Treatment with anticancer drugs for advanced pancreatic cancer: a systematic review.

BACKGROUND: Patients with advanced pancreatic cancer have a poor prognosis and high burden of cancer-related symptoms. It is necessary to assess the trade-off of clinical benefits and possible harms of treatments with anticancer drugs (TAD). This systematic review aims to compare the effectiveness of TAD versus supportive care or no treatment, considering all patient-important outcomes. METHODS: We searched PubMed, Embase, Cochrane Library, and Epistemonikos. Two reviewers performed selection, data extraction and risk of bias assessment. We assessed certainty of the evidence using the GRADE approach. RESULTS: We included 14 randomised controlled trials. Chemotherapy may result in a slight increase in overall survival (MD: 2.97 months (95%CI 1.23, 4.70)) and fewer hospital days (MD: -6.7 (-8.3, -5.1)), however, the evidence is very uncertain about its effect on symptoms, quality of life, functional status, and adverse events. Targeted/biological therapy may result in little to no difference in overall survival and a slight increment in progression-free survival (HR: 0.83 (95%CI 0.63, 1.10)), but probably results in more adverse events (RR: 5.54 (95%CI 1.24, 23.97)). The evidence is very uncertain about the effect of immunotherapy in overall survival and functional status. CONCLUSIONS: The evidence is very uncertain about whether the benefits of using treatment with anticancer drugs outweigh their risks for patients with advanced pancreatic cancer. This uncertainty is further highlighted when considering immunotherapy or a second line of chemotherapy and thus, best supportive care would be an appropriate alternative. Future studies should assess their impact on all patient-important outcomes to inform patients in setting their goals of care.

Efficacy and safety of N-acetylcysteine for preventing post-intravenous contrast acute kidney injury in patients with kidney impairment: a systematic review and meta-analysis.

OBJECTIVES: N-Acetylcysteine (NAC) may confer protection against post-contrast acute kidney injury (PC-AKI), although evidence is sparse and conflicting. The objective was to analyse the evidence on the efficacy and safety of NAC vs no administration of NAC in preventing PC-AKI in patients with pre-existing kidney impairment undergoing a non-interventional radiological examination requiring intravenous (IV) contrast media (CM) administration. METHODS: We carried out a systematic review including randomised controlled trials (RCTs) published in MEDLINE, EMBASE, and Clinicaltrials.gov up to May 2022. The primary outcome was PC-AKI. Secondary outcomes included the requirement of renal replacement therapy, all-cause mortality, serious adverse events, and length of hospital stay. We conducted the meta-analyses using the Mantel-Haenszel method and following a random-effects model. RESULTS: NAC was not associated with a significant reduction in PC-AKI (RR 0.47, 95%CI 0.20 to 1.11; 8 studies; 545 participants; I2: 56%; low certainty), all-cause mortality (RR 0.67, 95%CI 0.29 to 1.54; 2 studies; 129 participants; very low certainty), or length of hospital stay (mean difference 9.2 days, 95%CI - 20.08 to 38.48; 1 study; 42 participants; very low certainty). The impact on other outcomes could not be determined. CONCLUSIONS: NAC may not reduce the risk of PC-AKI or all-cause mortality in people with kidney impairment who receive an IV CM prior to radiological imaging, although the certainty of the evidence is very low or low. CLINICAL RELEVANCE STATEMENT: Our review concludes that prophylactic administration of N-acetylcysteine may not significantly reduce the risk of acute kidney injury in patients with kidney impairment receiving an intravenous contrast media prior to non-interventional radiological imaging, which may support decision making in this common clinical scenario. KEY POINTS: • N-Acetylcysteine may not significantly reduce the risk of acute kidney injury in patients with kidney impairment receiving an intravenous contrast media prior to non-interventional radiological imaging. • All-cause mortality and length of hospital stay would not be decreased with the administration of N-Acetylcysteine in this setting.

Role of Pharmacogenomics in the Efficacy and Safety of Thiopurines in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Thiopurines' toxicity often leads to dose reduction or discontinuation. This systematic review aims to synthesize the evidence on the effect of genotype-based dosing of thiopurines on treatment efficacy and safety in inflammatory bowel disease (objective #1), and the association between genotype status and the efficacy and safety profile (objective #2). METHODS: The Cochrane Library, MEDLINE, and EMBASE were searched in August 2021. A total of 80 studies (19,859 individuals) were included. Meta-analyses for mortality, different types of adverse events (AEs), withdrawal due to AE, change in disease activity and clinical remission were performed following mainly a fixed-effects model. PROSPERO registration: CRD42020148130. RESULTS: Genotype-based dosing was associated to a significantly lower incidence of hematologic AEs (risk ratio=0.71; 95% CI: 0.56-0.90; I2 : 47%; 4 randomized controlled trials; moderate quality), which may be attributable to nudix hydrolase 15 (NUDT15) testing more than to thiopurine methyltransferase (TPMT) genotyping. No differences were found in other outcomes. Mutations in TPMT and NUDT15 genes were associated to a higher probability of serious AEs [odds ratio (OR) TPMT=4.98; OR NUDT15=11.44], hematologic AEs (OR TPMT=3.18), and serious hematologic AEs (OR TPMT=7.88; OR NUDT15=12.83). TPMT was also associated with a higher risk of withdrawals due to AEs (OR=3.38), and NUDT15 with gastrointestinal AEs (OR=2.04). Mutations in the ITPA gene did not lead to significant differences. Evidence of an association between other genes and clinical outcomes is still scarce. CONCLUSIONS: Mutations in TPMT and NUDT15 genes predispose patients to suffer thiopurine-induced toxicity, and genotype-guided treatment has been shown to contribute to the prevention of thiopurine-induced toxicity, especially in the case of NUDT15 in Asians.

Effect of the combination of diuretics, renin-angiotensin-aldosterone system inhibitors, and non-steroidal anti-inflammatory drugs or metamizole (triple whammy) on hospitalisation due to acute kidney injury: A nested case-control study.

PURPOSE: Concomitant use of diuretics, renin-angiotensin-aldosterone system (RAAS) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs) or metamizole, known as 'triple whammy' (TW), has been associated with an increased risk of acute kidney injury (AKI). Nevertheless, there is still uncertainty on its impact in hospitalisation and mortality. The aim of the study was to analyse the association between exposure to TW and the risk of hospitalisation for AKI, all-cause mortality and the need for renal replacement therapy (RRT). METHODS: A case-control study nested in a cohort of adults exposed to at least one diuretic or RAAS inhibitor between 2009 and 2018 was carried out within the Pharmacoepidemiological Research Database for Public Health Systems (BIFAP). Patients hospitalised for AKI between 2010 and 2018 (cases) were matched with up to 10 patients of the same age, sex and region of Spain who had not been hospitalised for AKI as of the date of hospitalisation for AKI of the matching case (controls). The association between TW exposure versus non-exposure to TW and outcome variables was analysed using logistic regression models. RESULTS: A total of 480 537 participants (44 756 cases and 435 781 controls) were included (mean age: 79 years). The risk of hospitalisation for AKI was significantly higher amongst those exposed to TW [adjusted odds ratio (aOR) 1.36, 95% confidence interval (95%CI) 1.32-1.40], being higher with current (aOR 1.60, 95%CI 1.52-1.69) and prolonged exposure (aOR 1.65, 95%CI 1.55-1.75). No significant association was found with the need of RRT. Unexpectedly, mortality was lower in those exposed to TW (aOR 0.81, 95%CI 0.71-0.93), which may be influenced by other causes. CONCLUSION: Vigilance should be increased when diuretics, RAAS inhibitors, and NSAIDs or metamizole are used concomitantly, especially in patients at risk such as elderly patients.

Efficacy of educational interventions in adolescent population with feeding and eating disorders: a systematic review.

BACKGROUND: Educational interventions are a key element in the care of young patients with feeding and eating disorders, forming part of the majority of therapeutic approaches. The aim of this review is to evaluate the impact of educational interventions in adolescents with feeding and eating disorders. METHODS: Following the PRISMA recommendations electronic databases were searched up to 29 June 2023. Studies related to educational interventions in young population diagnosed with feeding and eating disorders (anorexia nervosa, avoidant/restrictive food intake disorder, bulimia nervosa, pica and ruminative disorders and binge- eating disorder) in Spanish and English language, without temporal limitation, were located in the databases: PubMed, Scopus, CINAHL, Cochrane Library, PsycINFO, CUIDEN, DIALNET, and ENFISPO. A search in the databases of grey literature was performed in OpenGrey and Teseo. The review protocol was registered in PROSPERO (CRD42020167736). RESULTS: A total of 191 articles were selected from the 9744 citations screened. Ten publications were included. The results indicated variability between educational programs, including individual and group interventions, learning techniques and various research methodologies. Variables such as learning, attitudinal and perceptual changes, anthropometric parameters, symptom improvement, normalization of eating patterns, evaluation of the program and cognitive flexibility were identified. The risk of bias was high due to the low methodological quality of a large number of studies analyzed. CONCLUSION: The results indicate that educational interventions can influence the improvement of knowledge level and have a positive effect on health outcomes. Although education is a common practice in the treatment of these pathologies, high-quality studies were not identified. Thus, this review concludes that additional evidence is needed to evaluate the effectiveness of educational programs, with further research studies, especially randomized controlled trials, to confirm these results. LEVEL OF EVIDENCE: Level I: Systematic review.

COVID-19 infection and complications according to ABO blood group in the elderly: A population-based subcohort and meta-analysis.

BACKGROUND AND OBJECTIVES: It is reported that ABO antibodies have a role in COVID-19 infection and severity; however, ABO antibody titres vary with advanced age. The aim was to analyse the association between ABO blood group and risk of COVID-19 infection and complications in elderly patients, and to contrast this data with findings in the overall adult population. MATERIALS AND METHODS: A prospective cohort study of the Navarre (Spain) population aged ≥60 years and a meta-analysis of published studies including participants of ≥60 years were carried out. RESULTS: In the Navarre elderly population, a higher risk of COVID-19 infection was identified in the A versus non-A and O group and lower risk in O versus non-O, with no significant association between hospitalization, intensive care unit admission or mortality and any of the blood groups, results that coincide with those of the overall Navarre adult population. The meta-analyses using studies that included participants of ≥60 years demonstrated a higher risk of hospitalization and mortality in A versus non-A and a lower mortality risk with B versus non-B. Similar mortality results were found in the meta-analyses of the overall adult population. CONCLUSION: There are no relevant differences between the overall adult population and population aged ≥60 years in the risk of COVID-19 infection and severity according to ABO blood groups, suggesting that age-related changes in ABO would be of limited clinical significance.

Role of the AB0 blood group in COVID-19 infection and complications: A population-based study.

Since the beginning of the COVID-19 pandemic, the ABO blood group has been described as a possible biological marker of susceptibility for the disease. This study evaluates the role of ABO group on the risk of SARS-CoV-2 infection and related complications in a population-based cohort including 87,090 subjects from the Navarre population (Northern Spain) with no history of SARS-CoV-2 infection and with known ABO blood group, after one year of the pandemic (May 2020 - May 2021). The risk of infection, hospitalization, Intensive Care Unit (ICU) admission and death was analyzed using multivariate logistic regression, adjusting for possible confounding variables. A lower risk of infection was observed in group 0 vs non-0 groups [OR 0.94 (95 %CI 0.90-0.99)], a higher risk of infection in group A vs non-A groups [OR 1.09 (95 %CI 1.04-1.15)] and a higher risk of infection in group A vs group 0 [OR 1.08 (95CI 1.03-1.14)] (when the 4 groups are analyzed separately). No association was observed between blood groups and hospitalization, ICU admission, or death in SARS-CoV-2 infected subjects. Regarding the risk of SARS-CoV-2 infection, we observed a protective role of group O and a greater risk in the A group.

STOPPFall (Screening Tool of Older Persons Prescriptions in older adults with high fall risk): a Delphi study by the EuGMS Task and Finish Group on Fall-Risk-Increasing Drugs.

BACKGROUND: Healthcare professionals are often reluctant to deprescribe fall-risk-increasing drugs (FRIDs). Lack of knowledge and skills form a significant barrier and furthermore, there is no consensus on which medications are considered as FRIDs despite several systematic reviews. To support clinicians in the management of FRIDs and to facilitate the deprescribing process, STOPPFall (Screening Tool of Older Persons Prescriptions in older adults with high fall risk) and a deprescribing tool were developed by a European expert group. METHODS: STOPPFall was created by two facilitators based on evidence from recent meta-analyses and national fall prevention guidelines in Europe. Twenty-four panellists chose their level of agreement on a Likert scale with the items in the STOPPFall in three Delphi panel rounds. A threshold of 70% was selected for consensus a priori. The panellists were asked whether some agents are more fall-risk-increasing than others within the same pharmacological class. In an additional questionnaire, panellists were asked in which cases deprescribing of FRIDs should be considered and how it should be performed. RESULTS: The panellists agreed on 14 medication classes to be included in the STOPPFall. They were mostly psychotropic medications. The panellists indicated 18 differences between pharmacological subclasses with regard to fall-risk-increasing properties. Practical deprescribing guidance was developed for STOPPFall medication classes. CONCLUSION: STOPPFall was created using an expert Delphi consensus process and combined with a practical deprescribing tool designed to optimise medication review. The effectiveness of these tools in falls prevention should be further evaluated in intervention studies.

Pharmacotherapy for hypertension-induced left ventricular hypertrophy.

BACKGROUND: Hypertension is the leading preventable risk factor for cardiovascular disease and premature death worldwide. One of the clinical effects of hypertension is left ventricular hypertrophy (LVH), a process of cardiac remodelling. It is estimated that over 30% of people with hypertension also suffer from LVH, although the prevalence rates vary according to the LVH diagnostic criteria. Severity of LVH is associated with a higher prevalence of cardiovascular disease and an increased risk of death. The role of antihypertensives in the regression of left ventricular mass has been extensively studied. However, uncertainty exists regarding the role of antihypertensive therapy compared to placebo in the morbidity and mortality of individuals with hypertension-induced LVH. OBJECTIVES: To assess the effect of antihypertensive pharmacotherapy compared to placebo or no treatment on morbidity and mortality of adults with hypertension-induced LVH. SEARCH METHODS: Cochrane Hypertension's Information Specialist searched the following databases for studies: Cochrane Hypertension Specialised Register (to 26 September 2020), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library; 2020, Issue 9), Ovid MEDLINE (1946 to 22 September 2020), and Ovid Embase (1974 to 22 September 2020). We searched the World Health Organization International Clinical Trials Registry Platform and the ClinicalTrials.gov for ongoing trials. We also searched Epistemonikos (to 19 February 2021), LILACS BIREME (to 19 February 2021), and Clarivate Web of Science (to 26 February 2021), and contacted authors and funders of the identified trials to obtain additional information and individual participant data. There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) with at least 12 months' follow-up comparing antihypertensive pharmacological therapy (monotherapy or in combination) with placebo or no treatment in adults (18 years of age or older) with hypertension-induced LVH were eligible for inclusion. The trials must have analysed at least one primary outcome (all-cause mortality, cardiovascular events, or total serious adverse events) to be considered for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors screened the search results, with any disagreements resolved by consensus amongst all review authors. Two review authors carried out the data extraction and analyses. We assessed risk of bias of the included studies following Cochrane methodology. We used the GRADE approach to assess the certainty of the body of evidence. MAIN RESULTS: We included three multicentre RCTs. We selected 930 participants from the included studies for the analyses, with a mean follow-up of 3.8 years (range 3.5 to 4.3 years). All of the included trials performed an intention-to-treat analysis. We obtained evidence for the review by identifying the population of interest from the trials' total samples. None of the trials provided information on the cause of LVH. The intervention varied amongst the included trials: hydrochlorothiazide plus triamterene with the possibility of adding alpha methyldopa, spironolactone, or olmesartan. Placebo was administered to participants in the control arm in two trials, whereas participants in the control arm of the remaining trial did not receive any add-on treatment. The evidence is very uncertain regarding the effect of additional antihypertensive pharmacological therapy compared to placebo or no treatment on mortality (14.3% intervention versus 13.6% control; risk ratio (RR) 1.02, 95% confidence interval (CI) 0.74 to 1.40; 3 studies; 930 participants; very low-certainty evidence); cardiovascular events (12.6% intervention versus 11.5% control; RR 1.09, 95% CI 0.77 to 1.55; 3 studies; 930 participants; very low-certainty evidence); and hospitalisation for heart failure (10.7% intervention versus 12.5% control; RR 0.82, 95% CI 0.57 to 1.17; 2 studies; 915 participants; very low-certainty evidence). Although both arms yielded similar results for total serious adverse events (48.9% intervention versus 48.1% control; RR 1.02, 95% CI 0.89 to 1.16; 3 studies; 930 participants; very low-certainty evidence) and total adverse events (68.3% intervention versus 67.2% control; RR 1.07, 95% CI 0.86 to 1.34; 2 studies; 915 participants), the incidence of withdrawal due to adverse events may be significantly higher with antihypertensive drug therapy (15.2% intervention versus 4.9% control; RR 3.09, 95% CI 1.69 to 5.66; 1 study; 522 participants; very low-certainty evidence). Sensitivity analyses limited to blinded trials, trials with low risk of bias in core domains, and trials with no funding from the pharmaceutical industry did not change the results of the main analyses. Limited evidence on the change in left ventricular mass index prevented us from drawing any firm conclusions. AUTHORS' CONCLUSIONS: We are uncertain about the effects of adding additional antihypertensive drug therapy on the morbidity and mortality of participants with LVH and hypertension compared to placebo. Although the incidence of serious adverse events was similar between study arms, additional antihypertensive therapy may be associated with more withdrawals due to adverse events. Limited and low-certainty evidence requires that caution be used when interpreting the findings. High-quality clinical trials addressing the effect of antihypertensives on clinically relevant variables and carried out specifically in individuals with hypertension-induced LVH are warranted.

Relationship between frailty, polypharmacy, and underprescription in older adults living in nursing homes.

PURPOSE: Frailty, polypharmacy, and underprescription are considered a major matter of concern in nursing homes, but the possible relationships between them are not well known. The aim is to examine the possible association between medication underprescription, polypharmacy, and frailty in older people living in nursing homes. METHODS: A cross-sectional analysis from a concurrent cohort study, including 110 subjects ≥ 65 years living in two nursing homes. Four frailty scales were applied; polypharmacy was defined as ≥ 5 medications and underprescription was measured with Screening Tool to Alert to Right Treatment (START) criteria. Logistic regression models were performed to assess the associations. RESULTS: The mean age was 86.3 years (SD 7.3) and 71.8% were female. 73.6% of subjects took ≥ 5 chronic medications and 60.9% met one or more START criteria. The non-frail participants took more medications than the frail subjects according to the imputated frailty Fried criteria (8.1 vs 6.7, p = 0.042) and the FRAIL-NH scale (7.8 vs 6.8, p = 0.026). Multivariate analyses did not find an association between frailty and polypharmacy. Frail participants according to the Fried criteria met a higher number of START criteria (1.9 vs 1.0, p = 0.017), and had a higher prevalence of underprescription (87.5 vs 50.0%), reaching the limit of statistical significance in multivariate analysis. CONCLUSION: The positive association found in previous studies between frailty and polypharmacy cannot be extrapolated to institutionalized populations. There is a trend towards higher rates of underprescription in frail subjects. Underprescription in frail older adults should be redefined and new strategies to measure it should be developed.

Anticholinergic burden and health outcomes among older adults discharged from hospital: results from the CRIME study.

PURPOSE: The purpose of this study is to investigate whether there is an association between anticholinergic burden and mortality or rehospitalization in older adults discharged from hospital. METHODS: Prospective multicenter cohort study carried out with patients aged 65 and older discharged from seven acute care hospitals. The primary outcomes of the study were rehospitalization and mortality within 1 year after discharge. The study population was classified in three groups according to the anticholinergic exposure measured by the Anticholinergic Risk Scale (ARS) and Durán's list at the time of hospital discharge: without risk (ARS/Durán = 0), low risk (ARS/Durán = 1), and high risk (ARS/Durán ≥ 2). Predictors of hospitalizations and mortality were examined using regression models adjusting for important covariates. RESULTS: The mean age of the 921 participants was 81.2 years (SD = 7.4 years). Prevalence of exposure to medications with anticholinergic activity ranged from 19.6% with ARS to 32.1% with Durán's list. During the follow-up period, 30.4% of participants were hospitalized and 19.4% died. Multivariate regression analysis showed that low anticholinergic burden quantified according to Durán's list was significantly associated with all-cause mortality (OR 1.69, 95% CI 1.02-2.82). This association was not present after adjustment when using ARS. No statistically significant association was found between anticholinergic burden and hospitalizations. CONCLUSIONS: Taking medications with anticholinergic activity is associated with greater risk of mortality in older adults discharged from acute care hospitals. Strategies to reduce anticholinergic burden in vulnerable elders could be useful to improve health outcomes. Further research is required to assess the association between anticholinergic burden and hospitalizations in older patients.

Optipharm: Enhancing pharmacological management skills in healthcare students for geriatric care through gamified e-learning.

BACKGROUND: Complexities in older patient care and frequent polypharmacy requires tailored tools, specific skills and interdisciplinary collaborations. Traditional disease-centered education often overlooks these issues. Despite digital gamification's relevance in health education, limited exploration exists for gamified platforms addressing polypharmacy, especially within comprehensive geriatric assessment (CGA). OBJECTIVE: This study outlines Optipharm's design, a gamified e-learning tool designed to enhance health students' education in managing polypharmacy among older adults. It also assesses its usability using a validated scale. METHODS: Optipharm development utilized gamification techniques guided by pedagogical principles. Learning objectives addressed clinical and educational gaps in older adult care. Hosted on a Moodle system, the platform housed a structured clinical case as a SCORM file, a usability scale, a certificate of achievement, and a literature library. Optipharm was assessed by 304 medical students from the University of Navarre, Spain, using the SUS-G-Sp scale. RESULTS: An immersive gamified e-learning tool simulating clinical practice settings was developed, requiring users to assume the role of healthcare professionals in multidisciplinary outpatient consultations. The interface, with a 2D cartoon-style aesthetic, aligns with learning objectives, integrating engaging storytelling and clear instructions for CGA in Phase 1 and pharmacological optimization in Phase 2. The evaluation of Optipharm's usability revealed very positive perceptions among users, with high agreement rates on usability items. CONCLUSION: Optipharm represents a pioneering gamified tool designed to simulate clinical scenarios, allowing users to engage as healthcare professionals within multidisciplinary teams and address medication-related challenges in older patients with polypharmacy. It provides a secure, interactive learning environment with clear educational objectives and seamless integration of gamification elements, enhancing users' knowledge and skills in managing complex medication regimens. As a platform for experiential learning and knowledge exchange, Optipharm contributes to shaping the future of health education and fostering a culture of patient-centred care among future healthcare professionals.

Systematic review and meta-analysis on the effectiveness of multidisciplinary interventions to address polypharmacy in community-dwelling older adults.

Interventions to address polypharmacy in community-dwelling older adults often focus on medication-related outcomes. The aim was to explore the impact of multidisciplinary interventions to manage polypharmacy on clinical outcomes for community-dwelling older adults. This systematic review and meta-analysis included randomized controlled trials (RCTs) on interventions by at least a pharmacist and a physician, indexed in MEDLINE, EMBASE or CENTRAL up to January 2023. Evidence certainty was assessed using the GRADE approach. Seventeen RCTs were included. Fifteen were rated as 'high' risk of bias. No relevant benefits were found in functional and cognitive status (primary outcomes), falls, mortality, quality of life, patient satisfaction, hospital admissions, emergency department or primary care visits. Interventions reduced medication costs, improved medication appropriateness (odds ratio [OR] 0.39), reduced number of medications (mean difference [MD] -0.57), resolved medication-related problems (MD -0.45), and improved medication adherence (relative risk [RR] 1.14). There was a low or very low certainty of the evidence for most outcomes. Multidisciplinary interventions to address polypharmacy appear effective in improving multiple dimensions of medication use. However, evidence for corresponding improvements in functional or cognitive status is scarce. New efficient models of multidisciplinary interventions to address polypharmacy impacting clinical outcomes should be explored.

Deprescribing Opportunities for Frail Residents of Nursing Homes: A Multicenter Study in Australia, China, Japan, and Spain.

OBJECTIVE: Deprescribing opportunities may differ across health care systems, nursing home settings, and prescribing cultures. The objective of this study was to compare the prevalence of STOPPFrail medications according to frailty status among residents of nursing homes in Australia, China, Japan, and Spain. DESIGN: Secondary cross-sectional analyses of data from 4 cohort studies. SETTING AND PARTICIPANTS: A total of 1142 residents in 31 nursing homes. METHODS: Medication data were extracted from resident records. Frailty was assessed using the FRAIL-NH scale (non-frail 0-2; frail 3-6; most-frail 7-14). Chi-square tests and prevalence ratios (PRs) were used to compare STOPPFrail medication use across cohorts. RESULTS: In total, 84.7% of non-frail, 95.6% of frail, and 90.6% of most-frail residents received ≥1 STOPPFrail medication. Overall, the most prevalent STOPPFrail medications were antihypertensives (53.0% in China to 73.3% in Australia, P < .001), vitamin D (nil in China to 52.7% in Australia, P < .001), lipid-lowering therapies (11.1% in Japan to 38.9% in Australia, P < .001), aspirin (13.5% in Japan to 26.2% in China, P < .001), proton pump inhibitors (2.1% in Japan to 32.0% in Australia, P < .001), and antidiabetic medications (12.3% in Japan to 23.5% in China, P = .010). Overall use of antihypertensives (PR, 1.15; 95% CI, 1.06-1.25), lipid-lowering therapies (PR, 1.78; 95% CI, 1.45-2.18), aspirin (PR, 1.31; 95% CI, 1.04-1.64), and antidiabetic medications (PR, 1.31; 95% CI, 1.00-1.72) were more prevalent among non-frail and frail residents compared with most-frail residents. Antihypertensive use was more prevalent with increasing frailty in China and Japan, but less prevalent with increasing frailty in Australia. Antidiabetic medication use was less prevalent with increasing frailty in China and Spain but was consistent across frailty groups in Australia and Japan. CONCLUSIONS AND IMPLICATIONS: There were overall and frailty-specific variations in prevalence of different STOPPFrail medications across cohorts. This may reflect differences in prescribing cultures, application of clinical practice guidelines in the nursing home setting, and clinician or resident attitudes toward deprescribing.

Long-term effectiveness and safety of tolvaptan in autosomal dominant polycystic kidney disease.

BACKGROUND AND OBJECTIVES: Evidence on the long-term use of tolvaptan in autosomal dominant polycystic kidney disease (ADPKD) is limited. The aim was to evaluate the tolvaptan effectiveness and safety in real clinical setting. MATERIAL AND METHODS: A single-center observational study (2016-2022) involving ADPKD patients treated with tolvaptan was conducted. Annual change in serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) before and after treatment initiation were evaluated. Change in total kidney volume (TKV), blood pressure (BP) and urinary albuminuria at 12, 24 and 36 months after initiation were also determined. Adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 were analyzed. RESULTS: A total of 22 patients were included. No significant differences pre- vs post tolvaptan treatment in annual rate of change in eGFR (-3.52ml/min/1.73m2 [-4.98%] vs -3.98ml/min/1.73m2 [-8.48%], p=0.121) and sCr (+0.06mg/dL [4.22%] vs +0.15mg/dL [7.77%], p=0.429) were observed. Tolvaptan improved urinary osmolality at 12 (p=0.019) and 24 months (p=0.008), but not at 36 months (p=0.11). There were no changes in TKV, BP control and urinary albuminuria at 12, 24 or 36 months. A worse response was shown in patients with rapid kidney function decline (p=0.042). A 36.4% of the patients developed grade III/IV AEs. A 22.7% discontinued treatment due to unacceptable toxicity. CONCLUSIONS: This study shows a modest benefit of tolvaptan in ADPKD patients, as well as safety concerns.

Restoring Study PRGF: a randomized clinical trial on plasma rich in growth factors for knee osteoarthritis.

BACKGROUND: A randomized clinical trial assessing plasma rich in growth factors (PRGF) versus hyaluronic acid for knee osteoarthritis was published in 2012 (sponsor trial ID BTI-01-EC/07/ART). Evidence of misreporting was discovered following access to unpublished materials. In accordance with the principles of the Restoring Invisible and Abandoned Trials (RIAT) initiative, we sought to re-analyse Study PRGF based on the unpublished trial materials. METHODS: Reanalysis was made possible primarily based on two unpublished study documents (original trial protocol and final report) obtained from the authors of the original publication. A call to action, calling on the authors to correct the original publication, was publicly issued. The involved ethics committee was repeatedly approached and extensive discussion with the authors ensued. After no agreement to correct the paper was reached, we embarked on this restoration. Reanalysis was focused on providing updated analyses for efficacy and safety. RESULTS: The efficacy of PRGF was not statistically different from hyaluronic acid for any prespecified primary or secondary efficacy outcomes. For the primary endpoint, the percent of patients on PRGF compared to hyaluronic acid with a decrease >40% in WOMAC pain subscale score was 5.4% higher; 95% confidence interval (CI) -10.4% to 21.3%; p = 0.505. This differs from the original publication that reported a non-prespecified primary endpoint (decrease >50% in WOMAC pain subscale score) which was 14.1% higher; 95% CI 0.5 to 27.6%; p=0.044. Furthermore, in contrast to the article statement that all the adverse events disappeared in 48 h, at least two patients in the hyaluronic arm and five patients in the PRGF arm reported persistent adverse events. Inadequate disclosure of conflicts of interest in the original publication was also noted. CONCLUSIONS: This reanalysis of Study PRGF found no clinically or statistically significant benefit from PRGF compared to hyaluronic acid. The restoration of Study PRGF shows the urgency of important changes to trial reporting and oversight practices. In the future, timely access to all clinical trial documents is needed to minimize the risk of reporting bias. Similarly, ethics committees should be ready to intervene whenever a case of potential misconduct arises. TRIAL REGISTRATION: This is a RIAT project, whose original trial was approved and registered on 19 December 2007 by the Ethics Committee of the Basque Country, Spain, as BTI-01-EC/07/ART.

Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in hematologic malignancies: a living systematic review on comparative studies.

Background: Chimeric antigen receptor T-cell (CAR-T) cell therapies have been claimed to be curative in responsive patients. Nonetheless, response rates can vary according to different characteristics, and these therapies are associated with important adverse events such as cytokine release syndrome, neurologic adverse events, and B-cell aplasia. Objectives: This living systematic review aims to provide a timely, rigorous, and continuously updated synthesis of the evidence available on the role of CAR-T therapy for the treatment of patients with hematologic malignancies. Design: A systematic review with meta-analysis of randomized controlled trials (RCTs) and comparative non-randomized studies of interventions (NRSI), evaluating the effect of CAR-T therapy versus other active treatments, hematopoietic stem cell transplantation, standard of care (SoC) or any other intervention, was performed in patients with hematologic malignancies. The primary outcome is overall survival (OS). Certainty of the evidence was determined using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Data sources and Methods: Searches were performed in the Epistemonikos database, which collates information from multiple sources to identify systematic reviews and their included primary studies, including Cochrane Database of Systematic Reviews, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, DARE, HTA Database, Campbell database, JBI Database of Systematic Reviews and Implementation Reports, EPPI-Centre Evidence Library. A manual search was also carried out. We included the evidence published up to 1 July 2022. Results: We included the evidence published up to 1 July 2022. We considered 139 RCTs and 1725 NRSI as potentially eligible. Two RCTs (N = 681) comparing CAR-T therapy with SoC in patients with recurrent/relapsed (R/R) B-cell lymphoma were included. RCTs did not show statistical differences in OS, serious adverse events, or total adverse events with grade ⩾ 3. Higher complete response with substantial heterogeneity [risk ratio = 1.59; 95% confidence interval (CI) = (1.30-1.93); I 2 = 89%; 2 studies; 681 participants; very low certainty evidence] and higher progression-free survival [hazard ratio for progression or death = 0.49; 95% CI = (0.37-0.65); 1 study; 359 participants; moderate certainty evidence] were reported with CAR-T therapies. Nine NRSI (N = 540) in patients with T or B-cell acute lymphoblastic leukemia or R/R B-cell lymphoma were also included, providing secondary data. In general, the GRADE certainty of the evidence for main outcomes was mostly low or very low. Conclusion: So far, assuming important limitations in the level of certainty due to scarce and heterogenous comparative studies, CAR-T therapies have shown some benefit in terms of progression-free survival, but no overall survival, in patients with R/R B-cell lymphoma. Despite one-arm trials have already facilitated approval of CAR-T cell treatments, additional evidence from large comparative studies is still needed to better characterize the benefit-harm ratio of the use of CAR-T in a variety of patient populations with hematological malignancies. Registration: https://doi.org/10.12688/openreseurope.14390.1. PROSPERO/OSF Preregistration: 10.17605/OSF.IO/V6HDX.