Standard of care for COVID-19 in randomized clinical trials registered in trial registries and published in preprint servers and scholarly journals: a cross-sectional study.

BACKGROUND: The concept of standard of care (SoC) treatment is commonly utilized in clinical trials. However, in a setting of an emergent disease, such as COVID-19, where there is no established effective treatment, it is unclear what the investigators considered as the SoC in early clinical trials. The aim of this study was to analyze and classify SoC reported in randomized controlled trial (RCT) registrations and RCTs published in scholarly journals and on preprint servers about treatment interventions for COVID-19. METHODS: We conducted a cross-sectional study. We included RCTs registered in a trial registry, and/or published in a scholarly journal, and/or published on preprint servers medRxiv and bioRxiv (any phase; any recruitment status; any language) that aim to compare treatment interventions related to COVID-19 and SoC, available from January 1, 2020, to October 8, 2020. Studies using "standard" treatment were eligible for inclusion if they reported they used standard, usual, conventional, or routine treatment. When we found such multiple reports of an RCT, we treated those multiple sources as one unit of analysis. RESULTS: Among 737 unique trials included in the analysis, 152 (21%) reported that SoC was proposed by the institutional or national authority. There were 129 (18%) trials that reported component(s) of SoC; the remaining trials simply reported that they used SoC, with no further detail. Among those 129 trials, the number of components of SoC ranged from 1 to 10. The most commonly used groups of interventions in the SoC were antiparasitics (62% of the trials), antivirals (57%), antibiotics (31%), oxygen (17%), antithrombotics/anticoagulants (14%), vitamins (13%), immunomodulatory agents (13%), corticosteroids (12%), analgesics/antipyretics (12%). Various combinations of those interventions were used in the SoC, with up to 7 different types of interventions combined. Posology, timing, and method of administration were frequently not reported for SoC components. CONCLUSION: Most RCTs (82%) about treatment for COVID-19 that were registered or published in the first 9 months of the pandemic did not describe the "standard of care" they used. Many of those interventions have, by now, been shown as ineffective or even detrimental.

Differences in the Pattern of Non-Recreational Sharing of Prescription Analgesics among Patients in Rural and Urban Areas.

INTRODUCTION: This study aimed to analyze differences in sharing of prescription analgesics between rural and urban populations. METHODS: We surveyed 1000 participants in outpatient family medicine settings in Croatia. We used a 35-item questionnaire to analyze patients' characteristics, pain intensity, prescription analgesic sharing behavior, and perception of risks regarding sharing prescription medications. RESULTS: Prescription analgesic sharing was significantly more frequent in the rural (64%) than in the urban population 55% (p = 0.01). Participants from rural areas more commonly asked for verbal or written information than those from urban areas when taking others' prescription analgesics (p < 0.001) or giving such analgesics (p < 0.001). Participants from rural areas more commonly informed their physician about such behavior compared to those from urban areas (p < 0.01), and they were significantly more often asked about such behavior by their physician (p < 0.01). Perceptions about risks associated with sharing prescription medication were similar between rural and urban populations. CONCLUSIONS: There are systematic differences in the frequency of prescription analgesics and associated behaviors between patients in family medicine who live in rural and urban areas. Patients from rural areas were more prone to share prescription analgesics. Future studies should examine reasons for differences in sharing prescription analgesics between rural and urban areas.

Research methodology and characteristics of journal articles with original data, preprint articles and registered clinical trial protocols about COVID-19.

BACKGROUND: The research community reacted rapidly to the emergence of COVID-19. We aimed to assess characteristics of journal articles, preprint articles, and registered trial protocols about COVID-19 and its causal agent SARS-CoV-2. METHODS: We analyzed characteristics of journal articles with original data indexed by March 19, 2020, in World Health Organization (WHO) COVID-19 collection, articles published on preprint servers medRxiv and bioRxiv by April 3, 2010. Additionally, we assessed characteristics of clinical trials indexed in the WHO International Clinical Trials Registry Platform (WHO ICTRP) by April 7, 2020. RESULTS: Among the first 2118 articles on COVID-19 published in scholarly journals, 533 (25%) contained original data. The majority was published by authors from China (75%) and funded by Chinese sponsors (75%); a quarter was published in the Chinese language. Among 312 articles that self-reported study design, the most frequent were retrospective studies (N = 88; 28%) and case reports (N = 86; 28%), analyzing patients' characteristics (38%). Median Journal Impact Factor of journals where articles were published was 5.099. Among 1088 analyzed preprint articles, the majority came from authors affiliated in China (51%) and were funded by sources in China (46%). Less than half reported study design; the majority were modeling studies (62%), and analyzed transmission/risk/prevalence (43%). Of the 927 analyzed registered trials, the majority were interventional (58%). Half were already recruiting participants. The location for the conduct of the trial in the majority was China (N = 522; 63%). The median number of planned participants was 140 (range: 1 to 15,000,000). Registered intervention trials used highly heterogeneous primary outcomes and tested highly heterogeneous interventions; the most frequently studied interventions were hydroxychloroquine (N = 39; 7.2%) and chloroquine (N = 16; 3%). CONCLUSIONS: Early articles on COVID-19 were predominantly retrospective case reports and modeling studies. The diversity of outcomes used in intervention trial protocols indicates the urgent need for defining a core outcome set for COVID-19 research. Chinese scholars had a head start in reporting about the new disease, but publishing articles in Chinese may limit their global reach. Mapping publications with original data can help finding gaps that will help us respond better to the new public health emergency.

Attitudes of dental practitioners towards antimicrobial therapy in Croatia and Bosnia and Herzegovina.

INTRODUCTION: The objective of this study was to assess perceptions and attitudes amongst dental practitioners in relation to antibiotic usage and antibiotic resistance. METHODS: Self-administered questionnaire was given to dental practitioners employed in south Croatia, west Herzegovina and Sarajevo, Bosnia and Herzegovina (N = 115). RESULTS: 81.7% of respondents agreed the usage of antimicrobials is frequently uncritical and unnecessary. 83.5% of dental practitioners reported that they have used guidelines in their practice; however, only 9 out of 115 stated valid guidelines. One-third of the respondents agreed or were undecided that the usage of antimicrobials in every oral inflammatory process treatment is justified. Furthermore, 13% was undecided and 26% agreed that pregnant women and breastfeeding women should not use any antimicrobials. However, three quarters of respondents considered they had satisfactory knowledge on antimicrobials. DISCUSSION: The respondents considered they had satisfactory knowledge on antimicrobials, which was in contrast to the knowledge shown, but also expressed the need for additional education. Therefore, adequate measures include the creation of the local guidelines, their implementation, and updating the practitioners' knowledge on antibiotic use and resistance through continuous educational courses.

PANDEMIC INFLUENZA A (H1N1) 2009 PRESENTING AS A MILD DISEASE IN CHILDREN IN A CROATIAN CLINICAL CENTRE.

Pandemic influenza A virus (H1N1) 2009 causes a disease that is epidemiologically and clinically not significantly different from seasonal influenza, but there are differences. The aim of the study was to display and compare epidemiological and clinical characteristics of pandemic influenza in children. At Dr. Fran Mihaljevic University Hospital for Infectious Diseases in Zagreb, in the first two seasons, the incidence of pandemic influenza virus A (H1N1) in particular was exhaustively analyzed only in patients with laboratory-confirmed pandemic influenza A virus (H1N1) 2009. In hospitalized children with documented influenza pandemic, moderate form of the disease predominated, which ultimately meant shorter hospital stay and fewer complications. Otitis media was the rarest complication in children in both seasons. In conclusion, children younger than 5 years, especially boys, were vulnerable groups for pandemic influenza, presenting as a mild disease with low mortality and few complications. Most of the affected children with influenza did not have important risk factors such as asthma and obesity, highlighted by other authors as significant risk factors.

Celecoxib for osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is the most common form of arthritis and is caused by degeneration of the joint cartilage and growth of new bone, cartilage and connective tissue. It is often associated with major disability and impaired quality of life. There is currently no consensus on the best treatment to improve OA symptoms. Celecoxib is a selective non-steroidal anti-inflammatory drug (NSAID). OBJECTIVES: To assess the clinical benefits (pain, function, quality of life) and safety (withdrawals due to adverse effects, serious adverse effects, overall discontinuation rates) of celecoxib in osteoarthritis (OA). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and clinical trials registers up to April 11, 2017, as well as reference and citation lists of included studies. Pharmaceutical companies and authors of published articles were contacted. SELECTION CRITERIA: We included published studies (full reports in a peer reviewed journal) of prospective randomized controlled trials (RCTs) that compared oral celecoxib versus no intervention, placebo or another traditional NSAID (tNSAID) in participants with clinically- or radiologically-confirmed primary OA of the knee or hip, or both knee and hip. DATA COLLECTION AND ANALYSIS: Two authors independently performed data extraction, quality assessment, and compared results. Main analyses for patient-reported outcomes of pain and physical function were conducted on studies with low risk of bias for sequence generation, allocation concealment and blinding of participants and personnel. MAIN RESULTS: We included 36 trials that provided data for 17,206 adults: 9402 participants received celecoxib 200 mg/day, and 7804 were assigned to receive either tNSAIDs (N = 1869) or placebo (N = 5935). Celecoxib was compared with placebo (32 trials), naproxen (6 trials) and diclofenac (3 trials). Studies were published between 1999 and 2014. Studies included participants with knee, hip or both knee and hip OA; mean OA duration was 7.9 years. Most studies included predominantly white participants whose mean age was 62 (± 10) years; most participants were women. There were no concerns about risk of bias for performance and detection bias, but selection bias was poorly reported in most trials. Most trials had high attrition bias, and there was evidence of selective reporting in a third of the studies. Celecoxib versus placeboCompared with placebo celecoxib slightly reduced pain on a 500-point Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain scale, accounting for 3% absolute improvement (95% CI 2% to 5% improvement) or 12% relative improvement (95% CI 7% to 18% improvement) (4 studies, 1622 participants). This improvement may not be clinically significant (high quality evidence).Compared with placebo celecoxib slightly improved physical function on a 1700-point WOMAC scale, accounting for 4% absolute improvement (95% CI 2% to 6% improvement), 12% relative improvement (95% CI 5% to 19% improvement) (4 studies, 1622 participants). This improvement may not be clinically significant (high quality evidence).There was no evidence of an important difference for withdrawals due to adverse events (Peto OR 0.99, 95% CI 0.85 to 1.15) (moderate quality evidence due to study limitations).Results were inconclusive for numbers of participants experiencing any serious AEs (SAEs) (Peto OR 0.95, 95% CI 0.66 to 1.36), gastro-intestinal events (Peto OR 1.91, 95% CI 0.24 to 14.90) and cardiovascular events (Peto OR 3.40, 95% CI 0.73 to 15.88) (very low quality evidence due to serious imprecision and study limitations). However, regulatory agencies have warned of increased cardiovascular events for celecoxib. Celecoxib versus tNSAIDsThere were inconclusive results regarding the effect on pain between celecoxib and tNSAIDs on a 100-point visual analogue scale (VAS), showing 5% absolute improvement (95% CI 11% improvement to 2% worse), 11% relative improvement (95% CI 26% improvement to 4% worse) (2 studies, 1180 participants, moderate quality evidence due to publication bias).Compared to a tNSAID celecoxib slightly improved physical function on a 100-point WOMAC scale, showing 6% absolute improvement (95% CI 6% to 11% improvement) and 16% relative improvement (95% CI 2% to 30% improvement). This improvement may not be clinically significant (low quality evidence due to missing data and few participants) (1 study, 264 participants).Based on low or very low quality evidence (downgraded due to missing data, high risk of bias, few events and wide confidence intervals) results were inconclusive for withdrawals due to AEs (Peto OR 0.97, 95% CI 0.74 to 1.27), number of participants experiencing SAEs (Peto OR 0.92, 95% CI 0.66 to 1.28), gastro-intestinal events (Peto OR 0.61, 0.15 to 2.43) and cardiovascular events (Peto OR 0.47, 95% CI 0.17 to 1.25).In comparisons of celecoxib and placebo there were no differences in pooled analyses between our main analysis with low risk of bias and all eligible studies. In comparisons of celecoxib and tNSAIDs, only one outcome showed a difference between studies at low risk of bias and all eligible studies: physical function (6% absolute improvement in low risk of bias, no difference in all eligible studies).No studies included in the main comparisons measured quality of life. Of 36 studies, 34 reported funding by drug manufacturers and in 34 studies one or more study authors were employees of the sponsor. AUTHORS' CONCLUSIONS: We are highly reserved about results due to pharmaceutical industry involvement and limited data. We were unable to obtain data from three studies, which included 15,539 participants, and classified as awaiting assessment. Current evidence indicates that celecoxib is slightly better than placebo and some tNSAIDs in reducing pain and improving physical function. We are uncertain if harms differ among celecoxib and placebo or tNSAIDs due to risk of bias, low quality evidence for many outcomes, and that some study authors and Pfizer declined to provide data from completed studies with large numbers of participants. To fill the evidence gap, we need to access existing data and new, independent clinical trials to investigate benefits and harms of celecoxib versus tNSAIDs for people with osteoarthritis, with longer follow-up and more direct head-to-head comparisons with other tNSAIDs.

Risk perception about medication sharing among patients: a focus group qualitative study on borrowing and lending of prescription analgesics.

BACKGROUND: One form of self-medication is sharing of medications, defined as borrowing or lending medications in situations where the receiver of these drugs is not the individual to whom the medications were allocated. OBJECTIVE: To explore experiences and opinions of patients about sharing prescription analgesics, reasons for sharing prescription analgesics, the way in which patients choose to share those medications, their awareness of risk regarding sharing prescription analgesics, and how they estimated the potential risk. METHODS: This qualitative study was conducted by focus group discussions with 40 participants led by a moderator trained in focus group methodology using a semi-structured moderator guide. Adults aged ≥18 years who had received a prescription for an analgesic at least once in a lifetime were included. Six separate focus groups were conducted to discuss participants' perception of risks associated with sharing of prescription analgesics among patients. Additionally, participants filled out two questionnaires on demographic data, their own behavior regarding sharing analgesics, and their attitudes about risks associated with sharing prescription analgesics. RESULTS: In a questionnaire, 55% of the participants indicated that they personally shared prescription analgesics, while subsequently in the focus group discussions, 76% confessed to such behavior. Participants recognized certain risks related to sharing of prescription analgesics, mentioned a number of reasons for engaging in such behavior, and indicated certain positive aspects of such behavior. Forty-five percent of the participants indicated that sharing prescription analgesics is riskier than sharing nonprescription analgesics. CONCLUSION: There is a prevalent attitude among participants that sharing prescription analgesics is a positive behavior, where potential benefits outweigh risks.

Risks associated with borrowing and sharing of prescription analgesics among patients observed by pain management physicians in Croatia: a qualitative study.

BACKGROUND: Understanding and improving patient safety is a key issue in medicine. One of the potential threats to patient safety is the sharing of medication among patients, which is a form of self-medication. This study analyzed experiences and attitudes of pain management physicians (PMPs) about sharing prescription analgesics among patients. METHODS: This qualitative study was conducted by semi-structured interviews among PMPs employed in Croatian pain clinics. The study involved two researchers and 15 PMPs. RESULTS: Among PMPs, 80% have seen patients who share their prescription analgesics with other patients for whom prescription is not intended. Most PMPs consider prescription analgesics sharing a risky and negative behavior. Some of them, however, found certain positive aspects associated to it, such as being a benevolent behavior, helping patients to get medications when they need them, and helping them cope with pain. CONCLUSION: The majority of physicians specialized in pain management encountered patients sharing prescription analgesics. Most of them considered this as risky behavior with a number of potential consequences. It has been noted that this problem is neglected and that physicians should inquire about medication sharing. Direct-to-consumers advertising was perceived as a factor contributing to such behavior. Patient education and more involvement of physicians in identifying this behavior were cited as potential remedies for preventing sharing of prescription analgesics.

Cochrane and its prospects in Bosnia and Herzegovina: Relying on Cochrane Croatia.

UNLABELLED: In this article we describe Cochrane and its products: Cochrane systematic reviews (CSRs) and other Cochrane evidence. Cochrane is a unique, international, non-profit organisation that offers health care providers, health care consumers and other decision makers unbiased and highly reliable information on health, which is pivotal for conscientious and responsible decision making in overall healthcare. Cochrane offers the highest ranked evidence in Evidence Based Medicine (EBM)--systematic reviews. Currently, CSRs are freely available in BH, and therefore, they ought to be widely used, and understood. We will present the new Cochrane Strategy to 2020, which was the main topic of the 6th Croatian Cochrane Symposium (CroCoS), as well as explore prospects for spreading Cochrane activities to Bosnia and Herzegovina (BH), through collaboration with Cochrane Croatia. BH has no officially organized Cochrane activity, as yet. We hope that this article will raise awareness about Cochrane in BH, help promote its activities, and deepen the existing collaboration with Cochrane Croatia. There are already some changes being introduced concerning Cochrane--at least, in one half, the Federation of BH (FBH). Two documents symbolising official recognition of policy changes towards Cochrane have recently been published in the Official Gazette of FBH. CONCLUSION: Since founding a BH Cochrane Branch would be costly and difficult to achieve in a complicated environment, such as the one we have, BH could use the good will, experience, knowledge, and translated educational, training and web materials of Cochrane Croatia, particularly given the language similarities, to promote evidence based medicine in BH.

Adherence to pharmacological treatment of chronic nonmalignant pain in individuals aged 65 and older.

BACKGROUND: Medication nonadherence is a frequent problem in the treatment of chronic conditions. OBJECTIVE: To study the adherence to pharmacological treatment of chronic nonmalignant pain, as well as factors and patient attitudes related to nonadherence in patients aged ≥65 years. METHODS: The cross-sectional study was conducted with a self-administered questionnaire among 100 patients aged ≥65 years by five family physicians at the Health Care Centre Mostar, Bosnia and Herzegovina. RESULTS: According to their own statements, 57% of the patients were nonadherent, while 84% exhibited some form of nonadherence on the Morisky scale. The patients reported a mean pain intensity of 6.6 ± 2.2 on a visual analog scale. The most common deviation from the prescribed therapy was self-adjustment of the dose and medical regimen based on the severity of pain. Polymedication correlated positively with nonadherence. Nonsteroidal anti-inflammatory drugs were the most frequently prescribed medications. The majority of the participants (59%) believed that higher pain intensity indicates progression of the disease, and half of the participants believed that one can easily become addicted to pain medications. Nonadherence was associated with patient attitudes about addiction to analgesics and ability of analgesics to control pain. CONCLUSION.: High pain intensity and nonadherence found in this study suggest that physicians should monitor older patients with chronic nonmalignant pain more closely and pay more attention to patients' beliefs regarding analgesics to ensure better adherence to pharmacological therapy.