Prior traumatic brain injury is a risk factor for in-hospital mortality in moderate to severe traumatic brain injury: a TRACK-TBI cohort study.

Objectives: An estimated 14-23% of patients with traumatic brain injury (TBI) incur multiple lifetime TBIs. The relationship between prior TBI and outcomes in patients with moderate to severe TBI (msTBI) is not well delineated. We examined the associations between prior TBI, in-hospital mortality, and outcomes up to 12 months after injury in a prospective US msTBI cohort. Methods: Data from hospitalized subjects with Glasgow Coma Scale score of 3-12 were extracted from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (enrollment period: 2014-2019). Prior TBI with amnesia or alteration of consciousness was assessed using the Ohio State University TBI Identification Method. Competing risk regressions adjusting for age, sex, psychiatric history, cranial injury and extracranial injury severity examined the associations between prior TBI and in-hospital mortality, with hospital discharged alive as the competing risk. Adjusted HRs (aHR (95% CI)) were reported. Multivariable logistic regressions assessed the associations between prior TBI, mortality, and unfavorable outcome (Glasgow Outcome Scale-Extended score 1-3 (vs. 4-8)) at 3, 6, and 12 months after injury. Results: Of 405 acute msTBI subjects, 21.5% had prior TBI, which was associated with male sex (87.4% vs. 77.0%, p=0.037) and psychiatric history (34.5% vs. 20.7%, p=0.010). In-hospital mortality was 10.1% (prior TBI: 17.2%, no prior TBI: 8.2%, p=0.025). Competing risk regressions indicated that prior TBI was associated with likelihood of in-hospital mortality (aHR=2.06 (1.01-4.22)), but not with hospital discharged alive. Prior TBI was not associated with mortality or unfavorable outcomes at 3, 6, and 12 months. Conclusions: After acute msTBI, prior TBI history is independently associated with in-hospital mortality but not with mortality or unfavorable outcomes within 12 months after injury. This selective association underscores the importance of collecting standardized prior TBI history data early after acute hospitalization to inform risk stratification. Prospective validation studies are needed. Level of evidence: IV. Trial registration number: NCT02119182.

Choosing the Appropriate HPV Testing and Treatment Algorithm: What Works for Different Contexts?

Cervical cancer can be eliminated, and the global community intends to achieve this goal in the next century. For this to successfully occur, concerted efforts to implement and scale-up available, evidence-based strategies including human papillomavirus vaccination, screening and treatment of precancerous lesions, and early detection and treatment for invasive cancers is paramount. While the World Health Organization has offered technical guidance and recommendations on implementation, several questions remain unanswered and require urgent high-quality research to inform policy and practice. We discuss the findings from the Cervical Cancer Screening and Treatment Algorithms pilot study in the context of the evidence synthesis conducted for the second edition of the World Health Organization guidelines for screening and treatment of cervical precancer lesions for cervical cancer prevention. Policymakers at the national level must consider the weight of evidence with country-level resources to make decisions on screening, triage, and treatment approaches. See related article by Sebitloane et al., p. 779.

Helpless infants are learning a foundation model.

Humans have a protracted postnatal helplessness period, typically attributed to human-specific maternal constraints causing an early birth when the brain is highly immature. By aligning neurodevelopmental events across species, however, it has been found that humans are not born with especially immature brains compared with animal species with a shorter helpless period. Consistent with this, the rapidly growing field of infant neuroimaging has found that brain connectivity and functional activation at birth share many similarities with the mature brain. Inspired by machine learning, where deep neural networks also benefit from a 'helpless period' of pre-training, we propose that human infants are learning a foundation model: a set of fundamental representations that underpin later cognition with high performance and rapid generalisation.

Re-pairing DNA: binding of a ruthenium phi complex to a double mismatch.

We report a crystal structure at atomic resolution (0.9 Å) of a ruthenium complex bound to a consecutive DNA double mismatch, which results in a TA basepair with flipped out thymine, together with the formation of an adenine bulge. The structure shows a form of metalloinsertion interaction of the Λ-[Ru(phen)2phi]2+ (phi = 9,10-phenanthrenediimine) complex at the bulge site. The metal complex interacts with the DNA via the major groove, where specific interactions between the adenines of the DNA and the phen ligands of the complex are formed. One Δ-[Ru(phen)2phi]2+ complex interacts via the minor groove, which shows sandwiching of its phi ligand between the phi ligands of the other two ruthenium complexes, and no interaction of its phen ligands with DNA. To our knowledge, this binding model represents a new form of metalloinsertion in showing major rather than minor groove insertion.

Predicting the onset of Alzheimer's disease and related dementia using Electronic Health Records: Findings from the Cache County Study on Memory in Aging (1995-2008).

Introduction: Clinical notes, biomarkers, and neuroimaging have been proven valuable in dementia prediction models. Whether commonly available structured clinical data can predict dementia is an emerging area of research. We aimed to predict Alzheimer's disease (AD) and Alzheimer's disease related dementias (ADRD) in a well-phenotyped, population-based cohort using a machine learning approach. Methods: Administrative healthcare data (k=163 diagnostic features), in addition to Census/vital record sociodemographic data (k = 6 features), were linked to the Cache County Study (CCS, 1995-2008). Results: Among successfully linked UPDB-CCS participants (n=4206), 522 (12.4%) had incident AD/ADRD as per the CCS "gold standard" assessments. Random Forest models, with a 1-year prediction window, achieved the best performance with an Area Under the Curve (AUC) of 0.67. Accuracy declined for dementia subtypes: AD/ADRD (AUC = 0.65); ADRD (AUC = 0.49). DISCUSSION: Commonly available structured clinical data (without labs, notes, or prescription information) demonstrate modest ability to predict AD/ADRD, corroborated by prior research.

Factors associated with exclusive breastfeeding by maternal HIV status: a population-based survey in Kenya.

BACKGROUND: Exclusive breastfeeding (EBF) in the first six months remains low globally, despite known benefits of lower morbidity and mortality among breastfed infants. It is important to understand factors associated with breastfeeding to support optimal breastfeeding practices, particularly in settings with a high burden of HIV. METHODS: We analyzed data from a population-level survey of mother-infant pairs attending 6-week or 9-month immunizations at 141 clinics across Kenya. Primary outcomes included maternal report of (1) EBF at 6-week visit, defined as currently feeding the infant breast milk only, (2) EBF for the first 6-months of life, defined as breastfeeding or feeding the infant breast milk only with no introduction of other liquids or solid foods until 6 months, and (3) continued breastfeeding with complementary feeding at 9-months. Correlates of breastfeeding practices were assessed using generalized Poisson regression models accounting for facility-level clustering. RESULTS: Among 1662 mothers at 6-weeks, nearly all self-reported breastfeeding of whom 93% were EBF. Among 1180 mothers at 9-months, 99% had ever breastfed, 94% were currently breastfeeding and 73% reported 6-month EBF. At 6-weeks, younger age (< 25 years) (adjusted Prevalence Ratio (aPR) 0.96; 95% CI 0.93, 0.99), lower education (aPR 0.96; 95% CI 0.93, 0.99) and recent infant illness (aPR 0.97; 95% CI 0.94, 1.00) were associated with lower EBF prevalence while women living with HIV (WLWH) had higher EBF prevalence (aPR 1.06; 95% CI 1.02, 1.10) than women without HIV. 6-month EBF prevalence was 26% higher in WLWH (aPR 1.26; 95% CI 1.15, 1.35) than women without HIV, 14% lower in women reporting mild or above depressive symptoms (aPR 0.86; 95% CI 0.76, 0.99) than those with none or minimal depressive symptoms, and 15% lower in women with versus without history of intimate partner violence (aPR 0.85; 95% CI 0.74, 0.98). At 9-months, WLWH had a lower prevalence of continued breastfeeding with complementary feeding (aPR 0.73; 95% CI 0.64, 0.84) than women without HIV. CONCLUSION: WLWH had higher EBF prevalence in the first 6-months, but lower prevalence of continued breastfeeding at 9-months. Strategies to support EBF and continued breastfeeding beyond 6-months postpartum, particularly among WLWH, are needed.

Cohort profile: longitudinal and population comparison of children who are HIV-exposed uninfected and children who are HIV unexposed in Kenya (HOPE study).

PURPOSE: Globally, the number of children/adolescents exposed to HIV but uninfected (HIV-exposed uninfected, HEU) is growing. The HEU outcomes: population-evaluation and screening strategies study was designed to provide population-level evidence of the impact of HIV and recent antiretroviral therapy regimen exposure on neurodevelopmental, hearing and mental health outcomes from infancy to adolescence. PARTICIPANTS: The study includes a prospective mother-infant cohort and cross-sectional child/youth-caregiver cohorts conducted in Kenya.Between 2021 and 2022, the study enrolled 2000 mother-infant pairs (1000 HEU and 1000 HIV-unexposed uninfected (HUU)) for longitudinal follow-up. Infants were eligible if they were aged 4-10 weeks and healthy. Mothers were eligible if their HIV status was known and were ≥18 years. Study visits are 6 monthly until the child reaches age 3 years.Cross-sectional cohorts spanning ages 3-18 years started enrolment in 2022. Target enrolment is 4400 children/youth (4000 HEU and 400 HUU). Children and youth are eligible if they are HIV negative, maternal HIV status and timing of diagnosis is known, and caregivers are ≥18 years.Data on infant/child/youth growth, neurodevelopment, mental health, morbidity and hearing are collected at enrolment using standardised tools. Dry blood spots samples are collected for telomere length assessment at baseline and yearly for the longitudinal cohort. Growth z-scores, neurodevelopmental scores, telomere length and prevalence of developmental and hearing problems will be compared between HEU/HUU populations. FINDINGS TO DATE: Full cohort enrolment for the longitudinal cohort is complete and participants are in follow-up. At 1 year of age, comparing HEU to HUU neurodevelopment using the Malawi developmental assessment tool, we found that HEU infants had higher language scores and comparable scores in fine motor, gross motor and social scores. The cross-sectional cohort has enrolled over 2000 participants and recruitment is ongoing. FUTURE PLANS: Longitudinal cohort follow-up and enrolment to the cross-sectional study will be completed in June 2024.

Acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) is a haematological malignancy characterized by the uncontrolled proliferation of immature lymphoid cells. Over past decades, significant progress has been made in understanding the biology of ALL, resulting in remarkable improvements in its diagnosis, treatment and monitoring. Since the advent of chemotherapy, ALL has been the platform to test for innovative approaches applicable to cancer in general. For example, the advent of omics medicine has led to a deeper understanding of the molecular and genetic features that underpin ALL. Innovations in genomic profiling techniques have identified specific genetic alterations and mutations that drive ALL, inspiring new therapies. Targeted agents, such as tyrosine kinase inhibitors and immunotherapies, have shown promising results in subgroups of patients while minimizing adverse effects. Furthermore, the development of chimeric antigen receptor T cell therapy represents a breakthrough in ALL treatment, resulting in remarkable responses and potential long-term remissions. Advances are not limited to treatment modalities alone. Measurable residual disease monitoring and ex vivo drug response profiling screening have provided earlier detection of disease relapse and identification of exceptional responders, enabling clinicians to adjust treatment strategies for individual patients. Decades of supportive and prophylactic care have improved the management of treatment-related complications, enhancing the quality of life for patients with ALL.

Unsuspected Positive Intraoperative Cultures in Aseptic Revision Knee Arthroplasty: Prevalence, Management, and Infection-Free Survivorship.

BACKGROUND: The purpose of this study was to evaluate the management and outcomes of aseptic revision total knee arthroplasty (arTKA) with unsuspected positive cultures (UPCs) compared to those with sterile cultures. METHODS: The institutional database at a single tertiary center was retrospectively reviewed for arTKA from January 2013 to October 2023. Patients who met Musculoskeletal Infection Society criteria for periprosthetic joint infection (PJI) based on available preoperative infectious workup, received antibiotic spacers, or did not have at least 1 year of follow-up were excluded. Patients were stratified based on intraoperative cultures into 4 cohorts: sterile cultures, 1 UPC, ≥ 2 UPCs with different organisms, and ≥ 2 UPCs with the same organism. Univariable analyses were used to compare these groups. Kaplan-Meier survivorship analysis assessed infection-free survival at 5 years, and Cox proportional hazards regressions were used to evaluate factors that influence infection-free survival. A total of 691 arTKAs at a mean follow-up of 4.2 years were included in the study. Of these, 49 (7.1%) had 1 UPC with a new organism, 10 (1.4%) had ≥2 UPCs of the same organism, and 2 (0.2%) had ≥2 UPCs with different organisms. RESULTS: Postoperative antibiotics were prescribed to 114 (16.5%) patients-13 (26.5%) with 1 UPC, 6 (60.0%) with ≥2 UPCs of the same organism, and 0 (0.0%) of patients who had ≥2 UPCs of different organisms. There were no differences in infection-free survival at 5 years between patients who had sterile cultures and 1 UPC (96 versus 89%; P = .39) nor between sterile cultures and ≥2 UPCs of different organisms (96 versus 100%; P < .72). However, patients who had ≥2 UPCs of the same organism had significantly worse infection-free survival at 5 years compared to patients who had sterile cultures (58 versus 96%; P < .001). Cox proportional hazards regression suggested that when adjusting for covariates, an American Society of Anesthesiologists classification of ≥3 (hazard ratio [HR] = 3.1; P = .007), ≥2 UPCs of the same organism (HR = 11.0; P < .001), 1 UPC (HR = 4.2; P = .018), and arTKA with hinge constructs (HR = 4.1; P = .008) were associated with increased risk of rerevision for PJI. CONCLUSIONS: Patients who had 1 UPC or ≥2 UPCs with different organisms had similar infection-free survival at 5 years as patients who had sterile cultures. However, patients who had ≥2 UPCs of the same organism had significantly worse infection-free survival at 5 years. Overall, 1 UPC or ≥2 UPCs of the same organism at the time of arTKA may suggest the patient is at higher risk of rerevision for PJI. More studies are needed to determine what interventions can be implemented to mitigate this risk.

Genetic alterations in lymphoblastic leukaemia / lymphoma - a practical guide to WHO HAEM5.

We present a practical guide for analyzing the genetic aspects of lymphoblastic leukaemia/lymphoma according to the 5th edition of the World Health Organization (WHO) classification of haematolymphoid neoplasms (WHO-HAEM5) issued in 2024. The WHO-HAEM5 acknowledges the increasing importance of genetics in the diagnosis of lymphoid neoplasia. Classification is based on the established genetic subtypes according to cell lineage, with precursor cell neoplasms followed by mature malignancies. This guide describes those genetic abnormalities in acute precursor B- and T-cell neoplasms required for risk stratification, and for treatment, providing diagnostic algorithms under the headings of 'essential' and 'desirable' diagnostic criteria.

Initial micafungin treatment does not improve outcomes compared to fluconazole treatment in immunocompromised and critically ill patients with candidaemia.

BACKGROUND: Candidaemia is associated with poor outcomes including high mortality rates. Controversy remains regarding whether fluconazole or an echinocandin is the optimal choice for initial candidaemia treatment, particularly among high-risk patients such as the immunocompromised or critically ill. OBJECTIVES: To understand optimal initial treatment of candidaemia. METHODS: We conducted a retrospective study of immunocompromised or ICU adult patients with candidaemia from 2010 to 2014. Patients who received ≥3 consecutive days of initial treatment with fluconazole or micafungin were included. The primary outcome was complete response at day 14, defined as clinical improvement and blood culture sterilization. Secondary outcomes included microbiological and clinical success, survival and recurrent candidaemia. RESULTS: A total of 197 patients were included; 76 received fluconazole and 121 received micafungin. There was no difference in complete response between the fluconazole and micafungin groups (ICU: 38% versus 40%, P = 0.87; immunocompromised: 57% versus 59%, P = 0.80). Secondary outcomes including survival were also similar. In multivariable analysis, among ICU patients, Pitt bacteraemia score < 4 (P = 0.002) and time to antifungal (P = 0.037) were associated with meeting the primary outcome; white blood cell count > 11 cells × 103/µL on day 0 (P < 0.001) and Candida isolated from a non-blood site (P = 0.025) were associated with not meeting the primary outcome. Among immunocompromised patients, white blood cells > 11 × 103/µL (P = 0.003) and Candida isolated from a non-blood site (P = 0.026) were associated with not meeting the primary outcome. CONCLUSIONS: These data suggest that among ICU or immunocompromised patients, severity of illness rather than initial antifungal choice drove clinical outcomes.

Geographic disparities in thyroid cancer staging at presentation: Insights from an Australian context.

BACKGROUND: Thyroid cancer diagnoses have increased over recent decades at a rate much higher than that of any other cancer in Australia. Rural patients are known to have reduced access to healthcare and may have different thyroid cancer presentation rates. This study examined the relationship between thyroid cancer diagnosis and patient rurality. METHODS: Data from the Australia and New Zealand Thyroid Cancer Registry from 2017 to 2022 were analyzed, stratifying patient postcodes into rurality groups using the Australian Statistical Geography Standard. The American Thyroid Association (ATA) guidelines were used to stratify risk categories and management to compare treatment adequacy between the groups. Statistical analysis assessed demographic, clinical, and management differences. RESULTS: Among 1766 patients, 70.6% were metropolitan (metro) and 29.4% were non-metropolitan (non-metro). Non-metro patients were older at diagnosis (median 56 vs. 50 years, p < 0.001), presented more frequently with T stage greater than 1 (stage 2-4, 41.9% vs. 34.8%, and p = 0.005), AJCC stage greater than 1 (stage 2-4, 18.5% vs. 14.6%, and p = 0.019), and cancers larger than 4 cm (14.3% vs. 9.9%, p = 0.005). No significant differences in treatment adequacy were observed between the groups for ATA low-risk cancers. CONCLUSIONS: Non-metropolitan patients in the registry present with more advanced thyroid cancer, possibly due to differences in healthcare access. Further research should assess long-term survival outcomes and influencing factors. Understanding the impact on patient outcomes and addressing healthcare access barriers can optimize thyroid cancer care across geographic regions in Australia.

Owners' experiences of administering meglumine antimoniate injections to dogs with leishmaniosis: An online questionnaire study.

BACKGROUND: This study examined the experiences of owners of dogs with leishmaniosis who treated their dogs with daily subcutaneous meglumine antimoniate injections. The owners' perceived ease of administering the injections, the occurrence of problems and the effects on the owners and on the dog‒owner bond were evaluated. METHODS: Dogs prescribed meglumine antimoniate as a treatment for leishmaniosis were identified using the database of the veterinary pharmacy of the Faculty of Veterinary Medicine, Utrecht University. An online questionnaire was sent to the owners of these dogs to evaluate the perceived ease of administering the injections, the occurrence of problems and the effects on the owner and the dog-owner bond. RESULTS: Responses were received from 64 dog owners. Most respondents (78%) reported that administering the injections was not difficult. Pain or the development of nodules at the injection site was reported in 50% and 40% of the dogs, respectively. Polyuria was reported in 44% of the dogs. Some owners reported that administering the injections had a negative impact on their psychological wellbeing (20%), and some would have liked more veterinary support (11%). LIMITATIONS: Some questions were answered by a limited number of people, and their responses may not be representative. CONCLUSION: Dog owners remain highly motivated to persevere with meglumine antimoniate treatment and are willing to administer the injections themselves. The availability of active support when needed during the therapy cycle may further improve their acceptance of and confidence in giving the injections.

Exploration of individual socioeconomic and health-related characteristics associated with human papillomavirus vaccination initiation and vaccination series completion among adult females: A comprehensive systematic evidence review with meta-analysis.

INTRODUCTION: Human papillomavirus (HPV) vaccination rates among females are lower than the World Health Organization target and vaccination rates specifically among adult females are even much lower. METHODS: We systematically evaluated individual socioeconomic and health-related characteristics associated with HPV vaccination initiation and vaccination series completion among adult females (PROSPERO: CRD42023445721). We performed a literature search on December 14, 2022, and supplemented the search on August 1, 2023. We pooled appropriate multivariable-adjusted results using an inverse variance random-effects model and expressed the results as odds ratios with associated 95 % confidence intervals. A point pooled significantly increased/decreased odds of 30-69 % was regarded to be strongly associated, and ≥ 70 % was very strongly associated. RESULTS: We included 63 cross-sectional studies. There were strongly increased odds of vaccination initiation among White women compared with Black or Asian women, and those with higher education, health insurance, a history of sexually transmitted infection (STI), receipt of influenza vaccination in the preceding year, not married/cohabiting, not smoking, using contraception, and having visited a healthcare provider in the preceding year. We observed very strongly increased odds of vaccination initiation among those younger and having been born in the country of study. Similarly, there were strongly increased odds of completing the vaccination series for the same variables as initiating vaccination, except for higher education, prior STI, smoking and contraception use. Additional variables associated with strongly increased odds of vaccination series completion not seen in initiation were higher annual household income, being lesbian/bisexual, and having a primary care physician. We observed very strongly increased odds of vaccination series completion similar to vaccination initiation but including for White compared with Black women, higher education, and prior cervical cancer screening. CONCLUSIONS: These individual characteristics may be the key to identifying women at increased risk of not being vaccinated against HPV and could inform targeted messaging to drive HPV vaccination.

Behavioral control through the direct, focal silencing of neuronal activity.

The ability to optically stimulate and inhibit neurons has revolutionized neuroscience research. Here, we present a direct, potent, user-friendly chemical approach for optically silencing neurons. We have rendered saxitoxin (STX), a naturally occurring paralytic agent, transiently inert through chemical protection with a previously undisclosed nitrobenzyl-derived photocleavable group. Exposing the caged toxin, STX-bpc, to a brief (5 ms) pulse of light effects rapid release of a potent STX derivative and transient, spatially precise blockade of voltage-gated sodium channels (NaVs). We demonstrate the efficacy of STX-bpc for parametrically manipulating action potentials in mammalian neurons and brain slice. Additionally, we show the effectiveness of this reagent for silencing neural activity by dissecting sensory-evoked swimming in larval zebrafish. Photo-uncaging of STX-bpc is a straightforward method for non-invasive, reversible, spatiotemporally precise neural silencing without the need for genetic access, thus removing barriers for comparative research.

Methods for investigating STAT3 regulation of lysosomal function in mammary epithelial cells.

The transcription factor STAT3 is activated by multiple cytokines and other extrinsic factors. It plays a key role in immune and inflammatory responses and, when dysregulated, in tumourigenesis. STAT3 is also an indispensable mediator of the cell death process that occurs during post-lactational regression of the mammary gland, one of the most dramatic examples of physiological cell death in adult mammals. During this involution of the gland, STAT3 powerfully enhances the lysosomal system to efficiently remove superfluous milk-producing mammary epithelial cells via a lysosomal-mediated programmed cell death pathway. The lysosome is a membrane-enclosed  cytoplasmic organelle that digests and recycles cellular waste, with an important role as a signalling centre that monitors cellular metabolism. Here, we describe key strategies for investigating the role of STAT3 in regulating lysosomal function using a mammary epithelial cell culture model system. These include protocols for lysosome enrichment and enzyme activity assays, in addition to microscopic analyses of the vesicular compartment in cell lines. Collectively, these approaches provide the tools to investigate multiple aspects of lysosome biogenesis and function, and to define both direct and indirect roles for STAT3.

Spiny Keratoderma: Clinical and Histopathological Findings in a Series of 3 Cases.

ABSTRACT: Spiny keratoderma is a rare entity presenting with minute keratotic spines on the palms and soles. Spiny keratoderma can be inherited or acquired, and the acquired form may be associated with underlying malignancy or systemic disease. Clinically, the differential diagnosis includes other digitate keratoses on acral sites, most notably arsenical keratosis, filiform verruca, and punctate porokeratosis. Biopsy findings typically include a column of parakeratosis overlying a diminished granular cell layer. In this article, we present 3 cases of acquired spiny keratoderma in patients with various systemic diseases, but no underlying malignancy.