While the accelerated approval (AA) program in the United States expedites the availability of drugs based on preliminary evidence to fulfill unmet medical needs, it has also raised significant concerns, including a lack of robust evidence of efficacy and subsequent withdrawals. Although drug lag and drug loss are growing regulatory concerns in Japan, considering the stricter withdrawal criteria in Japan, careful evaluation of clinical evidence of accelerated approval and approval timing differences is necessary. Here, we aimed to investigate differences in approval timing between the U.S. and Japan, as well as the clinical evidence of accelerated approval drugs that have not yet been approved in Japan. Using the U.S. Food and Drug Administration (FDA) and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) databases, we examined the Japanese and U.S. regulatory status of cancer drugs granted accelerated approval in the U.S. between 2012 and 2022 and the characteristics of evidence for drugs not yet approved in Japan. Of 132 drug-indication pairs that received accelerated approval between 2012 and 2022, 72 (54.5%) were approved in Japan by June 2024. Of the remaining 60 (45.5%) drugs not yet approved in Japan, the majority had methodological limitations, including a lack of comparators (93.2%) and scarcity of phase III trials (8.5%), as permitted by the accelerated approval program. Our findings suggest the need for an approach that addresses drug lag while ensuring both careful regulatory review and generation of robust evidence for efficacy and safety.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, and despite advances in frontline therapies such as rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone, approximately 30%-40% of patients develop relapsed or refractory (rel/ref) disease. This subgroup has historically faced poor prognoses with limited treatment options, prompting the development of novel immunotherapeutic strategies. Chimeric antigen receptor T-cell (CAR T) therapy and bispecific antibodies (BsAbs) have emerged as transformative approaches in this setting.

This narrative review compares these therapies across multiple domains, including mechanisms of action, clinical efficacy, safety profiles, logistics, cost, and accessibility.

CAR T therapies have demonstrated durable complete response rates (40%-60%) and extended progression-free survival (median 11-12.5 months), but they are limited by complex manufacturing, high cost, and potentially severe toxicities. In contrast, BsAbs offer immediate, off-the-shelf availability, with promising efficacy and a more favorable safety profile that enables outpatient administration, although long-term durability remains under investigation.

This review provides clinicians with a comprehensive comparison to support evidence-based treatment selection in rel/ref DLBCL.

Delayed breast cancer diagnosis in low- and middle-income countries (LMICs) reduces the survival rates. This review identifies the causes of these delays to inform strategies for improving early detection.

This scoping review followed the Arksey and O'Malley framework to explore the factors contributing to delayed breast cancer diagnosis in LMICs. Seven databases, including PubMed, Scopus, Web of Science, Cochrane Library, ProQuest, Embase, and Magiran, were searched for English and Persian studies published between January 2000 and September 2024. The search combined the keywords (e.g., "diagnostic delay," "missed diagnosis," "breast cancer," "late-stage," "barriers"), using Boolean operators. To focus on LMICs, we applied country filters, where available, and supplemented the search with manual screening of reference lists from the included studies.

The initial database search identified 5,313 records. After removing 1,036 duplicates, 4,277 studies were screened based on title, abstract, and country of origin. Of these, 4,217 were excluded for reasons including irrelevance to delayed breast cancer diagnosis, study design, population, setting (e.g., high-income countries), or publication date (outside 2000-2024). The remaining 60 studies met the inclusion criteria and were included in the narrative synthesis. Extracted data were organized and interpreted using the revised Penchansky framework (accessibility, availability, acceptability, affordability, accommodation, awareness). Additional themes included misdiagnosis, competing priorities, and personal factors.

Multiple modifiable factors contribute to diagnostic delays in LMICs. Addressing them can accelerate diagnosis, improve outcomes, and reduce harm. Targeted improvements in these areas offer significant potential to enhance breast cancer care and save lives in LMICs.

Human papillomavirus (HPV) vaccination is a cornerstone of global strategies to prevent HPV-associated malignancies; however, uncertainties persist regarding its long-term efficacy, immunogenicity, and safety across populations, vaccine formulations, and dosing schedules. We conducted a comprehensive systematic review and meta-analysis to evaluate the clinical and immunological effectiveness of prophylactic HPV vaccines.

This study followed PRISMA guidelines and was registered in PROSPERO (CRD420251050526). Randomized controlled trials (RCTs) were identified through comprehensive searches of six major databases. Risk of bias was assessed using the RoB 2 tool. Meta-analyses were performed using random- or fixed-effects models as appropriate. Subgroup and meta-regression analyses explored the effects of age, sex, vaccine type, dosing regimen, and HIV status. Certainty of evidence was appraised using the GRADE framework.

A total of 145 RCTs were included. HPV vaccination significantly reduced cervical intraepithelial neoplasia grade 1 (RR = 0.15, 95% CI: 0.09-0.24), grade 2 (0.20, 0.13-0.30), and grade 3 (0.48, 0.23-0.98). Persistent HPV16/18 infections were reduced by 84% (0.16, 0.12-0.21), and incident infections by 75% (0.25, 0.19-0.34). Immunogenicity analyses demonstrated robust antibody responses, with fold increases of 3.09 for HPV16, 3.10 for HPV18, 3.48 for HPV6, and 3.37 for HPV11. Tissue-resident CD4⁺ T cells were significantly reduced (SMD: -1.27, 95% CI: -2.24 to -0.31), while CD8⁺ T cells showed no significant change. Vaccination was not associated with an increased risk of serious adverse events (0.90, 0.82-0.99) or adverse pregnancy outcomes. Although, injection-site adverse events were modestly increased (1.26, 1.07-1.48).

Prophylactic HPV vaccination provides strong protection against HPV infections and precancerous lesions and induces robust humoral immunity with a favorable safety profile. The nonavalent vaccine, particularly when administered in a three-dose (0/1/6) regimen, offers the most comprehensive protection. These findings support the expansion of gender-neutral vaccination programs to maximize population-level cancer prevention.

https://www.crd.york.ac.uk/prospero/, identifier CRD420251050526.

Cerebral venous sinus thrombosis (CVST) is a rare type of stroke with a variable presentation. Without a prompt diagnosis, subacute presentation can delay treatment with devastating results. Our case presents an unusual clinical pattern of a young patient presenting with audio-visual hallucinations who was diagnosed with CVST. A 26-year-old man with no neurological or psychological history presented with audio-visual hallucinations, transient uncontrolled movements of his left upper extremities, and right-sided headache. Physical examination was nonfocal, and he demonstrated normal awareness, orientation, and motor function. CT angiography, CT venography (CTV) of the head, and magnetic resonance imaging of the brain were suggestive of multiple intracranial malformations versus neoplasm. The patient underwent digital subtraction angiography, which demonstrated nonocclusive thrombi in several right posterior temporal cortical veins. There was also a nonocclusive thrombus in the right sigmoid sinus. No intracranial aneurysm, arteriovenous malformation, or arteriovenous shunting was found. The patient was started on antiseizure medication as treatment for ongoing hallucinations and convulsions. After several days of intravenous heparin, the patient was transitioned to oral anticoagulant. CVST is a rare cerebrovascular disease, accounting for 0.5% of all strokes. Diagnosis is usually made in young adults with pre-existing hypercoagulable risk factors or positive family history. With symptoms such as those mentioned above, a high degree of suspicion is required to mitigate delay in diagnosis and therapy. Our case is the first documented case of a young patient with no relevant past medical history and risk factors developing hallucinations related CVST.

Human metapneumovirus (hMPV) causes mild and self-limiting disease in adults. However, the risk factors for serious adverse outcomes following hMPV infection in adult patients without preexisting chronic airway diseases remain poorly understood. We conducted a territory-wide retrospective study on adult patients (aged ≥ 18 years) without chronic airway diseases hospitalized for hMPV infections between January 1, 2016 and June 30, 2023 in Hong Kong. We assessed the incidence and risk factors for in-patient mortality, severe respiratory failure (SRF), secondary bacterial pneumonia and acute kidney injury (AKI) were assessed. A total of 1552 eligible adult patients without chronic airway diseases hospitalized for hMPV infections were analyzed. Within the index admission, 92 (5.9%) patients died. Ischemic heart disease (IHD) was associated with increased risks of SRF [adjusted odds ratio (aOR) 2.00 (95% CI 1.48-2.71), p < 0.001]. IHD, heart failure (HF), and history of ischemic stroke were significant predictors for AKI [aOR 1.51 (95% CI 1.12-2.04), 2.87 (95% CI 2.14-3.85), and 1.47 (95% CI = 1.12-1.93), p = 0.007, < 0.001, and 0.005, respectively). Patients with end-stage kidney disease (ESKD) requiring renal replacement therapy (RRT) were at increased risk of in-patient mortality [aOR 6.36 (95% CI 2.34-17.26), p < 0.001] and SRF [aOR 8.80 (95% CI 3.84-20.16), p < 0.001]. The presence of cardiovascular diseases and ESKD requiring RRT is a strong predictor of severe in-hospital outcomes among adult patients without chronic airway diseases who are hospitalized for hMPV infections.

The COVID-19 pandemic disproportionately affected Indigenous populations, yet Métis-specific data remain limited. We described COVID-19-related experiences, physical and mental health, health behaviours, and socio-economic wellbeing among Métis people in Alberta (Canada) during the early pandemic.

Misi Yehewin was a cross-sectional survey series conducted with the Otipemisiwak Métis Government of the Métis Nation within Alberta. Self-identified Métis aged ≥16 years completed surveys in three phases: December 2020-January 2021 (Wave 1), March-April 2021 (Wave 2), and November-December 2021 (Wave 3). Each wave included an independent sample of participants. We calculated weighted proportions for 28 key items and compared estimates across waves.

Overall, 2,439 participants completed the surveys. Confirmed COVID-19 cases were reported by 5% of participants in Wave 1 and 15% in Wave 3. Reports of worsening physical and mental health were less frequent in later phases; yet, across waves, 41% screened positive for depressive symptoms, 47% for anxiety, and 68% for high perceived stress. Food insecurity was reported by 39.4% of participants in Wave 1 and 52.9% in Wave 3. Reduced family time and cultural activities were common, particularly in earlier waves. Reports of financial strain (~56%), racism (~25%), and strong Métis identity (~89%) was similar across waves.

Findings highlight ongoing structural inequities influencing Métis health during COVID-19. Despite fewer reports of worsening overall health in later phases, symptom-based measures showed persistently high perceived stress and widespread food insecurity. Métis-led, culturally grounded strategies are needed to address both immediate and long-term determinants of health.

Tuberculosis (TB) primarily manifests as pulmonary TB (PTB), but extrapulmonary TB (EPTB) remains a major clinical challenge. Distinct diagnostic and therapeutic difficulties arise from differences in immune responses, pathogen behaviour and host susceptibility. However, the factors driving disease localisation are still incompletely understood. We conducted a comprehensive narrative review of studies examining differences between PTB and EPTB in terms of epidemiology, mycobacterial factors, genetic and epigenetic determinants, host immune responses, transcriptomic profiles, cytokine and chemokine patterns, and immunophenotypes. EPTB is more common among females, children, older adults and immunocompromised individuals with deficient granuloma formation. This review is intended to provide deeper insight for clinicians and researchers and provides an accessible synthesis of current basic science findings together with their relevance for clinical practice. Certain Mycobacterium tuberculosis lineages, notably lineage 1, and specific virulence factors are associated with extrapulmonary dissemination. While genetic polymorphisms influence TB localisation, no studies specifically addressing epigenetic predisposition to EPTB were identified. PTB typically is characterised by T-helper 1-driven immunity, high bacillary loads and robust macrophage activation, whereas EPTB involves compartmentalised immune responses, reduced cytotoxicity and broader cytokine variability. Transcriptomic analyses reveal site-specific gene expression differences and emerging diagnostic blood-based biomarkers show promise but require further validation. Cytokine profiles and immunophenotyping suggest greater immune exhaustion and regulatory T-cell activity in EPTB. We outline practical implications for diagnosis and management and highlight constraints in resource-limited settings and emphasise access and implementation considerations. Integrating these clinical and mechanistic insights can guide more timely recognition and tailored care.

The Non-Specific Pattern (NSP) is characterized by a reduced Forced Expiratory Volume in 1 s (FEV₁) and/or Forced Vital Capacity (FVC), a preserved FEV₁/FVC ratio, and a normal Total Lung Capacity (TLC). Although recognized in recent American Thoracic Society/European Respiratory Society (ATS/ERS) recommendations, this pattern remains poorly understood.

To systematically review the literature addressing the NSP in adult patients, with a focus on its physiological definition, clinical correlates, underlying mechanisms, and longitudinal outcomes.

A systematic search was conducted in PubMed and Embase from inception to 16 June 2025, following PRISMA guidelines. Eligible studies included adults presenting a physiologically defined NSP. Seven retrospective studies were included and appraised using the Joanna Briggs Institute checklist.

Across included studies, NSP was consistently defined using core physiological criteria, though specific thresholds and diagnostic strategies varied. Etiologies included asthma, obesity, obstructive sleep apnoea, interstitial lung disease, and neuromuscular disorders. Several functional markers, such as increased Residual Volume (RV)/TLC ratios, Slow Vital Capacity (SVC)-FVC differences >100 mL, and reduced FEV₁/SVC ratios, suggested early small airway involvement or masked restriction. Two longitudinal studies revealed that NSP may evolve toward obstruction or restriction, with baseline bronchodilator responsiveness and elevated airway resistance as predictors of obstruction. Despite the clinical implications, therapeutic management remains unexplored.

NSP is not a benign or incidental respiratory functional profile. It may represent an early or intermediate functional state between classic obstructive and restrictive defects. Complementary functional markers and structured follow-up may aid in clinical interpretation and risk stratification.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: Primary objective To assess the benefits and harms of tenecteplase compared to alteplase in people suffering from large vessel occlusion or non-large vessel occlusion acute ischemic stroke. Secondary objective To explore the effects of the interventions (tenecteplase and alteplase) in different groups based on age, sex, ethnicity, and place of residence (high-, middle-, low-income country), to inform health equity considerations.