The aim was to perform an umbrella review to summarise the existing evidence on proton-pump inhibitor (PPI) use and adverse outcomes and to grade the certainty of evidence.Methods: Electronic databases were searched up to July 2021 for meta-analyses of cohort studies and/or randomised controlled trials (RCTs). Summary effect sizes from a random-effects model, between-study heterogeneity, 95% prediction interval, small-study effect, excess significance and credibility ceilings were devised to classify the credibility of evidence from meta-analyses of cohort studies, whereas the GRADE approach was used for meta-analyses of RCTs.Results: In meta-analyses of cohort studies, 52 of the 91 examined associations were statistically significant (P ≤ .05). Convincing evidence emerged from main analysis for the association between PPI use and risk of all-site fracture and chronic kidney disease in the elderly population. However, none of these associations remained supported by convincing evidence after sensitivity analyses. The use of PPI is also associated with an increased risk of mortality due to COVID-19 infection and other related adverse outcomes, but the quality of evidence was weak. In meta-analyses of RCTs, 38 of the 63 examined associations were statistically significant. However, no associations were supported by high or moderate-quality evidence.Conclusion: This study's findings imply that most putative adverse outcomes associated with PPI use may not be supported by high-quality evidence and are likely to have been affected by underlying confounding factors. Future research is needed to confirm the causal association between PPI use and risk of fracture and chronic kidney disease.

To improve long-term outcomes of therapies for chronic diseases, health promotion and lifestyle modifications are the most promising and sustainable strategies. In addition, advances in digital technologies provide new opportunities to address limitations of drug-based treatments, such as medication non-adherence, adverse effects, toxicity, drug resistance, drug shortages, affordability, and accessibility. Pharmaceutical drugs and biologics can be combined with digital health technologies, including mobile medical apps (digital therapeutics), which offer additional clinical benefits and cost-effectiveness. Promises of drug+digital combination therapies are recognized by pharmaceutical and digital health companies, opening opportunities for integrating pharmacotherapies with non-pharmacological interventions (metapharmacology). Herein we present unique features of digital health technologies which can deliver personalized self-care modalities such as breathing exercises, mindfulness meditation, yoga, physical activity, adequate sleep, listening to preferred music, forgiveness and gratitude. Clinical studies reveal how aforementioned complimentary practices may support treatments of epilepsy, chronic pain, depression, cancer, and other chronic diseases. This article also describes how digital therapies delivering “medicinal” self-care and other non-pharmacological interventions can also be personalized by accounting for: 1) genetic risks for comorbidities, 2) adverse childhood experiences, 3) increased risks for viral infections such as seasonal influenza, or COVID-19, and 4) just-in-time stressful and traumatic circumstances. Development and implementation of personalized pharmacological-behavioral combination therapies (precision metapharmacology) require aligning priorities of key stakeholders including patients, research communities, healthcare industry, regulatory and funding agencies. In conclusion, digital technologies enable integration of pharmacotherapies with self-care, lifestyle interventions and patient empowerment, while concurrently advancing patient-centered care, integrative medicine and digital health ecosystems.

Introduction We utilized the Pooled Resource Open‐Access Clinical Trials (PRO‐ACT) database to investigate whether melatonin use among patients with amyotrophic lateral sclerosis (ALS) was associated with slower disease progression and prolonged survival. Methods This retrospective analysis of the PRO‐ACT database addresses the impact of melatonin on progression and overall survival of ALS. A Cox proportional hazards ratio model was performed to investigate the effect that melatonin had on time to death. For secondary outcome measures, linear mixed effects regression models were used to ascertain the effect of melatonin on change in standardized ALS Functional Rating Scale (sALSFRS) and percentage predicted forced vital capacity (FVC) scores. Results Melatonin users had a significantly decreased annualized hazard death rate compared with the non–melatonin users (hazard ratio, 0.241; 95% confidence interval, 0.088‐0.659; P = .0056). The melatonin users also had a slower rate of decline in sALSFRS score (t = 2.71; P = .0069) and change in percent predicted FVC score (t = 2.94; P = .0035) compared with the non–melatonin users. Discussion Our findings suggest that melatonin may be beneficial for patients with ALS. Due to the nature of this database, our results are solely intended to be hypothesis‐generating and no strong associations can be made. Given the low cost and favorable safety profile of melatonin, the hypotheses generated warrant further investigation.

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