Mesenchymal stem cells for chronic knee pain secondary to osteoarthritis: a systematic review and meta-analysis of randomized trials.

OBJECTIVE: To assess the effectiveness of mesenchymal stem cells (MSCs) for chronic knee pain secondary to osteoarthritis (OA). METHODS: We searched MEDLINE, EMBASE, CINAHL, and Cochrane Central to September 2023 for trials that: (1) enrolled patients with chronic pain associated with knee OA, and (2) randomized them to MSC therapy vs. placebo or usual care. We performed random-effects meta-analysis for all patient-important outcomes and used GRADE to assess the certainty of evidence. RESULTS: We included 16 trials (807 participants). At 3-6 months, when restricted to low risk of bias studies, MSC therapy probably results in little to no difference in pain relief (weighted mean difference [WMD] -0.74cm on a 10cm visual analogue scale [VAS], 95%CI -1.16 to -0.33; minimally important difference [MID] 1.5cm) or physical functioning (WMD 2.23 points on 100-point SF-36 physical functioning subscale, 95%CI -0.97 to 5.43; MID 10-points; both moderate certainty). At 12-months, injection of MSCs probably results in little to no difference in pain (WMD -0.73 cm on a 10cm VAS, 95%CI -1.69 to 0.24; moderate certainty, restricted to low risk of bias studies) and may improve physical functioning (WMD 19.36 points on 100-point SF-36 PF subscale, 95%CI -0.19 to 38.9; low certainty). MSC therapy may increase risk of any adverse events (RR 2.67, 95%CI 1.19 to 5.99; low certainty) and pain and swelling of the knee joint (RR 1.58, 95%CI 1.04 to 2.38; low certainty). CONCLUSIONS: When restricted to moderate certainty evidence, compared to placebo, intra-articular injection of MSCs for chronic knee pain associated with OA probably provides little to no improvement in pain or physical function.

Innovative approaches to Alzheimer's therapy: Harnessing the power of heterocycles, oxidative stress management, and nanomaterial drug delivery system.

Alzheimer's disease (AD) presents a complex pathology involving amyloidogenic proteolysis, neuroinflammation, mitochondrial dysfunction, and cholinergic deficits. Oxidative stress exacerbates AD progression through pathways like macromolecular peroxidation, mitochondrial dysfunction, and metal ion redox potential alteration linked to amyloid-beta (Aß). Despite limited approved medications, heterocyclic compounds have emerged as promising candidates in AD drug discovery. This review highlights recent advancements in synthetic heterocyclic compounds targeting oxidative stress, mitochondrial dysfunction, and neuroinflammation in AD. Additionally, it explores the potential of nanomaterial-based drug delivery systems to overcome challenges in AD treatment. Nanoparticles with heterocyclic scaffolds, like polysorbate 80-coated PLGA and Resveratrol-loaded nano-selenium, show improved brain transport and efficacy. Micellar CAPE and Melatonin-loaded nano-capsules exhibit enhanced antioxidant properties, while a tetra hydroacridine derivative (CHDA) combined with nano-radiogold particles demonstrates promising acetylcholinesterase inhibition without toxicity. This comprehensive review underscores the potential of nanotechnology-driven drug delivery for optimizing the therapeutic outcomes of novel synthetic heterocyclic compounds in AD management. Furthermore, the inclusion of various promising heterocyclic compounds with detailed ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) data provides valuable insights for planning the development of novel drug delivery treatments for AD.

Predictors of fatal and nonfatal overdose after prescription of opioids for chronic pain: a systematic review and meta-analysis of observational studies.

BACKGROUND: Higher doses of opioids, mental health comorbidities, co-prescription of sedatives, lower socioeconomic status and a history of opioid overdose have been reported as risk factors for opioid overdose; however, the magnitude of these associations and their credibility are unclear. We sought to identify predictors of fatal and nonfatal overdose from prescription opioids. METHODS: We systematically searched MEDLINE, Embase, CINAHL, PsycINFO and Web of Science up to Oct. 30, 2022, for observational studies that explored predictors of opioid overdose after their prescription for chronic pain. We performed random-effects meta-analyses for all predictors reported by 2 or more studies using odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Twenty-eight studies (23 963 716 patients) reported the association of 103 predictors with fatal or nonfatal opioid overdose. Moderate- to high-certainty evidence supported large relative associations with history of overdose (OR 5.85, 95% CI 3.78-9.04), higher opioid dose (OR 2.57, 95% CI 2.08-3.18 per 90-mg increment), 3 or more prescribers (OR 4.68, 95% CI 3.57-6.12), 4 or more dispensing pharmacies (OR 4.92, 95% CI 4.35-5.57), prescription of fentanyl (OR 2.80, 95% CI 2.30-3.41), current substance use disorder (OR 2.62, 95% CI 2.09-3.27), any mental health diagnosis (OR 2.12, 95% CI 1.73-2.61), depression (OR 2.22, 95% CI 1.57-3.14), bipolar disorder (OR 2.07, 95% CI 1.77-2.41) or pancreatitis (OR 2.00, 95% CI 1.52-2.64), with absolute risks among patients with the predictor ranging from 2-6 per 1000 for fatal overdose and 4-12 per 1000 for nonfatal overdose. INTERPRETATION: We identified 10 predictors that were strongly associated with opioid overdose. Awareness of these predictors may facilitate shared decision-making regarding prescribing opioids for chronic pain and inform harm-reduction strategies SYSTEMATIC REVIEW REGISTRATION: Open Science Framework (https://osf.io/vznxj/).

Fatty acid based antimicrobials from Streptomyces sp. SORS-24, an endophyte isolated from Sonchus oleraceus.

Due to the rise in bacterial resistance towards various therapeutic agents, interest is now developing towards fatty acid based antimicrobials because of their non-specific mode of action. A strain SORS 24 isolated from Sonchus oleraceus (Sow thistle) showed significant activity against Escherichia coli ATCC 25922 (25 mm), Chlorella vulgaris (20 mm), Bacillus subtilis DSM 10 (ATCC 6051) and Pseudomonas sp. (15 mm). It displayed an LC50 value of 10 µg/ml against Artemia salina (Brine shrimp) nauplii and an EC50 value of 0.8 µg/ml in the (DPPH) diphenylpicrylhydrazyl antioxidant assay. The strain also displayed genotoxicity against a PolA deficient strain, E. coli K-12 AB 3027 (15 mm). Mass spectrometry (HPLC-MS) showed that the strain produced oleamide (9-Octadecenamide) and erucamide (13-Docosenamide). Both of the purified fatty acid amides showed prominent activity against B. subtilis DSM 10 (ATCC 6051) (20 mm) and E. coli ATCC 25922 (15 mm). Significant genotoxicity was observed against E. coli K-12 AB 3027 (15 mm). The 16S gene sequencing revealed that the strain belonged to species, Streptomyces tanashiensis. As far as our understanding, this is the first report of this species producing these fatty acid based antimicrobials.

Microbial biochemical pathways of arsenic biotransformation and their application for bioremediation.

Arsenic is a ubiquitous toxic metalloid, the concentration of which is beyond WHO safe drinking water standards in many areas of the world, owing to many natural and anthropogenic activities. Long-term exposure to arsenic proves lethal for plants, humans, animals, and even microbial communities in the environment. Various sustainable strategies have been developed to mitigate the harmful effects of arsenic which include several chemical and physical methods, however, bioremediation has proved to be an eco-friendly and inexpensive technique with promising results. Many microbes and plant species are known for arsenic biotransformation and detoxification. Arsenic bioremediation involves different pathways such as uptake, accumulation, reduction, oxidation, methylation, and demethylation. Each of these pathways has a certain set of genes and proteins to carry out the mechanism of arsenic biotransformation. Based on these mechanisms, various studies have been conducted for arsenic detoxification and removal. Genes specific for these pathways have also been cloned in several microorganisms to enhance arsenic bioremediation. This review discusses different biochemical pathways and the associated genes which play important roles in arsenic redox reactions, resistance, methylation/demethylation, and accumulation. Based on these mechanisms, new methods can be developed for effective arsenic bioremediation.

Predictors of Recovery Following Lumbar Microdiscectomy for Sciatica: A Systematic Review and Meta-Analysis of Observational Studies.

Chronic post-surgical pain is reported by up to 40% of patients after lumbar microdiscectomy for sciatica, a complaint associated with disability and loss of productivity. We conducted a systematic review of observational studies to explore factors associated with persistent leg pain and impairments after microdiscectomy for sciatica. We searched eligible studies in MEDLINE, Embase, and CINAHL that explored, in an adjusted model, predictors of persistent leg pain, physical impairment, or failure to return to work after microdiscectomy for sciatica. When possible, we pooled estimates of association using random-effects models using the Grading of Recommendations Assessment, Development, and Evaluation approach. Moderate-certainty evidence showed that the female sex probably has a small association with persistent post-surgical leg pain (odds ratio (OR) = 1.15, 95% confidence interval (CI) = 0.63 to 2.08; absolute risk increase (ARI) = 1.8%, 95% CI = -4.7% to 11.3%), large association with failure to return to work (OR = 2.79, 95% CI = 1.27 to 6.17; ARI = 10.6%, 95% CI = 1.8% to 25.2%), and older age is probably associated with greater postoperative disability (ß = 1.47 points on the 100-point Oswestry Disability Index for every 10-year increase from age (>/=18 years), 95% CI = -4.14 to 7.28). Among factors that were not possible to pool, two factors showed promise for future study, namely, legal representation and preoperative opioid use, which showed large associations with worse outcomes after surgery. The moderate-certainty evidence showed female sex is probably associated with persistent leg pain and failure to return to work and that older age is probably associated with greater post-surgical impairment after a microdiscectomy. Future research should explore the association between legal representation and preoperative opioid use with persistent pain and impairment after microdiscectomy for sciatica.

Frequency of Congenital Cardiac Disease in Various Divisions of Khyber Pakhtunkhwa (KPK) Based on a Six-Month Analysis of Inpatients at a Tertiary Care Hospital's Pediatric Cardiology Unit.

OBJECTIVE: To identify the frequency of congenital heart disease (CHD) in various Khyber Pakhtunkhwa (KPK) divisions. MATERIALS AND METHODS: To perform this research, we reviewed the medical records of pediatric cardiology patients hospitalized between January 2022 and July 2022. Data was taken from the cardiology department's computerized data system between January 1 and July 31, 2022. To prevent any errors in diagnosis and address them during input by the ward clerk, patients' addresses, diagnoses, and gender were verified with the computerized medical record. Data were analyzed, and frequency and percentages were calculated. Per the digital mapping of KPK districts, we stratified and examined the data among various KPK divisions. RESULTS: Out Of the 371 patients with CHD who were admitted, 36.98% (137) were from the Peshawar division, 28.84% (107) from the Malakand division, 16.71% (62) from the Mardan division, 6.1% (23) from the Kohat division, 4.3% (16) from the Bannu division, 3.5% (13) from the Dera Ismail Khan division, and 3.5% (13) from the Hazara division. A total of 371 had CHD, of which 234 (63.07%) were cyanotic and 137 (36.92%) were cyanotic. The most prevalent acynotic congenital heart defect was patent ductus arteriosus (PDA) at 36.32% (85), followed by a ventricular septal defect (VSD) at 35.04 (82). The most frequent acyanotic congenital cardiac abnormality was tetralogy of Fallot (TOF) at 49.63% (68), which was followed by transposition of the great arteries (TGA) at 33.57% (46). CONCLUSION: In KPK, congenital heart disease is most prevalent in the divisions of Peshawar and Malakand, while it is least prevalent in Hazara.

Impact of osteopathic manipulative techniques on the management of dizziness caused by neuro-otologic disorders: systematic review and meta-analysis.

CONTEXT: Osteopathic manipulative treatment (OMT) has been utilized by osteopathic clinicians as primary or adjunctive management for dizziness caused by neuro-otologic disorders. To our knowledge, no current systematic reviews provide pooled estimates that evaluate the impact of OMT on dizziness. OBJECTIVES: We aimed to systematically evaluate the effectiveness and safety of OMT and analogous techniques in the treatment of dizziness. METHODS: We performed a literature search in CINAHL, Embase, MEDLINE, Allied and Complementary Medicine Database (AMED), EMCare, Physiotherapy Evidence Database (PEDro), PubMed, PsycINFO, Osteopathic Medicine Digital Library (OSTMED.DR), and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to March 2021 for randomized controlled trials (RCTs) and prospective or retrospective observational studies of adult patients experiencing dizziness from neuro-otological disorders. Eligible studies compared the effectiveness of OMT or OMT analogous techniques with a comparator intervention, such as a sham manipulation, a different manual technique, standard of care, or a nonpharmacological intervention like exercise or behavioral therapy. Assessed outcomes included disability associated with dizziness, dizziness severity, dizziness frequency, risk of fall, improvement in quality of life (QOL), and return to work (RTW). Assessed harm outcomes included all-cause dropout (ACD) rates, dropouts due to inefficacy, and adverse events. The meta-analysis was based on the similarities between the OMT or OMT analogous technique and the comparator interventions. The risk of bias (ROB) was assessed utilizing a modified version of the Cochrane Risk of Bias Tool for RCTs and the Cochrane Risk of Bias in Non-randomized Studies - of Interventions (ROBINS-I) for observational studies. The quality of evidence was determined utilizing the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. RESULTS: There were 3,375 studies identified and screened, and the full text of 47 of them were reviewed. Among those, 12 (11 RCTs, 1 observational study, n=367 participants) met the inclusion criteria for data extraction. Moderate-quality evidence showed that articular OMT techniques were associated with decreases (all p<0.01) in disability associated with dizziness (n=141, mean difference [MD]=-11, 95% confidence interval [CI]=-16.2 to -5.9), dizziness severity (n=158, MD=-1.6, 95% CI=-2.4 to -0.7), and dizziness frequency (n=136, MD=-0.6, 95% CI=-1.1 to -0.2). Low-quality evidence showed that articular OMT was not associated with ACD rates (odds ratio [OR]=2.2, 95% CI=0.5 to 10.2, p=0.31). When data were pooled for any type of OMT technique, findings were similar; however, disability associated with dizziness and ACD rates had high heterogeneity (I2=59 and 46%). No studies met all of the criteria for ROB. CONCLUSIONS: The current review found moderate-quality evidence that treatment with articular OMT techniques was significantly associated with decreased disability associated with dizziness, dizziness severity, and dizziness frequency. However, our findings should be interpreted cautiously because of the high ROB and small sample sizes in the eligible studies.

Predictors of Persistent Post-Surgical Pain Following Total Knee Arthroplasty: A Systematic Review and Meta-Analysis of Observational Studies.

OBJECTIVE: Approximately one in four total knee replacement patients develop persistent pain. Identification of those at higher risk could help inform optimal management. METHODS: We searched MEDLINE, EMBASE, CINAHL, AMED, SPORTDiscus, and PsycINFO for observational studies that explored the association between risk factors and persistent pain (≥3 months) after total knee replacement. We pooled estimates of association for all independent variables reported by >1 study. RESULTS: Thirty studies (26,517 patients) reported the association of 151 independent variables with persistent pain after knee replacement. High certainty evidence demonstrated an increased risk of persistent pain with pain catastrophizing (absolute risk increase [ARI] 23%, 95% confidence interval [CI] 12 to 35), younger age (ARI for every 10-year decrement from age 80, 4%, 95% CI 2 to 6), and moderate-to-severe acute post-operative pain (ARI 30%, 95% CI 20 to 39). Moderate certainty evidence suggested an association with female sex (ARI 7%, 95% CI 3 to 11) and higher pre-operative pain (ARI 35%, 95% CI 7 to 58). Studies did not adjust for both peri-operative pain severity and pain catastrophizing, which are unlikely to be independent. High to moderate certainty evidence demonstrated no association with pre-operative range of motion, body mass index, bilateral or unilateral knee replacement, and American Society of Anesthesiologists score. CONCLUSIONS: Rigorously conducted observational studies are required to establish the relative importance of higher levels of peri-operative pain and pain catastrophizing with persistent pain after knee replacement surgery.

Congenital Heart Disease and Its Association in Children With Down Syndrome.

Objective The objective is to determine the frequency of different congenital heart diseases and their association in children with Down syndrome (DS). Methodology This cross-sectional observational study was conducted in the pediatric department of Peshawar Institute of Cardiology, Peshawar, Pakistan from August 2021 to July 2022. A total of 123 children with DS and congenital heart disease (CHD) were included in this cross-sectional study. Detailed history and examination were performed, and findings were documented on performed pro forma. Diagnosis of CHD was confirmed through two-dimensional (2D) and Doppler echocardiography performed by a pediatric cardiologist. Patients were managed according to standard protocols and guidelines. The data including age, gender, mother's age at the time of birth, type of CHD and growth failure were documented and analyzed. Percentages were used to express frequencies. Results The mean age was 2.2 years ± 3.4 years (interquartile range (IQR): 10 days to 14 years). There were 65 (52.8%) male and 58 (47.1%) female patients. Out of 123 patients, 101 (82.1%) had acyanotic CHD and 22 (17.8%) had cyanotic CHD. Among acyanotic CHD, isolated ventricular septal defect (VSD) was the most common observation in 23 (22.3%) and among cyanotic CHD, tetralogy of Fallot (TOF) in seven (31.8%) patients. The most common associations of CHD were VSD+ patent ductus arteriosus (PDA) in 11 (9%) patients and atrial septal defect (ASD)+PDA in nine (7.3%) patients. The median age of the mother at delivery was 31 years (interquartile range (IQR): 20 years to 45 years). Growth failure was seen in 70 (56.9%) patients. Conclusion Based on our data, VSD is the most common CHD followed by a complete atrio-VSD (CAVSD) in children with DS. The most common association of CHD in DS is VSD with PDA. Growth failure is seen in most of the patients with DS having a CHD.

Pattern of Vascular Anomalies Associated With Sinus Venosus Atrial Septal Defect.

Objective To evaluate children with sinus venosus atrial septal defect (SV-ASD) for associated vascular anomalies. Methodology A total of 72 children with sinus venosus atrial septal defect with partial anomalous pulmonary venous return who presented to pediatric cardiology unit, Lady Reading Hospital Peshawar, from January 2019 till June 2021 were included in this cross-sectional study. Diagnosis of sinus venosus atrial septal defect was confirmed through two-dimensional (2D) and Doppler echocardiography performed by a pediatric cardiologist. Cardiac CT angiography was performed and assessed by a pediatric cardiac interventionist and radiologist. Patients were managed according to standard protocols and guidelines. The data were entered and analyzed with Statistical Package for the Social Sciences (SPSS) version 20. Percentages were used to express frequencies. Results Mean age was 8.3 ± 2.7 years (interquartile range (IQR): two months to 18 years). There were 37 (51.4%) male and 35 (48.6%) female patients. Out of 72 patients, 64 (88.8%) patients had superior sinus venosus atrial septal defect, while inferior sinus venosus atrial septal defect was found in eight (11.1%) patients. In six (8.3%) patients, associated secundum atrial septal defect was identified. Bilateral superior vena cava was found in seven (9.7%) patients. Left aortic arch was seen in 70 (97.2%) patients, whereas two (2.7%) patients had right aortic arch. Conclusion Sinus venosus ASD is a rare type of atrial septal defect which is also associated with both pulmonary and systemic vascular anomalies. Diagnosing these vascular anomalies is of paramount importance before any corrective intervention can be done. Recognizing the pattern of these anomalies should be known to every interventional cardiologist, radiologist, and cardiac surgeon. Echocardiography alone is not a good tool to assess these extracardiac structures. Imaging modalities like CT angiography and MRI have refined our preoperative workup which is essential for the ultimate outcome of the corrective intervention.

The Outcome of Trans-catheter Closure of Patent Ductus Arteriosus: A Single-Center Experience.

Objective The objective is to share our experience of trans-catheter device closure of patent ductus arteriosus (PDA) and review its efficacy and immediate complications. Methodology This cross-sectional observational study was done in the Department of Pediatric cardiology, Lady Reading Hospital, Peshawar from January 2020 to December 2020. A total of 51 patients with isolated PDA, who underwent PDA device closure, were enlisted in this study through consecutive sampling methods, irrespective of their age and gender. Data of the patients were collected on preformed pro forma. Data was entered in SPSS 20 (SPSS Inc., Chicago, IL, USA). Descriptive statistics like mean ± SD for numerical data (age, weight, and hospital stay), while frequency and percentage for categorical variables (Device type, complication, hospital stay, and type of anesthesia given) were calculated. Results Among total 51 patients (33 [64.7%] females and 18 [35.3%] males) with mean age 8.19 ± 6.96 years underwent attempted trans-catheter PDA device closure. In all cases PDA was successfully occluded with appropriate size devices. General anesthesia was given in 38 (74.5%) patients. Complications occurred in only four (7.8%) patients in the form of hemolysis followed by acute kidney injury in one patient, another had device embolization to descending aorta, which was retrieved in cath lab, one had device embolization to the right pulmonary artery, which was retrieved in cath lab and one had mild left ventricular systolic dysfunction. The mean duration of hospital stay was 22.0 ± 10.2 h. Conclusion Trans-catheter PDA device closure is a safe procedure with a high success rate and little morbidity.

Emergency Department Presentation and Outcome of Children With Cyanotic Congenital Heart Diseases.

Objective This study aimed to assess the outcome and see the spectrum of presenting symptoms of children with cyanotic congenital heart diseases (CHDs) admitted through the emergency department in Lady Reading Hospital (LRH) in Peshawar, Pakistan. Materials and methods This cross-sectional study included 104 children with cyanotic CHD admitted through the emergency department in the pediatric cardiology unit of LRH from February 2019 to January 2020. Diagnosis of cyanotic CHD was confirmed through two-dimensional echocardiography. Patients were treated according to standard protocols for their presenting symptoms. The data were analyzed using Statistical Package for the Social Sciences (SPSS), version 20.0 (IBM Corp., Armonk, NY) and frequencies were expressed as percentages. Results The study included 65 male cases (62.5%) and 39 female cases (37.5%), and participant ages ranged from 10 days to 15 years (mean, 2.7 ± 3.4 years). Of 104 patients, 70 presented with cyanotic spells (84.5%), 53 with fever (10.7%), 28 with respiratory distress (26.5%), 11 with loose stools (10.5%), 10 with hemiplegia (9.6%), and eight with seizures (7.6%). Pneumonia was a precipitating factor in 13 patients (12.5%), infective endocarditis in 12 patients (11%), gastroenteritis in 11 (11%), brain abscess and cerebrovascular accidents in seven patients each (6% each), meningitis in six patients (6%), and tuberculous pericardial effusion in one patient (<1%). The primary CHD was tetralogy of Fallot (TOF) in 52 patients, tricuspid atresia in 14 patients, pulmonary atresia in 13 patients, double outlet right ventricle in 10 patients, transposition of great arteries (TGA) in seven patients, and total anomalous pulmonary venous return (TAPVR), truncus arteriosus, congenitally corrected TGA, and critical pulmonary stenosis in two patients each. Twenty-six patients received treatment of the acute problem and instructions for follow-up monitoring. Twelve patients died during their hospital stay, and three left against medical advice. Fifteen patients received patent ductus arteriosus stenting, and six received right ventricular outflow tract stenting. One patient received a Blalock-Taussig (BT) shunt stent, and one received a left pulmonary artery stent. Two patients received a balloon pulmonary valvotomy, and one received pericardial effusion drainage. Eleven patients received surgical correction of TOF, 11 received surgical correction for BT shunt, four received surgical correction for brain abscess drainage, and two received TAPVR repair. Conclusion TOF was the most common cyanotic heart disease in our study. Cyanotic spells or increased cyanosis was the most common presenting concern. Cyanotic CHDs present with variable extracardiac signs and symptoms in emergencies. Appropriate assessment, immediate management of the acute problem, and timely intervention or surgical management result in good outcomes.

Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials.

OBJECTIVE: To determine the benefits and harms of medical cannabis and cannabinoids for chronic pain. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, EMBASE, AMED, PsycInfo, CENTRAL, CINAHL, PubMed, Web of Science, Cannabis-Med, Epistemonikos, and trial registries up to January 2021. STUDY SELECTION: Randomised clinical trials of medical cannabis or cannabinoids versus any non-cannabis control for chronic pain at ≥1 month follow-up. DATA EXTRACTION AND SYNTHESIS: Paired reviewers independently assessed risk of bias and extracted data. We performed random-effects models meta-analyses and used GRADE to assess the certainty of evidence. RESULTS: A total of 32 trials with 5174 adult patients were included, 29 of which compared medical cannabis or cannabinoids with placebo. Medical cannabis was administered orally (n=30) or topically (n=2). Clinical populations included chronic non-cancer pain (n=28) and cancer related pain (n=4). Length of follow-up ranged from 1 to 5.5 months. Compared with placebo, non-inhaled medical cannabis probably results in a small increase in the proportion of patients experiencing at least the minimally important difference (MID) of 1 cm (on a 10 cm visual analogue scale (VAS)) in pain relief (modelled risk difference (RD) of 10% (95% confidence interval 5% to 15%), based on a weighted mean difference (WMD) of -0.50 cm (95% CI -0.75 to -0.25 cm, moderate certainty)). Medical cannabis taken orally results in a very small improvement in physical functioning (4% modelled RD (0.1% to 8%) for achieving at least the MID of 10 points on the 100-point SF-36 physical functioning scale, WMD of 1.67 points (0.03 to 3.31, high certainty)), and a small improvement in sleep quality (6% modelled RD (2% to 9%) for achieving at least the MID of 1 cm on a 10 cm VAS, WMD of -0.35 cm (-0.55 to -0.14 cm, high certainty)). Medical cannabis taken orally does not improve emotional, role, or social functioning (high certainty). Moderate certainty evidence shows that medical cannabis taken orally probably results in a small increased risk of transient cognitive impairment (RD 2% (0.1% to 6%)), vomiting (RD 3% (0.4% to 6%)), drowsiness (RD 5% (2% to 8%)), impaired attention (RD 3% (1% to 8%)), and nausea (RD 5% (2% to 8%)), but not diarrhoea; while high certainty evidence shows greater increased risk of dizziness (RD 9% (5% to 14%)) for trials with <3 months follow-up versus RD 28% (18% to 43%) for trials with ≥3 months follow-up; interaction test P=0.003; moderate credibility of subgroup effect). CONCLUSIONS: Moderate to high certainty evidence shows that non-inhaled medical cannabis or cannabinoids results in a small to very small improvement in pain relief, physical functioning, and sleep quality among patients with chronic pain, along with several transient adverse side effects, compared with placebo. The accompanying BMJ Rapid Recommendation provides contextualised guidance based on this body of evidence. SYSTEMATIC REVIEW REGISTRATION: https://osf.io/3pwn2.

Opioid-sparing effects of medical cannabis or cannabinoids for chronic pain: a systematic review and meta-analysis of randomised and observational studies.

OBJECTIVE: To assess the efficacy and harms of adding medical cannabis to prescription opioids among people living with chronic pain. DESIGN: Systematic review. DATA SOURCES: CENTRAL, EMBASE and MEDLINE. MAIN OUTCOMES AND MEASURES: Opioid dose reduction, pain relief, sleep disturbance, physical and emotional functioning and adverse events. STUDY SELECTION CRITERIA AND METHODS: We included studies that enrolled patients with chronic pain receiving prescription opioids and explored the impact of adding medical cannabis. We used Grading of Recommendations Assessment, Development and Evaluation to assess the certainty of evidence for each outcome. RESULTS: Eligible studies included five randomised trials (all enrolling chronic cancer-pain patients) and 12 observational studies. All randomised trials instructed participants to maintain their opioid dose, which resulted in a very low certainty evidence that adding cannabis has little or no impact on opioid use (weighted mean difference (WMD) -3.4 milligram morphine equivalent (MME); 95% CI (CI) -12.7 to 5.8). Randomised trials provided high certainty evidence that cannabis addition had little or no effect on pain relief (WMD -0.18 cm; 95% CI -0.38 to 0.02; on a 10 cm Visual Analogue Scale (VAS) for pain) or sleep disturbance (WMD -0.22 cm; 95% CI -0.4 to -0.06; on a 10 cm VAS for sleep disturbance; minimally important difference is 1 cm) among chronic cancer pain patients. Addition of cannabis likely increases nausea (relative risk (RR) 1.43; 95% CI 1.04 to 1.96; risk difference (RD) 4%, 95% CI 0% to 7%) and vomiting (RR 1.5; 95% CI 1.01 to 2.24; RD 3%; 95% CI 0% to 6%) (both moderate certainty) and may have no effect on constipation (RR 0.85; 95% CI 0.54 to 1.35; RD -1%; 95% CI -4% to 2%) (low certainty). Eight observational studies provided very low certainty evidence that adding cannabis reduced opioid use (WMD -22.5 MME; 95% CI -43.06 to -1.97). CONCLUSION: Opioid-sparing effects of medical cannabis for chronic pain remain uncertain due to very low certainty evidence.PROSPERO registration numberCRD42018091098.

Cannabis in the management of PTSD: a systematic review.

INTRODUCTION: Existing reviews exploring cannabis effectiveness have numerous limitations including narrow search strategies. We systematically explored cannabis effects on PTSD symptoms, quality of life (QOL), and return to work (RTW). We also investigated harm outcomes such as adverse effects and dropouts due to adverse effects, inefficacy, and all-cause dropout rates. METHODS: Our search in MEDLINE, EMBASE, PsycInfo, CINAHL, Web of Science, CENTRAL, and PubMed databases, yielded 1 eligible RCT and 10 observational studies (n = 4672). Risk of bias (RoB) was assessed with the Cochrane risk of bias tool and ROBINS-I. RESULTS: Evidence from the included studies was mainly based on non-randomized studies with no comparators. Results from unpooled, high RoB studies showed that cannabis was associated with a reduction in overall PTSD symptoms and improved QOL. Dry mouth, headaches, and psychoactive effects such as agitation and euphoria were the commonly reported adverse effects. In most studies, cannabis was well tolerated, but small proportions of patients experienced a worsening of PTSD symptoms. CONCLUSION: Evidence in the current study primarily stems from low quality and high RoB observational studies. Further RCTs investigating cannabis effects on PTSD treatment should be conducted with larger sample sizes and explore a broader range of patient-important outcomes.

Dropout associated with osteopathic manual treatment for chronic noncancerous pain in randomized controlled trials.

CONTEXT: Reviews exploring harm outcomes such as adverse effects (AE), all cause dropouts (ACD), dropouts due to inefficacy, and dropouts due to AE associated with osteopathic manipulative treatment (OMT) or osteopathic manual therapy (OMTh) are scant. OBJECTIVES: To explore the overall AE, ACD, dropouts due to inefficacy, and AE in chronic noncancerous pain (CNCP) patients receiving OMTh through a systematic review of previous literature. METHODS: For this systematic review and meta-analysis, the authors searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Physiotherapy Evidence Database (PEDro), EMCare, and Allied and Complementary Medicine Database (AMED), and Ostmed.Dr, as well as the bibliographical references of previous systematic reviews evaluating OMTh for pain severity, disability, quality of life, and return to work outcomes. Randomized controlled trials with CNCP patients 18 years or older with OMTh as an active or combination intervention and the presence of a control or combination group were eligible for inclusion. In this sub-study of a previous, larger systematic review, 11 studies (n=1,015) reported data that allowed the authors to perform meta-analyses on ACD and dropouts due to AE. The risk of bias (ROB) was assessed with the Cochrane ROB tool and the quality of evidence was determined with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: The pooled analysis showed that ACD was not significantly different for visceral OMTh (vOMTh) vs. OMTh control (odds ratio [OR]=2.66 [95% confidence interval [[CI]], 0.28, 24.93]) or for OMTh vs. standard care (OR=1.26 [95% CI, 0.84, 1.89]; I2=0%). Single study analysis showed that OMTh results were nonsignificant in comparison with chemonucleolysis, gabapentin, and exercise. OMTh in combination with gabapentin (vs. gabapentin alone) and OMTh in combination with exercise (vs. exercise alone) showed nonsignificant ACD. Dropouts due to AE were not significantly different, but the results could not be pooled due to an insufficient number of studies. CONCLUSIONS: Most articles did not explicitly report AEs, ACD rates, or dropouts due to AEs and inefficacy. The limited data available on dropouts showed that OMTh was well tolerated compared with control interventions, and that the ACD and dropouts due to AEs were not significantly different than comparators. Future trials should focus on explicit reporting of dropouts along with beneficial outcomes to provide a better understanding of OMTh efficacy.

The extent of the neurocognitive impairment in elderly survivors of war suffering from PTSD: meta-analysis and literature review.

OBJECTIVES: We performed a meta-analysis and systematic review on elderly survivors of war suffering from PTSD to estimate the variability in their cognitive impairment based on individual neuropsychological tests. METHODS: We included case control studies that explored the association of cognitive deficits in elderly PTSD civilian survivor of wars (age >60 years), using MEDLINE, Embase and PsycINFO from the inception to January 2018. We compared the cognitive performances in three comparisons i) PTSD+ vs. PTSD- civilian survivors of war; ii) PTSD+ vs. Control and iii) PTSD- vs. Control. The risk of bias was assessed using the Newcastle-Ottawa Scale for case-control studies. RESULTS: Out of 2939 titles and abstracts, 13 studies were eligible for data extraction. As compared to PTSD- civilian survivors of war, PTSD+ civilian survivors of war demonstrated significant deficits on TMT-A, TMT-B, Digit span backward, explicit memory low pair associate, CVLT recognition, WAIS-verbal and non-verbal tests. As compared to health controls, PTSD+ survivors demonstrated significantly lower performance on explicit memory low pair and high associate, RAVLT immediate and delayed recall, CVLT delayed and short cued recall. Performance on the neuropsychological test between PTSD- survivors of war and controls was not significant for all tests. CONCLUSION: The pattern suggests that PTSD+ survivors of war had poorer performance in tasks requiring processing speed, executive function, attention, working memory and learning. The magnitude of the cognitive deficits in our pooled analysis was small to moderate depending on the neuropsychological test. Most of our pooled analysis suffered from a high risk of bias, which lowered the confidence in our results.

Outcome Of Balloon Valvuloplasty In Children With Pulmonary Stenosis - Single Center Experience.

BACKGROUND: Pulmonary valve stenosis (PS) is common congenital heart disease in children and patient can present with cyanosis, chest pain, dyspnea and failure with severe form. The objective of this study was to enlighten the short outcome of balloon pulmonary valvuloplasty in children with severe pulmonary stenosis. METHODS: This cross sectional observational study was done in paediatric cardiology department of Lady Reading Hosptial, Peshawer form June 2019 to December 2020 over 1.5 years. Children aged 6 months to 16 years of either sex diagnosed as case of severe stenosis with doming pulmonary valve and having symptoms of chest pain and dysnea on exeration and pregradient pressure of 64 mm Hg or more on echocardiography were included. Patients were interviened with ballon-valvuloplasty. Outcome was taken as discharge from hospital with complications after procedure if any. Patients were followed up for 3 months. Data including age, sex, pre cath echocardiography, cath pulmonary valve annulus, post ballooning pulmonary valve (PV) gradient, PV gradient on echocardiography after intervention and follow up gradient on echocardiography at three months was documented. Data was analyzed by SPSS 20. Chi square test and paired T - Test was applied where required. Results were taken as significant with p value <0.05. RESULTS: There were 51 patients, 35 (68.6%) male and 16 (31.4%) female. Mean age was 8.35±4.93 years. Mean pre cath gradient across the pulmonary valve on echocardiography was 109.14±31.44 mm Hg. Post intervention mean pressure gradient across PV was 32.41±11.49 mm Hg. Pulmonary valve annulus on echocardiography before intervention ranged from 7 to 25 mm with mean of 14.67±3.79 mm. There was no complication in majority (82.4%) of patients. Mild PR was in 5 (9.8%) patients. There was significant relationship between pre and post intervention pressure gradient across PV valve with p value of <0.001. CONCLUSIONS: Balloon pulmonary valvuloplasty in one of the safest intervention for PS in children with few complications.