Objective: We conducted a systematic review and meta-analysis of randomised studies in humans comparing the outcomes of switching to heated tobacco products (HTPs) versus continuing conventional tobacco smoking by burning. Methods: We searched the electronic databases which included PubMed, Web of Science, Cochrane Controlled Trials Register, and Google Scholar from inception to May 2023. Randomised Controlled Trials (RCTs) in humans comparing HTPs with conventional burnt tobacco products were selected. Our search yielded 4817 search results, of which six RCTs (number of participants 1362, all from high-income countries) were selected. Five of the six included RCTs had low risk in four of five domains of bias; only one study had a high risk of bias in one domain. PRISMA guidelines were followed. Results: There were 40 biomarkers of harm reduction reported categorised into six categories. One cancer biomarker (nitrosamine) and two cardiovascular biomarkers (eosinophils and total bilirubin) showed statistically significant harm reduction (total NNAL SMD=0·82, 95% CI 0·67-0·98, eosinophils SMD=0·38, 95% CI 0·12-0·65, total bilirubin SMD=0·71, 95% CI 0·28-1·31). The remaining biomarkers of harm in cardiovascular, inflammatory, metabolic, pulmonary, and renal categories showed imprecise findings. Conclusions: In RCTs of moderate quality, some biomarkers show harm reduction associated with switching from burnt tobacco smoking to HTPs. The majority of the findings are imprecise due to the small sample sizes of the included studies. Sufficiently powered, robust RCTs targeting key harm reduction biomarkers within both upper and low-middle income country settings are required in the future. doi: https://doi.org/10.12669/pjms.41.1.10820 How to cite this: Akram J, Akram SJ, Naseem N, Shehzad S, Rana A, Ashraf V, et al. Harm reduction associated with heated tobacco products: A systematic review and meta-analysis. Pak J Med Sci. 2025;41(1):295-301. doi: https://doi.org/10.12669/pjms.41.1.10820 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Diabetic kidney disease (DKD) is a major global burden, especially in Asia. This study aimed to evaluate the efficacy and safety of finerenone in diabetic kidney disease, comparing outcomes between Asian and non-Asian populations through a systematic review and meta-analysis. A systematic search was conducted across PubMed, Cochrane Library, ClinicalTrials.gov, Google Scholar, and the Undermind AI platform from inception through March 2025. Studies included randomized controlled trials (RCTs) and subgroup analyses that evaluated finerenone in DKD patients. Primary outcomes included a reduction in the urinary albumin-to-creatinine ratio (UACR) and a decline in the estimated glomerular filtration rate (eGFR) of ≥40%. Secondary outcomes included cardiovascular events, mortality due to kidney failure, hyperkalemia (serum potassium >5.0 mmol/L), treatment discontinuation, hospitalization, and adverse event–related mortality. Risk ratios (RRs) and mean differences (MDs) were pooled using a random-effects model, and subgroup analyses were performed by ethnicity. Five eligible studies, comprising 8,763 participants, were included in this analysis. Finerenone significantly reduced UACR compared with placebo (MD = −0.38, 95% CI −0.42 to −0.35; p < 0.001), with consistent effects across Asian and non-Asian populations (subgroup p = 0.28). It also significantly reduced the risk of eGFR decline ≥40% (MD = −0.24 [−0.40, −0.09]; p = 0.002), with a greater benefit in the Asian subgroup (subgroup p = 0.03). Cardiovascular event risk was also reduced (RR = 0.85 [0.77–0.95]; p = 0.004), while mortality due to kidney failure showed a non-significant reduction (RR = 0.83 [0.64–1.07]; p = 0.15). Hyperkalemia risk was higher with finerenone (RR = 1.73, 95% CI 1.39–2.14), whereas adverse event–related mortality was lower (RR = 0.65, 95% CI 0.46–0.91). Finerenone provides robust renoprotective and cardioprotective effects in DKD, with broadly consistent efficacy across Asian and non-Asian populations. A greater renal benefit was observed in Asians for eGFR decline ≥40%, though this requires cautious interpretation. Hyperkalemia risk was increased but largely manageable. These findings support integration into DKD therapy and highlight the need for ethnically inclusive, long-term, real-world trials. Not applicable.

After following up of more than 9 years, we report three affected male siblings from a consanguineous family (PKSOK) in rural Baluchistan, Pakistan, presenting with a novel, levodopa/carbidopa-responsive Nocturnal Akinesia Syndrome (NAS). Clinical features include nocturnal hypotonia, developmental delay, mild intellectual disability, speech impairment, and psychomotor delay without classical metabolic crises or spasticity. Exome sequencing identified a predicted pathogenic homozygous missense variant [c.313G>A; p.(Gly105Ser)] in the Isovaleryl-CoA dehydrogenase (IVD) gene, traditionally associated with Isovaleric Acidemia (IVA). However, the clinical phenotype of affected individuals of family PKSOK deviates from classical IVA, exhibiting unique levodopa-responsive motor symptoms rather than metabolic decompensation. Protein-protein interaction analyses predicted IVD interactions with dopamine receptors DRD1 and DRD4, suggesting a functional link between metabolic enzymes and dopaminergic neurotransmission and circadian rhythm. The potential involvement of GABAergic pathways may further explain the motor phenotype and therapeutic responsiveness. This study expands the phenotypic spectrum of IVD variants, highlighting new mechanisms underlying movement disorders and offering important implications for diagnosis and targeted treatment in similar rare neurometabolic syndromes.

After more than 9 years of follow-up, we describe three affected male siblings from a consanguineous family (PKSOK) in rural Baluchistan, Pakistan, who presented with levodopa–carbidopa responsive nocturnal akinesia associated with tyrosine hydroxylase deficiency. The affected individuals also show delayed motor milestones, mild intellectual disability, speech and psychomotor delay, without epilepsy, spasticity, cerebellar ataxia, or daytime motor weakness. The marked improvement in nocturnal motor symptoms following levodopa–carbidopa (100 mg/25 mg) treatment raised the possibility of an underlying disorder of dopamine biosynthesis. Exome sequencing of the two affected siblings (IV:16 and IV:18) revealed twenty rare (frequency < 0.001) homozygous coding variants shared between them. However, segregation analysis with the disease phenotype ruled out the potential involvement of all these twenty variants. Therefore, we extended the analysis beyond the coding region variants to non-coding variants, which revealed a homozygous variant, c.-70G>A, in the regulatory region of TH (tyrosine hydroxylase). The c.-70G>A variant has been previously reported in three studies; however, our study represents the first report in the South Asian population. Our study also expands the phenotypic spectrum of disorders associated with variants in TH and highlights the importance of considering variants in regulatory regions of TH in patients with atypical but levodopa-responsive neurological phenotypes.