Coenzyme Q10 benefits symptoms in Gulf War veterans: results of a randomized double-blind study.

We sought to assess whether coenzyme Q10 (CoQ10) benefits the chronic multisymptom problems that affect one-quarter to one-third of 1990-1 Gulf War veterans, using a randomized, double-blind, placebo-controlled study. Participants were 46 veterans meeting Kansas and Centers for Disease Control criteria for Gulf War illness. Intervention was PharmaNord (Denmark) CoQ10 100 mg per day (Q100), 300 mg per day (Q300), or an identical-appearing placebo for 3.5 ± 0.5 months. General self-rated health (GSRH), the primary outcome, differed across randomization arms at baseline, and sex significantly predicted GSRH change, compelling adjustment for baseline GSRH and prompting sex-stratified analysis. GSRH showed no significant benefit in the combined-sex sample. Among males (85% of participants), Q100 significantly benefited GSRH versus placebo and versus Q300, providing emphasis on Q100. Physical function (summary performance score, SPS) improved on Q100 versus placebo. A rise in CoQ10 approached significance as a predictor of improvement in GSRH and significantly predicted SPS improvement. Among 20 symptoms each present in half or more of the enrolled veterans, direction-of-difference on Q100 versus placebo was favorable for all except sleep problems; sign test 19:1, p=0.00004) with several symptoms individually significant. Significance for these symptoms despite the small sample underscores large effect sizes, and an apparent relation of key outcomes to CoQ10 change increases prospects for causality. In conclusion, Q100 conferred benefit to physical function and symptoms in veterans with Gulf War illness. Examination in a larger sample is warranted, and findings from this study can inform the conduct of a larger trial.

Recruiting a special sample with sparse resources: lessons from a study of Gulf War veterans.

BACKGROUND: Recruitment is the most common failure point for clinical studies, with recruitment failure adversely affecting science, dollar costs, human capital, and the ethical risk-benefit trade-off to study participants. Added problems attend recruitment of special and/or challenging candidate populations, particularly in settings of sparse recruitment resources. Obstacles to study recruitment and participation of ill Gulf War veterans (GWVs) include health barriers, work and family obligations, mistrust of the medical/scientific community, and challenges to identifying/reaching potential participants. PURPOSE: We sought to identify and implement a minimal-cost multipronged recruitment approach for a small single-site (<50 participants) study of a special group, ill GWVs, with approaches substantially applicable to other recruitment settings and larger multisite studies. METHODS: Categories of recruitment approach included directed as well as general media, collaborations with support groups/interest groups, local free advertising resources (Craigslist and Backpage), physician outreach, Internet-based approaches, and referrals from study participants and screenees. We describe the subcategories and yield of each approach within each approach. RESULTS: Each approach contributed candidates to the final recruitment tally, with the largest fractional contribution by directed media (52%). Among the remainder, no other individual approach was clearly dominant (largest contribution: 13%). LIMITATIONS: Special population subsamples present special challenges; all approaches cited may not be useful in all settings and subpopulations. CONCLUSIONS: A multipronged suite of minimal-cost approaches led to successful recruitment to target for this single-site clinical trial for a special population with significant recruitment challenges. It additionally yielded a nation-wide corpus of several hundred individuals interested in participation in future studies of GWVs. While certain approaches produced disproportionate yield, it was not possible to predict these a priori. We suggest that this model, which incorporates a suite of approaches, and delineates backup approaches in the event of recruitment shortfall, may provide a template applicable to recruitment of other special samples in settings of limited resources and also is germane to cost-effective recruitment in studies more generally.

Adverse effect propensity: A new feature of Gulf War illness predicted by environmental exposures.

A third of 1990-1 Gulf-deployed personnel developed drug/chemical-induced multisymptom illness, "Gulf War illness" (GWI). Veterans with GWI (VGWI) report increased drug/exposure adverse effects (AEs). Using previously collected data from a case-control study, we evaluated whether the fraction of exposures that engendered AEs ("AE Propensity") is increased in VGWI (it was); whether AE Propensity is related to self-rated "chemical sensitivity" (it did); and whether specific exposures "predicted" AE Propensity (they did). Pesticides and radiation exposure were significant predictors, with copper significantly "protective"-in the total sample (adjusted for GWI-status) and separately in VGWI and controls, on multivariable regression. Mitochondrial impairment and oxidative stress (OS) underlie AEs from many exposures irrespective of nominal specific mechanism. We hypothesize that mitochondrial toxicity and interrelated OS from pesticides and radiation position people on the steep part of the curve of mitochondrial impairment and OS versus symptom/biological disruption, amplifying impact of new exposures. Copper, meanwhile, is involved in critical OS detoxification processes.

COVID-19-associated rhabdomyolysis: A scoping review.

OBJECTIVES: SARS-CoV-2 infection ("COVID-19") and the hypoxemia that has attended some cases may predispose to rhabdomyolysis. We sought to identify reported cases of COVID-19-associated rhabdomyolysis, examining concurrent risk factors (RFs) and mortality outcomes. METHODS: We searched PubMed for articles conveying individual-level information on COVID-19-associated rhabdomyolysis, published between January 2020 and July 2022, with an English-language abstract. Two independent parties performed the search, and then abstracted information on cases including rhabdomyolysis RFs and mortality. RESULTS: In total, 117 individual reported cases of COVID-19-associated rhabdomyolysis were identified from 89 articles. A total of 80 cases (68.4%) had at least one reported non-COVID-19 RF (i.e. not considering COVID-19 or hypoxemia). On average, 1.27 additional RFs were reported, including age ≥65, metabolic syndrome features, hypothyroidism, previous rhabdomyolysis, hemoglobinopathy, trauma/compression, pregnancy, exertion, inborn errors of metabolism, concurrent (co-)infection, capillary leak syndrome, and selected rhabdomyolysis-associated medications. Concurrent RFs are understated, as many articles omitted comorbidities/medications. Of 109 cases with ascertainable survival status, 31 (28%) died. CONCLUSIONS: COVID-19 and hypoxemia confer risk of rhabdomyolysis, but additional rhabdomyolysis RFs are commonly present. Mortality is substantial irrespective of the presence of such RFs. Clinicians should be aware of COVID-19-associated rhabdomyolysis, and caution may be warranted in administering agents that may amplify rhabdomyolysis risk.

Statin Use in Relation to COVID-19 and Other Respiratory Infections: Muscle and Other Considerations.

Statins have been widely advocated for use in COVID-19 based on large favorable observational associations buttressed by theoretical expected benefits. However, past favorable associations of statins to pre-COVID-19 infection outcomes (also buttressed by theoretical benefits) were unsupported in meta-analysis of RCTs, RR = 1.00. Initial RCTs in COVID-19 appear to follow this trajectory. Healthy-user/tolerator effects and indication bias may explain these disparities. Moreover, cholesterol drops in proportion to infection severity, so less severely affected individuals may be selected for statin use, contributing to apparent favorable statin associations to outcomes. Cholesterol transports fat-soluble antioxidants and immune-protective vitamins. Statins impair mitochondrial function in those most reliant on coenzyme Q10 (a mevalonate pathway product also transported on cholesterol)-i.e., those with existing mitochondrial compromise, whom data suggest bear increased risks from both COVID-19 and from statins. Thus, statin risks of adverse outcomes are amplified in those patients at risk of poor COVID-19 outcomes-i.e., those in whom adjunctive statin therapy may most likely be given. High reported rates of rhabdomyolysis in hospitalized COVID-19 patients underscore the notion that statin-related risks as well as benefits must be considered. Advocacy for statins in COVID-19 should be suspended pending clear evidence of RCT benefits, with careful attention to risk modifiers.

Mitochondrial impairment but not peripheral inflammation predicts greater Gulf War illness severity.

Gulf War illness (GWI) is an important exemplar of environmentally-triggered chronic multisymptom illness, and a potential model for accelerated aging. Inflammation is the main hypothesized mechanism for GWI, with mitochondrial impairment also proposed. No study has directly assessed mitochondrial respiratory chain function (MRCF) on muscle biopsy in veterans with GWI (VGWI). We recruited 42 participants, half VGWI, with biopsy material successfully secured in 36. Impaired MRCF indexed by complex I and II oxidative phosphorylation with glucose as a fuel source (CI&CIIOXPHOS) related significantly or borderline significantly in the predicted direction to 17 of 20 symptoms in the combined sample. Lower CI&CIIOXPHOS significantly predicted GWI severity in the combined sample and in VGWI separately, with or without adjustment for hsCRP. Higher-hsCRP (peripheral inflammation) related strongly to lower-MRCF (particularly fatty acid oxidation (FAO) indices) in VGWI, but not in controls. Despite this, whereas greater MRCF-impairment predicted greater GWI symptoms and severity, greater inflammation did not. Surprisingly, adjusted for MRCF, higher hsCRP significantly predicted lesser symptom severity in VGWI selectively. Findings comport with a hypothesis in which the increased inflammation observed in GWI is driven by FAO-defect-induced mitochondrial apoptosis. In conclusion, impaired mitochondrial function-but not peripheral inflammation-predicts greater GWI symptoms and severity.

What's in placebos: who knows? Analysis of randomized, controlled trials.

BACKGROUND: No regulations govern placebo composition. The composition of placebos can influence trial outcomes and merits reporting. PURPOSE: To assess how often investigators specify the composition of placebos in randomized, placebo-controlled trials. DATA SOURCES: 4 English-language general and internal medicine journals with high impact factors. STUDY SELECTION: 3 reviewers screened titles and abstracts of the journals to identify randomized, placebo-controlled trials published from January 2008 to December 2009. DATA EXTRACTION: Reviewers independently abstracted data from the introduction and methods sections of identified articles, recording treatment type (pill, injection, or other) and whether placebo composition was stated. Discrepancies were resolved by consensus. DATA SYNTHESIS: Most studies did not disclose the composition of the study placebo. Disclosure was less common for pills than for injections and other treatments (8.2% vs. 26.7%; P = 0.002). LIMITATION: Journals with high impact factors may not be representative. CONCLUSION: Placebos were seldom described in randomized, controlled trials of pills or capsules. Because the nature of the placebo can influence trial outcomes, placebo formulation should be disclosed in reports of placebo-controlled trials.

Chocolate Consumption and Sex-Interest.

Media and popular literature link chocolate and sex-interest in women, but there is little research examining their association. This cross-sectional analysis sought to address this gap by assessing the relation of chocolate-consumption frequency to self-rated interest in sex. Seven-hundred twenty-three (723) Southern California men and women, age >20, completed surveys providing chocolate-consumption frequency (Choc0, x/week) and interest in sex (rated 0-10).  Regression (robust standard errors) examined the relationship of chocolate-consumption frequency (Choc0, x/week) to sex-interest, adjusted for potential confounders. Tests for gender and age interactions guided gender- and age-stratified analyses. The mean sex-interest was 7.0±3.0 overall; 5.7±3.1 in women and 7.4±2.8 in men. The reported chocolate frequency was 2.0±2.5x/week overall; 2.5±2.8x/week in women and 1.8±2.4x/week in men. Those who ate chocolate more frequently reported lower interest in sex. Significance was sustained with an adjustment: per-time-per-week chocolate was eaten, ß=-0.11(SE=0.050), p=0.02. The gender interaction was significant (p=0.03). The gender-stratified analysis showed the effect was driven by the much stronger relation in women: full model, per time-per-week chocolate consumed, ß=-0.26(SE=0.08), p=0.002. Chocolate-consumption frequency was the strongest assessed predictor of sex-interest in women. A relationship was not observed in men, though a trend was present in younger men. Women who ate chocolate more frequently reported less interest in sex, a finding not explained by assessed potential confounders. Popular portrayals in which chocolate is represented as substituting for sex and "satisfying" the need for sex in women represent one possible explanation for these findings.

Sodium azide poisoning: a narrative review.

CONTEXT: Sodium azide is a highly toxic chemical. Its production has increased dramatically over the last 30 years due to its widespread use in vehicular airbags, and it is available for purchase online. Thus, accidental exposure to azide or use as a homicidal or suicidal agent could be on the rise, and secondary exposure to medical personnel can occur. No antidote exists for azide poisoning. We conducted a systematic review of azide poisoning to assess recent poisoning reports, exposure scenarios, clinical presentations, and treatment strategies. METHODS: We searched both medical and newspaper databases to review the literature between 01/01/2000 and 12/31/2020, pairing the controlled vocabulary and keyword terms "sodium azide" or "hydrazoic acid" with terms relating to exposures and outcomes, such as "ingestion," "inhalation," "exposure," "poisoning," and "death." We included all peer-reviewed papers and news articles describing human azide poisoning cases from English and non-English publications that could be identified using English keywords. Data abstracted included the number, age, and gender of cases, mode of exposure, exposure setting, azide dose and route of exposure, symptoms, outcome, and treatment modalities. RESULTS: We identified 663 peer-reviewed papers and 303 newspaper articles. After removing duplicated and non-qualifying sources, 54 publications were reviewed describing 156 cases, yielding an average of 7.8 reported azide poisoning cases per year. This rate is three times higher than in a previous review covering the period of 1927 to 1999. Poisoning occurred most commonly in laboratory workers, during secondary exposure of medical personnel, or from a ripped airbag. Hypotension occurred commonly, in some cases requiring vasopressors and one patient received an intra-aortic ballon pump. Gastric lavage and/or activated charcoal were used for oral azide ingestion, and sodium nitrite, sodium thiosulfate, and/or hydroxocobalamin were used in severely poisoned patients. CONCLUSIONS: Recent increases in azide poisoning reports may stem from greater commercial use and availability. Treatment of systemic poisoning may require aggressive hemodynamic support due to profound hypotension. Based on mechanistic considerations, hydroxocobalamin is a rational choice for treating azide poisoning.

A Pilot Study of Bioenergetic Marker Relationships in Gulf War Illness: Phosphocreatine Recovery vs. Citric Acid Cycle Intermediates.

Impaired bioenergetics have been reported in veterans with Gulf War illness (VGWIs), including prolonged post-exercise recovery of phosphocreatine (PCr-R) assessed with 31Phosphorus magnetic resonance spectroscopy. The citric acid cycle (CAC) is considered the most important metabolic pathway for supplying energy, with relationships among CAC markers reported to shift in some but not all impaired bioenergetic settings. We sought to assess relations of CAC markers to one another and to PCr-R. Participants were 33 VGWIs and 33 healthy controls 1:1 matched on age-sex-ethnicity. We assessed seven CAC intermediates, and evaluated PCr-R in a subset of matched case-control pairs (N = 14). CAC markers did not significantly differ between cases and controls. Relationships of alpha-ketoglutarate to malate, isocitrate, and succinate were strongly significant in cases with materially weaker relationships in controls, suggesting possible shifts in these markers in concert in VGWIs. PCr-R correlated strongly with five of seven CAC markers in controls (succinate, malate, fumarate, citrate, isocitrate, range r = -0.74 to -0.88), but bore no relationship in VGWIs. In summary, PCr-R related significantly to CAC markers in healthy controls, but not VGWIs. In contrast, relations of CAC markers to one another appeared to shift (often strengthen) in VGWIs.

Prevalence and psychological correlates of traumatic brain injury in operation iraqi freedom.

OBJECTIVE: To describe the prevalence and psychological correlates of traumatic brain injury (TBI) among injured male combatants in the Iraq conflict. PARTICIPANTS: A total of 781 men injured during military combat between September 2004 and February 2005. MAIN OUTCOME MEASURES: Mental health diagnosis (ICD-9 290-319), particularly posttraumatic stress disorder and mood/anxiety disorders, assigned through November 2006. RESULTS: 15.8% met criteria for TBI (13.4% mild, 2.4% moderate-severe TBI), 35.0% other head injury, and 49.2% non-head injury. Multivariate logistic regression suggested lower rates of posttraumatic stress disorder and mood/anxiety disorders among those with mild and moderate-severe TBI. CONCLUSIONS: These findings could reflect a problem with differential diagnosis or, conversely, a low rate of self-presentation for symptoms. Further research is needed to elucidate the psychological consequences, clinical implications, and overall impact of TBI among military combat veterans.

Radiation Exposure Predicts Reported Vaccine Adverse Effects in Veterans with Gulf War Illness.

Most people have no problems when administered vaccines; however, as with all drugs, reported adverse effects (rAEs) do occur. There is a need to better understand the potential predictors of reported vaccine AEs (rVaxAEs), including modifiable (environmental) predictors. Gulf War Veterans (GWV) who have Gulf War illness (GWI) report increased experiences of drug and chemical rAEs, extending to rVaxAEs. GWV provide an opportunity to examine the relationship between their reported exposures and rAEs. Forty one GWV with GWI and 40 healthy controls reported exposure and rAEs to exposure, including for 14 vaccines. Individual and summed vaccine exposures, rVaxAEs, and reported Vaccine AE Propensity (summed rVaxAEs/summed vaccines exposures) were compared in cases vs. controls. Exposure-outcome assessments focused on GWV, using a multivariable regression with robust standard error. More designated vaccines were reported in cases than in controls: 9.0 (2.3) vs. 3.8 (2.3), p < 0.0001. The fraction of vaccines received that led to rAEs was ten-fold higher in cases: 0.24 (0.21), vs. 0.023 (0.081), p < 0.0001. Multivariable assessment confirmed that radiation and pesticides remained significant statistical predictors of reported Vaccine AE Propensity. Exposure tied to excess rVaxAEs in GWV may contribute to, or underlie, the reported link between rVaxAEs in GWV and later ill health.

Reduction in blood pressure with statins: results from the UCSD Statin Study, a randomized trial.

BACKGROUND: Some studies have suggested reductions in blood pressure (BP)with statin treatment, particularly in persons with hypertension. Randomized trial evidence is limited. METHODS: We performed a randomized, double-blind, placebo-controlled trial with equal allocation to simvastatin, 20 mg; pravastatin sodium,40 mg; or placebo for 6 months. Nine hundred seventy-three men and women without known cardiovascular disease or diabetes mellitus, with low-density lipoprotein cholesterol screening levels of 115 to 190 mg/dL, had assessment of systolic and diastolic BP (SBP and DBP, respectively). Blood pressure values were compared for placebo vs statins by intention-to-treat (ITT) analysis. Additional analyses were performed that (1) were confined to subjects with neither high baseline BP (SBP>140 mm Hg or DBP>90 mm Hg) nor receiving BP medications, to exclude groups in whom BP medications or medication changes may have influenced results, and (2) separately evaluated simvastatin and pravastatin (vs placebo). The time course of BP changes after statin initiation and the effect of stopping statins on BP were examined. RESULTS: Statins modestly but significantly reduced BP relative to placebo,by 2.2 mm Hg for SBP (P=.02) and 2.4 mm Hg for DBP (P<.001) in ITT analysis. Blood pressure reductions ranged from 2.4 to 2.8 mm Hg for both SBP and DBP with both simvastatin and pravastatin, in those subjects with full follow-up, and without potential for influence by BP medications (ie, neither receiving nor meriting BP medications). CONCLUSIONS: Reductions in SBP and DBP occurred with hydrophilic and lipophilic statins and extended to normotensive subjects. These modest effects may contribute to the reduced risk of stroke and cardiovascular events reported on statins. Trial Registration clinicaltrials.gov Identifier: NCT00330980.

Psychological correlates of battle and nonbattle injury among Operation Iraqi Freedom veterans.

Limited research exists on the relationship between physical injury and PTSD within military populations. The present study assessed postinjury rates of PTSD and other psychological correlates among battle and non-battle injuries. A total of 1,968 men (831 battle injuries and 1,137 nonbattle injuries) injured between September 2004 and February 2005 during Operation Iraqi Freedom (OIF) composed the study sample. Patients were followed through November 2006 for mental health diagnosis (ICD-9 290-319). Compared with nonbattle injuries, those with battle injuries had a greater risk of PTSD and other mental health diagnosis, and there was a positive association with injury severity. Self-reported mental health symptoms were significantly higher for both minor and moderate-severe battle injury in comparison to nonbattle injury and previous population estimates from an earlier OIF period. More research is needed to further define this relationship by examining potential mechanisms and addressing the possible contributing effect of combat exposure.

Metabolic features of Gulf War illness.

BACKGROUND: More than 230,000 veterans-about 1/3 of US personnel deployed in the 1990-1991 Persian Gulf War-developed chronic, multi-symptom health problems now called "Gulf War illness" (GWI), for which mechanisms and objective diagnostic signatures continue to be sought. METHODS: Targeted, broad-spectrum serum metabolomics was used to gain insights into the biology of GWI. 40 male participants, included 20 veterans who met both Kansas and CDC diagnostic criteria for GWI and 20 nonveteran controls without similar symptoms that were 1:1 matched to GWI cases by age, sex, and ethnicity. Serum samples were collected and archived at -80° C prior to testing. 358 metabolites from 46 biochemical pathways were measured by hydrophilic interaction liquid chromatography and tandem mass spectrometry. RESULTS: Veterans with GWI, compared to healthy controls, had abnormalities in 8 of 46 biochemical pathways interrogated. Lipid abnormalities accounted for 78% of the metabolic impact. Fifteen ceramides and sphingomyelins, and four phosphatidylcholine lipids were increased. Five of the 8 pathways were shared with the previously reported metabolic phenotype of males with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, 4 of the 5 shared pathways were regulated in opposite directions; key pathways that were up-regulated in GWI were down-regulated in ME/CFS. The single pathway regulated in the same direction was purines, which were decreased. CONCLUSIONS: Our data show that despite heterogeneous exposure histories, a metabolic phenotype of GWI was clearly distinguished from controls. Metabolomic differences between GWI and ME/CFS show that common clinical symptoms like fatigue can have different chemical mechanisms and different diagnostic implications. Larger studies will be needed to validate these findings.

Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism.

HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.

Amyotrophic Lateral Sclerosis Associated with Statin Use: A Disproportionality Analysis of the FDA's Adverse Event Reporting System.

INTRODUCTION: Apparent elevations in reporting of amyotrophic lateral sclerosis (ALS)-like conditions associated with statin use have been previously described from data obtained via US and European databases. OBJECTIVE: The aim of this study was to examine US FDA Adverse Event Reporting System (FAERS) data to compare reporting odds ratios (RORs) of ALS and ALS-like conditions between statins and other drugs, for each statin agent. METHODS: We assessed for disproportional rates of reported ALS and ALS-related conditions for each statin agent separately by using the ROR formula. FAERS data were analyzed through September 2015. RESULTS: RORs for ALS were elevated for all statins, with elevations possibly stronger for lipophilic statins. RORs ranged from 9.09 (6.57-12.6) and 16.2 (9.56-27.5) for rosuvastatin and pravastatin (hydrophilic) to 17.0 (14.1-20.4), 23.0 (18.3-29.1), and 107 (68.5-167) for atorvastatin, simvastatin, and lovastatin (lipophilic), respectively. For simvastatin, an ROR of 57.1 (39.5-82.7) was separately present for motor neuron disease. CONCLUSION: These findings extend previous evidence showing that significantly elevated ALS reporting extends to individual statin agents, and add to concerns about potential elevated occurrence of ALS-like conditions in association with statin usage.

International Group for Reducing Inappropriate Medication Use & Polypharmacy (IGRIMUP): Position Statement and 10 Recommendations for Action.

Globally, the number of drug prescriptions is increasing causing more adverse drug events, which is now a significant cause of mortality, morbidity, and disability that has reached epidemic proportions. The risk of adverse drug events is correlated to very old age, multiple co-morbidities, dementia, frailty, and limited life expectancy, with the major contributor being polypharmacy. Each characteristic alters the risk-benefit balance of medications, typically reducing anticipated benefits and amplifying risk. Current clinical guidelines are based on evidence proven in younger/healthier adult populations using a single disease model and their application to older adults with multimorbidity, in whom testing has not been conducted, yields a different risk-benefit prospect and makes inappropriate medication use and polypharmacy inevitable. Applying inappropriate clinical practice guidelines to older adults is antithetical to good healthcare, is likely to increase health inequity, and is associated with substantial negative clinical, economic, and social implications for health systems. The casualties are on the scale of a war or epidemic, yet are usually invisible in measures of healthcare quality and formal recommendations. Radical and rapid action is required to achieve a better quality of life for older populations and to remain true to the principles of medical professionalism and evidence-based medicine that place patients' interests and autonomy at the fore. This first International Group for Reducing Inappropriate Medication Use & Polypharmacy position statement briefly details the causes, consequences, and extent of inappropriate medication use and polypharmacy. This article outlines current strategies to reduce inappropriate medication use, provides evidence for their effect, and then proposes recommendations for moving forward with 10 recommendations for action and 12 recommendations for research. We conclude that an urgent integrated effort to reduce inappropriate medication use and polypharmacy should be a leading global target of the highest priority. The cornerstone of this position statement from the International Group for Reducing Inappropriate Medication Use & Polypharmacy is the understanding that without evidence of definite relevant benefit, when it comes to prescribing, for many older patients 'less is more'. This approach differs from most other current recommendations and guidance in medical care, as the focus is on what, when, and how to stop, rather than on when to start medications/interventions. Disrupting the framework that indiscriminately applies standard guidelines to older adults requires a new approach that better serves patients with multimorbidity. This transition requires a shift in medical education, research, and diagnostic frameworks, and re-examination of the measures used as quality indicators. In achieving this objective, we promote a return to some of the original concepts of evidence-based medicine: which considers scientific data (where it exists), clinical judgment, patient/family preference, and context. A shift is needed: from the current model that focuses on single conditions to one that simultaneously considers multiple conditions and patient priorities. This approach reframes the clinician's role as a professional providing care, rather than a disease technician.

Physician response to patient reports of adverse drug effects: implications for patient-targeted adverse effect surveillance.

OBJECTIVE: Using a patient targeted survey, we sought to assess patient representations of how physicians responded when patients presented with possible adverse drug reactions (ADRs). As a demonstration case, we took one widely prescribed drug class, the HMG-CoA reductase inhibitors ('statins'). This information was used to assess whether a patient-targeted ADR surveillance approach may complement provider reporting, potentially fostering identification of additional patients with possible or probable ADRs. METHODS: A total of 650 adult patients taking statins with self-reported ADRs completed a survey. Depending on the problems reported, some patients completed additional surveys specific to the most commonly cited statin ADRs: muscle, cognitive or neuropathy related. Patients were asked to report drug, dose, ADR character, time course of onset with drug, recovery with discontinuation, recurrence with rechallenge, quality-of-life impact, and interactions with their physician in relation to the perceived ADR. This paper focuses on patients' representation of the doctor-patient interaction and physicians' attribution, when patients report perceived ADRs. RESULTS: Eighty-seven percent of patients reportedly spoke to their physician about the possible connection between statin use and their symptom. Patients reported that they and not the doctor most commonly initiated the discussion regarding the possible connection of drug to symptom (98% vs 2% cognition survey, 96% vs 4% neuropathy survey, 86% vs 14% muscle survey; p < 10(-8) for each). Physicians were reportedly more likely to deny than affirm the possibility of a connection. Rejection of a possible connection was reported to occur even for symptoms with strong literature support for a drug connection, and even in patients for whom the symptom met presumptive literature-based criteria for probable or definite drug-adverse effect causality. Assuming that physicians would not likely report ADRs in these instances, these patient-submitted ADR reports suggest that targeting patients may boost the yield of ADR reporting systems. CONCLUSIONS: Since low reporting rates are considered to contribute to delays in identification of ADRs, findings from this study suggest that additional putative cases may be identified by targeting patients as reporters, potentially speeding recognition of ADRs.