Prolonged conservative treatment or 'early' surgery in sciatica caused by a lumbar disc herniation: rationale and design of a randomized trial [ISRCT 26872154]

BACKGROUND: The design of a randomized multicenter trial is presented on the effectiveness of a prolonged conservative treatment strategy compared with surgery in patients with persisting intense sciatica (lumbosacral radicular syndrome). METHODS/DESIGN: Patients presenting themselves to their general practitioner with disabling sciatica lasting less than twelve weeks are referred to the neurology outpatient department of one of the participating hospitals. After confirmation of the diagnosis and surgical indication MRI scanning is performed. If a distinct disc herniation is discerned which in addition covers the clinically expected site the patient is eligible for randomization. Depending on the outcome of the randomization scheme the patient will either be submitted to prolonged conservative care or surgery. Surgery will be carried out according to the guidelines and between six and twelve weeks after onset of complaints. The experimental therapy consists of a prolonged conservative treatment under supervision of the general practitioner, which may be followed by surgical intervention in case of persisting or progressive disability. The main primary outcome measure is the disease specific disability of daily functioning. Other primary outcome measures are perceived recovery and intensity of legpain. Secondary outcome measures encompass severity of complaints, quality of life, medical consumption, absenteeism, costs and preference. The main research question will be answered at 12 months after randomization. The total follow-up period covers two years. DISCUSSION: Evidence is lacking concerning the optimal treatment of lumbar disc induced sciatica. This pragmatic randomized trial, focusses on the 'timing' of intervention, and will contribute to the decision of the general practictioner and neurologist, regarding referral of patients for surgery

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Facilitators and barriers to birth preparedness and complication readiness in rural Rwanda among community health workers and community members: a qualitative study

Abstract Background Birth preparedness and complication readiness (BP/CR) comprise a strategy to make women plan for birth and encourage them to seek professional care in order to reduce poor pregnancy outcome. We aimed to understand the facilitators and barriers to BP/CR among community health workers (CHWs) and community members in rural Rwanda. Methods Eight focus group discussions were conducted with 88 participants comprising of CHWs, elderly women aged 45–68 and men aged 18–59, as well as two key informant interviews in Musanze district, Rwanda, between November and December 2015. Qualitative data were digitally recorded, transcribed verbatim and analysed using content analysis. Results Participants perceived the importance of family assistance, medical insurance and attending antenatal care (ANC) to facilitate BP/CR and enhance professional care at birth. CHWs reinforced BP/CR messages by SMS alerts and during community gatherings. ‘Ubudehe (collective action to combat poverty)’ was known as a tool to identify the poorest families in need of government aid to pay for medical care. Disrespect and abuse of women during labor by health workers were perceived as important barriers to access professional care, as well as conflicting health policies such as user fees for ANC and family planning services, and imposing fines on women giving birth outside health facilities. Conclusion CHWs, ANC and medical insurance are perceived to be important facilitators of BP/CR. Respectful care is paramount for improved maternal health. There is a need for addressing inconsistent health policies hindering the intention to access professional care

Birth preparedness and complication readiness among pregnant women admitted in a rural hospital in Rwanda

Background: With an aim to prevent adverse pregnancy outcomes, 'birth preparedness and complication readiness' (BP/CR) promotes timely access to skilled maternal and neonatal services. Objective of this study was to assess implementation of BP/CR among pregnant women admitted with obstetric emergencies in rural Rwanda. Methods: A cross-sectional study among pregnant women who were referred to Ruhengeri hospital between July and November 2015. The 'Safe Motherhood questionnaire' as developed by Jhpiego's Maternal and Neonatal Health Program was used to collect data. Women were asked to mention key danger signs and respond as to whether they had identified: (A) skilled birth attendant, (B) location to give birth, (C) mode of transport, (D) money to cover health care expenditure. Women who answered 'yes' to three or four items were labeled 'well prepared'. Multivariate logistic regression analysis was conducted to compare the 'well prepared' and 'less prepared'. Results: With regard to complication readiness, out of 350 women, 296 (84.6%), 271 (77.4%) and 288 (82.3%) could mention at least one key danger sign during pregnancy, labor and postpartum respectively, but only 23 (6.6%) could mention three or more key danger signs during all three periods. With regard to birth preparedness, 46 (13.1%) women had identified a skilled birth attendant, 68 (19.4%) birth location, 76 (21.7%) mode of transport, and 306 (87.4%) had saved money for health care costs. Seventy-eight women (22.3%) were 'well prepared', associated factors being first time pregnancy (adjusted Odds Ratio (aOR) = 3.2; 95% CI; 1.2-5.8), knowledge of at least two danger signs (aOR = 2.8; 95% CI; 1.7-3.9) and having been assisted by a community health worker at the antenatal clinic (aOR = 2.2, 95% CI; 1.3-3.7). Conclusion: Knowledge of obstetric danger signs was suboptimal and birth preparedness low. We recommend review of practices regarding health promotion in antenatal care, taking care not to exclude multiparous women from messages related to birth preparedness, and do promote use of community health workers to enhance effectiveness of BP/CR

Morbidity and cost differences between free flap reconstruction and pedicled flap reconstruction in oral and oropharyngeal cancer: Matched control study

To compare morbidity and cost in patients who underwent primary reconstruction with free tissue transfer with those with pectoralis major myocutaneous flap (PMMF) reconstructions after ablation of oral and oropharyngeal squamous cell carcinoma. Over a 6-year period, 36 patients had PMMF reconstructions and 127 patients had a variety of free flap (FRF) reconstructions after oral and oropharyngeal cancer ablation. Correction for confounding patient and disease variables was performed by matching all PMMF patients to a randomly selected cohort of FRF patients for age, sex, International Union Against Cancer-American Joint Committee on Cancer T category, tumour subsite, and radiotherapy status. This resulted in two groups of 32 patients each, with the flap reconstruction being the only variable. The following outcome variables were analyzed: operative time; blood loss; admission length, including intensive care unit and coronary care unit stay; complications; secondary interventions; readmissions; and feeding status. Cumulative costs of nursing care, hospital supplies and charges, surgeon's fees, and anesthesiologist's fees were calculated. Statistical analysis applied the paired Student's t-test and the chi-square test. Of all morbidity parameters, only operative time was significantly longer for FRF (p .05). There is no evidence that morbidity and cost differ between the pedicled flap and free tissue transfer reconstruction strategies, other than lengthier operating room time for FR

Cardiac safety of imatinib for the treatment of Covid-19: a secondary analysis of a randomised, double blind, placebo-controlled trial

ABSTRACT: While previous studies support the clinical benefit of imatinib with regard to respiratory status in hospitalised Covid-19 patients, potential cardiotoxicity may limit its clinical application. This study aimed to investigate the cardiac safety of imatinib in Covid-19. In the CounterCOVID study, 385 hospitalised hypoxemic COVID-19 patients were randomly assigned to receive 10 days of oral imatinib or placebo in a 1:1 ratio. Patients with a QTc interval >500ms or left ventricular ejection fraction 40%

Additional file 1: of Birth preparedness and complication readiness among pregnant women admitted in a rural hospital in Rwanda

Consent form and questionnaire. Consent form as used in the study and questionnaire adapted from the ‘Safe Motherhood questionnaire’, as developed by the Maternal Neonatal Program of JHPIEGO, an affiliate of John Hopkins University. (DOCX 63 kb

Differences in incidence, nature of symptoms, and duration of long COVID among hospitalised migrant and non-migrant patients in the Netherlands: a retrospective cohort study

Background: Comprehensive data on long COVID across ethnic and migrant groups are lacking. We investigated incidence, nature of symptoms, clinical predictors, and duration of long COVID among COVID-19 hospitalised patients in the Netherlands by migration background (Dutch, Turkish, Moroccan, and Surinamese origin, Others). Methods: We used COVID-19 admissions and follow up data (January 2021–July 2022) from Amsterdam University Medical Centers. We calculated long COVID incidence proportions per NICE guidelines by migration background and assessed for clinical predictors via robust Poisson regressions. We then examined associations between migration background and long COVID using robust Poisson regressions and adjusted for derived clinical predictors, and other biologically relevant factors. We also assessed long COVID symptom persistence at one-year post-discharge. Findings: 1886 patients were included. 483 patients had long COVID (26%, 95% CI 24–28%) at 12 weeks post-discharge. Symptoms like dizziness, joint pain, insomnia, and headache varied by migration background. Clinical predictors of long COVID were female sex, hospital admission duration, intensive care unit admission, and receiving oxygen, or corticosteroid therapy. Long COVID risk was higher among patients with migration background than Dutch origin patients after adjustments for derived clinical predictors, age, smoking, vaccination status, comorbidities and remdesivir treatment. Only 14% of long COVID symptoms persisted at one-year post-discharge. Interpretation: There are significant differences in occurrence, nature of symptoms, and duration of long COVID by migration background. Studies assessing the spectrum of functional limitation and access to post-COVID healthcare are needed to help plan for appropriate and accessible healthcare interventions. Funding: The Amsterdam UMC COVID-19 biobank is supported by the Amsterdam UMC Corona Research Fund and the Talud Foundation (Stichting Talud). The current analyses were supported by the Novo Nordisk Foundation [ NNF21OC0067528]

Immunomodulation and endothelial barrier protection mediate the association between oral imatinib and mortality in hospitalised COVID-19 patients

INTRODUCTION: Imatinib reduced 90-day mortality in hospitalised COVID-19 patients in a recent clinical trial, but the biological effects that cause improved clinical outcomes are unknown. We aimed to determine the biological changes elicited by imatinib in patients with COVID-19, and what baseline biological profile moderates the effect of imatinib. METHODS: Secondary analysis of a randomised, double-blind, placebo-controlled trial of oral imatinib in hospitalised, hypoxemic COVID-19 patients. Mediating effects of changes in plasma concentration of 25 plasma host response biomarkers on the association between randomisation group and 90-day mortality were studied by combining linear mixed-effect modelling and joint modelling. Moderation of baseline biomarker concentrations was evaluated by Cox regression modelling. We identified subphenotypes using Ward's method clustering and evaluated moderation of these subphenotypes using the above-described method. RESULTS: 332 out of 385 participants had plasma samples available. Imatinib increased the concentration of surfactant protein D (SP-D), and decreased the concentration of interleukin-6, procalcitonin, angiopoietin 2 to 1 ratio, E-selectin, tumour necrosis factor (TNF)α, and TNF receptor I. The effect of imatinib on 90-day mortality was fully mediated by changes in these biomarkers.Cluster analysis revealed three host response subphenotypes. Mortality benefit of imatinib was only present in the subphenotype characterised by alveolar epithelial injury indicated by increased SP-D levels in the context of systemic inflammation and endothelial dysfunction (HR 0.29, 95%-CI: 0.10-0.92). CONCLUSIONS: The effect of imatinib on mortality in hospitalised COVID-19 patients is mediated through modulation of innate immune responses and reversal of endothelial dysfunction, and possibly moderated by biological subphenotypes

Immunomodulation and endothelial barrier protection mediate the association between oral imatinib and mortality in hospitalised COVID-19 patients

Background Imatinib reduced 90-day mortality in hospitalised coronavirus disease 2019 (COVID-19) patients in a recent clinical trial, but the biological effects that cause improved clinical outcomes are unknown. We aimed to determine the biological changes elicited by imatinib in patients with COVID-19 and what baseline biological profile moderates the effect of imatinib. Methods We undertook a secondary analysis of a randomised, double-blind, placebo-controlled trial of oral imatinib in hospitalised, hypoxaemic COVID-19 patients. Mediating effects of changes in plasma concentration of 25 plasma host response biomarkers on the association between randomisation group and 90-day mortality were studied by combining linear mixed effect modelling and joint modelling. Moderation of baseline biomarker concentrations was evaluated by Cox regression modelling. We identified subphenotypes using Ward's method clustering and evaluated moderation of these subphenotypes using the aforementioned method. Results 332 out of 385 participants had plasma samples available. Imatinib increased the concentration of surfactant protein D (SP-D), and decreased the concentration of interleukin-6, procalcitonin, angiopoietin (Ang)-2/Ang-1 ratio, E-selectin, tumour necrosis factor (TNF)-α, and TNF receptor I. The effect of imatinib on 90-day mortality was fully mediated by changes in these biomarkers. Cluster analysis revealed three host response subphenotypes. Mortality benefit of imatinib was only present in the subphenotype characterised by alveolar epithelial injury indicated by increased SP-D levels in the context of systemic inflammation and endothelial dysfunction (hazard ratio 0.30, 95% CI 0.10-0.92). Conclusions The effect of imatinib on mortality in hospitalised COVID-19 patients is mediated through modulation of innate immune responses and reversal of endothelial dysfunction, and possibly moderated by biological subphenotypes