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The respiratory system examination showed normal chest skin, the right side was moving less, tactile vocal resonance was more on the right side, percussion note was dull on the right lower side, and there was decreased air entry at the right side but no added sounds. Showing massive swelling affecting the knee region, studded with multiple sinuses discharging purulent and seropurulent discharge containing black grains. https://doi.org/10.1371/journal.pntd.0010867.g001 Her full blood count showed WBCS of 5.7 * 103 micro/L, RBCs of 5.10 * 106 micro/L, haemoglobin of 10.4 g/dl, MCV of 66.7 fL, MCH of 20.4, MCHC of 30.6 pg, platelets of 339103 micro/L, neutrophils of 59%, lymphocytes of 31%, and monocytes of 8%. Photograph showing the secondary right inguinal mycetoma lesion. https://doi.org/10.1371/journal.pntd.0010867.g005 At a recent presentation to the MRC, on general examination, he looked unwell, pale, and vitally stable, with pulse rate of 72 beats/minute, respiratory rate of 20 breaths/minute, and blood pressure of 131/87 mm Hg. The renal profile showed blood urea of 11 mg/dl, low creatinine of 0.3 mg/dl with slightly low Na+ of 134 mmol/l, and K+ of 3.1 mmol/l.

Background: S3-level clinical practice guidelines represent the highest standard of evidence-based healthcare, integrating systematic reviews, formal evidence grading, and structured expert consensus. In periodontology, current S3-level guidelines provide robust recommendations for the management of stage I–III periodontitis. However, increasing clinical complexity, emerging diagnostic technologies, and the need for patient-centred and implementation-oriented care highlight important gaps that warrant further methodological refinement. Objective: This review aims to critically appraise the conceptual foundations, strengths, and limitations of existing S3-level periodontal guidelines and to propose a structured roadmap for the development of next-generation S3 guidance. Methods: A narrative and methodological review was conducted focusing on key European S3-level guidelines in periodontology and endodontics, with emphasis on guideline methodology, evidence grading, outcome prioritization, and consensus processes. Results: Current S3-level periodontal guidelines demonstrate strong methodological rigor but show limited coverage of stage IV periodontitis, peri-implant diseases, and endo–perio lesions. In addition, emerging domains such as biomarker-based diagnostics, artificial intelligence-assisted decision support, and implementation science are not yet systematically integrated. Conclusions: Future S3-level periodontal guidelines should incorporate clinical complexity, patient-reported outcomes, precision diagnostics, digital technologies, and real-world implementation strategies to enhance personalization, transparency, and clinical impact.

The 2018 classification of periodontal and peri-implant diseases introduced a multidimensional diagnostic framework integrating staging, grading, and disease extent, representing a major advance over earlier severity-based systems. By incorporating structural destruction, treatment complexity, spatial distribution, and estimated risk of progression, the classification aimed to support more individualized and biologically informed diagnosis. However, increasing clinical application has revealed interpretive challenges, particularly in cases where different components of the system appear discordant. This perspective examines these challenges through a conceptual and clinical lens, focusing on the distinction between focal severity and overall disease burden in staging, the biological meaning of disease distribution, the interpretation of tooth loss as a historical rather than current indicator of disease status, and the need to differentiate between observed progression and risk-based modifiers in grading. Rather than reflecting deficiencies of the classification itself, these discordances are understood as a consequence of applying categorical systems to a biologically heterogeneous and temporally dynamic disease. A biologically grounded interpretive hierarchy is proposed, prioritizing observed tissue behavior and realized tissue destruction over probabilistic risk indicators while integrating structural parameters, historical outcomes, and susceptibility modifiers within their appropriate conceptual roles. This approach enhances diagnostic coherence and supports a more phenotype-oriented interpretation of periodontal disease.

Periodontitis is a highly prevalent chronic inflammatory disease with significant oral and systemic consequences, including associations with cardiovascular disease, diabetes, and adverse pregnancy outcomes. Although mechanical debridement remains the cornerstone of therapy, adjunctive antibiotic use is increasingly limited by antimicrobial resistance, biofilm-associated tolerance, pharmacokinetic constraints, and disruption of the commensal microbiome, leading to inconsistent outcomes and disease recurrence. This review highlights the mechanistic limitations of conventional antibiotic therapies in periodontitis and critically examines emerging next-generation therapeutic strategies aimed at overcoming these challenges. Specifically, it explores antimicrobial peptides, quorum sensing inhibitors, nanotechnology-based drug delivery systems, host modulation approaches, and microbiome-targeted therapies, with emphasis on their molecular mechanisms, clinical relevance, and translational potential. By integrating microbial, host, and pharmacological perspectives, this review provides a comprehensive framework for advancing precision-guided periodontal therapy and supports the shift toward targeted, sustainable, and personalized treatment strategies.

Background Mental disorders are the leading cause of disability for youth worldwide. However, there is a dearth of validated, brief instruments to assess mental health in low- and middle-income countries (LMIC). We aimed to facilitate identification of mental disorders in LMIC contexts by adapting and validating measures of internalizing and externalizing disorders for adolescents in Mozambique, an LMIC in southeastern Africa. Methods We selected instruments with good support for validity in high-income and other LMIC settings: the Patient Health Questionnaire Adolescent (PHQ-A), Generalized Anxiety Disorders 7 (GAD-7), and Strengths and Difficulties Questionnaire (SDQ). Instruments were adapted by local and international mental health specialists followed by cognitive interviews ( n  = 48) with Mozambican adolescents. We administered the instruments along with the Miniature International Neuropsychiatric Interview for Children and Adolescents (MINI-KID)to 485 adolescents aged 12–19 years attending two secondary schools in Maputo City, Mozambique. One week later, we re-administered instruments to a randomly selected sample of 49 adolescents. Results Participants were 66.2% ( n  = 321) female and the average age was 15.9 (S.D = 1.7).Internal consistency (alpha = 0.80, PHQ-A; 0.84, GAD-7; 0.80, SDQ) and test–retest reliabilty (ICC = 0.74, PHQ-A; 0.70, GAD-7; 0.77, SDQ) were acceptabe for the PHQ-A, GAD-7, and the full SDQ. The SDQ internalizing subscale showed poor test–retest reliability (ICC = 0.63) and the SDQ externalizing subscale showed poor internal consistency (alpha = 0.65). All instruments demonstrated good sensitivity and specificity (> 0.70). Youden’s index identified optimal cutoff scores of 8 for the PHQ-A, 5 for the GAD-7, 10 for the SDQ internalizing and 9 for the SDQ externalizing subscales, though a range of scores provided acceptable sensitivity and specificity. Conclusions Our data supports reliability and validity of the PHQ-A, GAD-7, and SDQ instruments for rapidly assessing mental health problems in Mozambican adolescents. Use of these tools in other contexts with limited specialists may asist with expanding mental health assessment. Specific instrument and cutoff selection should be based on screening goals, treatment resources, and program objectives.

Two years into Sudan’s prolonged war, the collapse of health systems has fueled multiple concurrent epidemics, triggering a complex humanitarian emergency with regional spillover risks. Over 30 million people need aid, more than 11 million displaced internally, and cross-border movement has exacerbated the spread of vaccine-preventable diseases, including Cholera, Measles, and circulating vaccine-derived Poliovirus type 2 (cVDPV2). This review analyzes emerging epidemiological patterns and operational barriers to epidemic control in the context of armed conflict, displacement, and infrastructure collapse. It concludes with targeted recommendations for conflict-sensitive public health interventions.

Systemic antibiotics are among the most widely prescribed therapeutic agents worldwide, and their effects on host-microbe equilibrium extend well beyond the infection for which they are intended. Periodontitis is conventionally framed as a biofilm-initiated, host-mediated inflammatory disease, although recent work has shifted this framework toward microbial homeostasis as a regulator of periodontal stability. We hypothesize that antibiotics are not direct etiologic agents of periodontitis but instead act as risk-modifying factors that lower the threshold at which plaque-mediated inflammation progresses to destructive disease. We propose that this effect may operate through several mechanisms: broad-spectrum or repeated exposure could deplete protective commensals and narrow microbial diversity, creating ecological space for opportunistic and pathogenic taxa; antibiotics may also alter host neutrophil function, cytokine profiles, and antimicrobial peptide regulation and may interfere with the osteoblastic and osteoclastic dynamics governing alveolar bone remodelling; and antibiotic-induced gut dysbiosis may propagate systemic inflammatory signals that further modulate periodontal susceptibility. To evaluate this hypothesis, we synthesize the available clinical, epidemiological, and experimental data across four converging axes-oral microbial ecology, immune regulation, alveolar bone remodelling, and the gut-oral axis-and identify the predictions the hypothesis generates and the evidence gaps it exposes. We emphasize that no clinical study has yet demonstrated a causal link between antibiotic exposure and periodontitis; the framework advanced here is therefore intended to inform antimicrobial stewardship in dentistry and to define a research agenda for determining whether antibiotic exposure constitutes a clinically meaningful modifier of periodontal disease susceptibility.

Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1 + T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent ‘back-signaling’ in CD4 + T cells, which prevented activation, reduced T H 1-polarization and directed T H 17-differentiation. PD-L1 signaling also induced an anergic T-bet − IFN-γ − phenotype in CD8 + T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1 + T cells restrained effector T cells via the canonical PD-L1–PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1 + T cells engaged PD-1 + macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1 + T cells have diverse tolerogenic effects on tumor immunity. PD-L1 on tumor cells exerts an important dampening effect on T cells via their expression of PD-1. Miller and colleagues find that PD-L1 ‘back-signaling’ into T cells and macrophages can also dampen immune responses within the tumor microenvironment.

The drivers and the specification of CD4 T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique T -program. Specifically, CD11b CD103 DC predominate in PDA, express high IL-23 and TGF-β, and induce FoxP3 tumor-promoting IL-10 IL-17 IFNγ regulatory CD4 T cells. The balance between this distinctive T program and canonical FoxP3 T is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This T -signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b CD103 DC promote CD4 T cell tolerance in PDA which may underscore its resistance to immunotherapy.

The drivers and the specification of CD4 + T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique T H -program. Specifically, CD11b + CD103 − DC predominate in PDA, express high IL-23 and TGF-β, and induce FoxP3 neg tumor-promoting IL-10 + IL-17 + IFNγ +  regulatory CD4 + T cells. The balance between this distinctive T H program and canonical FoxP3 +  T REGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This T H -signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b + CD103 − DC promote CD4 + T cell tolerance in PDA which may underscore its resistance to immunotherapy. Pancreatic ductal adenocarcinoma is characterized by a highly immunosuppressive tumour microenvironment. Here, the authors show that specialized subsets of tumour-infiltrating dendritic cells induce distinct CD4 + T cell programs and specifically identify a CD103 – CD11b + subset which induces tumor-promoting FoxP3 – Type-1 regulatory T cells.