PLOS Medicine recently published

by Christine Laine, Dianne Babski, Vivienne C. Bachelet, Till W. Bärnighausen, Christopher Baethge, Kirsten Bibbins-Domingo, Frank Frizelle, Laragh Gollogly, Sabine Kleinert, Elizabeth Loder, João Monteiro, Eric J. Rubin, Peush Sahni, Christina C. Wee, Jin-Hong Yoo, Lilia Zakhama

In this Editorial, representatives of the International Committee of Medical Editors discuss the need for multi-stakeholder involvement to recognize and counter the actions of predatory journals.

by Lin Geng, Lilith K. Whittles, Borame L. Dickens, Martin T. W. Chio, Yihao Chen, Rayner Kay Jin Tan, Azra Ghani, Jue Tao Lim

by Reina Tonegawa-Kuji, Yuan Hou, Bo Hu, Noah Lorincz-Comi, Andrew A. Pieper, Babak Tousi, James B. Leverenz, Feixiong Cheng

Background

While recently U.S. FDA-approved anti-amyloid beta (anti-Aβ) monoclonal antibodies (mAbs) offer new treatment approaches for patients suffering from Alzheimer’s disease (AD), these medications also carry potential safety concerns and uncertainty about their efficacy for improving cognitive function. This study presents an updated meta-analysis of cognitive outcomes and side effects of anti-Aβ mAbs from phase III randomized controlled trials (RCTs) in patients with sporadic AD.

Methods and Findings

Phase III randomized, placebo-controlled blinded trial evaluating the efficacy and safety of anti-Aβ mAbs in patients with AD were identified through a search in clinical trials.gov, PubMed and Embase on January 14th, 2024. The retrieved studies were further screened from January 15th, 2024, to February 14th, 2024. We included studies that had been published in any language. Quality of trials was assessed using the Jadad score and publication bias was assessed using Egger’s test and Funnel plot. Primary outcomes were mean changes from baseline to post-treatment in Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) and AD Assessment Scale-Cognitive Subscale (ADAS-Cog) scores, and secondary outcomes were adverse events including amyloid-related imaging abnormalities with edema (ARIA-E), and ARIA with hemorrhage (ARIA-H). Random-effects meta-analysis and meta-regression analyses were conducted. The literature search identified 13 phase III RCTs, which included 18,826 patients with mild cognitive impairment or dementia due to AD. Compared with placebo, treatment with mAbs significantly improved cognitive performance on CDR-SB (mean difference −0.25, 95% confidence interval [CI] [−0.38, −0.11]) and ADAS-Cog (standardized mean difference −0.09, 95% CI [−0.12, −0.06]), in which a negative change indicates improvement for both scores. Meta-regression analysis suggested that trials enrolling patients with early-stage AD were associated with better efficacy. Elevated risk of ARIA-E (risk ratio [RR] 9.79, 95% CI [5.32,18.01]), ARIA-H (RR 1.94, 95% CI [1.47,2.57]), and headaches (RR 1.21, 95% CI [1.10,1.32]) were noted. Statistical heterogeneity was relatively high for ARIA-E and ARIA-H, leading to wide confidence intervals and considerable variability in effect sizes, though meta-regression was conducted to address this. Furthermore, differences in trial designs introduce limitations in cross-trial comparisons.

Conclusions

Anti-Aβ mAb therapy slows cognitive decline, but with small effect sizes, and raises potential concerns about ARIA and headaches.

by Melese Siyoum, Rahel Nardos, Biniyam Sirak, Theresa Spitznagle, Wondwosen Teklesilasie, Ayalew Astatkie

Background

Pelvic organ prolapse (POP) is a common condition that can significantly impact a woman’s quality of life. Pelvic floor muscle training (PFMT) is recommended as a first-line conservative treatment for prolapse, but evidence on its effectiveness from low-resource settings is limited. This study aimed to assess the effect of midwife-led PFMT on prolapse symptoms and health-related quality of life (HRQoL) among women with mild-to-moderate POP in Ethiopia.

Methods and findings

A community-based, parallel-groups, two-arm cluster-randomized controlled trial was conducted in Dale and Wonsho districts of Sidama Region, Ethiopia. Women with symptomatic POP stages I–III were randomized by cluster to receive either midwife-led PFMT plus lifestyle counseling (intervention group) or lifestyle counseling alone (control group). The participants and counselors knew what the women were receiving, but they were not aware of the other group. The outcome assessors, who collected data at the end of intervention, were blinded to the participants’ treatment allocation. The primary outcomes were changes in prolapse symptom score (POP-SS) and prolapse quality of life (P-QoL). Mixed-effects generalized linear model was used to determine the effect of PFMT on prolapse symptoms and P-QoL at 99% confidence level. Adjusted β coefficients were used as effect measures. The level of significance was adjusted for multiple comparisons.A total of 187 women were randomized to intervention (n = 86) from four clusters and control (n = 101) arms from another four clusters. At sixth months, the intervention group showed significantly greater improvements both in prolapse symptoms and P-QoL. The mean change difference in POP-SS was −4.11 (99% CI [−5.38, −2.83]; p < 0.001). Similarly, the mean change difference was: −8.86 (99% CI [−13.84, −3.89]; p < 0.001) in physical domain of P-QoL; −11.18 (99% CI [−15.03, −7.32]; p < 0.001) in psychological domain of P-QoL, and −9.01 (99% CI [−10.49, −5.54]; p < 0.001) in personal relationship domain of P-QoL. A significantly higher proportion (83.72%) of women in the intervention group perceived their condition as “better” after the intervention as compared to 41.58% in the control group. Women with earlier stages of prolapse (stages I and II) experienced higher benefits compared to those in stage III.

Conclusions

A midwife-led PFMT combined with lifestyle counseling significantly improves prolapse symptoms and quality of life in mild-to-moderate POP. This strategy can be integrated into the existing maternal and reproductive health programs to address POP in low-income settings where access to trained specialist is limited.

Trial registration

The trial was registered at the Pan African Clinical Trial Registry (https://pactr.samrc.ac.za) database, with the registration number PACTR202302505126575 (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=24311).

by Emma F. Magavern, Maia Megase, Jack Thompson, Gabriel Marengo, Julius Jacobsen, Damian Smedley, Mark J. Caulfield

Background

Adverse drug reactions (ADRs) harm patients and are costly for healthcare systems. Genetic variation contributes to variability in medication response and prospective knowledge of these variants can decrease risk of ADRs, as shown in the PREPARE trial. Reduction in ADRs would affect only those reactions to drugs contained in well-validated pharmacogene–drug pairs. The scope of ADRs represented by these drugs on a population scale is unclear. The objective of this study was to characterize the pharmacogene–drug-associated ADR reporting landscape from a national regulatory pharmacovigilance dataset to elucidate the scale of potential ADR mitigation by pharmacogenomics (PGx) implementation.

Methods and findings

All publicly available Yellow Card ADR reports to the United Kingdom Medicines and Healthcare Products Regulatory Agency, from 1963 to 2024, were compiled using programmatic data extraction. The ADRs were analysed with descriptive statistics, stratified by PGx status and by associated genes. Prescribing prevalence from the literature was compared with age range matched ADR reports for PGx-associated drugs. There were 1,345,712 ADR reports, attributed to 2,499 different substances. 115,789 adverse drug reports (9%) were associated with drugs for which ADR risk can be modified based on pharmacogenomic prescribing guidance. Seventy-five percent of these (n = 87,339) were due to medicines which interact with only three pharmacokinetic pharmacogenes (CYP2C19, CYP2D6, SLCO1B1). Forty-seven percent of all the PGx mitigatable ADRs identified were attributed to psychiatric medications (n = 54,846), followed by 24% attributed to cardiovascular medications (n = 28,279). Those experiencing PGx mitigatable ADRs, as compared with non-PGx mitigatable ADRs, were older and the ADRs more often consisted of severe non-fatal reactions. Many PGx-associated psychiatric drug ADRs were overrepresented as compared with prescribing prevalence, but fatal cardiac arrhythmias were uncommon consequences, comprising only 0.4% of these ADRs (n = 172 of n = 48,315 total ADRs). Limitations of this data source include under reporting of ADRs and reporting bias. These findings are based on analysis of the Yellow Card dataset described and may not represent all ADRs from a generalised patient population.

Conclusions

Nine percent of all reported ADRs are associated with drugs where a genetic variant can cause heightened risk of an ADR and inform prescribing. A panel of only three pharmacogenes could potentially mitigate three in every four PGx modifiable ADRs. Based on our findings, Psychiatry may be the single highest impact specialty to pilot PGx to reduce ADRs and associated morbidity, mortality and costs.

by Xingxing Chen, Enying Gong, Jie Tan, Elizabeth L. Turner, John A. Gallis, Shifeng Sun, Siran Luo, Fei Wu, Bolu Yang, Yutong Long, Yilong Wang, Zixiao Li, Yun Zhou, Shenglan Tang, Janet P. Bettger, Brian Oldenburg, Xiaochen Zhang, Jianfeng Gao, Brian S. Mittman, Valery L. Feigin, Ruitai Shao, Shah Ebrahim, Lijing L. Yan

Background

Despite growing evidence of primary care-based interventions for chronic disease management in resource-limited settings, long-term post-trial effects remain inconclusive. We investigated the association of a 12-month system-integrated technology-enabled model of care (SINEMA) intervention with mortality outcomes among patients experiencing stroke at 6-year post-trial.

Methods and findings

This study (clinicltiral.gov registration number: NCT05792618) is a long-term passive observational follow-up of participants and their spouse of the SINEMA trial (clinicaltrial.gov registration number: NCT03185858). The original SINEMA trial was a cluster-randomized controlled trial conducted in 50 villages (clusters) in rural China among patients experiencing stroke during July 2017–July 2018. Village doctors in the intervention arm received training, incentives, and a customized mobile health application supporting monthly follow-ups to participants who also received daily free automated voice-messages. Vital status and causes of death were ascertained using local death registry, standardized village doctor records, and verbal autopsy. The post-trial observational follow-up spanned from 13- to 70-months post-baseline (up to April 30, 2023), during which no intervention was requested or supported. The primary outcome of this study was all-cause mortality, with cardiovascular and stroke cause-specific mortality also reported. Cox proportional hazards models with cluster-robust standard errors were used to compute hazard ratios (HRs) and 95% confidence intervals (95% CIs), adjusting for town, age, and sex in the main analysis model. Analyses were conducted on an intention-to-treat basis.Of 1,299 patients experiencing stroke (mean age 65.7 years, 42.6% females) followed-up to 6 years, 276 (21.2%) died (median time-to-death 43.0 months [quantile 1–quantile 3: 26.7–56.8]). Cumulative incidence of all-cause mortality was 19.0% (121 among 637) in the intervention arm versus 23.4% (155 among 662) in the control arm (HR 0.73; 95% CI 0.59, 0.90; p = 0.004); 14.4% versus 17.7% (HR 0.73; 95% CI 0.58, 0.94; p = 0.013) for cardiovascular cause-specific mortality; and 6.0% versus 7.9% (HR 0.71; 95% CI 0.44, 1.15; p = 0.16) for stroke cause-specific mortality. Although multisource verification was used to verify the outcomes, limitations exist as the survey- and record-matching-based nature of the study, unavailability of accurate clinical diagnostic records for some cases and the potential confounders that may influence the observed association on mortality.

Conclusions

Despite no observed statistically difference on stroke cause-specific mortality, the 12-month SINEMA intervention, compared with usual care, significantly associated with reduced all-cause and cardiovascular cause-specific mortality during 6 years of follow-up, suggesting potential sustained long-term benefits to patients experiencing stroke.

by Hiroki Shinmura, Youhei Tsunoda, Takashi Matsushima, Ryuhei Kurashina, Asako Watanabe, Eika Harigane, Nozomi Ouchi, Shunji Suzuki

Background

In Japan, the lateral position method is known as a postural therapy for breech presentation wherein the mother lies down in lateral position according to the orientation of the fetal back. Few studies have formally tested lateral position management for breech presentation, and no method exists to prevent breech recurrence after cephalic version. We hypothesized that postural management comprising a combination of opposite-side lateral position for breech presentation and same-side lateral position after cephalic version demonstrates a clinically relevant effect size on breech presentation.

Methods and findings

We conducted a stratified, open-label randomized controlled trial at an academic hospital in Kawasaki, Japan. A total of 200 women diagnosed with breech presentation between 28 +  0 and 30 +  0 gestational weeks were randomized to postural management (n =  100) or control (no intervention, n =  100) group. The intervention was instruction every 2 weeks on lying in the lateral position on the opposite-side of fetal back for breech presentation and on the same-side of fetal back for head-first presentation. The primary outcome was the rate of fetuses in breech presentation at 37 weeks of gestation, and the secondary outcomes were cesarean delivery, cesarean delivery for breech presentation, head presentation 2, 4, and 6 weeks later, breech presentation recurrence, and adverse events. Breech presentation rate at 37 gestational weeks was 11% in the intervention group, using the combination of the opposite-side and same-side lateral positions, compared with 19% in the control group. However, we found no statistical significance in the intention-to-treat analysis (11% [11/100] versus 19% [19/100]; relative risk, 0.58 [95% CI, 0.29 to 1.15]; p =  0.11). In the control group, 23 participants (23%) unknowingly took the same posture as the intervention group, and the prespecified per-protocol analysis excluding crossover found the same direction of effect but with statistical significance. In the intention-to-treat analysis, the intervention group had a higher cephalic version rate 2 weeks after the instruction (69% [69/100] versus 54% [54/100]; relative risk, 0.67 [95% CI, 0.47 to 0.96]; p =  0.029), and lower breech presentation recurrence rates (2% [2/91] versus 10% [9/88]; relative risk, 0.22 [95% CI, 0.048 to 0.97]; p =  0.031) than the control group. Regarding adverse events in the intervention group, three participants experienced discomfort and one participant complained of pain in the lateral abdomen; these symptoms resolved spontaneously.

Conclusions

For breech presentation at the beginning of the third trimester, providing postural therapy instruction on opposite-side lateral positioning and same-side lateral positioning was associated with 8% reduction of breech fetuses at 37 gestational weeks compared with the control group, but this primary endpoint did not reach statistical significance. Regarding the secondary endpoints, the intervention group showed a significantly higher rate of cephalic version after 2 weeks and lower rate of breech recurrence. The direction of the effect of postural therapy based on fetal back position on breech presentation was promising, and further research to validate this approach, with consideration for unplanned participant crossover, may be warranted.

Trial registration

UMIN Clinical Trials Registry (UMIN000043613, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000049800).

by Yulong Ma, Siyuan Liu, Faqiang Zhang, Xuhui Cong, Bingcheng Zhao, Miao Sun, Huikai Yang, Min Liu, Peng Li, Yuxiang Song, Jiangbei Cao, Yingfu Li, Wei Zhang, Kexuan Liu, Jiaqiang Zhang, Weidong Mi

Background

Perioperative stroke is a serious and potentially fatal complication following non-cardiac surgery. Thus, it is important to identify the risk factors and develop an effective prognostic model to predict the incidence of perioperative stroke following non-cardiac surgery.

Methods and findings

We identified potential risk factors and built a model to predict the incidence of perioperative stroke using logistic regression derived from hospital registry data of adult patients that underwent non-cardiac surgery from 2008 to 2019 at The First Medical Center of Chinese PLA General Hospital. Our model was then validated using the records of two additional hospitals to demonstrate its clinical applicability. In our hospital cohorts, 223,415 patients undergoing non-cardiac surgery were included in this study with 525 (0.23%) patients experiencing a perioperative stroke. Thirty-three indicators including several intraoperative variables had been identified as potential risk factors. After multi-variate analysis and stepwise elimination (P < 0.05), 13 variables including age, American Society of Anesthesiologists (ASA) classification, hypertension, previous stroke, valvular heart disease, preoperative steroid hormones, preoperative β-blockers, preoperative mean arterial pressure, preoperative fibrinogen to albumin ratio, preoperative fasting plasma glucose, emergency surgery, surgery type and surgery length were screened as independent risk factors and incorporated to construct the final prediction model. Areas under the curve were 0.893 (95% confidence interval (CI) [0.879, 0.908]; P < 0.001) and 0.878 (95% CI [0.848, 0.909]; P < 0.001) in the development and internal validation cohorts. In the external validation cohorts derived from two other independent hospitals, the areas under the curve were 0.897 and 0.895. In addition, our model outperformed currently available prediction tools in discriminative power and positive net benefits. To increase the accessibility of our predictive model to doctors and patients evaluating perioperative stroke, we published an online prognostic software platform, 301 Perioperative Stroke Risk Calculator (301PSRC). The main limitations of this study included that we excluded surgical patients with an operation duration of less than one hour and that the construction and external validation of our model were from three independent retrospective databases without validation from prospective databases and non-Chinese databases.

Conclusions

In this work, we identified 13 independent risk factors for perioperative stroke and constructed an effective prediction model with well-supported external validation in Chinese patients undergoing non-cardiac surgery. The model may provide potential intervention targets and help to screen high-risk patients for perioperative stroke prevention.

by Juan Carlos Salgado, Lilia S. Pedraza, Alejandra Contreras-Manzano, Tania C. Aburto, Lizbeth Tolentino-Mayo, Simon Barquera

Background

In late March 2020, the Mexican government announced an updated norm to include front-of-pack warning labels for packaged foods and non-alcoholic beverages. Warning labels came into effect in October 2020. To avoid displaying warning labels, producers can reformulate their products by reducing the content of calories or critical nutrients targeted by the policy (added sugars, saturated fat, and sodium) or removing non-caloric sweeteners or added caffeine. The objective of this study is to assess changes in the percentage of products above warning-label cutoffs for calories and critical nutrients and changes in the content of calories and critical nutrients associated with warning labels in Mexico.

Methods and findings

We used nutritional panel data collected by the Mexican National Institute of Public Health from ≈1,000 top-purchased products, which represented ≥60% of the market share for each of the included food groups according to household purchases in the Nielsen Consumer Panel commercial dataset for Mexico in 2016. Nutritional panel data is available for three periods: 2016−2017, T0 (pre-policy); Jul–Sep 2020, T1 (post-warning-label announcement); and Feb–Apr 2021, T2 (post-warning-label implementation). We assessed changes in T1 versus T0 (potential anticipatory reformulation before the warning-label implementation) and T2 versus T0 (reformulation after the warning-label implementation) by food group using generalized estimating equations for the percentage of products above warning-label cutoffs or containing non-caloric sweeteners or added caffeine, and fixed-effects linear models and quantile regressions for the content of calories and critical nutrients. Included food groups were cereal-based desserts, bread and other cereals, salty snacks, sweetened beverages, solid dairy, liquid dairy, instant food, and candies. At T0, the food group level with the lowest percentage of products with at least one calorie/nutrient content above warning-label cutoffs was instant food (77.8%); at T2, this fell to 52.6%. Based on our statistical models, we found that all food groups showed reductions in at least one type of warning label. The most common reductions in the percentage of products exceeding warning-label cutoffs were for sodium (up to −63.1 percentage points for bread and other cereals; 95% CI: −77.5, −48.6; p-value < 0.001), saturated fat (up to −26.3 percentage points for salty snacks; 95% CI: −35.8, −16.8; p-value < 0.001), and products containing non-caloric sweeteners (up to −29.0 percentage points for solid dairy; 95% CI: −40.7, −17.2; p-value < 0.001). The reductions in products above warning-label cutoffs were coupled with reductions in products’ content of calories and critical nutrients. According to quantile regressions, these reductions mostly occurred at the 50th–75th percentiles. Product reformulation mainly occurred in T2.

Conclusion

Our findings show product reformulation due to reductions in critical nutrients/calories after the warning-label policy implementation, which entails improving the nutritional profile of the packaged food and beverage supply in Mexico.

by Sara Ahmadi-Abhari, Piotr Bandosz, Martin J. Shipley, Joni V. Lindbohm, Abbas Dehghan, Paul Elliott, Mika Kivimaki

Background

The direct and indirect impacts of the COVID-19 pandemic on life expectancy (LE) and years of life lost with and without disability remain unclear. Accounting for pre-pandemic trends in morbidity and mortality, we assessed these impacts in 18 European countries, for the years 2020–2022.

Methods and Findings

We used multi-state Markov modeling based on several data sources to track transitions of the population aged 35 or older between eight health states from disease-free, combinations of cardiovascular disease, cognitive impairment, dementia, and disability, through to death. We quantified separately numbers and rates of deaths attributable to COVID-19 from those related to mortality from other causes during 2020–2022, and estimated the proportion of loss of life expectancy and years of life with and without disability that could have been avoided if the pandemic had not occurred. Estimates were disaggregated by COVID-19 versus non-COVID causes of deaths, calendar year, age, sex, disability status, and country. We generated the 95% uncertainty intervals (UIs) using Monte Carlo simulations with 500 iterations. Among the 289 million adult population in the 18 countries, person-years of life lost (PYLL) in millions were 4.7 (95% UI 3.4–6.0) in 2020, 7.1 (95% UI 6.6–7.9) in 2021, and 5.0 (95% UI 4.1–6.2) in 2022, totaling 16.8 (95% UI 12.0–21.8) million. PYLL per capita varied considerably between the 18 countries ranging between 20 and 109 per 1,000 population. About 60% of the total PYLL occurred among persons aged over 80, and 30% in those aged 65–80. If the pandemic were avoided, over half (9.8 million (95% UI 4.7–15.1)) of the 16.8 million PYLL were estimated to have been lived without disability. Of the total PYLL, 11.6–13.2 million were due to registered COVID-19 deaths and 3.6–5.3 million due to non-COVID mortality. Despite a decrease in PYLL attributable to COVID-19 after 2021, PYLL associated with other causes of death continued to increase from 2020 to 2022 in most countries. Lower income countries had higher PYLL per capita as well as a greater proportion of disability-free PYLL during 2020–2022. Similar patterns were observed for life expectancy. In 2021, LE at age 35 (LE-35) declined by up to 2.8 (95% UI 2.3–3.3) years, with over two-thirds being disability-free. With the exception of Sweden, LE-35 in the studied countries did not recover to 2019 levels by 2022.

Conclusions

The considerable loss of life without disability and the rise in premature mortality not directly linked to COVID-19 deaths during 2020–2022 suggest a potential broader, longer-term and partially indirect impact of the pandemic, possibly resulting from disruptions in healthcare delivery and services for non-COVID conditions and unintended consequences of COVID-19 containment measures. These findings highlight a need for better pandemic preparedness in Europe, ideally, as part of a more comprehensive global public health agenda.