Early Cases Research Articles

Whole genome sequencing in early onset advanced heart failure

The genetic contributions to early onset heart failure (HF) are incompletely understood. Genetic testing in advanced HF patients undergoing heart transplantation (HTx) may yield clinical benefits, but data is limited. We performed deep-coverage whole genome sequencing (WGS) in 102 Swedish HTx recipients. Gene lists were compiled through a systematic literature review. Variants were prioritized for pathogenicity and classified manually. We also compared polygenic HF risk scores to a population-based cohort. We found a pathogenic (LP/P) variant in 34 individuals (34%). Testing yield was highest in hypertrophic (63% LP/P carriers), dilated (40%) and arrhythmogenic right ventricular (33%) cardiomyopathy and lower in ischemic cardiomyopathy (10%). A family history was more common in LP/P variant carriers than in non-carriers but was present in less than half of carriers (44% vs 13%, P < 0.001), whereas age was similar. Polygenic risk scores were similar in HTx recipients and the population cohort. In conclusion, we observed a high prevalence of pathogenic cardiomyopathy gene variants in individuals with early-onset advanced HF, which could not accurately be ruled out by family history and age. In contrast, we did not observe higher polygenic risk scores in early onset advanced HF cases than in the general population.

Detecting and Quantifying Glaucomatous Visual Function Loss With Continuous Visual Stimulus Tracking: A Case-Control Study.

Continuous visual stimulus tracking could be used as an easy alternative to standard automated perimetry (SAP) for visual function screening. With continuous visual stimulus tracking, we simplified the perimetric task to following a moving dot on a screen with the eyes. Here, we determined whether tracking performance (the agreement between gaze and stimulus position) enables the detection and quantification of glaucomatous visual function loss (in terms of SAP), and whether it shows a learning effect. We evaluated the tracking performance of 36 cases with early, moderate, or severe glaucoma (median with interquartile range [IQR] age = 70 [67-74] years) and 36 controls (median = 70, IQR = 67-72 years). All participants monocularly tracked a moving stimulus (Goldmann size III) at 3 Weber contrast levels: 40, 160, and 640%, while their eye movements were recorded. Glaucoma decreased the tracking performance, with the most severe reduction in the severe glaucoma cases. A distinction between groups was possible, but depended on the contrast level: tracking performance of early glaucoma cases was significantly different from controls only at 40% contrast. Within the cases, glaucomatous visual function loss (SAP Mean Sensitivity [MS]) was best correlated with tracking performance when using 160% contrast. There was no significant learning effect. Overall, the data indicate that it is possible to detect and quantify glaucomatous visual function loss with continuous visual stimulus tracking. Continuous visual stimulus tracking is an easy, fast, and intuitive technique that has the potential for diagnostic applications in detection of new glaucoma cases and monitoring of previously diagnosed cases.

A rare variant in the UQCRC1 gene, p.(Gly405Val) in three Austrian Parkinson's patients.

Variants in the UQCRC1 gene have been proposed to cause autosomal dominant Parkinson's disease with neuropathy. However, definitive confirmation of UQCRC1 as an authentic Parkinson's gene remains elusive, as follow-up studies have not yet provided conclusive evidence. 382 Austrian Parkinson's patients, particularly selected for familial and/or early onset cases, were Exome sequenced. We found three unrelated patients with a positive family history of the disease who shared the same rare missense variant in the UQCRC1 gene: c.1214G>T; p.(Gly405Val). The variant is very rare in the control population, with an allele frequency of 2×10-6 in the gnomAD database. None of the three patients carries a rare variant in a monogenic Parkinson's disease gene. We suggest that UQCRC1 p.(Gly405Val) probably contributes to the development of the disease in these three patients. Our findings provide further evidence that UQCRC1 is a 'bona fide' Parkinson's disease gene.

Loss of tumor cell surface hepatocyte growth factor activator inhibitor-1 predicts worse prognosis in esophageal squamous cell carcinoma.

Hepatocyte growth factor activator inhibitor-1 (HAI-1) is an epithelial type-1 transmembrane protease inhibitor that regulates the pericellular activities of hepatocyte growth factor activator and type-2 transmembrane serine proteases. It is strongly expressed in the stratified squamous epithelium and functions on the cell surface. We previously reported that the cell surface immunoreactivity of HAI-1 was reduced at the invasion front of oral squamous cell carcinoma. In this study, we investigate the relationship between cell surface HAI-1 (csHAI-1) and prognosis of esophageal squamous cell carcinoma (ESCC) after surgery. The effect of HAI-1 knockdown on cultured ESCC cells was also analyzed in vitro. HAI-1 exhibited distinct cell surface immunoreactivity in normal esophageal epithelium. In contrast, alterations in HAI-1 immunoreactivity were frequent in cancer cells, which exhibited aberrant intracytoplasmic localization and decreased cell surface immunoreactivity. The preservation of csHAI-1 immunoreactivity was a sign of a well-differentiated phenotype of ESCC cells. The decreased csHAI-1 was associated with shorter overall survival (OS) and disease-free survival (DFS) in the patients. In 55 cases of early (T1) ESCC cases, decreased csHAI-1 also predicted poor OS and DFS. The loss of HAI-1 enhanced migration and invasion of ESCC cells in vitro. These results suggest that the decreased cell surface immunoreactivity of HAI-1 is associated with a less differentiated phenotype and worse prognosis in ESCC. The cell surface-localized HAI-1 may serve as a promising marker for predicting recurrence and prognosis of ESCC.

Improving clinical care of patients in Nipah outbreaks: moving beyond 'compassionate use'.

The 2024 Nipah outbreak in Kerala, India-its fifth in six years-and the recurring annual outbreaks in Bangladesh underscore the persistent threat posed by the Nipah virus (NiV) in the region. With a high mortality rate, human-to-human transmission potential, and the widespread presence of Pteropus bats, the natural reservoir, NiV remains a significant epidemic threat. Despite being a WHO priority pathogen, there has been no systematic effort to improve patient care for NiVD, leading to consistently poor outcomes. Current care relies on supportive measures and the 'compassionate use' of unapproved drugs like ribavirin and remdesivir. Drugs used 'off-label' during outbreaks can become the 'standard of care' without robust evidence of their safety or efficacy, complicating the testing of new therapies and perpetuating uncertainty about their true effectiveness. To improve NiVD care, we propose four key strategies: 1) Enhance early case detection, 2) optimize supportive care to improve outcomes and create a standard for future trials, 3) adopt a syndromic approach centered on encephalitis, and 4) explore innovative trial designs tailored to low case numbers as an alternative to 'compassionate use'. By integrating these strategies, healthcare systems in NiV-endemic regions will be better equipped to manage both current and future outbreaks.

Healthcare performance of leprosy management in peripheral health facilities of Dhanusa and Mahottari, Nepal

BackgroundThe global elimination of leprosy transmission by 2030 is a World Health Organization (WHO) target. Nepal’s leprosy elimination program depends on early case diagnosis and the performance of health workers and facilities. The knowledge and skills of paramedical staff (Leprosy Focal Person, LFP) and case documentation and management by health facilities are therefore key to the performance of health care services.MethodsThe performance of health workers and facilities was evaluated through a combined cross-sectional and retrospective study approach of 31 health facilities and their LFPs in Dhanusa and Mahottari Districts in Madhesh Province, Nepal. An average of 6 patients (paucibacillary, PB, or multibacillary, MB) per health facility registered within the 2018/2019 fiscal year were also enrolled in the study. LFP knowledge (e.g., of the three cardinal signs) and skills (e.g., nerve palpation) and facility processes (e.g., record keeping) were scored (e.g., 0, 1) and then rescaled to a proportion, where 1 is perfect. Internal benchmarking was used to guide performance management.ResultsOverall LFP knowledge and skill scores of health workers ranged from 0.16 to 0.63 (median 0.53, 95% confidence interval (CI), 0.46–0.6). Case documentation scores ranged from 0.15 to 0.87 (median 0.37, 95% CI 0.36–0.38), case management scores from 0.38 to 0.79 (median 0.54, 95% CI 0.53–0.55) and overall healthcare scores from 0.36–0.62 (median 0.48, 95% CI 0.47–0.49). Leprosy-related training was significantly related to the knowledge and skills of the health workers. All identified cases (n = 187) adhered to the complete treatment and release after treatment (RFT) scheme, out of which 84.5% were satisfied with the service they were provided. Leprosy disability and ear hand and feet (EHF) scores were not significantly reduced in treated patients during the study period, but counseling by LFPs significantly improved cases’ positive beliefs and practices regarding self-care.ConclusionOverall leprosy care median performance was low (53%) and can be improved by evidenced-based training, onsite coaching, monitoring, and supervision to facilitate leprosy transmission elimination. The results highlight many of the challenges facing leprosy elimination programs.

Rare malignant ovarian tumors: a review.

There are many histologic types of gynecologic malignancies. I reviewed three rare ovarian tumor types that have poor prognoses. Ovarian mesonephric-like adenocarcinoma (MLA) is a newly described histological type known for its aggressive behavior. It is thought to arise from mesonephric duct remnants of the female genital tract and is typically associated with endometriosis. Although MLA has some similarities to endometrioid carcinoma, they have different prognoses. Recurrence of MLA is common, even in early stage cases, and distant metastases, especially in the lungs, are often seen. MLA is characterized by positive immunohistochemical-staining for TTF-1, GATA3, PAX2, and CD10, and negative staining for estrogen and progesterone receptors. Data on treatment for MLA are scarce, and further studies are needed. Adult granulosa cell tumors, the most common type of malignant ovarian sex cord-stromal tumors, have an indolent growth pattern. Chemotherapy, hormone therapy, and radiotherapy have all shown some efficacy. However, debulking surgery remains the most important treatment because tumor disruption or remnants are risk factors for recurrence. Late recurrence is also characteristic of this tumor. Malignant transformations of mature teratoma are suspected when the patient is relatively old and the tumor is large. Squamous cell carcinoma is the most common somatic malignancy. Treatment must be tailored to the transformed histology. Chemotherapy and radiation have shown some efficacy; however, the prognosis is extremely poor in advanced cases. Because these three types of ovarian tumors are rare, research on possible treatments has been difficult, but recent significant advances in drug therapy are expected to lead to the development of effective treatments.

Enhancing ‘disease x’ responsiveness: a risk-averse distributionally robust optimization approach for resource allocation under infectious disease transmission variability

Testing stands out as a crucial element in the public health response during a pandemic, serving diverse purposes pivotal for controlling the spread of the infectious agent. It enables early case detection, facilitating prompt isolation and treatment, thereby reducing the severity of individual cases and interrupting the transmission chain within communities. Recognizing the pivotal role of testing in managing and mitigating the impact of a pandemic, this paper addresses the distribution of test kits, taking into account the spatiotemporal uncertainty in demand and the ambiguity of the demand's probability distribution over a multi-period horizon. Determining decisions about location, allocation, operational distribution, and shipment is the main goal in order to guarantee equity and fairness in the distribution of resources among different populations. A two-stage distributionally robust optimisation (DRO) model is proposed to address the ambiguity in the probability distribution of demand. An equivalent reformulation is derived for this model over L 1 -norm and joint L 1 - and L ∞ -norm ambiguity sets. Additionally, a risk-averse criterion is employed to more accurately account for some of the worst realizations of random future demand scenarios. To demonstrate the proposed DRO model's practicality, a numerical analysis of COVID-19 test kit distribution in the US is carried out.

P-1305. Identifying Animal Exposures from Clinical Documents Using Large Language Models

Abstract Background Information about animal exposure is crucial to understanding zoonotic infectious diseases; however, it is typically unavailable in structured clinical data. We evaluated the automated extraction of animal exposure mentions from clinical notes and summarized initial observations.Figure 1.Example snippets and labels assigned during annotation. While some mentions are Affirmed exposure, others be Denied or Negated. Other keywords may not be related to animals or exposure at all. Methods Clinical notes from the Department of Veterans Affairs (VA) data were extracted if associated with indicators for diseases which included CDC Nationally Notifiable Diseases (NND) as well as early cases of COVID-19 and mpox (i.e., positive labs, chart review, or diagnosis codes). These were then processed into text snippets containing animal keywords (e.g., cats, cattle, birds, etc.) and given to annotators who then assigned a category of: affirmed, denied/negated, or no exposure, including pets and farm animals. To augment the size of our training set, large language models (LLM) were also used to generate snippets for each category. A machine learning classification model was trained using a LLM and few-shot learning. After validation, this model was used to infer animal exposure mentions among infectious disease cases which were not part of annotation to examine the distribution of animals mentioned.Figure 2.Prevalence of Affirmed Animal Exposures by disease category among documents which had at least one animal keyword so that the model could perform a classification. Results The model’s accuracy on the held out test set of 115 (40%) text instances was 90% PPV and 91% sensitivity. Example snippets and annotations are shown in Figure 1. Following validation, the model was applied to 82,937 documents related to a selection of disease categories. The distribution of classified exposures among these documents was 2.7% affirmed, 0.1% denied/negated, and 97.2% no exposure. Figure 2 shows that prevalence of affirmed exposure varied by disease where non-zoonotic diseases such as COVID-19 were relatively lower. Some top animals terms in affirmed exposures are shown in Figure 3. Figure 4 is a distribution of top terms affirmed in tularemia cases.Figure 3.Top three animal terms associated with affirmed exposure according to inferences in the proposed model for each disease. A mention in text is simply an exposure and does not imply that the animal caused an infection. Since pets can be documented in notes along with other social history information, “dog” and “cat” may occur in any clinical note regardless of etiology. Conclusion Automated extraction of animal exposure is feasible with small, manually generated training sets and acceptable accuracy. Our approach summarized exposures documented among several categories of infectious disease. While this work was performed retrospectively, it has been used to enhance case-finding for the biosurveillance of zoonotic diseases.Figure 4.Percentages of animal terms associated with affirmed exposure according to inferences in the proposed model among tularemia cases. A mention in text is simply an exposure and does not imply that the animal caused an infection. Disclosures All Authors: No reported disclosures

Genetic diversity and transmission pattern of multidrug-resistant tuberculosis based on whole-genome sequencing in Wuhan, China

BackgroundInvestigating the molecular epidemiological characteristics of multidrug-resistant tuberculosis (MDR-TB) in China’s moderate-burden regions, such as Wuhan, is crucial for understanding and controlling disease transmission.Materials and methodsThis study analyzed MDR-TB isolates from pulmonary tuberculosis cases registered at Wuhan Pulmonary Hospital in 2017. Whole genome sequencing (WGS) was used to identify resistance-conferring mutations, examine their associations with specific Mycobacterium tuberculosis lineages or sublineages, and assess clustering profiles.ResultsAmong the 149 analyzed strains, the most prevalent mutations associated with resistance to 11 anti-tuberculosis drugs were identified as follows: rpoB Ser450Leu (59.73%, rifampicin), katG Ser315Thr (62.42%, isoniazid), embB Met306Val (42.86%, ethambutol), rpsL Lys43Arg (68.13%, streptomycin), pncA Trp68Arg (10.53%, pyrazinamide), gyrA Asp94Gly (22.50%, fluoroquinolones), and rrs 1401A &amp;gt; G (50.00–100.00%, second-line injectable aminoglycosides). Additional mutations were detected in fabG1 c-15C &amp;gt; T (42.86%, ethionamide) and thyX c-16C &amp;gt; T (21.43%, p-aminosalicylic acid). Notably, rare mutations absent from the WHO mutation catalog, such as ahpC c-52C &amp;gt; T and rpsL Lys43Thr, were also observed. The mutation frequency of embB Met306Ile was significantly higher in Lineage 4 (L4) strains than in Lineage 2 (L2) strains (p = 0.0150), while the rpsL Lys43Arg mutation frequency was lower in L4 compared to L2 (p = 0.0333). A total of 31 MDR MTB Mycobacterium tuberculosis isolates formed clusters, resulting in a clustering rate of 20.81% and a recent transmission rate of 11.41%. The clustering rates between L4 and L2 strains were not significantly different (χ2 = 0.0017, p &amp;gt; 0.05).ConclusionThe genetic diversity of MDR-TB in Wuhan demonstrates unique characteristics, with evidence of localized transmission. These findings highlight the urgent need to strengthen measures to detect early cases of MDR-TB and control transmission of MDR-TB in the region.

Xenotransplantation: future frontiers and challenges.

Recent advancements in genetic engineering have propelled the field of xenotransplantation from preclinical models to early compassionate use cases. As first-in-human clinical trials (FIHCTs) approach, we examine recent developments, ethical and regulatory challenges, immunological considerations, and the clinical infrastructure necessary for successful xenotransplantation trials. Expanded access transplants of pig hearts, kidneys, and livers have identified key challenges. Heart xenotransplants revealed risks of antibody-mediated rejection and zoonotic infections, while kidney xenotransplants suggest that patient selection, rather than immune rejection, may have caused failures. While there has been a report of auxiliary liver transplantation conducted abroad, profound thrombocytopenia poses an obstacle. As FIHCTs draw near, critical clinical challenges include determining the optimal donor genetic constructs and immunosuppressive regimens. Enrollment criteria and patient selection pose additional complexity, alongside ethical concerns such as lifelong zoonosis monitoring. Only a limited number of centers have the expertise needed to conduct these complex trials. Xenotransplantation holds great promise as a solution to organ shortages, but success in FIHCTs will require careful design, multidisciplinary collaboration, and strong infrastructure. Addressing immunologic, ethical, and patient selection challenges will be critical. With proper preparation, xenotransplantation could transform organ transplantation.

The learning curve for the Shouldice Repair: a pilot analysis of post-training specialized surgeons at the Shouldice Hospital

PurposeThe aim of the study was to evaluate operative time and postoperative complications of 4 post-training specialized surgeons.MethodsThis was a pilot retrospective chart review to determine the learning curve of a Shouldice primary inguinal hernia repair (Shouldice Repair) of 4 post-training specialized surgeons, at the Shouldice Hospital. The first 300 Shouldice Repairs (early learning block) were compared to their 900-1,000 repairs as the primary operating surgeon (late learning block). Data was collected from the hospital’s database. The learning curve was examined using cumulative sum analysis (CUSUM).ResultsDuring the early learning block cases, the surgeons had a mean operating time of 59.2 ± 11.2 min. The late learning block cases had significantly reduced operative time (53.4 ± 10.5 min, p = 0.001). According to the CUSUM analysis all four surgeons had a plateau after 78 to 88 operations in terms of operative time. A nonsignificant reduction in the rate of reported recurrences (n = 16 vs. n = 0) and surgical site occurrences (haematoma, seroma, infection; n = 27 vs. n = 2) was found between the early and late learning block cases.ConclusionThe operating time plateaued after 78–88 Shouldice Repairs for the 4 surgeons trained and working at the Shouldice Hospital. A nonsignificant trend towards fewer complications were noted among late learning block cases.

Unveiling hidden leprosy in underserved populations of the Amazonas state through active case-finding-the Amazon Skin Health Program (2023).

Active case-finding is an effective strategy for combating leprosy, especially in early multibacillary cases in endemic regions. This early approach includes systematic actions such as epidemiological investigations, community surveys, and awareness campaigns to identify leprosy cases. This study reports new leprosy cases diagnosed through an active case-finding initiative conducted in 12 underserved populations from Amazonas in 2023. This is a cross-sectional descriptive study focused on patients diagnosed with leprosy and other dermatological diseases during the multi-professional Amazon Skin Health Program. Data collected for all suspected cases of leprosy encompassed epidemiological information, clinical details, slit skin smear test, histopathological examination, and polymerase chain reaction (PCR) test. Among 13,023 individuals examined, 69 (0.53%) new cases of leprosy were detected: 46.38% were characterized as paucibacillary and 53.62% as multibacillary. Regarding their age and neurologic involvement, 10.1% were detected in children under 15 years, and 20.9% had grade II disability. This effort accounted for an increase of 21.8% in the year-based diagnoses of leprosy in the state of Amazonas. Active case-finding can unveil hidden cases of leprosy in endemic areas, contributing to early detection to prevent neurological impairment and limit disease transmission. Additionally, the results advocate for targeted public health interventions, including the involvement of dermatologists in the diagnostic process and enhanced training for health professionals in differentiating leprosy from other cutaneous diseases.

Incidence of First-ever Stroke, Stroke Events, and Early Case Fatality Rate in China: Results from a National Population-based Survey.

In recent years, stroke has become the leading cause of death in the Chinese population，and the burden of stroke is huge. The aim of this study is to describe the epidemiological characteristics of population-based stroke incidence and case fatality rates in China, which are nationally representative. In 2013, a nationally representative household survey was conducted at 155 survey sites in 31 provinces. All stroke cases occurring within 1 year before the start of the survey period, including first-ever and recurrent strokes, were considered event cases. According to computed tomography, magnetic resonance imaging, and autopsy results, stroke was classified as ischemic, hemorrhagic, subarachnoid hemorrhagic, or difficult-to-classify stroke. The 7- and 30-day case fatality rates after stroke onset were investigated. A total of 595,711 people were surveyed, with 2164 diagnosed stroke events and 1645 first-ever strokes. The age-standardized incidence of first-ever stroke and stroke event incidence in the Chinese population were 229.5 and 300.61 per 100,000 person-years, respectively. The world population age-standardized incidence of first-ever stroke and stroke events by the World Health Organization were 188.5 and 246.3 per 100,000 person-years, respectively. Among the 31 provinces, the top five incidence rates of first-ever stroke were recorded in Shannxi, Heilongjiang, Ningxia, Henan, and Tianjin (518.0, 400.8, 389.5, 366.6, and 344.0 per 100,000 person-years, respectively). The top five incidence rates of stroke events were documented in Heilongjiang, Shannxi, Henan, Tianjin, and Ningxia (672.7, 603.1, 580.2, 469.0, and 456.2 per 100,000 person-years, respectively). The 7- and 30-day case fatality rates were 14.3% and 17.8% for patients with first-ever stroke, respectively. Significant differences in the 30-day mortality rate of different stroke subtypes were recorded: 8.3% (95% CI, 8.2-8.5) for ischemic stroke, 44.4% (95% CI, 42.2-46.5) for cerebral hemorrhage, and 3.1% (95% CI, 3.0-3.3) for subarachnoid hemorrhage (P < 0.0001). Compared with the area of residence, the 30-day mortality rate of first-ever stroke in rural areas was 19.8% (95% CI, 19.3-20.3), which was higher than that in urban areas (14.9% [95% CI, 14.5-15.3]) (P = 0.011). In China, the incidences of first-ever stroke and stroke events are increasing, whereas the early case fatality rate is declining, which will inevitably lead to a higher stroke prevalence and a greater stroke burden. Therefore, the primary and secondary prevention strategies should be strengthened to reduce the incidence and burden of stroke.

Large-scale genetic characterization of Parkinson's disease in the African and African admixed populations.

Elucidating the genetic contributions to Parkinson's disease (PD) etiology across diverse ancestries is a critical priority for the development of targeted therapies in a global context. We conducted the largest sequencing characterization of potentially disease-causing, protein-altering and splicing mutations in 710 cases and 11,827 controls from genetically predicted African or African admixed ancestries. We explored copy number variants (CNVs) and runs of homozygosity (ROHs) in prioritized early onset and familial cases. Our study identified rare GBA1 coding variants to be the most frequent mutations among PD patients, with a frequency of 4% in our case cohort. Out of the 18 GBA1 variants identified, ten were previously classified as pathogenic or likely pathogenic, four were novel, and four were reported as of uncertain clinical significance. The most common known disease-associated GBA1 variants in the Ashkenazi Jewish and European populations, p.Asn409Ser, p.Leu483Pro, p.Thr408Met, and p.Glu365Lys, were not identified among the screened PD cases of African and African admixed ancestry. Similarly, the European and Asian LRRK2 disease-causing mutational spectrum, including LRRK2 p.Gly2019Ser and p.Gly2385Arg genetic risk factors, did not appear to play a major role in PD etiology among West African-ancestry populations. However, we found three heterozygous novel missense LRRK2 variants of uncertain significance overrepresented in cases, two of which - p.Glu268Ala and p.Arg1538Cys - had a higher prevalence in the African ancestry population reference datasets. Structural variant analyses revealed the presence of PRKN CNVs with a frequency of 0.7% in African and African admixed cases, with 66% of CNVs detected being compound heterozygous or homozygous in early-onset cases, providing further insights into the genetic underpinnings in early-onset juvenile PD in these populations. Novel genetic variation overrepresented in cases versus controls among screened genes warrants further replication and functional prioritization to unravel their pathogenic potential. Here, we created the most comprehensive genetic catalog of both known and novel coding and splicing variants potentially linked to PD etiology in an underserved population. Our study has the potential to guide the development of targeted therapies in the emerging era of precision medicine. By expanding genetics research to involve underrepresented populations, we hope that future PD treatments are not only effective but also inclusive, addressing the needs of diverse ancestral groups.

Tempo-Spatial Tungsten Metallogeny in the Xing’an–Mongolia Orogenic Belt: Insights from the Early Cretaceous Shamai Tungsten Deposit Case Study in Northeastern China

The Xing’an–Mongolia Orogenic Belt (XMOB) is located in the eastern part of the Central Asian Orogenic Belt (CAOB). The region’s notable tectonic complexity and extensive tungsten mineralization offer a unique opportunity to explore metallogeny mechanisms in orogenic areas. This study focuses on the Shamai tungsten deposit as a case study, presenting results from LA–ICP–MS U–Pb dating of fine-grained, medium-grained, and porphyritic biotite monzogranite samples from the deposit, along with in situ zircon Hf isotopic and plagioclase Pb isotopic analyses. The fine-grained, medium-grained, and porphyritic biotite monzogranite were emplaced at 142.5, 141.9, and 140.2 Ma, respectively. These samples contain zircons with εHf(t) values ranging from 3.2 to 7.9 and 4.2 to 7.6, respectively, yielding TDM2 model ages from 996 to 692 Ma and 923 to 708 Ma. These findings suggest that the magmas in the Shamai deposit were produced by partial melting of juvenile crustal material mixed with mantle-derived components. The tungsten mineralization periods in the Eastern XMOB region can be divided into three stages: Early Paleozoic (ca. 520–475 Ma), Triassic (ca. 250–200 Ma), and Jurassic to Early Cretaceous (ca. 190–130 Ma). The highest concentration of tungsten mineralization in the XMOB occurs within the Xing’an Block during the Jurassic to Early Cretaceous period. Yanshanian magmatism and the most significant tungsten metallogenic events are likely influenced by an extensional setting and oceanic slab rollback, shaped by the tectonic evolution of the Mongol-Okhotsk Ocean and the Paleo-Pacific Ocean.

The clinical presentation and genetic diagnosis of Tangier disease in the pediatric age group.

Tangier disease (TD) is a rare autosomal recessive condition characterized by high-density lipoprotein (HDL) deficiency; involving symptoms of polyneuropathy, hyperplastic orange-yellow tonsils, vision disorder, and sudden cardiac death. The major clinical symptoms of TD may not all be co-present. This study evaluates patients diagnosed with TD in childhood to improve the possibility of early diagnosis ofasymptomatic cases by reporting our patients' clinical characteristics in order to minimize delayed diagnosis and emphasize the importance of TD, easily detected by HDL measurement. This retrospective and cross-sectional study investigated seven patients from three different families diagnosed with TD. Four of seven patients were girls. Median age was 5.7 years at symptom onset and 6.5 years at diagnosis. The index case presented with neuropathy findings, and TD was diagnosed based on genetic analysis. Low lipid levels were determined in a sibling and cousins with cardiac death and gait disturbance in the family. TD was confirmed by genetic investigation. Our other patients were evaluated due to anemia, thrombocytopenia, yellow-orange hypertrophy in the tonsils, and organomegaly. Diagnosis was established with genetic analysis and low HDL. No coronary artery disease or ocular involvement was observed in any case. All patients presenting with neuropathy and gait disorders should undergo detailed tonsil examinations and HDL tests. Genetic analysis should be carried out if necessary. Family screening should be recommended to patients with consanguineous marriages after diagnosis of TD.

Innovators and transformers: envisioning a revolution in middle mile logistics with extended range cargo drones

PurposeThis paper investigates the integration of middle mile drones (MMD) into logistics operations, addressing two key questions: (1) What are the drivers, financial implications and upcoming innovations associated with integrating drones into MM logistics? and (2) What challenges need to be overcome for successful implementation of drones in MM logistics?Design/methodology/approachThe study combines expertise from an industry professional with over ten years of experience in drone operations and logistics applications, along with insights gained from discussions with 33 industry executives.FindingsThe research identifies several unique advantages of integrating drones into MM logistics, including their potential to improve operational efficiency in challenging environments. However, significant challenges related to scalability, evolving airframe designs and operational constraints remain. Early-stage use cases demonstrate the viability of MMD technologies in lower-risk logistics environments, but broader implementation requires overcoming the identified challenges.Research limitations/implicationsAs MMD logistics is a nascent field, the study is exploratory and based on early-stage use cases and expert discussions. The limited scope of practical implementations may restrict the generalizability of the findings. Future research should focus on larger-scale operations and empirical studies of MMD integration in diverse logistics contexts.Practical implicationsThe findings offer valuable insights for practitioners related to the costs, benefits and challenges of integrating drones into logistics operations and for policymakers related to societal implications, workforce development, privacy and safety concerns, and environmental impact.Originality/valueThis paper contributes to the evolving understanding of drone applications in MM logistics by presenting early use cases and identifying both challenges and opportunities for MMD technology and offers a foundation for future research and practice in this emerging domain.

Tetracyclines in Rheumatoid Arthritis: Dual Anti-Inflammatory and Immunomodulatory Roles, Effectiveness, and Safety Insights.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation, joint pain, and progressive cartilage and bone erosion. Despite advancements in RA management with disease-modifying antirheumatic drugs (DMARDs) and biologics, some patients remain refractory to conventional treatments. Tetracyclines, such as minocycline and doxycycline, exhibit anti-inflammatory and immunomodulatory properties, making them potential supplementary treatments. This narrative review explores their effectiveness, mechanisms of action, safety profiles, and current challenges in RA care. Tetracyclines have demonstrated significant immunomodulatory effects, including the inhibition of pro-inflammatory cytokines and matrix metalloproteinases (MMPs), which are critical in RA pathology. Clinical trials, including double-blind, placebo-controlled studies, have shown efficacy in reducing RA symptoms, particularly in early and refractory cases. However, their use remains limited by inconsistent evidence, small sample sizes, and concerns about antimicrobial resistance. Current guidelines for RA management do not explicitly recommend tetracyclines due to these limitations, although off-label use may be considered in specific cases. The use of tetracycline for RA is restricted by drug interactions causing bacterial resistance alongside unpredictable patient responses, hence the necessity for prudence in its prescription within a clinical setting. To overcome these limitations, the development of safer compounds, in-depth in silico analyses, and integration with personalized medicine approaches are needed. Overall, tetracyclines show promise as adjunct therapies in RA management due to their dual anti-inflammatory and immunomodulatory actions. This review highlights the need for further research to address gaps in evidence, including the development of modified tetracyclines with reduced antimicrobial effects and improved safety profiles, as well as the integration of personalized medicine approaches to optimize patient outcomes.

Doxycycline Postexposure Prophylaxis and Sexually Transmitted Infection Trends

Increasing rates of sexually transmitted infections (STIs) have been associated with rises in serious morbidity. While doxycycline postexposure prophylaxis (doxyPEP), a strategy in which individuals take doxycycline, 200 mg, after condomless sex to prevent bacterial STIs, has been shown to be efficacious in randomized clinical trials, doxyPEP's potential effect on population-level STI incidence is unknown. To assess the association of citywide doxyPEP guideline release with reported chlamydia, gonorrhea, and early syphilis cases in men who have sex with men (MSM) and in transgender women in San Francisco, California. This population-level interrupted time series analysis of reported San Francisco STI cases measured monthly cases of chlamydia, gonorrhea, and early syphilis prior to (July 2021-October 2022) and after (November 2022-November 2023) release of citywide doxyPEP guidelines in October 2022. All reported chlamydia, gonorrhea, and early syphilis cases among MSM and transgender women in San Francisco during the period of analysis were included. Data were analyzed November 2023 to July 2024. Release of doxyPEP citywide guidelines. The primary outcome was the percentage change between projected and observed chlamydia, gonorrhea, and early syphilis cases in the 13-month postexposure period. Citywide, there were 6694 cases of chlamydia, 9603 cases of gonorrhea, and 2121 cases of early syphilis among MSM and transgender women during the analytic period. STI cases among MSM and transgender women decreased significantly compared with model projections for chlamydia (-6.58% per month; 95% CI, -7.99% to -5.16%) and early syphilis (-2.68% per month; 95% CI, -3.75% to -1.60%) after doxyPEP implementation. By the end of the 13-month postperiod in November 2023, chlamydia and early syphilis cases decreased -49.64% (95% CI, -59.05% to -38.06%) and -51.39% (95% CI, -58.21% to -43.46%), respectively, compared with projected cases. There was a significant increase in monthly gonorrhea cases compared with projections (1.77% per month; 95% CI, 0.87% to 2.67%). This study suggests that San Francisco's doxyPEP guideline release was associated with decreases in reported cases of chlamydia and early syphilis, but not gonorrhea, among MSM and transgender women in San Francisco. Further analyses are needed to assess whether declines are sustained and monitor for adverse consequences, including antimicrobial resistance. Supporting doxyPEP implementation for MSM and transgender women at risk for STIs could have a significant impact on the nationwide STI epidemic.