Medicine and Pharmacology

Abstract: The widespread use of leaded petrol during the twentieth century resulted in substantial population exposure to lead, particularly among individuals growing up in urban environments during peak emissions. Although the phase-out of leaded petrol markedly reduced environmental and blood-lead concentrations, historically absorbed lead can remain stored in the skeleton for decades. Bone remodelling releases accumulated lead into circulation, potentially contributing to continuing endogenous exposure during ageing, menopause, pregnancy, lactation and other periods of increased bone turnover. Epidemiological studies have associated cumulative lead exposure with cognitive decline, dementia and amyotrophic lateral sclerosis (ALS), although the specific contribution of skeletal lead mobilisation to neurodegenerative disease remains uncertain. This paper examines whether interventions modifying bone turnover or calcium availability could reduce endogenous lead exposure associated with historical leaded petrol emissions. Preliminary human evidence suggests that alendronate, a bisphosphonate that inhibits bone resorption, can reduce circulating lead concentrations, with lead-isotope evidence consistent with reduced skeletal mobilisation. Romosozumab, a monoclonal antibody that stimulates bone formation and suppresses resorption, represents another potential intervention, although its effects on circulating lead remain uninvestigated. Randomised controlled trials have also demonstrated that calcium supplementation can reduce blood-lead concentrations in some pregnant and lactating women, potentially through reduced gastrointestinal absorption and altered skeletal mobilisation. However, its effectiveness among older adults with elevated skeletal lead burdens remains uncertain. We propose controlled investigations incorporating skeletal lead measurements, serial blood-lead concentrations, bone turnover markers, dietary calcium assessment and lead-isotope analysis to determine whether pharmacological and nutritional interventions produce sustained reductions in endogenous exposure. Particular attention should be given to historically exposed ageing populations and menopause-associated skeletal lead mobilisation. Establishing whether these interventions reduce circulating lead is a necessary first step before investigating potential neurological benefits. Neither bone-modifying therapies nor calcium supplementation has been demonstrated to prevent lead-associated neurodegenerative disease.

Abstract: Background/Objectives: Nationwide evidence on gallbladder disease in Central Asia remains limited. We assessed trends, care-related associations and projected burden of cholecystitis and other gallbladder diseases (ICD-10 K80–K82) in Kazakhstan. Methods: This retrospective ecological time-series study used official national statistics for 2012–2024. Rates were crude because complete age-specific annual series were unavailable. Stratified comparisons were descriptive, and reported associations represent population-level patterns rather than individual risk factors. The final analytical dataset comprised thirteen complete annual observations for each modelled indicator. Joinpoint regression identified changes in incidence trends. Negative binomial, quasi-binomial and linear models evaluated temporal associations and the 2020 pandemic disruption. Case growth was decomposed into population-size and incidence-rate components. ARIMA and explicit scenarios projected annual cases to 2039. Results: Registered incidence increased from 343.0 to 406.2 per 100,000, peaking in 2017. Annual changes were +10.6% during 2012–2017 and −4.2% during 2017–2024; the average annual percent change was +1.7% (95% confidence interval 0.2–3.2). Incidence in 2020 was lower than expected from the adjusted trend (incidence rate ratio 0.857, 95% confidence interval 0.749–0.981). Population growth accounted for 51.8% of the 24,401-case increase. Emergency-treatment rates increased by 1.6% annually, while the odds of late presentation declined by 6.2% annually and hospital stay shortened by 0.21 days annually. Central projections indicated approximately 95,000–124,000 annual cases by 2039, with wide model-based prediction intervals. Conclusions: Increasing absolute caseloads despite recent declines in registered incidence support scenario-based capacity planning. Shorter hospital stays and fewer late presentations suggest improvements in care indicators, although individual-level explanations require further investigation.

Abstract: Background. Chest-radiograph classifiers are usually evaluated against healthy controls, and the resulting AUROC is often read as evidence of clinical viability. Two properties of such benchmarks remain invisible in that number: which patients supply the negatives, and how the score distribution aligns with the population the model is applied to. Methods. One EfficientNet-B0 pneumonia classifier was trained on 46,238 ChestX-ray14 images (788 positive; positive-class weight 57.7; no resampling) and prior-corrected to population prevalence. The operating threshold was fixed at 90% sensitivity on a patient-disjoint validation slice (88 positives) and then transferred unchanged to a held-out set of 17,494 images. Held-out negatives were healthy controls (9,861), co-prevalent disease without pneumonia (effusion, oedema or atelectasis; 7,078; withheld from training), or externally sourced normal films (10,192). Wilson and bootstrap 95% confidence intervals are reported throughout, together with an untrained-network negative control and a site-separability probe. Results. Validation AUROC was 0.813. Transferring the validation threshold to held-out healthy controls gave sensitivity 0.962 (95% CI 0.943–0.975) and specificity 0.262 (0.253–0.271); specificity at a matched 90% sensitivity, obtained by placing the threshold on the evaluation positives, was 0.459. Replacing healthy negatives with co-prevalent disease, holding the same 555 positive patients, reduced AUROC from 0.759 (0.740–0.777) to 0.589 (0.563–0.615) and specificity at matched sensitivity from 0.459 to 0.129. Mean predicted probability was 0.0443 for pneumonia, 0.0362 for co-prevalent disease and 0.0206 for healthy controls, so pneumonia was separated from other abnormality by a factor of 1.22, against 2.15 for health. The gap persisted within both view positions separately (+0.119 AP, +0.224 PA), so view composition cannot account for it. Prior correction reduced expected calibration error from 0.195 to 0.008 without moving the operating point. Reaching 90% specificity at 90% sensitivity would require an AUROC of approximately 0.965. Conclusions. For this model, specificity at a clinically defensible sensitivity was determined by the ranking and by the choice of negative stratum, not by calibration or thresholding; a well-calibrated classifier can remain unusable at the operating point a screening programme needs. Benchmarks that report a single aggregate against healthy controls do not measure disease discrimination. Whether label quality bounds achievable AUROC is not tested here.

Abstract: As of 5 November 2026, Bundibugyo virus disease in the Democratic Republic of the Congo had produced 10,741 confirmed cases and 5,230 deaths, with close to two of every three deaths in an earlier WHO reporting interval occurring in communities rather than treatment centres. No vaccine or treatment is approved for this species, and the agents in trials are monoclonal antibodies and direct-acting antivirals. In 2021 I proposed reclassifying COVID-19, Ebola virus disease and Nipah virus infection as a novel acute onset immune dysrhythmia syndrome. Read through it, the pathology now described in Bundibugyo-infected macaques points to two arms: fatal animals showed a myeloid hyperinflammatory profile with raised interleukin-6 and myeloperoxidase, survivors transcripts of an intact T cell response. Basing on that convergence I propose doxycycline and nitazoxanide as an early immunomodulatory combination, each acting on a different arm. Doxycycline inhibits matrix metalloproteinases at exposures achievable in man, and nitazoxanide amplifies the RIG-I and PKR arm the virus suppresses. To be noted that none of this establishes efficacy in Bundibugyo disease. What it offers is a mechanism worth testing in two licensed, oral, inexpensive drugs on the shelf, with the host-directed concentration still unmeasured. I therefore ask for species-specific work: activity in relevant cells and in the macaque model, the unbound concentration-response relationship, and a two-by-two factorial evaluation, preclinical and clinical, powered for the interaction. I strongly believe the search for safe immunomodulators is the one most likely to end in a drug available on the day it is needed.

Abstract: Post-Acute Sequelae of SARS-CoV-2 (PASC), clinically designated as Long COVID, affects over 400 million individuals globally, presenting as a multisystem disorder characterized by chronic microvascular endotheliitis, exertional exhaustion, pathological cardiac remodeling, and systemic autoimmunity [1–3]. While acute COVID-19 is primarily initiated by viral entry via ACE2, persistent post-viral sequelae are driven by sustained expression of viral accessory factors and host transcriptional hijacking [1,2,4]. Here, we establish a comprehensive systems-biology framework demonstrating that SARS-CoV-2 accessory protein Orf7b overexpression drives high-amplitude transactivation of master oncogene c-Myc, which hypertranscribes long non-coding RNA PVT1 [1,2]. The resultant multi-isoform surge of PVT1 linear, circPVT1, and ecDNA transcripts acts as a high-capacity competing endogenous RNA (ceRNA) network that sequesters protective host microRNA-145-5p (miR-145-5p) and miR-214 [1,2]. This dual microRNA depletion initiates a secondary derepression cascade involving hypoxia-inducible factor-2α (HIF-2α / EPAS1) and Transferrin Receptor 1 (TFRC / TfR1) [1,2,4,5]. Dense TFRC accumulation accelerates diferric transferrin endocytosis, expanding the intracellular labile iron pool, driving ROS-dependent transcription and secretion of chemokine CCL2, and provoking concentric cardiac hypertrophy, microvascular endotheliitis, ACE2-independent viral entry, and TLR7-regulated TFR1-driven B-cell autoimmunity [1–6]. Crucially, we demonstrate that this entire pathological network can be reversed upstream by host-directed p53/NRF2-based epigenetic shielding via miR-145-5p transactivation, 3'-UTR transcript cleavage, and mitochondrial cristae restoration [1,2,7].

Abstract: Background: Kidney disease is an increasingly important comorbidity in people with HIV (PWH), owing to its association with mortality and cardiovascular (CV) disease, a leading cause of non-AIDS-related death. Sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors) have demonstrated renal and cardiovascular protective effects in the general population, but evidence in PWH remains scarce. We aimed to evaluate the safety and clinical effects of dapagliflozin in PWH with chronic kidney disease (CKD). Methods: We enrolled adult PWH with an estimated glomerular filtration rate (eGFR) of 25–75 mL/min/1.73 m² who were receiving stable antiretroviral therapy and had sustained HIV virological suppression. Participants received dapagliflozin 10 mg once daily according to routine clinical practice. Safety and efficacy outcomes, blood and urine biochemistry, 24-hour ambulatory blood pressure monitoring, adipose and muscle composition, and body water distribution were assessed. Analyses were performed in the overall cohort and stratified by gender and diabetes status. Results: Thirty-seven participants were included. Most were cisgender men (78%), and the median age was 60 years. One participant discontinued treatment because of dizziness. Renal parameters showed a consistent, although non-significant, trend toward improvement. Haematocrit and haemoglobin increased significantly in the overall cohort (both p < 0.001). HDL cholesterol increased significantly among participants with diabetes (p = 0.034). Body mass index (BMI) decreased from 26.48 kg/m² (IQR 24.00–29.38) to 26.22 kg/m² (IQR 23.58–28.42; p < 0.001), and waist circumference decreased from 102.3 cm (IQR 92.4–108.8) to 101.6 cm (IQR 90.85–107.55; p = 0.009). In men, rectus femoris cross-sectional area decreased significantly from 7.12 cm² to 6.65 cm² (p = 0.033), although no significant DXA-assessed changes in muscle composition were observed. All ultrasound-assessed abdominal fat layers decreased, but only omental fat thickness reached statistical significance, decreasing from 75.2 mm (IQR 39.6–81.9) to 58.6 mm (IQR 44.1–73.5; p = 0.029). The extracellular water-to-total body water ratio increased significantly in the overall cohort, from 0.378 (IQR 0.372–0.387) to 0.379 (IQR 0.372–0.387; p = 0.044), and among participants with diabetes, from 0.381 (IQR 0.375–0.388) to 0.383 (IQR 0.383–0.392; p = 0.014). Conclusions: In this cohort of PWH with CKD, dapagliflozin was well tolerated and associated with a trend toward improved renal function, together with significant reductions in BMI, waist circumference and omental fat thickness, a marker of cardiometabolic risk. Longer follow-up and larger studies are needed to confirm these benefits and determine their impact on cardiovascular outcomes.

Abstract: Severe COVID-19 is accompanied by marked remodeling of airway myeloid compartments, yet how infiltrating monocytes are routed toward inflammatory versus pro-fibrotic fates, and why resident alveolar macrophages fail to recover, remains incompletely understood. We re-analyzed BALF single-cell data (GSE145926; 3 healthy, 3 mild/moderate, 6 severe; 27,807 cells), re-clustering myeloid cells (n = 19,485) into 37 fine states (13 families) with functional module scoring, diffusion pseudotime, PAGA, a curated ligand–receptor screen, and per-donor decomposition; validation used the independent fatal-COVID-19 BALF cohort GSE157344 and the healthy-BALF cohort GSE151928 as a specificity control, a human endotoxin bone-marrow comparator (GSE212092), two sepsis blood cohorts (GSE175453; GSE167363, paired 0 h/6 h), three cross-pathogen blood cohorts (influenza A GSE243629, infant RSV GSE283746, bacterial ARDS GSE157789), and cross-disease comparison with IPF lung (GSE128033). Healthy BALF comprised resident alveolar macrophages, depleted in severe disease and replaced by interferon-activated, CXCL8-high, and SPP1+ populations. A CD14+SPP1−FCN1+ population co-expressing interferon-stimulated genes and IL1RN—an interferon-braked state distinct from LPS-type trained immunity—was enriched in severe disease, driven predominantly by one patient. PAGA delineated an FCN1+→intermediate→SPP1+ continuum; severe-enriched circuits included MIF–CD74 and an autocrine CXCL8–CXCR2 loop. The interferon-braked signature and SPP1+ compartments were reproduced in an independent fatal-COVID-19 BALF cohort and were at baseline in a healthy-BALF reference cohort (0.343 ± 0.091); LPS-challenged marrow showed the reciprocal pattern (TLR4-high, interferon-silent); and IPF lung shared SPP1/TREM2 induction with resident-AM collapse (SPP1 p = 0.0005). In sepsis blood, monocytes retained the interferon-braked signature with the LPS/TLR4 module near baseline; the signature was likewise elevated in bacterial ARDS, influenza A, and infant RSV monocytes, extending the compartment model beyond COVID-19. The data support a two-signal model: interferon restrains recruited monocytes at entry, while TLR4/HIF-1α- and SPP1-associated programs act downstream. The brake state is a measurable, stage-specific marker; MIF–CD74, CXCL8–CXCR2, and SPP1–CD44 are candidate nodes for stage-specific intervention. These mechanistic interpretations are grounded in the data and are proposed as testable hypotheses.

Abstract: Inappropriate antibiotic prescribing remains a major challenge for antimicrobial stewardship, partic-ularly in secondary-care hospitals. This study evaluated the association between a nurse-led antimi-crobial stewardship intervention and inappropriate prescribing in a hospital in Mexico. A prospec-tive, quasi-experimental before-and-after study without a control group was conducted across 27 weekly reporting periods in 2026. A total of 458 antibiotic prescriptions from 390 hospitalized pa-tients were assessed using predefined clinical criteria. Multivariable logistic regression incorporated patient-clustered robust standard errors. Inappropriate prescribing decreased from 51.97% (119/229) before the intervention to 37.12% (85/229) afterward (absolute difference, −14.85 percentage points; p = 0.0014). The adjusted odds ratio was 0.544 (95% CI, 0.368–0.804). Nurses reviewed 95.63% of post-intervention prescriptions, and 79.55% of communicated recommendations were fully or par-tially accepted. Mean antibiotic treatment duration decreased from 7.05 to 6.18 days (p < 0.001). The intervention was associated with less inappropriate antibiotic prescribing and shorter treatment du-ration, although the uncontrolled design precludes causal attribution.

Abstract: Biofilms on implanted devices tolerate antibiotics and host defences, and established device infection is usually treated by removing the device. This review examines the clinical trial record across nine implanted-device settings. A consistent asymmetry emerges: every intervention that has reached approval or guideline endorsement prevents biofilm formation on an uninfected device by delivering an antimicrobial locally in a high-risk population, whereas attempts to eradicate established biofilm remain conflicting or uncontrolled. Trials that failed did so largely for reasons unrelated to antibiofilm pharmacology, including endpoints measuring colonisation rather than disease, extrapolation from animal models, event rates too low for feasible sample sizes, manufacturing instability and sponsor insolvency. Silver illustrates the problem, showing consistent laboratory activity but no benefit in adequately powered trials. The principal obstacle may therefore be the design of trials rather than the discovery of new molecules.

Abstract: Introduction: Healthcare workers (HCWs), especially cancer care teams, are at an increased risk of SARS-CoV-2 infection, which may be amplified in rural areas. Therefore, we aimed to determine SARS-CoV-2 seroprevalence among HCWs in our rural cancer care network. Methods: We conducted a multisite, longitudinal, three-part SARS-CoV-2 seroprevalence study within the MaineHealth Cancer Care Network between November 2020 and April 2023, spanning metropolitan (one site), micropolitan (four), and rural (six) practices in south-central Maine and eastern New Hampshire. Follow-up was completed in January 2024. We followed 435 HCWs who provided cancer care during the pandemic. Participants reported their own medical history and that of household members and job duties, completed Occupational Risk and End-of-Study surveys, and underwent serial SARS-CoV-2 antibody testing. Results: In Part 1, the primary outcome SARS-CoV-2 period seroprevalence rate was 1.6% (3/192; 95% CI 0.5–4.5%). Nearly 8% of participants and 10% of their household members reported immunocompromising conditions. We observed persistence of spike protein antibody response &gt;2,500 U/mL over the course of the study. Survey response rates were high and remarkably consistent, given the diversity of participants. Outside the workplace, our care team members practiced a high level of personal safety measures during the pandemic. Conclusion: Our findings showed a low SARS-CoV-2 seroprevalence, consistent with the national and international data reported early in the pandemic. We also observed higher-than-expected immunocompromising conditions in rural HCWs and their households. These results underscore the importance of longitudinal sero-surveillance, particularly for high-risk rural healthcare networks.

Abstract: Background. For more than two decades, opioid-involved overdose mortality in the United States followed a steep upward trajectory — from prescription opioids in the 1990s ("first wave") to heroin (~2010s), illicit fentanyl (~2013–2020), and a "fourth wave" combining fentanyl with stimulants (cocaine, methamphetamine). After peaking above 110,000 deaths in a rolling twelve-month window in 2023, mortality reversed: the Centers for Disease Control and Prevention (National Center for Health Statistics [NCHS], 2026) estimated 81,313 deaths in 2024 and 69,973 in 2025, a 14% decline and the third consecutive year of decrease. Methods. We conducted an analytic review integrating three bodies of evidence: (a) federal statistics and official reports (CDC/NCHS, DEA, DOJ, GAO, CBO, CRS); (b) peer-reviewed research, including the HEALing Communities Study cluster-randomized trial ("New England Journal of Medicine", 2024), a supply-shock analysis published in "Science" (January 2026), and systematic reviews of drug checking and supervised consumption (2022–2025); and (c) U.S. policy instruments issued between April 2025 and May 2026, including Executive Order 14321 (July 24, 2025) and two SAMHSA Dear Colleague letters (July 2025; April 24, 2026). Results. The dominant driver of the 2023–2025 decline appears to be a disruption of the global illicit fentanyl supply — a "supply shock" associated with precursor-chemical restrictions — rather than expansion of treatment or harm reduction (Caulkins et al., 2026). At the same time, U.S. federal policy moved away from harm reduction: the April 24, 2026 SAMHSA letter removes fentanyl and xylazine test strips, sterile water, saline, ascorbic acid, and overdose support hotlines from funding eligibility, while retaining naloxone, nalmefene, education, and HIV/hepatitis prevention services. "Conclusions. " The mortality decline is neither a "victory" of enforcement-centered policy nor a validation of harm reduction alone; it is a supply-side event whose durability is uncertain. In a market that is stabilizing in some respects while becoming pharmacologically more hazardous (xylazine, medetomidine, nitazenes), harm reduction instruments serve as an early-warning and shock-absorbing layer. U.S. policy should integrate — rather than dislodge — that layer, while restoring systematic surveillance of the illicit drug supply.

Abstract: Background: Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease endemic to in Africa, Asia, and Europe. This study examined the association between climate variables and CCHF in Iran, Iraq, Kazakhstan, and Russia from 2000 to 2022. Methods: CCHF case counts were collected from published, unpublished, and surveillance data sources. Cross-correlation analysis was used to evaluate the temporal effects of rainfall and temperature on CCHF incidence, applying generalized additive mixed models (GAMMs). The Akaike information criterion (AIC) was used to determine the most appropriate model. Kendall's W examined case peaks across countries and identified significant synchronicity among CCHF cases, temperature, and rainfall across countries (p< 0.05). Results: Synchronization analysis using GAMMs identified an optimal model describing the relationship between CCHF cases and annual rainfall and temperature, with temporal lags of five and the same year, respectively. Conclusions: Lower temperatures and increased rainfall were linked to a rise in CCHF cases, indicating that these climatic factors significantly influence tick population growth and activity. Additional environmental and ecological variables should be considered in future studies to develop a more comprehensive model.

Abstract: Public genomic and wastewater surveillance data for highly pathogenic avian influenza A(H5N1) in the United States are open, large, and held in systems that do not speak to one another. We describe H5N1 Marker Watch, an open dataset that tabulates published antiviral-resistance and mammalian-adaptation marker positions in publicly deposited U.S. A(H5N1) protein sequences by state, collection year and host group, and places those counts alongside CDC National Wastewater Surveillance System H5 detections for the same state and year. Version 1.0.0 covers 95,582 protein sequences from 18,378 distinct isolates collected between 2022 and 2026 across 52 states and territories, screened at 36 marker positions drawn from WHO and CDC sources, producing 688,287 individual calls, joined to 124,427 wastewater results from 49 states of which 3,010 detected H5. Markers associated with reduced susceptibility to clinically used antivirals are rare: the neuraminidase substitution H275Y, the one substitution WHO identifies as a known clinical resistance marker, appears in 7 of 19,141 covering sequences (0.037%). The mammalian-adaptation picture differs: PB2 E627K rises across the period, from 0.126% of covering sequences in 2022 to 5.18% in the partial year 2026, while two further markers sit at frequencies better read as fixed features of the circulating clade. We report a methodological finding of general relevance: published marker positions arrive in several numbering conventions and some sources list the same site twice under two of them, so every position is validated against a named reference before it is counted. 11 of 36 markers required a numbering translation and 3 proved to be duplicates. Marker status throughout is genotype, not confirmed phenotype; no susceptibility testing was performed or is implied. Data, code and documentation are released openly and the pipeline is built for annual refresh.

Abstract: Background: Older adults experienced a disproportionate burden of COVID-19 mortality, but national evidence is limited. We described COVID-19 mortality among adults aged ≥65 years (March 2020–December 2022) and vaccination coverage among adults aged ≥60 years (March 2021–December 2022). Methods: We conducted a retrospective national descriptive and ecological study using ONMNE mortality surveillance and aggregated EVAX vaccination data. We calculated mortality, age-standardized, and proportional mortality rates; vaccination coverage; dropout proportions; and no-show rates. Results: Of 29,306 COVID-19 deaths, 20,467 (69.8%) occurred among adults aged ≥65 years; 8,725 (42.6%) were aged ≥80 years and 11,463 (56.0%) were male. Cumulative mortality was 1,809.9 per 100,000, with the highest period-specific rate during Delta predominance (750.1 per 100,000). Coverage among adults aged ≥60 years was 95.4% for at least one dose, 88.3% for primary-schedule completion, and 38.4% for a third dose; cumulative uptake was 215.1 doses per 100. Coverage varied by governorate; no-show rates increased in 2022. Conclusions: Mortality was concentrated among the oldest-old and during Delta predominance. Coverage was high nationally but uneven geographically, and booster uptake and attendance declined. Targeted outreach and equitable access remain priorities.

Abstract: China has hosted the world's largest and longest epidemic of macrolide-resistant Mycoplasma pneumoniae (MRMP) and, in 2024, issued what is to our knowledge the first national consensus document dedicated exclusively to its governance. We reconstructed this seventeen-year trajectory (2008–2024) and structurally compared three national systems. Genotypic resistance rose from ~70% (Beijing, 2008) to >90% (97.4% in Beijing, 2019), driven by the A2063G 23S rRNA mutation on the ST3/ST14 clonal pair. Zero-COVID then collapsed transmission by >90%, yet the resistant clones entered the trough entrenched and emerged unchanged, rebuilding dominance within months of the 2023 resurgence — an 'unsuppressible tail' of clonal persistence, not a fixed resistant proportion (§3.2). The comparators sharpen the lesson: Japan achieved a fall from peak values of 80–90% to 14.3%, alongside sustained stewardship and clonal turnover, while Taiwan extinguished circulation entirely yet saw clinical macrolide non-response return at 54.4% by 2024–2025 — suppression starves resistant clones; only governance — or clonal turnover — replaces them. The 2024 consensus resolved the paediatric tetracycline dilemma through a genotype- and age-gated algorithm, but left two gaps: no coupling to antibiotic consumption, and no enforcement mechanism. Comparison with Japan and the United States (macrolide-first empiricism, no MRMP surveillance) distils a transferable six-element playbook — sentinel resistance surveillance, genotype- and age-gated treatment, age-stratified second-line positioning, consumption coupling, diagnostic linkage, and iterative revision. Countries entering their own MRMP epidemics should run this sequence — measure, stratify, legislate, couple, iterate — before their own crisis arrives.

Abstract: Background: Mycoplasma pneumoniae, a leading cause of paediatric community-acquired pneumonia, nearly disappeared under COVID-19 non-pharmaceutical interventions and re-emerged with a delay relative to other respiratory pathogens. Whether its timing tracks national and regional COVID-19 waves has not been quantified globally. Methods: From the Global Burden of Disease Study 2023 Results Tool we extracted, for 204 countries and seven GBD super-regions, deaths and disability-adjusted life years (DALYs) at ages 0–19 years from lower respiratory infections attributable to Mycoplasma pneumoniae (2019–2023) and deaths and incident cases of COVID-19 (2020–2023; 2019 set to zero by definition). For each geography we located the COVID-19 peak year, the Mycoplasma trough (minimum 2020–2023) and the post-trough rebound maximum, computed the peak-to-peak interval, and tested Spearman correlations between COVID-19 peak intensity and trough depth or rebound amplitude, with lagged z-score cross-correlations and alternative COVID-19 calibres (all-ages deaths; 0–19-year incidence) as sensitivity analyses. Results: Globally, Mycoplasma-attributed deaths at ages 0–19 years fell from 27,388 in 2019 to a trough of 22,711 in 2021 (−17.1%) and partially recovered to 26,366 in 2023 (−3.7% versus 2019), while paediatric COVID-19 deaths peaked at 147,850 in 2021. The modal interval from the COVID-19 peak to the Mycoplasma rebound peak was +2 years in five of seven super-regions and in 115 of 204 countries (56%; median 2 years). COVID-19 peak intensity showed no significant correlation with trough depth or rebound amplitude (|r| ≤ 0.21; p ≥ 0.09). Because rebound maxima fell in 2023—the final data year—in six of seven super-regions, the +2-year interval is partly a right-censoring artefact. The pattern strengthened under all-ages COVID-19 mortality (64% of countries at +2 years), shifted to +1 year under 0–19-year incidence, and was unchanged under the DALY calibre. Conclusions: Paediatric Mycoplasma-attributed mortality troughs followed COVID-19 mortality peaks with a modal two-year lag, consistent with suppression and delayed re-emergence under pandemic interventions, but with no detectable intensity gradient. The timing signal is robust to all-ages mortality calibration, calibre-dependent for incidence, and bounded by right-censoring at 2023; continued surveillance is required to observe complete rebound cycles.

Abstract: Respiratory viruses continue to challenge global preparedness because antiviral strategies remain largely pathogen specific. RSV, SARS-CoV-2, influenza, and emerging zoonotic viruses differ genetically, yet increasing evidence suggests that they converge on a common host vulnerability: suppression of the cellular stress-response regulators p53 and NRF2. RSV promotes p53 degradation and NRF2 loss, while SARS-CoV-2 similarly impairs these pathways and amplifies inflammatory signalling. Restoration of p53 and NRF2 reactivates antiviral microRNAs, suppresses viral-entry and inflammatory pathways, restores antioxidant defences, and induces p62/SQSTM1, a broad-spectrum antiviral restriction factor. These observations suggest that host-directed therapies could complement vaccines and direct-acting antivirals by establishing a mutation-resistant layer of protection. We argue that global preparedness frameworks should formally evaluate host-directed antiviral strategies as a third pillar of pandemic readiness.

Abstract: The conventional account of Jenner’s cowpox vaccine attributes a series of enabling properties to pre-laboratory inoculation: harvesting, preserving and transmitting infectious material; attenuating disease first through variolation and again through cowpox substitution; and a visible ‘take’ validating the procedure. Applying Occam’s razor, this review considers simpler alternative explanations. A recurring pattern is revealed in which early assumptions became established premises that were insufficiently challenged even as scientific standards advanced. Thus, the take alone did not establish poxvirus transmission, and variolation’s 0.5–2% versus 20–30% mortality comparison improperly contrasted healthy recipients with patients already ill with smallpox. Jennerian vaccination inherited and compounded these limitations and was not demonstrably superior to contemporary refined variolation. The major/minor division did not independently explain the decline in smallpox burden, and the attributed 300-million twentieth-century death toll could not be substantiated from contemporary population-level mortality records. Most importantly, eradication coincided with a diagnostic discontinuity: 1978 marked both the first year without recognised naturally acquired cases and the first year in which laboratory confirmation became a de facto requirement for validating suspected smallpox outbreaks. These findings challenge the traditional interpretation of smallpox and its eradication.

Abstract: Bacteriophage (phage) therapy is an emerging adjunctive strategy for treatment-resistant periprosthetic joint infections (PJI), but evidence on long-term outcomes and criteria for sustained control of infection remains limited. We previously reported the first use of personalized phage therapy in Canada for a life-threatening, multidrug-resistant (MDR) Staphylococcus epidermidis PJI. Here, we report longer-term clinical and microbiological follow up over two years, demonstrating sustained clinical control of infection with microbiological evidence of no recurrence. This study provides longitudinal clinical and microbiological evidence supporting sustained control of infection following phage therapy, and highlights the importance of standardized clinical and microbiological outcomes to define long-term response to treatment. We propose standardized endpoints for assessing phage therapy in PJI.

Abstract: Diabetic neuropathy is one of the most common diabetes-related complications but also one of the most complex in terms of diagnosis and management. This complication refers to a heterogeneous group of peripheral nerve disorders resulting from a combination of metabolic, vascular, and neurodegenerative factors, typically triggered by chronic hyperglycemia, which has a significant impact on quality of life. Despite its clinical relevance, the diagnosis of diabetic neuropathy remains challenging due to its diverse clinical manifestations and the lack of a single diagnostic approach capable of identifying all diabetic neuropathy types. Available diagnostic approaches range from clinical assessment and symptom-based scales to neurophysiological and small-fiber-specific techniques, each with distinct diagnostic performance and methodological requirements. Consequently, reported prevalence estimates may vary considerably among populations and studies. In Mexico, this variability is particularly relevant, as the prevalence of diabetic neuropathy has been reported across a wide range, making it difficult to establish a reliable national estimate. Differences in study populations, diagnostic criteria, and assessment methods may substantially contribute to this heterogeneity.