Methodological Quality of Pulmonary Arterial Hypertension Treatment Evidence-Based Guidelines: A Systematic Review Using the AGREE II and AGREE REX Tools.

PURPOSE: Pulmonary arterial hypertension (PAH) is a progressive disease with a poor prognosis, and its management should be grounded in well-developed clinical practice guidelines (CPG). Thus, we critically assess the methodological quality of the available CPG for pharmacological treatments for PAH. METHODS: A systematic review (CRD42023387168) was performed in PubMed, Cochrane, Embase, and Tripdatabase (Jan-2023). Eligible records were appraised by four reviewers using the Appraisal of Guidelines, Research, and Evaluation Collaboration tool (AGREE II) and the complementary tool for assessing recommendations' quality and certainty, AGREE REX. Descriptive statistics were used to summarize the data. RESULTS: Overall, 31 guidelines, mainly authored by professional societies (90%), targeting only physicians as primary users (84%), were identified. Guidelines presented a moderate overall quality (scores of 63% and 51% in AGREE II and AGREE REX, respectively), with a few domains showing slight improvements over the years. AGREE II "Scope and Purpose" (94%) and "Presentation Clarity" (99%) domains obtained the highest scores. The items related to "Stakeholder involvement," "Editorial independence," and "Clinical applicability" (AGREE REX) were fairly reported. Conversely, CPG lacks rigor in development (32% score, AGREE II), scarcely discusses the role of stakeholders, and provides deficient data on the implementation of recommendations (scores of 35% and 46% in AGREE II and AGREE REX, respectively). No differences in the quality of guidelines published by different developers or countries were observed (p > 0.05). CONCLUSION: Methodological weaknesses are common among guidelines addressing PAH treatment, especially regarding scientific rigor, stakeholders' values and preferences, and facilitators and barriers to implementability. Particular attention should be given to developing future guidelines.

Efficacy and safety of pharmacological interventions for managing sickle cell disease complications in children and adolescents: Systematic review with network meta-analysis.

This study aimed to synthesize the evidence on the effects of disease-modifying agents for managing sickle cell disease (SCD) in children and adolescents by means of a systematic review with network meta-analyses, surface under the cumulative ranking curve (SUCRA) and stochastic multicriteria acceptability analyses (SMAA) (CRD42022328471). Eightteen randomized controlled trials (hydroxyurea [n = 7], l-arginine [n = 3], antiplatelets [n = 2], immunotherapy/monoclonal antibodies [n = 2], sulfates [n = 2], docosahexaenoic acid [n = 1], niprisan [n = 1]) were analyzed. SUCRA and SMAA demonstrated that hydroxyurea at higher doses (30 mg/kg/day) or at fixed doses (20 mg/kg/day) and immunotherapy/monoclonal antibodies are more effective for preventing vaso-occlusive crisis (i.e., lower probabilities of incidence of this event; 14, 25, and 30%, respectively), acute chest syndrome (probabilities ranging from 8 to 30%), and needing of transfusions (11-31%), while l-arginine (100-200 mg/kg) and placebo were more prone to these events. Therapies were overall considered safe; however, antiplatelets and sulfates may lead to more severe adverse events. Although the evidence was graded as insufficient and weak, hydroxyurea remains the standard of care for this population, especially if a maximum tolerated dose schedule is considered.

Systematic review with network meta-analysis on the treatments for latent tuberculosis infection in children and adolescents.

BACKGROUND: We aimed to synthesize the evidence on the efficacy and safety of different treatment regimens for latent tuberculosis infection (LTBI) in children and adolescents. METHODS: A systematic review with network meta-analysis was performed (CRD142933). Searches were conducted in Pubmed and Scopus (Nov-2021). Randomized controlled trials comparing treatments for LTBI (patients up to 15 years), and reporting data on the incidence of the disease, death or adverse events were included. Networks using the Bayesian framework were built for each outcome of interest. Results were reported as odds ratio (OR) with 95% credibility intervals (CrI). Rank probabilities were calculated via the surface under the cumulative ranking analysis (SUCRA) (Addis-v.1.16.8). GRADE approach was used to rate evidence's certainty. RESULTS: Seven trials (n = 8696 patients) were included. Placebo was significantly associated with a higher incidence of tuberculosis compared to all active therapies. Combinations of isoniazid (15-25 mg/kg/week) plus rifapentine (300-900 mg/week), followed by isoniazid plus rifampicin (10 mg/kg/day) were ranked as best approaches with lower probabilities of disease incidence (10% and 19.5%, respectively in SUCRA) and death (20%). Higher doses of isoniazid monotherapy were significantly associated to more deaths (OR 18.28, 95% ICr [1.02, 48.60] of 4-6 mg/kg/day vs. 10 mg/kg/3x per week). CONCLUSIONS: Combined therapies of isoniazid plus rifapentine or rifampicin for short-term periods should be used as the first-line approach for treating LTBI in children and adolescents. The use of long-term isoniazid as monotherapy and at higher doses should be avoided for this population.

Efficacy and safety of oral phosphodiesterase 5 inhibitors for erectile dysfunction: a network meta-analysis and multicriteria decision analysis.

PURPOSE: To quantitatively assess the benefit-risk ratio on the efficacy and safety of all phosphodiesterase type 5 inhibitors (PDE5i) in men with erectile dysfunction. METHODS: A systematic review with network meta-analysis, surface under the cumulative ranking analysis and stochastic multicriteria acceptability analyses were performed. Searches were conducted in Pubmed, Scopus, Web of Science without limits for time-frame or language. Randomized controlled trials evaluating the efficacy or safety of any PDE5i compared to a placebo or to other PDE5i in males with erectile disfunction were included. RESULTS: Overall, 184 articles representing 179 randomized controlled trials (50,620 patients) were included. All PDE5i were significantly more efficient than placebo. Sildenafil 25 mg was statistically superior to all interventions in enhancing IIEF (with a 98% probability of being the most effective treatment), followed by sildenafil 50 mg (80% of probability). Taladafil 10 mg and 20 mg also presented good profiles (73% and 76%, respectively). Avanafil and lodenafil were less effective interventions. Mirodenafil 150 mg was the treatment that caused more adverse events, especially flushing and headaches. Sildenafil 100 mg was more related to visual disorders, while vardenafil and udenafil were more prone to cause nasal congestion. CONCLUSION: Sildenafil at low doses and tadalafil should be the first therapeutic options. Avanafil, lodenafil and mirodenafil use are hardly justified given the lack of expressive efficacy or high rates of adverse events.

Implications of a defined daily dose fixed database for drug utilization research studies: The case of statins in Portugal.

AIMS: Given the discrepancies between PDDs (prescribed daily doses) and DDDs (defined daily doses), we aimed to assess the extent of error in the results of an 18-year population-level study on statin utilization in Portugal. METHODS: The Portuguese regulatory agency provided data for the period 2000-2018 on statin dispensing (C10AA). The DDDs were gathered from the ATC/DDD database. DDDs were calculated by the DDD year-by-year approach (DDDYEAR ) and by the DDD last-year approach (DDDLAST ). PDDs were calculated according to the year-by-year approach (PDDYEAR ). Statin annual utilization rates per 1000 inhabitants per day were also calculated. Percent errors were calculated for PDDYEAR and DDDYEAR units. RESULTS: The DDDYEAR approach revealed decreases in the consumption of atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin in 2009, when their DDD was modified. Conversely, the results from both DDDLAST and PDDYEAR approaches indicated gradual changes in the actual consumption of all statins in Portugal. Before 2009, atorvastatin, pravastatin and simvastatin utilization was greatly overestimated by DDDYEAR /1000 inhabitants/day. The average dose of lovastatin prescribed in the past 18 years (20 mg) was below the assigned DDDs during the study period, varying from 30 mg to 45 mg. Conversely, the PDD for fluvastatin was above the DDD values (ranging from 40 mg in 2000 to 70 mg in 2016). For atorvastatin, pravastatin and simvastatin, national PDDs were above the assigned DDD until the DDD modification in 2009. CONCLUSIONS: A more dynamic system, based on national and annually updated DDDs, should be able to reduce discrepancies between DDDs and PDDs and the bias in utilization studies.

Five-year survival analysis and predictors of death in HIV-positive serology patients attending the Military Hospital of Nampula, Mozambique.

An observational retrospective study was conducted over a 5-year period to assess survival and predictors of death in people with HIV-positive serology undergoing antiretroviral treatment with first-line regimens at the Military Hospital of Nampula, Mozambique. We collected data from 332 patient records. Kaplan-Meier boundary product estimator, log-rank, Gehan-Breslow, Tarone-Ware, time-dependent Cox models and estimates of hazard ratios (HR), with 95% confidence interval (CI) were calculated. Meantime survival for females and males was 54.8 months [95% CI 50.32-55.40] and 49.7 months [95% CI 45.89-53.53], respectively. Cox regressions indicated higher death rates significantly or potentially associated with: male sex (HR = 1.3; [95% CI 0.7-2.39]); suspected diagnosis reported only by the physician (HR = 3.6; [95% CI 1.8-7.4]); disease stages III (HR=1.2 [95% CI 0.3-3.6]) or IV (HR 1.4 [95% CI 0.4-5.8]); first TCD4+ lymphocyte count lower than 350 cells per ml (HR = 3.2; [95% CI 0.9-11.2]) or between 350-500 cells per ml (HR = 1.3; [95% CI 0.3-5.8]); or do not present cells count (HR = 3.6; [95% CI 1.2-10.2]). The above variables were significant for HIV prognosis and as predictors of death and should be considered in the clinical care of these patients.

Haematological adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukaemia: A network meta-analysis.

AIMS: Despite their overall favourable safety profile, tyrosine kinase inhibitors (TKIs) are related to severe adverse events including haematological toxicities such as anaemia, leucopenia, neutropenia and thrombocytopenia. We designed a systematic review and network meta-analysis of randomised controlled trials to compare safety among TKIs (bosutinib, dasatinib, imatinib, nilotinib, ponatinib and radotinib) used by patients diagnosed with chronic myeloid leukaemia. METHODS: We obtained data from the PubMed, Scopus, Web of Science, and SciELO databases. The Bayesian approach was used for direct and indirect comparisons, and the treatments were ranked by the surface under the cumulative ranking curve (SUCRA). RESULTS: Seventeen studies were included in the network meta-analysis. Our data show that dasatinib was generally considered worse than the other TKIs, with SUCRA values ​​for 140 mg dasatinib of 90.3% for anaemia, 87.4% for leucopenia, 90.6% for neutropenia and 97.2% for thrombocytopenia. In addition, nilotinib was shown to be safer, with SUCRA values ​​for 600 and 800 mg doses of 21.9 and 35.8% for anaemia, 23.8 and 14.6% for leucopenia, 33.0 and 17.7% for neutropenia, and 28.7 and 32.6% for thrombocytopenia, respectively. CONCLUSION: Dasatinib appeared as the least safe drug for chronic myeloid leukaemia, probably because it binds to multiple key kinase targets, being more prone to cause serious haematological adverse events. Nilotinib demonstrated a safer profile, mostly due to its selective binding capacity.

Medical Treatments for Acromegaly: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Acromegaly results from the hypersecretion of growth hormone. Because of the low incidence rates of this disease worldwide, few clinical trials evaluating drug treatments have been conducted. OBJECTIVES: To conduct the first network meta-analysis simultaneously comparing all available drugs used in acromegaly treatment so as to provide more robust evidence in this field. METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane Collaboration recommendations (PROSPERO database under the registration number CRD42017059880). The electronic searches were conducted in PubMed (MEDLINE), Scopus, and Web of Science databases. Randomized controlled trials comparing any drug for the treatment of acromegaly head-to-head or versus placebo were included. Outcomes concerning the efficacy and safety of treatments were evaluated. The statistical analyses were performed using Aggregate Data Drug Information System version 1.16.8 (drugis.org, Groningen, The Netherlands). RESULTS: The initial search retrieved 2059 articles. Of these, 10 randomized controlled trials were included in a qualitative analysis and 7 in a quantitative analysis. The network meta-analysis for the efficacy outcome (number of patients achieving insulinlike growth factor 1 control) showed that pegvisomant and lanreotide autogel were statistically superior to placebo (odds ratio [95% credible interval] 0.06 [0.00-0.55] and 0.09 [0.01-0.88]). No further differences were found. The probability rank indicated that pegvisomant and pasireotide have the highest probabilities (33% and 34%, respectively) of being the best therapeutic options. No major side effects were noted. CONCLUSIONS: Pegvisomant is still a good option for acromegaly treatment, but pasireotide seems to be a promising alternative. Nevertheless, other important key factors such as drug costs and effectiveness (real-world results) should be taken into account when selecting acromegaly treatment.

Discontinuation of non-anti-TNF drugs for rheumatoid arthritis in interventional versus observational studies: a systematic review and meta-analysis.

PURPOSE: Although randomized controlled trials (RCTs) are the gold standard for the assessment of clinical outcomes, long-term extension trials (LTEs) and observational cohorts may help generate evidence. Our goal was to compare the discontinuation rates of abatacept, rituximab, and tocilizumab in rheumatoid arthritis (RA) reported in different study designs. METHODS: A systematic review was conducted with searches in PubMed, Scopus, and the Cochrane Library, plus a manual search, for RCTs, LTEs, and observational cohorts reporting discontinuation rates by any of three causes (all-cause, inefficacy, adverse events). Meta-analyses with sensitivity analyses and meta-regressions were conducted. RESULTS: Of the 111 studies included, 74 were RCTs (n = 55) or LTEs (n = 17) reporting data on abatacept (n = 33), rituximab (n = 10), and tocilizumab (n = 31) and 37 were observational cohort studies (abatacept = 11, rituximab = 8, tocilizumab = 18). The follow-up duration did not differ among the study designs. Discontinuation rates were similar among the drugs but varied among the study designs. Discontinuation rates were significantly higher in cohort studies than those in interventional studies for the three drugs. Sensitivity analyses could not identify patient characteristics associated with these differences. Meta-regression analyses demonstrated no correlation between study follow-up duration and discontinuation rates. CONCLUSIONS: The discontinuation rates reported for non-anti-TNF drugs varied relative to the study design in which they were investigated. Regulatory agencies, price-setting entities, and evidence-gathering researchers should consider the effect of the real-life environment in their decisions and conclusions.

DIRECT COSTS OF TYPE 2 DIABETES: A BRAZILIAN COST-OF-ILLNESS STUDY.

OBJECTIVES: The aim of this study was to evaluate the direct costs of type 2 diabetes mellitus patients treated in a Brazilian public hospital. METHODS: This was an exploratory retrospective cost-of-illness study with quantitative approach, using medical records of patients treated in a public hospital (2012-14), with at least one consultation over a period of 12 months. Data on patient's profile, exams, number of consultations, medications, hospitalizations, and comorbidities were collected. The cost per patient per year (pppy) was calculated as well as the costs related to glycated hemoglobin (HbA1c) values, using thresholds of 7 and 8 percent. RESULTS: Data of 726 patients were collected with mean age of 62 ± 11 years (68.3 percent female). A total of 67.1 percent presented HbA1c > 7 percent and 44.9 percent > 8 percent. The median cost of diabetes was United States dollar (USD) 197 pppy. The median costs of medication were USD 152.49 pppy, while costs of exams and consultations were USD 40.57 pppy and 8.70 pppy, respectively. Thirty-eight patients (4 percent) were hospitalized and presented a median cost of 3,656 per patient per hospitalization with a cost equivalent to 53.1 percent of total expenses. Total costs of patients with HbA1c ≤ 7 percent were lower for this group and also costs of medications and consultations, whereas for patients with HbA1c ≤ 8 percent, only total costs and costs of medications were lower when compared with HbA1c > 8 percent patients. CONCLUSIONS: Medications and hospitalizations were the major contributor of diabetes expenses. Preventing T2DM, or reducing its complications through adequate control, may help avoid the substantial costs related to this disease.

Efficacy and safety of drugs for attention deficit hyperactivity disorder in children and adolescents: a network meta-analysis.

The aim of this study is to gather evidence of head-to-head double-blind randomized-controlled trials on the efficacy and safety of available treatments for attention deficit hyperactivity disorder (ADHD) in children and adolescents. A systematic review was conducted by two independent reviewers in ten electronic databases (PROSPERO register CRD42016043239). Methodological quality of included studies was evaluated according to the Jadad scale. Network meta-analyses were performed including double-blinded head-to-head trials comparing active allopathic drugs in patients (0-18 years old) diagnosed with ADHD. The results of efficacy and safety of atomoxetine (ATX), bupropion, buspirone (BSP), dexamphetamine, edivoxetine (EDX), guanfacine (GXR), lisdexamfetamine (LDX), methylphenidate (MPH), mixed amphetamine salts, modafinil, pindolol (PDL), reboxetine (RBX), selegiline, and venlafaxine were analyzed using ADDIS software v.1.16.5. Forty-eight trials were identified (n = 4169 participants), of which 12 were used for efficacy analysis and 33 for safety analysis. On the CGI-I scale, the analysis revealed that MPH was more effective than ATX and GXR. For the safety outcomes, according to drug ranks, LDX was more likely to cause sleep disorders (39%) as well as loss of appetite (65%) and behavior problems such as irritability (60%). BSP (71%) and EDX (44%) caused less appetite decrease. For behavioral effects, PDL was considered safest (50%). For any adverse events, RBX (89%) was the safest alternative. The lack of head-to-head trials properly reporting outcomes of interest limited some comparisons. Network meta-analysis offered a broader overview on the available treatments for ADHD, especially for safety issues, and contributes towards evidence gathering and clinical practice decisions. A core outcome set for ADHD should be designed to guide the conduction and report of clinical trials.

Ledipasvir/sofosbuvir with or without ribavirin for the treatment of chronic hepatitis C genotype 1: A pairwise meta-analysis.

BACKGROUND AND AIM: Ledipasvir with sofosbuvir (LED/SOF) for the treatment of patients infected with genotype 1 hepatitis C virus can be used with or without ribavirin (RBV). RBV is well known to promote significant adverse events (AE). The aim of this study was to compare the efficacy and safety of treatment with LED/SOF, with or without RBV, in patients infected with hepatitis C virus genotype 1. METHODS: We performed a systematic review followed by a pairwise meta-analysis including randomized controlled trials that reported efficacy (rapid virological response, sustained virological response at 4 and 12 weeks post-treatment (SVR4 and 12), and viral relapse) and safety outcomes (any AE, serious AE, discontinuation owing to AE, anemia, and rash). It was performed a subgroup analysis evaluating the SVR12 including only cirrhotic patients. Results were reported as risk ratios (RR) and with 95% confidence intervals (95% CI). RESULTS: Seven randomized controlled trials were analyzed. LED/SOF with RBV showed a worse safety profile when compared with LED/SOF without RBV for the following outcomes: any AE (RR 0.56 [95% CI 0.46-0.69]), anemia (RR 0.08 [95% CI 0.04-0.17]), and rash (RR 0.35 [95% CI 0.19-0.65]). No significant differences were observed regarding serious AE, rapid virological response, SVR4, SVR12, or viral relapse. The subgroup analysis did not show significant differences between either treatment groups. CONCLUSION: Administration of LED/SOF + RBV to treatment-naïve patients with or without cirrhosis, and non-cirrhotic treatment-experienced patients, did not promote significant additional benefits. Furthermore, it is still unclear whether cirrhotic treatment-experienced patients could benefit from combined therapy.

Network meta-analysis of first- and second-generation protease inhibitors for chronic hepatitis C genotype 1: efficacy based on RVR and SVR 24.

PURPOSE: This study aimed to compare the efficacy among direct-acting antiviral agents (first and second-generation direct-acting antiviral agents (DAAs)) with placebo and with standard dual therapy (pegylated interferon + ribavirin (Peg-IFN + RBV)) in terms of rapid virologic response (RVR) and sustained virologic response (SVR) in chronic hepatitis C genotype 1 treatment. METHODS: We performed a systematic review of randomized controlled trials (RCTs) in MEDLINE, International Pharmaceutical Abstracts, Cochrane Library, SCIELO, and Scopus and conducted a network meta-analysis to compare the efficacy of boceprevir (BOC), daclatasvir (DCV), grazoprevir, simeprevir (SMV) and telaprevir (TVR), in treatment-naive and treatment-experienced patients. RESULTS: Sixteen studies encompassing 7171 patients were analysed. Associations between DAAs therapies (IFN-free regimens) could not be addressed since no common comparator was found in the RCTs among these associations and the other agents included in the present analysis. All agents were more efficacious than placebo or Peg-IFN + RBV in terms of RVR, while only BOC and SMV showed statistically significant superiority for the SVR outcome when compared to placebo or standard dual therapy. No significant differences between the DAAs were observed. The analysis prioritized treatment with DCV for both efficacy outcomes. Node-splitting analysis showed that our networks are robust (p > 0.05). CONCLUSIONS: The superiority of DAAs over placebo or standard dual therapy with Peg-IFN + RBV was confirmed, indicating the greater efficacy of DCV. This study is the first network meta-analysis that included RVR as an outcome in the evaluation of these agents via indirect comparison. Further investigation should be carried out addressing safety and tolerability outcomes.

Efficacy and safety of amphotericin B lipid-based formulations-A systematic review and meta-analysis.

Invasive fungal infections, an important cause of mortality, are primarily treated using amphotericin B, which is available in different formulations, both conventional and lipid-based (liposomal, lipid complex, colloidal dispersion and Intralipid® infusion). The aim of our study was to determine the efficacy and safety of conventional amphotericin B vs its lipid-based formulations. A systematic review followed by pairwise meta-analysis was performed, including randomised controlled trials (RCTs) that evaluated the use of lipid-based amphotericin B in patients with any degree of immunosuppression and susceptibility to invasive fungal infection. An electronic search was conducted using PubMed, Scopus, Web of Science and Scielo databases. Extracted outcomes were related to efficacy (cure) and safety (incidence of adverse events). Results were evaluated and meta-analyses were performed. Twenty-three RCTs were identified (n=2677 participants) for meta-analysis. No significant differences between conventional amphotericin B and any of the five formulations evaluated were observed, with regard to the efficacy analysis. With respect to the adverse events of nephrotoxicity, fever, chills and vomiting, all lipid formulations presented better profiles than the conventional formulation. The present systematic review and meta-analysis showed that conventional amphotericin B presents the same efficacy profile as lipid-based formulations, although the latter were associated with a safer profile.

Impact of Natural Juice Consumption on Plasma Antioxidant Status: A Systematic Review and Meta-Analysis.

BACKGROUND: Oxidative stress may lead to overproduction of reactive species and a decrease in antioxidant defenses, resulting in chronic diseases such as diabetes and cancer. The consumption of natural compounds with an antioxidant profile may be a preventive alternative. Therefore, we aimed to obtain evidence regarding the potential antioxidant activity of juices in human plasma. METHODS: A systematic review and meta-analysis was performed, which included randomized controlled trials that compared the use of fruit or vegetable juices vs. placebo or other beverages. An electronic search was conducted in PubMed, Scopus, International Pharmaceutical Abstracts, and SciELO. The outcome measures extracted were related to antioxidant status, e.g., vitamin C, superoxide dismutase (SOD), and catalase (CAT) levels and reduction in malondialdehyde (MDA) and antioxidant capacity measured as TEAC. RESULTS: Twenty-eight trials were identified (n = 1089), of which 16 were used for meta-analysis. No significant differences were observed between juices and placebo with regard to TEAC, SOD, and CAT. However, juices were superior to control in enhancing vitamin C and reducing MDA. CONCLUSIONS: Natural juices are possible candidates for the management of oxidative stress. The effects of juices should be further investigated by conducting larger and well-defined trials of longer duration.

Evaluation of Medical Subject Headings assignment in simulated patient articles.

OBJECTIVES: To evaluate human-based Medical Subject Headings (MeSH) allocation in articles about 'patient simulation'-a technique that mimics real-life patient scenarios with controlled patient responses. METHODS: A validation set of articles indexed before the Medical Text Indexer-Auto implementation (in 2019) was created with 150 combinations potentially referring to 'patient simulation'. Articles were classified into four categories of simulation studies. Allocation of seven MeSH terms (Simulation Training, Patient Simulation, High Fidelity Simulation Training, Computer Simulation, Patient-Specific Modelling, Virtual Reality, and Virtual Reality Exposure Therapy) was investigated. Accuracy metrics (sensitivity, precision, or positive predictive value) were calculated for each category of studies. KEY FINDINGS: A set of 7213 articles was obtained from 53 different word combinations, with 2634 excluded as irrelevant. 'Simulated patient' and 'standardized/standardized patient' were the most used terms. The 4579 included articles, published in 1044 different journals, were classified into: 'Machine/Automation' (8.6%), 'Education' (75.9%) and 'Practice audit' (11.4%); 4.1% were 'Unclear'. Articles were indexed with a median of 10 MeSH (IQR 8-13); however, 45.5% were not indexed with any of the seven MeSH terms. Patient Simulation was the most prevalent MeSH (24.0%). Automation articles were more associated with Computer Simulation MeSH (sensitivity = 54.5%; precision = 25.1%), while Education articles were associated with Patient Simulation MeSH (sensitivity = 40.2%; precision = 80.9%). Practice audit articles were also polarized to Patient Simulation MeSH (sensitivity = 34.6%; precision = 10.5%). CONCLUSIONS: Inconsistent use of free-text words related to patient simulation was observed, as well as inaccuracies in human-based MeSH assignments. These limitations can compromise relevant literature retrieval to support evidence synthesis exercises.

Impact of harm minimization interventions on reducing blood-borne infection transmission and some injecting behaviors among people who inject drugs: an overview and evidence gap mapping.

BACKGROUND: This study aimed to synthetize the evidence on the effectiveness of harm minimization interventions on reducing blood-borne infection transmission and injecting behaviors among people who inject drugs (PWID) through a comprehensive overview of systematic reviews and evidence gap mapping. METHODS: A systematic review was conducted with searches in PubMed and Scopus to identify systematic reviews assessing the impact of interventions aimed at reducing the harms associated with injectable drug use. The overall characteristics of the studies were extracted and their methodological quality was assessed using AMSTAR-2. An evidence gap map was constructed, highlighting the most frequently reported outcomes by intervention (CRD42023387713). RESULTS: Thirty-three systematic reviews were included. Of these, 14 (42.2%) assessed the impact of needle/syringe exchange programs (NSEP) and 11 (33.3%) examined opioid agonist therapy (OAT). These interventions are likely to be associated with reductions of HIV/HCV incidence (10-40% risk reduction for NSEP; 50-60% for OAT) and sharing injecting paraphernalia (50% for NSEP, 25-85% for OAT), particularly when combined (moderate evidence). Behavioral/educational interventions were assessed in 12 reviews (36.4%) with most authors in favor/partially in favor of the use of these approaches (moderate evidence). Take-home naloxone programs and supervised-injection facilities were each assessed in two studies (6.1%), which reported inconclusive results (limited/inconsistent evidence). Most authors reported high levels of heterogeneity and risk of bias. Other interventions and outcomes were inadequately reported. Most systematic reviews presented low or critically low quality. CONCLUSION: The evidence is sufficient to support the effectiveness of OAT, NSEP and their combination in reducing blood-borne infection transmission and certain injecting behaviors among PWID. However, evidence of other harm minimizations interventions in different settings and for some outcomes remain insufficient.

Genetic Profile of Rotavirus Type A in Children under 5 Years Old in Africa: A Systematic Review of Prevalence.

Human type A rotavirus (RV-A) is world-recognized as the major pathogen causing viral gastroenteritis in children under 5 years of age. The literature indicates a substantial increase in the diversity of rotavirus strains across continents, especially in Africa, which can pose significant challenges including an increase of disease burden and a reduction of vaccines' effectiveness. However, few studies have mapped the variety of circulating virus strains in different regions, which may hamper decisions on epidemiological surveillance and preventive public health measures. Thus, our aim was to compile the most updated available evidence on the genetic profile of RV-A among children in Africa and determine the prevalence of different genotypes according to the geographical regions by means of a broad systematic review. Systematic searches were performed in PubMed, Scopus, Web of Science, and Scielo without language, time limits, or geographical restrictions within the African continent. We selected full-text peer-reviewed articles assessing the genetic profile (i.e., genotyping) of RV-A in children up to 5 years old in Africa. Overall, 682 records were retrieved, resulting in 75 studies included for evidence synthesis. These studies were published between 1999 and 2022, were conducted in 28 countries from the five African regions, and 48% of the studies were carried out for 24 months or more. Most studies (n = 55; 73.3%) evaluated RV-A cases before the introduction of the vaccines, while around 20% of studies (n = 13) presented data after the vaccine approval in each country. Only seven (9.3%) studies compared evidence from both periods (pre- and post-vaccine introduction). Genotyping methods to assess RV-A varied between RT-PCR, nested or multiplex RT-PCR, testing only the most common P and G-types. We observed G1 and P[8] to be the most prevalent strains in Africa, with values around 31% and 43%, respectively. Yet if all the genotypes with the following highest prevalence were added ((G1 + G2, G3, G9) and (P[8] + P[6], P[4])), these figures would represent 80% and 99% of the total prevalence. The combination G1P[8] was the most reported in the studies (around 22%). This review study demonstrated an increased strain diversity in the past two decades, which could represent a challenge to the efficacy of the current vaccine.

The Initial Journey of Patients with Metastatic Pancreatic Cancer (PaCTO Project): A Nationwide Survey among Portuguese Specialist Physicians.

Introduction: We aimed to characterize the initial healthcare journey of metastatic pancreatic ductal adenocarcinoma (mPDAC) patients in Portugal, including healthcare provision and factors affecting therapeutic decisions, namely BRCA mutations testing. Methods: This is a descriptive cross-sectional, web-based survey using a convenience sampling approach. Portuguese oncologists and pathologists that routinely work with mPDAC patients from the different geographical regions and settings were invited to participate in the study via email (December 2020). Descriptive statistical analyses were performed, with categorical variables reported as absolute and relative frequencies, and continuous variables with non-normal distribution as median and interquartile range (IQR) (Stata v.15.0). Results: Seventy physicians participated in the study (43 oncologists, 27 pathologists). According to the responses, a median of 28 patients per center (IQR 12-70) was diagnosed with PDAC in the previous year; 22 of them referring (IQR 8-70) to mPDAC. The pointed median time from patients' first hospital admission until disease diagnosis/staging is between 2 and 4 weeks. Endoscopic ultrasound with fine-needle biopsy is available in most hospitals (86%). Around 50% of physicians request BRCA testing; the assessment of additional biomarkers besides BRCA is requested by 40% of professionals. Half of them stated that BRCA testing should be requested earlier-upon histological diagnosis, especially because the median time for results is of 4.0 weeks (IQR 4-8). PARP inhibitors such as olaparib, when available, would be the therapy of choice for most oncologists (71%) if no disease' progression occurs after 4 months. Treatments' selection is usually grounded on clinical criteria (e.g., performance status, liver function). Around 45% of patients use FOLFIRINOX/mFOLFIRINOX as the first-line therapy. Gemcitabine + nab-paclitaxel is used by 35% of patients as the second-line therapy. Conclusions: Physicians in Portugal support the increasing role of patient-tailored treatments in mPDAC, whose selection should be grounded on tumoral subtyping and molecular profiling. Further efforts to develop multidisciplinary teams, standardized clinical practice, and optimize the implementation of new target therapies are needed.

Introdução: Este estudo teve como objetivo caracterizar o percurso inicial dos doentes com adenocarcinoma ductal pancreático metastático (ACDPm) em Portugal, incluindo a prestação de cuidados de saúde e determinação de fatores que afetam as decisões terapêuticas, nomeadamente o teste de mutações BRCA. Métodos: Trata-se de um estudo descritivo transversal (web-based) usando uma abordagem de amostragem por conveniência. Médicos oncologistas e anatomopatologistas portugueses dedicados ao ACDPm e de diferentes regiões geográficas e instituições foram convidados a participar do estudo por email (Dez-2020). Foram realizadas análises estatísticas descritivas, com variáveis categóricas relatadas como frequências absolutas e relativas, e variáveis contínuas com distribuição não-normal como mediana e intervalo interquartil (IIQ) (Stata v.15.0). Resultados: Setenta médicos participaram do estudo (43 oncologistas, 27 patologistas). De acordo com as respostas, uma mediana de 28 doentes por centro (IIQ 12­70) foi diagnosticada com ACDP no ano anterior; 22 deles (IIQ 8­70) referentes a ACDPm. O tempo médio desde a primeira admissão hospitalar dos doentes até o diagnóstico/estadiamento da doença foi entre 2­4 semanas. A ultrassonografia endoscópica com biópsia por agulha fina é realizada pela maioria dos hospitais (86%). Aproximadamente 50% dos médicos referem solicitar o teste BRCA; a avaliação de biomarcadores adicionais além do BRCA é solicitada por 40% dos profissionais. Metade dos médicos assume que o teste BRCA deveria ser solicitado mais precocemente ­ durante o diagnóstico histológico, principalmente porque o tempo médio para obtenção do resultado é de 4,0 semanas (IIQ 4­8). Os inibidores PARP, como o olaparibe, quando disponíveis, seriam a terapia de escolha para a maioria dos oncologistas (71%) caso não haja progressão da doença após quatro meses. A seleção dos tratamentos é usualmente baseada em critérios clínicos (por exemplo, performance status, função hepática). Em cerca de 45% dos doentes é utilizado FOLFIRINOX/mFOLFIRINOX como terapia de primeira linha. Um esquema com Gemcitabina + nab-paclitaxel é usado em 35% dos doentes como terapia de segunda linha. Conclusões: Os médicos em Portugal apoiam o papel crescente do tratamento individualizado no ACDPm, cuja seleção deve ser baseada na subtipagem tumoral e no perfil molecular. São necessários mais esforços para capacitar as equipas multidisciplinares, desenvolver práticas clínicas padronizadas e otimizar a implementação de novas terapias-alvo.

The Effects of Benralizumab on Lung Volumes and Airway Resistance in Severe Eosinophilic Asthma: A Real-World Study.

INTRODUCTION: Add-on biological monoclonal antibodies such as benralizumab (anti-IL-5Ra) are recommended by international guidelines to reduce exacerbations in severe eosinophilic asthma (SEA). However, few studies have assessed the impact of these therapies on lung function-related outcomes. Our goal was to evaluate the effectiveness of benralizumab on lung function, including lung volumes and airway resistance, in SEA patients in Portugal. METHODS: This was a real-world, observational, prospective, multicentric study including adult patients diagnosed with SEA (January-June 2023). Spirometry and plethysmography were performed at baseline (T0) and after six months of treatment (T6) with benralizumab to assess: total lung capacity (TLC), residual volume (RV), forced expiratory volume in one second (FEV1), forced vital capacity (FVC), mean forced expiratory flow between 25% and 75% of FVC (mFEF-25/75), intrathoracic gas volume (ITGV), and respiratory airway resistance (Raw). Descriptive statistics (with categorical variables described as frequencies and continuous values as mean and standard deviation (SD)) and paired t-test and Cohen's d effect size were calculated (analyses performed in StataCorp v.15.1; StataCorp LLC, TX, USA). RESULTS: Overall, 30 SEA patients were evaluated, mostly women (n=18, 60.0%), with atopy (n=22, 73.3%), a mean age of 58.4 years (SD 11.7), and assisted by pulmonology (n=19, 63.3%) or immunology-allergology (n=11, 36.7%) services. Mean eosinophilia at baseline was 1103.57 cells/mcL (SD 604.88; minimum-maximum 460-2400); after the use of benralizumab, the count dropped to zero. After six months of treatment, a significant increase (p<0.0001) in FVC (15.3%), FEV1 (22.6%), and mFEF-25/75 (17.7%) were observed from baseline (Cohen's d between 0.78 and 1.11). ITGV, RV, RV/TLC, and Raw significantly decreased (p<0.0001) during the study period (-17.3%, -29.7%, -8.9%, and -100.6%, respectively) (Cohen's d between -0.79 and -1.06). No differences in TLC were obtained (p=0.173). No differences between sexes were observed for any measure. Patients with more significant eosinophilia (>900 cells/mcL count; n=15) presented better responses in FEV1 (p=0.001) and mFEF-25/75 (p=0.007). CONCLUSIONS: A notable eosinophil depletion with add-on benralizumab led to significant improvements in SEA patients' respiratory function (static lung volumes and airway resistance) in real-world settings after six months. The significant deflating effect of benralizumab on patients' hyperinflated lungs led to enhanced expiratory flow (increased FEV1 and mFEF-25/75) and air trapping (decreased RV/TLC), suggesting this antibody improves bronchial obstruction, lung hyperinflation, and airway resistance. Further studies in a larger population are required to confirm these findings.