A signal-seeking phase 2 study of Trastuzumab emtansine in tumours harbouring HER2 amplification or mutation.

This single-arm phase II non-randomised trial (ACTRN12619001265167) evaluated trastuzumab emtansine in solid cancers with HER2 amplification or mutation detected by comprehensive genomic profiling. The primary objective was objective response (OR), while secondary objectives included the time to progression (TTP) on study to TTP on prior therapy ratio, progression-free survival (PFS) and overall survival (OS). The cohort included 16 tumours with HER2 mutations (group 1) and 16 with HER2 amplification (group 2). After 17 months median follow-up, ORs occurred in 19% of group 1 (1 salivary gland carcinoma (SGC), 2 lung cancers) and 25% of group 2 (3 SGCs, 1 uterine carcinoma). Fourteen of 29 TTP-evaluable patients achieved a TTP ratio ≥1.3, including 10 without an OR. Median PFS and OS were 4.5 (95% CI 2.1-7.0) and 18.2 months (95% CI 8.1-not reached) respectively. Trastuzumab emtansine showed modest ORs and a favourable change in disease trajectory in select HER2-altered solid cancers.

Early, robust mucosal secretory IgA but not IgG response to SARS-CoV-2 spike in oral fluid is associated with faster viral clearance and COVID-19 symptom resolution.

BACKGROUND: High priority efforts are underway to support the development of novel mucosal COVID-19 vaccines, such as the US Government's Project NextGen and the Center for Epidemic Preparedness Innovations' goal to respond to the next pandemic with a new vaccine in 100 days. However, there is limited consensus about the complementary role of mucosal immunity in disease progression and how to evaluate immunogenicity of mucosal vaccines. This study investigated the role of oral mucosal antibody responses in viral clearance and COVID-19 symptom duration. METHODS: Participants with PCR-confirmed SARS-CoV-2 infection provided oral fluid for testing with SARS-CoV-2 antibody multiplex assays, nasal swabs for RT-PCR and symptom information at up to eight follow-ups from April 2020 to February 2022. RESULTS: High and moderate oral fluid anti-spike (S) secretory IgA (SIgA) post infection was associated with significantly faster viral clearance and symptom resolution across age groups with effect sizes equivalent to having COVID-19 vaccine immunity at the time of infection. Those with high and moderate anti-S SIgA cleared the virus 14 days (95% CI: 10-18) and recovered 9-10 days (95% CI: 6-14) earlier. Delayed and higher anti-S IgG was associated with significantly longer time to clearance and recovery. Experiencing symptoms longer than four weeks was associated with lower anti-RBD SIgA 15-30 days after infection onset (p<0.001). CONCLUSION: Robust mucosal SIgA early post infection appears to support faster clearance of SARS-CoV-2 and recovery from COVID-19 symptoms. This research underscores the importance of harmonizing mucosal immune response assays to evaluate new mucosal vaccines.

Criteria for assessing evidence for biomarker-targeted therapies in rare cancers-an extrapolation framework.

Background: Advances in targeted therapy development and tumor sequencing technology are reclassifying cancers into smaller biomarker-defined diseases. Randomized controlled trials (RCTs) are often impractical in rare diseases, leading to calls for single-arm studies to be sufficient to inform clinical practice based on a strong biological rationale. However, without RCTs, favorable outcomes are often attributed to therapy but may be due to a more indolent disease course or other biases. When the clinical benefit of targeted therapy in a common cancer is established in RCTs, this benefit may extend to rarer cancers sharing the same biomarker. However, careful consideration of the appropriateness of extending the existing trial evidence beyond specific cancer types is required. A framework for extrapolating evidence for biomarker-targeted therapies to rare cancers is needed to support transparent decision-making. Objectives: To construct a framework outlining the breadth of criteria essential for extrapolating evidence for a biomarker-targeted therapy generated from RCTs in common cancers to different rare cancers sharing the same biomarker. Design: A series of questions articulating essential criteria for extrapolation. Methods: The framework was developed from the core topics for extrapolation identified from a previous scoping review of methodological guidance. Principles for extrapolation outlined in guidance documents from the European Medicines Agency, the US Food and Drug Administration, and Australia's Medical Services Advisory Committee were incorporated. Results: We propose a framework for assessing key assumptions of similarity of the disease and treatment outcomes between the common and rare cancer for five essential components: prognosis of the biomarker-defined cancer, biomarker test analytical validity, biomarker actionability, treatment efficacy, and safety. Knowledge gaps identified can be used to prioritize future studies. Conclusion: This framework will allow systematic assessment, standardize regulatory, reimbursement and clinical decision-making, and facilitate transparent discussions between key stakeholders in drug assessment for rare biomarker-defined cancers.

Measurement of blood-brain barrier water exchange rate using diffusion-prepared and multi-echo arterial spin labelling: Comparison of quantitative values and age dependence.

Water exchange rate (Kw) across the blood-brain barrier (BBB) is an important physiological parameter that may provide new insight into ageing and neurodegenerative disease. Recently, two non-invasive arterial spin labelling (ASL) MRI methods have been developed to measure Kw, but results from the different methods have not been directly compared. Furthermore, the association of Kw with age for each method has not been investigated in a single cohort. Thirty participants (70% female, 63.8 ± 10.4 years) were scanned at 3 T with Diffusion-Prepared ASL (DP-ASL) and Multi-Echo ASL (ME-ASL) using previously implemented acquisition and analysis protocols. Grey matter Kw, cerebral blood flow (CBF) and arterial transit time (ATT) were extracted. CBF values were consistent; approximately 50 ml/min/100 g for both methods, and a strong positive correlation in CBF from both methods across participants (r = 0.82, p < 0.001). ATT was significantly different between methods (on average 147.7 ms lower when measured with DP-ASL compared to ME-ASL) but was positively correlated across participants (r = 0.39, p < 0.05). Significantly different Kw values of 106.6 ± 19.7 min-1 and 306.8 ± 71.7 min-1 were measured using DP-ASL and ME-ASL, respectively, and DP-ASL Kw and ME-ASL Kw were negatively correlated across participants (r = -0.46, p < 0.01). Kw measured using ME-ASL had a significant linear relationship with age (p < 0.05). In conclusion, DP-ASL and ME-ASL provided estimates of Kw with significantly different quantitative values and inconsistent dependence with age. We propose future standardisation of modelling and fitting methods for DP-ASL and ME-ASL, to evaluate the effect on Kw quantification. Also, sensitivity and bias analyses should be performed for both approaches, to assess the effect of varying acquisition and fitting parameters. Lastly, comparison with independent measures of BBB water transport, and with physiological and clinical biomarkers known to be associated with changes in BBB permeability, are essential to validate the ASL methods, and to demonstrate their clinical utility.

Overview of ADNI MRI.

The magnetic resonance imaging (MRI) Core has been operating since Alzheimer's Disease Neuroimaging Initiative's (ADNI) inception, providing 20 years of data including reliable, multi-platform standardized protocols, carefully curated image data, and quantitative measures provided by expert investigators. The overarching purposes of the MRI Core include: (1) optimizing and standardizing MRI acquisition methods, which have been adopted by many multicenter studies and trials worldwide and (2) providing curated images and numeric summary values from relevant MRI sequences/contrasts to the scientific community. Over time, ADNI MRI has become increasingly complex. To remain technically current, the ADNI MRI protocol has changed substantially over the past two decades. The ADNI 4 protocol contains nine different imaging types (e.g., three dimensional [3D] T1-weighted and fluid-attenuated inversion recovery [FLAIR]). Our view is that the ADNI MRI data are a greatly underutilized resource. The purpose of this paper is to educate the scientific community on ADNI MRI methods and content to promote greater awareness, accessibility, and use. HIGHLIGHTS: The MRI Core provides multi-platform standardized protocols, carefully curated image data, and quantitative analysis by expert groups. The ADNI MRI protocol has undergone major changes over the past two decades to remain technically current. As of April 25, 2024, the following numbers of image series are available: 17,141 3D T1w; 6877 FLAIR; 3140 T2/PD; 6623 GRE; 3237 dMRI; 2846 ASL; 2968 TF-fMRI; and 2861 HighResHippo (see Table 1 for abbreviations). As of April 25, 2024, the following numbers of quantitative analyses are available: FreeSurfer 10,997; BSI 6120; tensor based morphometry (TBM) and TBM-SYN 12,019; WMH 9944; dMRI 1913; ASL 925; TF-fMRI NFQ 2992; and medial temporal subregion volumes 2726 (see Table 4 for abbreviations). ADNI MRI is an underutilized resource that could be more useful to the research community.

Individual Heterogeneity and Trends in Hepatitis C Infection Risk Among People Who Inject Drugs: A Longitudinal Analysis.

Hepatitis C virus (HCV) causes substantial morbidity and mortality, particularly among people who inject drugs (PWID). While elimination of HCV as a public health problem may be possible through treatment-as-prevention, reinfection can attenuate the impact of treatment scale-up. There is a need to better understand the distribution and temporal trends in HCV infection risk, including among HCV-seropositive individuals who will be eligible for treatment and at risk for subsequent reinfection. In this analysis of 840 seronegative and seropositive PWID in Baltimore, MD USA, we used random forest methods to develop a composite risk score of HCV infection from sociodemographic and behavioural risk factors. We characterised the individual heterogeneity and temporal trajectories in this composite risk score using latent class methods and compared that index with a simpler, conventional measure, injection drug use frequency. We found that 15% of the population remained at high risk of HCV infection and reinfection by the composite metric for at least 10 years from study enrolment, while others experienced transient periods of moderate and low risk. Membership in this high-risk group was strongly associated with higher rates of HCV seroconversion and post-treatment viraemia, as a proxy of reinfection risk. Injection frequency alone was a poor measure of risk, evidenced by the weak associations between injection frequency classes and HCV-associated outcomes. Together, our results indicate HCV infection risk is not equally distributed among PWID nor well captured by injection frequency alone. HCV elimination programmes should consider targeted, multifaceted interventions among high-risk individuals to reduce reinfection.

Role of Mitofusin 1 in mediating reactive oxygen species in alveolar macrophages during Streptococcuspneumoniae.

Alveolar macrophages (AM) are key effectors of the immune response and are essential for host responses to S. pneumoniae. Mitochondria are highly dynamic organelles whose function aids in regulating the cell cycle, innate immunity, autophagy, redox signaling, calcium homeostasis, and mitochondrial quality control in AM. In response to cellular stress, mitochondria can engage in stress-induced mitochondrial hyperfusion (SIMH). The current study aimed to investigate the role of Mfn1 on mitochondrial control of reactive oxygen species (ROS) in AMs and the role of Mfn1 deficiency on immune responses to S. pneumoniae. Compared to Mfn1FloxCre- controls, there were distinct histological differences in lung tissue collected from Mfn1Floxed; CreLysM mice, with less injury and inflammation observed in mice with Mfn1 deficient myeloid cells. There was a significant decrease in lipid peroxidation and ROS production in Mfn1 deficient AM that was associated with increased superoxide dismutase (SOD) and antioxidant activity. Our findings demonstrate that Mfn1 deficiency in myeloid cells decreased inflammation and lung tissue injury during S. pneumoniae infection.

Design and validation of the ADNI MR protocol.

Phase four of the Alzheimer's Disease Neuroimaging Initiative (ADNI4) magnetic resonance imaging (MRI) protocols aim to maintain longitudinal consistency across two decades of data acquisition, while adopting new technologies. Here we describe and justify the study's design and targeted biomarkers. The ADNI4 MRI protocol includes nine MRI sequences. Some sequences require the latest hardware and software system upgrades and are continuously rolled out as they become available at each site. The main sequence additions/changes in ADNI4 are: (1) compressed sensing (CS) T1-weighting, (2) pseudo-continuous arterial spin labeling (ASL) on all three vendors (GE, Siemens, Philips), (3) multiple-post-labeling-delay ASL, (4) 1 mm3 isotropic 3D fluid-attenuated inversion recovery, and (5) CS 3D T2-weighted. ADNI4 aims to help the neuroimaging community extract valuable imaging biomarkers and provide a database to test the impact of advanced imaging strategies on diagnostic accuracy and disease sensitivity among individuals lying on the cognitively normal to impaired spectrum. HIGHLIGHTS: A summary of MRI protocols for phase four of the Alzheimer's Disease Neuroimaging Initiative (ADNI 4). The design and justification for the ADNI 4 MRI protocols. Compressed sensing and multi-band advances have been applied to improve scan time. ADNI4 protocols aim to streamline safety screening and therapy monitoring. The ADNI4 database will be a valuable test bed for academic research.

Oxidative stress-induced YAP1 expression is regulated by NCE102, CDA2, and BCS1.

Maintaining cellular homeostasis in the face of stress conditions is vital for the overall well-being of an organism. Reactive oxygen species (ROS) are among the most potent cellular stressors and can disrupt the internal redox balance, giving rise to oxidative stress. Elevated levels of ROS can severely affect biomolecules and have been associated with a range of pathophysiological conditions. In response to oxidative stress, yeast activator protein-1 (Yap1p) undergoes post-translation modification that results in its nuclear accumulation. YAP1 has a key role in oxidative detoxification by promoting transcription of numerous antioxidant genes. In this study, we identified previously undescribed functions for NCE102, CDA2, and BCS1 in YAP1 expression in response to oxidative stress induced by hydrogen peroxide (H2O2). Deletion mutant strains for these candidates demonstrated increased sensitivity to H2O2. Our follow-up investigation linked the activity of these genes to YAP1 expression at the level of translation. Under oxidative stress, global cap-dependent translation is inhibited, prompting stress-responsive genes like YAP1 to employ alternative modes of translation. We provide evidence that NCE102, CDA2, and BCS1 contribute to cap-independent translation of YAP1 under oxidative stress.

Coxiella burnetii protein CBU2016 supports CCV expansion.

Coxiella burnetii is a globally distributed obligate intracellular pathogen. Although often asymptomatic, infections can cause acute Q fever with influenza-like symptoms and/or severe chronic Q fever. Coxiella burnetii develops a unique replicative niche within host cells called the Coxiella-containing vacuole (CCV), facilitated by the Dot/Icm type IV secretion system translocating a cohort of bacterial effector proteins into the host. The role of some effectors has been elucidated; however, the actions of the majority remain enigmatic and the list of true effectors is disputable. This study examined CBU2016, a unique C. burnetii protein previously designated as an effector with a role in infection. We were unable to validate CBU2016 as a translocated effector protein. Employing targeted knock-out and complemented strains, we found that the loss of CBU2016 did not cause a replication defect within Hela, THP-1, J774, or iBMDM cells or in axenic media, nor did it affect the pathogenicity of C. burnetii in the Galleria mellonella infection model. The absence of CBU2016 did, however, result in a consistent decrease in the size of CCVs in HeLa cells. These results suggest that although CBU2016 may not be a Dot/Icm effector, it is still able to influence the host environment during infection.

Plastic pollution and human pathogens: Towards a conceptual shift in risk management at bathing water and beach environments.

Emerging evidence indicates that micro- and macro-plastics present in water can support a diverse microbial community, including potential human pathogens (e.g., bacteria, viruses). This interaction raises important concerns surrounding the role and suitability of current bathing water regulations and associated pathogen exposure risk within beach environments. In response to this, we critically evaluated the available evidence on plastic-pathogen interactions and identified major gaps in knowledge. This review highlighted the need for a conceptual shift in risk management at public beaches recognising: (i) interconnected environmental risks, e.g., associations between microbial compliance parameters, potential pathogens and both contemporary and legacy plastic pollution; and (ii) an appreciation of risk of exposure to plastic co-pollutants for both water and waterside users. We present a decision-making framework to identify options to manage plastic-associated pathogen risks alongside short- and longer-term research priorities. This advance will help deliver improvements in managing plastic-associated pathogen risk, acknowledging that human exposure potential is not limited to only those who engage in water-based activity. We argue that adopting these recommendations will help create an integrated approach to managing and reducing human exposure to pathogens at bathing, recreational water and beach environments.

Percutaneous Internal Ring Suturing for Inguinal Hernia Repair in Children: Retrospective Cohort of 714 Patients with Minimum 3-Year Follow-Up.

Background and Objectives: Despite numerous described techniques, laparoscopy has yet to replace open surgery as the gold standard for inguinal hernia (IH) repair in children. This may be due to many variables, including the lack of long-term follow-up and concern for increased recurrence. In this study, we present our long-term follow-up data on children undergoing percutaneous internal ring suturing (PIRS) for IH repair. Materials and Methods: This retrospective cohort study included children who underwent PIRS for IH between May 2013 and May 2021 at three tertiary care institutions, with at least three years of follow-up. Age at surgery, side of IH, presence of contralateral patent processus vaginalis, surgical and anesthesia time, and complications were noted. Parents were contacted to enquire about long-term complications, such as recurrence. Results: Long-term follow-up (average 6.9 ± 2.3 years) was available for 714 patients. For unilateral and bilateral procedures, the average surgical time was 13.6 ± 5.4 and 19.9 ± 3.0, and the average anesthesia time was 27.7 ± 12.9 and 33.9 ± 14.1 min, respectively. Complications were seen in 0.84% of patients and 1.2% of procedures, and recurrence was observed in 0.98% of patients and 0.78% of procedures. Conclusions: Our study, with a nearly 7-year follow-up, provides substantial evidence that PIRS is a safe and effective technique for IH repair in children, with low recurrence and complication rates. Despite the study's retrospective nature and limited sample size, it contributes valuable data supporting the use of PIRS in pediatric IH repair.

Hepatitis B Virus in People who Inject Drugs and Men who Have Sex With Men With HIV in India: A Cross-sectional Study.

Background: People with HIV (PWH) who are coinfected with hepatitis B virus (HBV) have a higher risk of mortality compared with PWH alone. Populations such as people who inject drugs (PWID) and men who have sex with men (MSM) are particularly at high risk for HBV acquisition; yet, limited epidemiological data from these populations exist on HBV prevalence from low- and middle-income country settings (LMICs). Methods: We characterized the prevalence and correlates of HBV serological markers in a sample of PWID and MSM with HIV recruited across 15 Indian cities using hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), and hepatitis B surface antibody (anti-HBs). Testing of stored specimens for the presence of these markers was performed on the Abbott ARCHITECT i1000 as per the manufacturer's instructions. Correlates of ever being infected with HBV (reactive for anti-HBc and/or HBsAg) and chronic HBV (reactive for HBsAg) among those ever infected were assessed using univariable and multivariable multilevel logistic regression models accounting for site-level clustering. Results: A total of 2198 (95%) of the 2314 participants recruited for the trial were screened for HBV markers. The median age among the PWID and MSM participants was 30 and 32 years, respectively. The prevalence of ever being infected with HBV was 75.6% vs 46.9% in PWID vs MSM, respectively (P < .01); prevalence of chronic infection was also higher in PWID vs MSM (14.1% vs 9.5%; P < .01). Correlates of ever being infected with HBV among PWID included unstable housing (adjusted odds ratio [aOR], 5.02) and sharing injection paraphernalia (aOR, 2.70), and among MSM, correlates included history of injection drug use (aOR, 4.87) and gender identity. The prevalence of isolated core (anti-HBc in the absence of anti-HBs) was 34.7% vs 29.4% in PWID vs MSM (P < .05). Vaccination serostatus was <10% in both populations. Conclusions: In this large sample of PWID and MSM with HIV, we observed a high prevalence of serology consistent with HBV infection and low vaccination, highlighting the need for routine screening and catch-up vaccination. The high prevalence of isolated anti-HBc reactivity highlights the need to understand the risk of reactivation with this serological pattern.

Surgical Management of Complex Ankle Fractures in Patients with Diabetes: A National Retrospective Multicentre Study.

Objectives: Patients with ankle fractures associated with diabetes experience more complications following standard open reduction-internal fixation (ORIF) than those without diabetes. Augmented fixation strategies, namely extended ORIF and hindfoot nails (HFNs), may offer better results and early weightbearing in this group. The aim of this study was to define the population of patients with diabetes undergoing primary fixation for ankle fractures. Secondarily, we aimed to assess the utilisation of standard and augmented strategies and the effect of these choices on surgical outcomes, including early post-operative weightbearing and surgical complications. Methods: A national multicentre retrospective cohort study was conducted between January and June 2019 in 56 centres (10 major trauma centres and 46 trauma units) in the United Kingdom; 1360 patients with specifically defined complex ankle fractures were enrolled. The patients' demographics, fixation choices and surgical and functional outcomes were recorded. Statistical analysis was performed to compare high-risk patients with and without diabetes. Results: There were 316 patients in the diabetes cohort with a mean age of 63.9 yrs (vs. 49.3 yrs. in the non-diabetes cohort), and a greater frailty score > 4 (24% vs. 14% (non-diabetes cohort) (p < 0.03)); 7.5% had documented neuropathy. In the diabetes cohort, 79.7% underwent standard ORIF, 7.1% extended ORIF and 10.2% an HFN, compared to 87.7%, 3.0% and 10.3% in the non-diabetes cohort. Surgical wound complications after standard-ORIF were higher in the diabetes cohort (15.1% vs. 8.7%) (p < 0.02), but patients with diabetes who underwent augmented techniques showed little difference in surgical outcomes/complications compared to non-diabetes patients, even though early-weightbearing rates were greater than for standard-ORIF. Conclusions: Ankle fractures in diabetes occur in older, frailer patients, whilst lower-than-expected neuropathy rates suggest a need for improved assessment. Augmented surgical techniques may allow earlier weightbearing without increasing complications, in keeping with modern guidelines in ankle fracture management.

Kinetics and mapping of Ca-driven calmodulin conformations on skeletal and cardiac muscle ryanodine receptors.

Calmodulin transduces [Ca2+] information regulating the rhythmic Ca2+ cycling between the sarcoplasmic reticulum and cytoplasm during contraction and relaxation in cardiac and skeletal muscle. However, the structural dynamics by which calmodulin modulates the sarcoplasmic reticulum Ca2+ release channel, the ryanodine receptor, at physiologically relevant [Ca2+] is unknown. Using fluorescence lifetime FRET, we resolve different structural states of calmodulin and Ca2+-driven shifts in the conformation of calmodulin bound to ryanodine receptor. Skeletal and cardiac ryanodine receptor isoforms show different calmodulin-ryanodine receptor conformations, as well as binding and structural kinetics with 0.2-ms resolution, which reflect different functional roles of calmodulin. These FRET methods provide insight into the physiological calmodulin-ryanodine receptor structural states, revealing additional distinct structural states that complement cryo-EM models that are based on less physiological conditions. This technology will drive future studies on pathological calmodulin-ryanodine receptor interactions and dynamics with other important ryanodine receptor bound modulators.

Modification of the Antibiotic, Colistin, with Dextrin Causes Enhanced Cytotoxicity and Triggers Apoptosis in Myeloid Leukemia.

Introduction: Acute myeloid leukemia (AML) remains difficult to treat due to its heterogeneity in molecular landscape, epigenetics and cell signaling alterations. Precision medicine is a major goal in AML therapy towards developing agents that can be used to treat patients with different 'subtypes' in combination with current chemotherapies. We have previously developed dextrin-colistin conjugates to combat the rise in multi-drug resistant bacterial infections and overcome dose-limiting nephrotoxicity. Recent evidence of colistin's anticancer activity, mediated through inhibition of intracellular lysine-specific histone demethylase 1 (LSD1/KDM1A), suggests that dextrin-colistin conjugates could be used to treat cancer cells, including AML. This study aimed to evaluate whether dextrin conjugation (which reduces in vivo toxicity and prolongs plasma half-life) could enhance colistin's cytotoxic effects in myeloid leukemia cell lines and compare the intracellular uptake and localization of the free and conjugated antibiotic. Results: Our results identified a conjugate (containing 8000 g/mol dextrin with 1 mol% succinoylation) that caused significantly increased toxicity in myeloid leukemia cells, compared to free colistin. Dextrin conjugation altered the mechanism of cell death by colistin, from necrosis to caspase 3/7-dependent apoptosis. In contrast, conjugation via a reversible ester linker, instead of an amide, had no effect on the mechanism of the colistin-induced cell death. Live cell confocal microscopy of fluorescently labelled compounds showed both free and dextrin-conjugated colistins were endocytosed and co-localized in lysosomes, and increasing the degree of modification by succinoylation of dextrin significantly reduced colistin internalization. Discussion: Whilst clinical translation of dextrin-colistin conjugates for the treatment of AML is unlikely due to the potential to promote antimicrobial resistance (AMR) and the relatively high colistin concentrations required for anticancer activity, the ability to potentiate the effectiveness of an anticancer drug by polymer conjugation, while reducing side effects and improving biodistribution of the drug, is very attractive, and this approach warrants further investigation.

Testing dilemmas in the clinic: Lessons learned from biomarker-based drug development.

Various tests based on different biomarkers have been developed to identify the best candidates for poly(ADP-ribose) polymerase (PARP)-inhibitor therapy. However, due to the absence of harmonization regarding these complex biomarkers, along with various cutoff points and unknown spatial and temporal variations, it is difficult to define the clinical utility of each test and ensure uniformity in treatment decision-making. Here, we propose measures to align biomarker definitions and minimum analytical performance characteristics for diagnostics to ensure equitable and sustainable access to precision medicine.

Unveiling the Uncommon: A Rare Case of Group A Streptococcus Axillary Lymphadenitis With Ambiguous Presentation Leading to Multiple Misdiagnoses.

Axillary lymphadenitis in adults presents a diagnostic challenge due to its diverse etiology and variable clinical manifestations. We present a rare case of suppurative Group A Streptococcus (GAS) axillary lymphadenitis secondary to a puncture wound, emphasizing the critical importance of differential diagnosis and immediate intervention. A 36-year-old male initially presented with left axillary pain and discomfort following a traumatic injury to the left thumb. Despite multiple healthcare encounters and misdiagnoses including viral illness and shingles, the patient's condition deteriorated, manifesting as fever, edema, and erythema in the left axilla. This case underscores the paramount significance of considering lymphadenitis in patients with axillary symptoms, particularly following trauma or skin breaches. Early recognition and appropriate management are crucial to prevent grave complications such as abscess formation, thrombophlebitis, and bacteremia. Streptococcal axillary lymphadenitis should be included at the forefront of the differential diagnosis to expedite treatment and mitigate potential life-threatening consequences associated with delayed diagnosis.