation in Science and Technology). DJH is supported by the Duke-National University Singapore Medical School, Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (NMRC/CSA-SI/0011/2017) and Collaborative Centre Grant scheme (NMRC/CGAug16C006). SL is supported by grants from the South African Department of Science and Technology and the South African National Research Foundation. SMD is supported by grants from the British Heart Foundation (PG/19/51/34493 and PG/16/85/32471). GH is supported by the German Research Foundation (SFB 1116 B8). MRM is supported by the Spanish Institute of Health Carlos III (FIS PI19/01196 and CIBER-CV). RS is supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [Project number 268555672—SFB 1213, Project B05]. PF is supported by the National Research, Development and Innovation Office of Hungary (Research Excellence Program—TKP, National Heart Program NVKP 16-1-2016-0017) and by the Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary, within the framework of the Therapeutic Development thematic program of the Semmelweis University.

Background : Pain after Morton neuroma surgery is difficult to treat. Targeted muscle reinnervation (TMR) is proposed as a treatment of painful neuromas. We hypothesized that motor branches innervating the lumbrical muscles of the foot could provide a potential acceptor site for TMR of the proximal sensory nerve affected in Morton neuroma. Methods : We dissected 5 fresh frozen cadavers from adult donors. We performed dissection as follows: (1) identification of the common digital nerves; (2) identification of the lateral plantar nerve and potential acceptor branches; (3) transecting the sensory nerve proximal to a potential neuroma site and transposing it to the acceptor branch; (4) determining the proportion of motor nerve fascicles in nerve specimen. Results : We were able to reach all sites of interest through a V-shaped incision placed at the nonweightbearing area of the foot. The common digital nerves and the location of the deep branch of the lateral plantar nerve was identical in all cadavers. In all of our cadavers we were able to transpose, either the second or the third common digital nerve, towards the deep branch of the lateral plantar nerve without any tension. Conclusion : We present a potential surgical technique for TMR in patients suffering from treatment resistant pain after Morton neuroma surgery with the deep branch of the lateral plantar nerve as the target nerve. This study is an anatomical cadaver study and therefore the success rate for pain reduction and the possible morbidity of this technique are unknown.

In recent years, the Department of Higher Education and Training in South Africa has undertaken several initiatives to increase the number and quality of Foundation Phase (Grades R–3) teachers. In this chapter, we discuss one such initiative, the development of a rural school to become a training site for pre-service student teachers. Over 3 years, we undertook case study research relating to the programme’s implementation. We used Cultural Historical Activity Theory as the theoretical framework to analyse the data. Central to this theory is the tensions that arise when a new activity is introduced into a so-called activity system, and we discuss the tensions that arose during the implementation of the development programme. We then highlight key themes that we drew from the data that related to the design of the programme, and we conclude by making recommendations for professional development programmes in educational contexts.

BACKGROUND This study aimed to (1) describe long-term patient-reported outcomes of surgically treated symptomatic radial sensory nerve neuromas on function, pain interference, pain intensity, and satisfaction; (2) assess which factors were associated with worse function, higher pain intensity, and more pain interference; and (3) describe the secondary surgery rate and factors associated with secondary surgery. METHODS The authors conducted a retrospective review of patients surgically treated for radial sensory nerve neuroma from 2002 to 2016 (n = 54). Twenty-five of these 54 patients completed a follow-up survey including the Patient-Reported Outcomes Measurement Information System (PROMIS) upper extremity, pain interference, and depression scales; numerical rating scale pain and satisfaction instruments; and the global rating scale of change, at a mean period of 10.7 ± 4.3 years after neuroma surgery. RESULTS The mean PROMIS scores were 45.0 ± 12.1 for upper extremity, 55.5 ± 10.3 for pain interference, and 49.9 ± 10.2 for depression, and were within 1 SD of the general population. Eight patients (32 percent) reported symptoms as unchanged or worse following neuroma surgery. The median numerical rating scale pain was 3 (interquartile range, 1 to 6) and the global rating scale of change satisfaction was 10 (interquartile range, 7 to 10). Older patients (p = 0.002) and patients with higher PROMIS pain interference (p < 0.001), higher numerical rating scale for pain (p = 0.012), and lower global rating scale of change scores (p = 0.01) had worse PROMIS upper extremity scores. The secondary surgery rate was 20 percent and was associated with the presence of multiple neuromas (p = 0.001). CONCLUSIONS Radial sensory nerve neuromas remain difficult to treat. They have a high secondary surgery rate (20 percent), with only 68 percent of patients reporting improvement after surgical intervention. Patient-reported outcomes after surgery are similar to conditions of the general population; however, the range of outcomes is wide.

Background and Purpose: Delayed cerebral ischemia (DCI) is a major contributor to the high morbidity in patients with aneurysmal subarachnoid hemorrhage (aSAH). Spreading depolarizations may play a role in DCI pathophysiology. Because patients with migraine are probably more susceptible to spreading depolarizations, we investigated whether patients with aneurysmal subarachnoid hemorrhage with migraine are at increased risk for DCI. Methods: We included patients with aneurysmal subarachnoid hemorrhage from 3 hospitals in the Netherlands. We assessed lifetime migraine history with a short screener. DCI was defined as neurological deterioration lasting >1 hour not attributable to other causes by diagnostic work-up. Adjustments were made for possible confounders in multivariable Cox regression analyses and adjusted hazard ratios (aHR) were calculated. We assessed the interaction effects of age and sex. Results: We included 582 patients (mean age 57 years, 71% women) mostly with mild to moderate aneurysmal subarachnoid hemorrhage of whom 108 (19%) had a history of migraine (57 with aura). Patients with migraine were not at increased risk of developing DCI compared with patients without migraine (22% versus 24%, aHR, 0.89 [95% CI, 0.56–1.43]). Additionally, no increased risk was found in patients with migraine with possible aura (aHR, 0.74 [95% CI, 0.39–1.43]), in women (aHR, 0.88 [95% CI, 0.53–1.45], P interaction =0.859), or in young patients aged P interaction =0.075). Conclusions: Patients with migraine are in general not at increased risk of DCI. Future studies should focus in particular on young SAH patients, in whom there might be an association between migraine history and development of DCI.

Residual limb pain (RLP) is associated with (partial) extremity amputations and is defined as pain felt in the remaining part of the amputated limb. A common cause of RLP is neuroma formation after nerve transections. Neuromas can be very painful and severely debilitating pathologies, preventing prosthetic use, reducing quality of life, and requiring medication. Residual limb pain and symptomatic neuromas are often not properly recognized by physicians explaining the varying prevalence in the literature. This systematic review and meta-analysis aim to provide a comprehensive overview of published literature on the prevalence of RLP and symptomatic neuroma after lower extremity amputation. Studies reporting the prevalence of RLP and symptomatic neuroma pain in patients who have had a lower extremity amputation published between 2000 and 2020 were identified in PubMed and Embase. Random-effects meta-analyses of proportions were performed to quantify the prevalence of RLP and symptomatic neuroma. Subgroups were identified and analysed. For RLP, the pooled prevalence was 59% (95% CI: 51-67). For symptomatic neuromas, the pooled prevalence was 15% (95% CI: 7-28). Residual limb pain subgroup analysis showed statistically significant higher prevalence in patients aged >50 years, follow-up >2 years, and in studies using a self-administered questionnaire for data collection. The prevalence of RLP and symptomatic neuroma in patients who have had a lower extremity amputation is 59% and 15%, respectively. Knowledge of their high prevalence may result in better awareness among physicians, in turn providing timely and adequate management.

Background And Purpose: In patients with SAH, the amount of blood is strongly associated with clinical outcome. However, it is commonly estimated with a coarse grading scale, potentially limiting its predictive value. Therefore, we aimed to develop and externally validate prediction models for clinical outcome, including quantified blood volumes, as candidate predictors. Materials And Methods: Clinical and radiologic candidate predictors were included in a logistic regression model. Unfavorable outcome was defined as a modified Rankin Scale score of 4-6. An automatic hemorrhage-quantification algorithm calculated the total blood volume. Blood was manually classified as cisternal, intraventricular, or intraparenchymal. The model was selected with bootstrapped backward selection and validated with the R 2, C-statistic, and calibration plots. If total blood volume remained in the final model, its performance was compared with models including location-specific blood volumes or the modified Fisher scale. Results: The total blood volume, neurologic condition, age, aneurysm size, and history of cardiovascular disease remained in the final models after selection. The externally validated predictive accuracy and discriminative power were high (R 2= 56% ± 1.8%; mean C-statistic = 0.89 ± 0.01). The location-specific volume models showed a similar performance (R 2= 56% ± 1%, P=.8; mean C-statistic = 0.89 ± 0.00, P=.4). The modified Fisher models were significantly less accurate (R 2= 45% ± 3%, P < .001; mean C-statistic = 0.85 ± 0.01, P=.03). Conclusions: The total blood volume-based prediction model for clinical outcome in patients with SAH showed a high predictive accuracy, higher than a prediction model including the commonly used modified Fisher scale.

The Borlaug Higher Education for Agricultural Research and Development (Award Number BSF-G-11-00002).

Objective To prevent complications following decompressive craniectomy (DC), such as sinking skin flap syndrome, studies suggested early cranioplasty (CP). However, several groups reported higher complication rates in early CP. We studied the clinical characteristics associated with complications in patients undergoing CP, with special emphasis on timing. Methods A single-center observational cohort study was performed, including all patients undergoing CP from 2006 to 2018, to identify predictors of complications. Results 145 patients underwent CP: complications occurred in 33 (23%): 18 (12%) epi/subdural hemorrhage, 10 (7%) bone flap infection, 4 (3%) hygroma requiring drainage, and 1 (1%) post-CP hydrocephalus. On univariate analysis, acute subdural hematoma as etiology of DC, symptomatic cerebrospinal fluid (CSF) flow disturbance (hydrocephalus) prior to CP, and CP within three months after DC were associated with higher complication rates. On multivariate analysis, only acute subdural hematoma as etiology of DC (OR 7.5; 95% CI 1.9–29.5) and symptomatic CSF flow disturbance prior to CP (OR 2.9; 95% CI 1.1–7.9) were associated with higher complication rates. CP performed within three months after DC was not (OR 1.4; 95% CI 0.5–3.9). Pre-CP symptomatic CSF flow disturbance was the only variable associated with the occurrence of epi/subdural hemorrhage. (OR 3.8; 95% CI 1.6–9.0) Conclusion Cranioplasty has high complication rates, 23% in our cohort. Contrary to recent systematic reviews, early CP was associated with more complications (41%), explained by the higher incidence of pre-CP CSF flow disturbance and acute subdural hematoma as etiology of DC. CP in such patients should therefore be performed with highest caution.

Summary Objective To compare direct evaluation of cartilage with high resolution Magnetic resonance imaging (MRI) (hrMRI) to indirect cartilage evaluation using MRI inter-bone distance in hand OA patients and healthy controls. Design 41 hand OA patients and 18 healthy controls underwent hrMRI of the 2 nd and 3 rd metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints. The images were read by two independent readers using OMERACT hand OA MRI inter-bone distance score (0–3 scale) and a new hrMRI cartilage score with direct evaluation of the cartilage (0–3 scale). Inter-reader and intra-reader reliability was calculated using exact and close agreement and kappa values. The prevalence of abnormal scores and agreement between methods was assessed in both hand OA patients and healthy controls. Results The intra- and inter-reader reliability of both scores was comparable, with exact agreement in 73–83% and close agreement in 95–100%. In hand OA patients 27% of 161 joints had both cartilage damage and loss of inter-bone distance, cartilage damage by hrMRI only was present in 20% of joints and reduced inter-bone distance only in 4% of joints. In the healthy controls, 1 of 71 joints were scored as abnormal by both hrMRI and inter bone distance scoring, 1 joint was scored as abnormal using the hrMRI cartilage score only, whereas 15% of joints had only reduced inter bone distance. Conclusions Direct cartilage evaluation of MCP and PIP joints using hrMRI has a good reliability, and the higher prevalence of hrMRI cartilage damage in hand OA patients and the lower prevalence in healthy controls in comparison to evaluation of inter-bone distance suggests a better validity.