A Systematic Review and Meta-analysis

[Posted 16/Aug/2022]

AUDIENCE: Neurology, Pediatric, Internal Medicine

KEY FINDINGS: Temporal trends in stroke incidence are diverging by age in high-income countries, with less favorable trends at younger vs older ages, highlighting the urgent need to better understand etiology and prevention of stroke at younger ages.

BACKGROUND: Overall stroke incidence is falling in high-income countries, but data on time trends in incidence of young stroke (ie, stroke in individuals younger than 55 years) are conflicting. An age-specific divergence in incidence, with less favorable trends at younger vs older ages, might be a more consistent underlying finding across studies. Purpose of this study was to compare temporal trends in incidence of stroke at younger vs older ages in high-income countries.

DETAILS: For all retrieved studies, 2 authors independently reviewed the full text against the inclusion criteria to establish their eligibility. Meta-analysis was performed with the inverse variance-weighted random-effects model. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. The main outcome was age-specific divergence (55 vs >=55 years) in temporal trends in stroke incidence (relative temporal rate ratio [RTTR]) in studies extending to at least 2000. RTTRs were calculated for each study and pooled by random-effects meta-analysis, with stratification by administrative vs prospective population-based methodology, sex, stroke subtype (ischemic vs intracerebral hemorrhage vs subarachnoid hemorrhage) and geographical region. Among 50 studies in 20 countries, 26 (13 prospective population-based and 13 administrative studies) reported data allowing calculation of the RTTR for stroke incidence at younger vs older ages across 2 or more periods, the latest extending beyond 2000. Reported trends in absolute incidence of young individuals with stroke were heterogeneous, but all studies showed a less favorable trend in incidence at younger vs older ages (pooled RTTR = 1.57 [95% CI, 1.42-1.74]). The overall RTTR was consistent by stroke subtype (ischemic, 1.62 [95% CI, 1.44-1.83]; intracerebral hemorrhage, 1.32 [95% CI, 0.91-1.92]; subarachnoid hemorrhage, 1.54 [95% CI, 1.00-2.35]); and by sex (men, 1.46 [95% CI, 1.34-1.60]; women, 1.41 [95% CI, 1.28-1.55]) but was greater in studies reporting trends solely after 2000 (1.51 [95% CI, 1.30-1.70]) vs solely before (1.18 [95% CI, 1.12-1.24]) and was highest in population-based studies in which the most recent reported period of ascertainment started after 2010 (1.87 [95% CI, 1.55-2.27]).

Copyright © American Medical Association. All Rights Reserved.

Source: Scott, C. A., Li, L., Rothwell, P. M. (2022). Diverging Temporal Trends in Stroke Incidence in Younger vs Older People: A Systematic Review and Meta-analysis. JAMA Neurology. Published: August 9, 2022. DOI: 10.1001/jamaneurol.2022.1520.

A Cohort Study Investigating Adherence of Dose and Duration to UK Clinical Guidelines

[Posted 14/Oct/2025]

AUDIENCE: Psychiatry, Family Medicine

KEY FINDINGS: This study highlights how antipsychotic prescribing in dementia is discordant with current NICE guidelines on both duration and dose. More than half of those who discontinued their treatment then restarted treatment. These findings emphasise a persistent gap between clinical guidelines and real-world prescribing, underscoring the need for interventions that prioritise safety and person-centred dementia care.

BACKGROUND: In the UK, it is recommended by the National Institute for Health and Care Excellence (NICE) that if antipsychotics are initiated in people living with dementia, treatment should be at the lowest dose for the shortest time possible (1-3 months). In this study, authors aimed to investigate how dose and duration of antipsychotic medication adhere to UK clinical guidelines and explore treatment restart details in those who stop treatment.

DETAILS: Authors did a retrospective cohort study using longitudinal UK primary care data from the IQVIA Medical Research Database. Authors included people living with dementia aged 60-85 years who received their first antipsychotic prescription between Jan 1, 2000, and Dec 31, 2023. Individuals with any previous antipsychotic prescriptions in their records more than 1 year before a dementia diagnosis and those who had missing social deprivation information were excluded from the study. Duration of first and subsequent antipsychotic treatment episodes, medication dosage, and treatment discontinuation and reinitiation rates were investigated. Duration and discontinuation were defined by grouping consecutive prescriptions into treatment episodes using the waiting time distribution method (80% inter-arrival density, 59 days). Daily doses were derived from strength and frequency information and categorised as low or moderate or high based on established minimum effective dose equivalences. People with lived experience of dementia care contributed throughout this project, shaping the research question and advising on interpretation and dissemination strategies. In the dataset search, authors identified 108,910 people with a record indicating dementia at any time. In total, 99,091 cases were excluded (ie, individuals with no antipsychotic prescription between the ages of 60 and 85 years between 2000 and 2023, a previous history of antipsychotics, missing deprivation information, or only one eligible prescription). Authors included 9819 people living with dementia aged 60-85 years who received their first antipsychotic prescription between 2000 and 2023 in the study. 5310 (54.1%) were female and 4509 (45.9%) were male, with a mean age of 77.1 years (SD 5.6 years), and ethnicity data were not available. The first treatment episode lasted a median of 7 months (IQR 6.6-8.7), exceeding NICE guidelines of 1-3 months and 18.1% [95% CI 17.4-18.9]) were initiated on a prescription above the minimum effective dose (ie, low dose). Of the 1781 participants who started on a moderate or high dose, 519 (29.1%) had a moderate or high dose in all quarters of the first year of treatment. 1 year after treatment initiation, 5136 (78.3%) of 6559 eligible individuals remained on medication (48.9% [95% CI 47.7-50.1] on low dose, 14.8% [13.9-15.6] on moderate or high dose of haloperidol, olanzapine, quetiapine or risperidone; and 14.6% [13.8-15.5] on other antipsychotics). Of the 5547 individuals eligible to restart treatment after initial discontinuation, 3106 (56%) restarted with a median treatment duration of 2.6 months (IQR 0.0-9.9).

Copyright © Elsevier Ltd. All rights reserved.

Source: Smsith, H. C., Petersen, I., Hayes, J. F., et al. (2024). Antipsychotic Prescriptions in People With Dementia in Primary Care: A Cohort Study Investigating Adherence of Dose and Duration to UK Clinical Guidelines. The Lancet Psychiatry. 2025; 12(10): 758-767. Published: October, 2025. DOI: 10.1016/S2215-0366(25)00261-5.

[Posted 10/Oct/2025]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: Having a family history of PD predicts slower progression of cognitive decline and caudate dopaminergic degeneration, and less FOG compared with those without a family history independent of PRS. Taken together, information on family history could be used as a proxy for the clinical heterogeneity of PD.

BACKGROUND: Evidence suggests that either family history or polygenic risk score (PRS) is associated with developing Parkinson disease (PD). However, little is known about the longitudinal prognosis of PD according to family history and higher PRS.

DETAILS: From the Parkinson's Progression Markers Initiative database, 395 patients with PD who followed up for more than 2 years were grouped into those with family history within first-degree, second-degree, and third-degree relatives (N = 127 [32.2%]) vs those without (N = 268 [67.8%]). The PRS of 386 patients was computed using whole-genome sequencing data. Longitudinal assessment of motor, cognition, and imaging based on dopaminergic degeneration was conducted during the regular follow-up period. Effects of family history, PRS, or both on longitudinal changes of cognition, motor severity, and nigrostriatal degeneration were tested using a linear mixed model. The risk of freezing of gait (FOG) according to family history was assessed using the Kaplan-Meier analysis and Cox regression models. During a median follow-up of 9.1 years, PD with positive family history showed a slower decline of caudate dopamine transporter uptake (ß estimate of family history x time = 0.02, 95% CI = 0.002-0.036, p = 0.027). Family history of PD and higher PRS were independently associated with a slower decline of Montreal Cognitive Assessment (ß estimate of family history x time = 0.12, 95% CI = 0.02-0.22, p = 0.017; ß estimate of PRS x time = 0.09, 95% CI = 0.03-0.16, p = 0.006). In those 364 patients without FOG at baseline, PD with positive family history had a lower risk of FOG (hazard ratio of family history = 0.57, 95% CI = 0.38-0.84, p = 0.005).

Copyright © American Academy of Neurology. All Rights Reserved.

Source: Park, M. and Lee, Y. (2025). Association of Family History and Polygenic Risk Score With Longitudinal Prognosis in Parkinson Disease. Neurology Genetics. 2025; Published: October, 2025. DOI: 10.1212/NXG.0000000000200115.

A Retrospective Repeated Cross-Sectional Study

[Posted 3/Oct/2025]

AUDIENCE: Family Medicine, Infectious Disease

KEY FINDINGS: Medicare beneficiaries aged 65 years and older with HIV in the USA were more likely to receive opioid prescriptions and have OUD indicators than matched beneficiaries without HIV. Findings could help guide clinical opioid prescription guidelines and public health surveillance among this vulnerable ageing population.

BACKGROUND: There is longstanding concern that people with HIV receive prescription opioids at higher rates and have a disproportionate burden of opioid use disorder (OUD) compared with their counterparts without HIV. We aimed to evaluate trends of opioid prescriptions and indicators of OUD in an understudied but growing population of older adults with HIV.

DETAILS: For this retrospective repeated cross-sectional study, authors constructed annual cohorts through a nationally representative sample of fee-for-service Medicare beneficiaries aged 65 years and older in the USA with Part D coverage (ie, prescription drug) enrolled between Jan 1, 2008, and Dec 31, 2021. Beneficiaries were eligible for inclusion in each cross-sectional cohort if they had reached the age of 65 years by Jan 1 of the calendar year and had 1 year of continuous Medicare enrolment in Part A (inpatient hospital care), B (outpatient care), and D. Beneficiaries with HIV were matched in a 1:3 ratio to beneficiaries without HIV on age, sex, race or ethnicity, US state, and dual eligibility status (Medicare and Medicaid). The main outcomes were receipt of at least one opioid prescription and any indicator of OUD (ie, formal diagnosis, medication for OUD, or opioid-related or emergency department visits) during each calendar year. Generalised estimating equations were used to estimate odds ratios (ORs) of each outcome, comparing matched beneficiaries with or without HIV. Due to data availability, our analysis of indicators of OUD was restricted to 2008-16. Across all years, 163,429 beneficiaries with HIV and 490,287 beneficiaries without HIV were included (475,516 [72.7%] were male, 178,200 [27.3%] were female; 305,776 [46.8%] were non-Hispanic White, 238,172 [36.4%] were Black [or African American], 84,128 [12.9%] were Hispanic, 8964 [1.4%] were Asian or Pacific Islander, and 16,676 [2.6%] were other races or ethnicities). During 2008-21, 57,373 (35.1%) of 163,429 people with HIV and 138,547 (28.3%) of 490,287 people without HIV received at least one opioid prescription. During 2008-16, 2408 (3.1%) of 76,637 people with HIV and 2831 (1.2%) of 229,911 people without HIV had any indicator of OUD. Across all analysed years, beneficiaries with HIV had significantly increased odds of receiving at least one opioid prescription (OR 1.38, 95% CI 1.36-1.39) and having indicators of OUD (2.61, 2.47-2.76) compared with their matched counterparts without HIV.

Copyright © The Author(s). Elsevier Ltd. All rights reserved.

Source: Shiau, S., Drago, F., Kinkade, C. W., et al. (2024). Prescription Opioid Use and Opioid Use Disorder Among Older Adults With HIV in the USA From 2008 to 2021: A Retrospective Repeated Cross-Sectional Study. The Lancet Primary Care. 2025; 1(3): 100017. Published: September, 2025. DOI: 10.1016/j.lanprc.2025.100017.

A Systematic Review and Individual Patient Data Meta-Analysis

[Posted 15/Sep/2025]

AUDIENCE: Infectious Disease, Pediatric

KEY FINDINGS: Regardless of malaria transmission intensity and age group, a single dose of 0.25 mg/kg primaquine is safe and efficacious for reducing P falciparum transmission. These findings underscore the need for primaquine formulations suitable for young children, and also provide supportive evidence to expand the use of single low-dose primaquine in regions with a moderate-to-high transmission rate that are threatened by artemisinin partial resistance.

BACKGROUND: Adding a single dose of primaquine to artemisinin-based combination therapy (ACT) for the treatment of falciparum malaria can reduce the transmission of Plasmodium falciparum and could limit the spread of artemisinin partial resistance, including in Africa, where the disease burden is greatest. Authors aimed to compare the safety and efficacy of single-dose primaquine plus ACT between young children (aged <5 years) and older children (aged 5 years to <15 years) and adults (aged >=15 years), and between low and moderate-to-high transmission areas.

DETAILS: For this systematic review and individual patient data meta-analysis, authors searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, WHO Global Index Medicus, OpenGrey.eu, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform, from database inception to April 3, 2024, with no language restrictions. Authors included prospective studies on efficacy against falciparum malaria that enrolled at least one child younger than 15 years and involved a study group given a single dose of primaquine (<=0.75 mg/kg) plus ACT. Studies involving mass drug administration, healthy volunteers, or patients with severe malaria or mixed (with non-falciparum) infections were excluded. For inclusion in the efficacy analysis, data on transmission potential (as determined by gametocytaemia, infectivity, or both) at enrolment and follow-up (day 3, day 7, or day 14) were required; the safety analysis required data on haemoglobin concentrations or haematocrit values at enrolment and at one or more follow-up visits by day 7, any data on adverse events, or both. After independent screening of the search results by two reviewers, the investigators of eligible studies were invited to contribute individual patient data. Authors quantified day 7 gametocyte carriage, probability of infecting a mosquito, decreases (>25%) in haemoglobin concentration associated with anaemia, and adverse events until day 28 using regression analyses, with random study-site intercepts to account for clustered data. These analyses were registered with PROSPERO, CRD42021279363 (safety) and CRD42021279369 (efficacy). Of 5697 records identified by the search, 30 studies were eligible for analysis. Of these, individual patient data were shared for 23 studies, including 6056 patients from 16 countries: 1171 (19.3%) young children (aged <5 years), 2827 (46.7%) older children (aged 5 years to <15 years), and 2058 (34.0%) adults (aged >=15 years). Adding a single low dose of primaquine (0.2-0.25 mg/kg) to ACTs reduced day 7 gametocyte positivity (adjusted odds ratio [aOR] 0.34, 95% CI 0.22-0.52; p<0.001) and infectivity to mosquitoes over time (aOR per day 0.02, 0.01-0.07, p<0.001). No difference was found in the effect of single low-dose primaquine both on gametocyte positivity in young children compared with older children (1.08, 0.52-2.23; p=0.84) and adults (0.50, 0.20-1.25; p=0.14) and between low-transmission and moderate-to-high transmission settings (1.07, 0.46-2.52; p=0.86), and on infectivity to mosquitoes in young children compared with older children (1.36, 0.07-27.71; p=0.84) and adults (0.31, 0.01-8.84; p=0.50) and between low-transmission and moderate-to-high transmission settings (0.18, 0.01-2.95; p=0.23). Gametocyte clearance was also similar for different ACTs (dihydroartemisinin-piperaquine vs artemether-lumefantrine) when combined with a primaquine target dose of 0.25 mg/kg (1.56, 0.65-3.79; p=0.32 at day 7). However, patients given a primaquine dose of less than 0.2 mg/kg with dihydroartemisinin-piperaquine were more likely to have gametocytaemia than those treated with artemether-lumefantrine (5.68, 1.38-23.48; p=0.016 at day 7). There was no increase in anaemia-associated declines in haemoglobin concentration (>25%) at a primaquine dose of 0.25 mg/kg, regardless of age group, transmission setting, and glucose-6-phosphate dehydrogenase status. The risks of adverse events of grade 2 or higher and of serious adverse events were similar between primaquine and no-primaquine groups, including in young children.

Copyright © The Author(s). Published by Elsevier Ltd. All rights reserved.

Source: Yilma, D., Stepniewska, K., Bousema, T., et al. (2024). Safety and Efficacy of Single-Dose Primaquine to Interrupt Plasmodium Falciparum Malaria Transmission in Children Compared With Adults: A Systematic Review and Individual Patient Data Meta-Analysis. The Lancet Infectious Diseases. 2025; 25(9): 965-976. Published: September, 2025. DOI: 10.1016/S1473-3099(25)00078-7.

A Quantitative Susceptibility Mapping MRI and PET Study

[Posted 12/Sep/2025]

AUDIENCE: Psychiatry, Family Medicine

KEY FINDINGS: The findings suggest that lower levels of non-neuromelanin-bound iron in the SN-VTA contribute to striatal hyperdopaminergia in schizophrenia. Further investigation is warranted to understand the role of low iron in schizophrenia and its potential as a treatment target.

BACKGROUND: Neuroimaging studies have independently associated schizophrenia with low iron and elevated dopamine synthesis. While preclinical research demonstrates that midbrain iron deficiency leads to striatal hyperdopaminergia, this relationship has not been studied in schizophrenia. The authors conducted a case-control study to examine differences in tissue magnetic susceptibility, a marker of brain iron, and correlated these with striatal dopamine synthesis capacity.

DETAILS: Magnetic susceptibility in the substantia nigra and ventral tegmental area (SN-VTA) was measured using quantitative susceptibility mapping (QSM) MRI in 159 participants (control subjects, N=80; early-course schizophrenia, N=79, including patients who were antipsychotic-naïve or antipsychotic-free). Because magnetic susceptibility is increased by neuromelanin and reduced by myelin, neuromelanin-sensitive MRI (NM-MRI) and diffusion tensor imaging (DTI) were employed to investigate the influence of neuromelanin and myelin on the QSM findings in 99 participants (control subjects, N=38; schizophrenia patients, N=61). Dopamine synthesis capacity (K_i ^cer) was then assessed with [¹⁸F]-DOPA positron emission tomography in 40 people from the schizophrenia group to test whether low SN-VTA magnetic susceptibility was related to high striatal K_i ^cer. SN-VTA magnetic susceptibility was lower in patients with schizophrenia than in control subjects (d=-0.66, 95% CI=-0.98, -0.34). This difference remained significant in analyses controlling for mean diffusivity (a DTI measure inversely correlating with myelin concentration) and NM-MRI contrast-to-noise ratios. SN-VTA magnetic susceptibility was significantly inversely correlated with striatal K_i ^cer, independent of mean diffusivity and NM-MRI contrast-to-noise ratios (r=-0.44). In both analyses, the strongest effects were observed in the ventral SN-VTA.

Copyright © American Psychiatric Association. All rights reserved.

Source: Vano, L. J., McCutcheon, R. A., Sedlacik, J., et al. (2024). Reduced Brain Iron and Striatal Hyperdopaminergia in Schizophrenia: A Quantitative Susceptibility Mapping MRI and PET Study. American Journal of Psychiatry. 2025; 182(9): 830–839. Published: September, 2025. DOI: 10.1176/appi.ajp.20240512.