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This study analyzed data from the National Coordinating Center for the Regional Genetics Networks (NCC) 2023 electronic survey to gather insights on current workforce trends and challenges faced by clinical laboratory geneticists in the United States. The analysis included demographics, certifications, career stages, practice patterns, staffing, reimbursement practices, and burnout levels. A total of 375 clinical laboratory geneticists responded to the survey (36.9% response rate). The workforce predominantly identifies as White and female, with limited representation from African-American/Black, Latinx/Hispanic, and Native American groups. The field includes both experienced professionals and newer entrants, with up to 25% of respondents anticipating retirement within the next decade and another 27% uncertain of retirement timeline. Technician/technologist staffing shortages were reported by over half of respondents and included other key laboratory roles such as genetic counselors and variant scientists. Concerns about reimbursement practices for new technologies and increased complexity in test interpretation were expressed by nearly 33% of respondents. Inequities in reimbursement for PhD-trained clinical laboratory directors were identified, along with increased staff strain and heightened burnout, especially among mid-career professionals. Together, these findings underscore the urgent need for dedicated strategic initiatives to enhance workforce diversity, address staffing and compensation disparities, improve resource allocation, and alleviate burnout to ensure a sustainable future for clinical laboratory geneticists.
To compare anesthetic recovery quality and seizure incidence after cervical myelography in horses with or without cervical spinal cord compression. Anesthesia and medical records from January 2017 to December 2022 of horses anesthetized for myelography were retrieved. Patients with incomplete records, equine protozoal myeloencephalitis diagnosis, or an anesthetic protocol outside an established standard were excluded. Demographic analysis, ataxia score, and anesthetic management variables were recorded in an observational retrospective fashion. Each variable was compared between groups, and multivariable regression models were constructed to evaluate the correlation of each factor with 2 outcomes: recovery quality and seizure incidence. Of 270 cases, 194 were included in the analysis, with 44 cases in the compression group and 150 in the noncompression group. An association between an increase in body weight and worse recovery quality was found (score of 25 [relative risk ratio, 1.04; 95% CI, 1.00 to 1.08]). Compression may increase the risk of a worse recovery (relative risk ratio, 8.89; 95% CI, 1.84 to 42.97). Horses with compressive lesions showed a higher, but statistically insignificant, incidence of seizures in the late recovery period. Heavier horses have a greater risk of worse anesthetic recovery after myelography, independent of age, breed, or ataxia status. Horses with cervical compression potentially present a higher seizure risk within the first 24 hours after myelography than those without compression but not in the immediate recovery. Heavier horses require more attention to the recovery phase. Horses with cervical compression may need close monitoring for seizures during the first 24 hours after myelography.
Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis, remains one of the major causes of death from infection worldwide, with over a million associated deaths each year. The study of biomarkers for TB is critical for advancing our understanding and management of the disease. Biomarkers, defined as measurable indicators of biological states or conditions, are invaluable for the diagnosis, prognosis and treatment monitoring of TB. Clinical studies have provided critical knowledge on the matter but are also notoriously constrained by economical, ethical and sampling limitations. The use of animal models provides a simpler, more controllable, cost-effective setting with great potential for translation to humans. They also allow the evaluation of biomarkers within the respiratory compartment, when available, which is of particular interest due to the nature of TB pathogenesis. This Review focuses on the current landscape of TB biomarker discovery in several animal models, from invertebrates to large mammals. Here we summarize the basics of host-pathogen immune interaction, describe the main methodological approaches used and highlight the most substantial findings for each animal model studied. Furthermore, we discuss the advantages, challenges and limitations associated with species-specific differences in animal models. We conclude that integrating the data obtained from animal models and human studies is absolutely required to advance the TB field to accelerate the management of this disease.
Understanding how protective factors and strengths operate to promote positive youth development is critical for supporting youth who have experienced childhood maltreatment. Guided by the Resilience Portfolio Model, including the poly-strengths framework, this study examined how both the configuration (i.e., strengths portfolios) and cumulative presence (i.e., number of strengths) of multi-level strengths predict adolescents' prosocial behaviors and academic achievement. Data were drawn from the second cohort of the National Survey of Child and Adolescent Well-Being and included 357 adolescents (M_age = 13.21 years; 40.34% boys). Latent class analysis was conducted to identify distinct patterns of strengths, and Ordinary Least Squares regression analysis was used to examine the cumulative effects of poly-strengths. Results indicated that adolescents in the Multi-domain resilience portfolios group consistently demonstrated the best prosocial and academic outcomes. A future-oriented group that struggled with regulation generally appeared to have higher functioning than a well-regulated group with limited meaning and connection. Although the overall number of strengths (i.e., poly-strengths) predicted greater prosocial skills, it did not significantly predict academic achievement. These findings provide empirical support for resilience models that account for both the cumulative and configurational nature of strengths in youth development following maltreatment.
Tobacco industry introduced cigarettes with synthetic cooling agents (hereafter, 'flavour ban-proof' cigarettes) with similar packaging to menthol cigarettes and targeted at people who smoke menthol in response to the California flavour ban. We chemically analysed (a) seven flavour ban-proof cigarettes purchased in California (Camel and Newport), (b) three brand-matched 'unflavoured' regular and two menthol cigarettes purchased in Ohio and Georgia and (c) four Marlboro cigarettes with labels emphasising cooling sensation purchased in Ohio. We tested filtered little cigars and loose pipe tobaccos for comparison. We used liquid-liquid extraction followed by gas chromatography-mass spectrometry analysis to quantify nicotine and cooling agents in the cigarette and cigar rod, and total particulate matter (TPM) collected on filter pads from machine smoking according to standardised puffing regime. We assessed the transfer of nicotine and cooling agents from the rod to the smoke and compared the cooling strength of tested cigarettes. We only detected Wilkinson Sword (WS-3) in flavour ban-proof cigarettes (0.88-1.77 mg/rod). The level of WS-3 per rod was approximately 10% of nicotine (9.3-15.52 mg/rod) and similar to menthol levels in the mentholated counterparts (0.59-3.78 mg/rod). The transfer of nicotine, WS-3 and menthol to the TPM ranged from 7%-14%, 14%-30% and 20%-51%, respectively. However, the calculated cooling strengths of flavour ban-proof cigarettes and menthol cigarettes were similar. Menthol was replaced with WS-3 in flavour ban-proof cigarettes, and WS-3's higher cooling power may result in a comparable cooling experience and thus has the potential to undermine local, state or federal bans on menthol cigarettes.
Low grade serous ovarian tumors present a therapeutic challenge in gynecologic oncology. This has led to increased interest in antibody-drug conjugates such as trastuzumab deruxtecan (T-DXd), which have produced promising responses but carry toxicities potentially limiting their use. A patient in her early 50s was initially diagnosed with advanced stage borderline serous ovarian tumor and subsequently developed recurrent low-grade serous ovarian tumor. She progressed on multiple lines of therapy and given HER-2 positivity (IHC 2+), was treated with T-DXd. After her first cycle, she had a remarkable radiographic response; however, she developed intractable nausea, vomiting, and diarrhea leading to hospitalization. Flexible sigmoidoscopy with biopsies supported a diagnosis of drug-induced colitis. She was treated with a methylprednisolone taper, budesonide and infliximab, resulting in resolution of symptoms. She was subsequently re-challenged with a lower dose of T-DXd for cycle 2, which she tolerated well without colitis. T-DXd-associated colitis represents a rare toxicity that has not been classified in major clinical trials or prescribing information. In this case, colitis was successfully managed with corticosteroids and infliximab, allowing for safe re-challenge at a reduced dose. This case highlights the importance of recognizing and managing rare toxicities associated with antibody-drug conjugates to optimize their safe use in ovarian cancer treatment.
We investigated inclusion complexation of levamisole (LEV+), a common adulterant of cocaine (COC+), with six molecular baskets 13--618- of increasing cavity depth and anionic charge at the portal. 1H NMR and mass spectrometry showed that 13- to 618- bind to LEV+ to form binary complexes in water, with the stability increasing across the series and highest for dendritic basket 618- (Kd = 10 µM). From 1H NMR magnetic shielding and OPLS4 calculations, we deduced that LEV+ inserts its benzene in the binding pocket of 13--618- while the protonated heterocycle remains near the anionic portal. The stability of [LEV⊂6]17- arises from C-H…π/cation…π/π-π contacts, ion pairing, and hydrophobic effect (ΔH°< 0, ITC). Dendritic basket 618- was subsequently used to develop a fluorescent displacement assay (FDA) for the detection of LEV+ with alizarin red S (ALZ-) as a fluorescence reporter. LEV+ displaced the dye to generate a fluorescence response suitable for its detection in water over circa 10-300 µM range. In contrast, COC+ bound more strongly to basket 618-, forming binary (Kd = 1 µM) and ternary complexes (1H NMR, calorimetry, and FDA). The binding mode of COC+ differs from that of LEV+, with the drug's cationic fragment occupying the basket's cavity.
Motives for and contexts of cannabis use (CU) are typically examined as independent characteristics of CU events in ecological momentary assessment (EMA) studies. However, theories posit that some combinations of motives and contexts (e.g., using to cope in a solitary setting) may contribute to heavier substance use than others (e.g., using to cope in a social setting). The current study aimed to test whether these combinations are associated with heavier substance use at the event-level. We aimed to do so among a sample of young adult females given sex differences in cannabis risk processes, which oversampled sexual minority women and gender diverse individuals due to their high rates of CU. We utilized EMA data from a study of young adult females who regularly used cannabis (n = 571; 77.6% sexual minority women and gender diverse individuals). Coping motives and solitary settings interacted such that coping motives for CU were associated with longer and higher subjective intoxication but only in solitary settings. Social and enhancement motives did not interact with social contexts; however, social and enhancement motives, as well as social contexts, were associated with longer intoxication and higher subjective intoxication. Findings indicated that coping motives were only associated with CU when combined with solitary use. Social and enhancement motives and social contexts produced additive effects. Findings indicate that studies examining the effects of coping motives or solitary cannabis use in isolation may not accurately characterize these effects.
Hepatic encephalopathy is a neurologic syndrome caused by hepatic insufficiency or portosystemic shunting, leading to the accumulation of ammonia and other neurotoxins. Clinical signs range from subtle behavioral changes to seizures and recumbency. Diagnosis relies on neurologic signs together with laboratory evidence of liver dysfunction, imaging, and sometimes biopsy. Importantly, hyperammonemia may occur without underlying hepatic dysfunction. Treatment focuses on addressing the underlying hepatic disease, reducing ammonia production and absorption, managing inflammation and cerebral edema, and providing supportive care. Prognosis varies widely and depends primarily on the underlying etiology, severity of hepatic damage, and response to therapy.
Tumor-infiltrating lymphocytes (TILs) are established determinants of clinical outcomes in breast cancer.1-6 While stromal TILs (sTILs) are commonly evaluated due to easier scoring and higher interobserver reproducibility, intraepithelial TILs may provide additional insights into anti-tumor immunity.7 We aimed to comprehensively characterize immunotype-associated cellular landscapes in triple-negative breast cancer (TNBC) and identify features associated with clinical outcomes. 212 TNBC tumors were classified into three immunotypes based on immune infiltrate location and density: immune desert (ID), immune excluded (IE), and immune inflamed (IN).8 Single-cell spatial transcriptomics was performed on 75 tumors to define the cellular composition and functional states of the tumor microenvironment across immunotypes. Findings were validated and integrated with bulk RNA sequencing data and clinical outcome datasets from FinXX, CALGB-40603, I-SPY 2, and Real-World Clinico-Genomic Data (RWCGD) cohorts. Patients with IN tumors had significantly improved outcomes compared with ID tumors. Despite high sTILs, IE tumors showed poor outcomes similar to ID tumors. Single-cell spatial analysis revealed that ID and IE tumors exhibited reduced major histocompatibility complex I/II expression and fewer tumor-resident plasmacytoid dendritic cells (pDCs) compared with IN tumors, which were enriched for interferon-alpha (IFNα) and interferon-gamma (IFNγ) responses. High IFN response scores were associated with favorable outcomes across multiple therapy types in independent datasets. Deconvolution of RWCGD bulk RNA-seq data confirmed that pDC abundance correlated with improved outcomes specifically in hormone receptor-negative subtypes. Our study highlights pDCs and IFN signaling as hallmarks of effective anti-tumor immunity in TNBC. Immunotype-based profiling underscores the limited prognostic value of sTILs alone in immune-excluded tumors and supports pDCs and IFN pathways as potential biomarkers for prognosis and therapeutic development in TNBC.
We examined whether severe maternal morbidity (SMM) at delivery was associated with the initiation and duration of breastfeeding among nulliparous individuals in the United States in a secondary analysis from the prospective nuMoM2b-HHS (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be Heart Health Study). Among 6,762 nulliparous individuals, the frequency of any breastfeeding by duration was as follows: 759 (11.2%) breastfed for less than 6 weeks; 1,847 (27.3%) breastfed for 6 weeks to 6 months; and 3,359 (49.7%) breastfed for more than 6 months, and the frequency of exclusive breastfeeding among those with any breastfeeding was 4,653 (85.4%). The frequency of any SMM was 160 (2.4%) and nontransfusion SMM was 124 (1.8%). Breastfeeding initiation did not vary by SMM status. Among those who breastfed, SMM was associated with a lower likelihood of breastfeeding for more than 6 months (adjusted odds ratio [aOR] 0.50; 95% CI, 0.36-0.68) and a lower likelihood of exclusive breastfeeding (aOR 0.60; 95% CI, 0.37-0.98). In a prospective cohort of nulliparous pregnant individuals from across the United States, SMM at delivery was not associated with breastfeeding initiation, but was associated with a significantly lower likelihood of breastfeeding duration and exclusive breastfeeding.
Head and neck squamous cell carcinoma (SCC) has many subtypes, including basaloid (BSCC) and adenosquamous carcinoma (ASC). We describe a surface-derived carcinoma with features of both BSCC and ASC, along with frequent myoepithelial differentiation. Five cases were retrieved, slides were reviewed and results tabulated. DNA- and RNA-sequencing were performed in 4 and 5 cases, respectively. Patients were 4 men and 1 woman, from 55 to 78 years (mean, 68.6). Sites of origin were 2 hypopharynx, 2 oral cavity and 1 oropharynx. All cases demonstrated basaloid morphology and duct formation. Squamous dysplasia was in the overlying epithelium in 4 of 5. The tumors showed marked pleomorphism, mitotic activity, and necrosis. By immunohistochemistry, the tumors demonstrated non-diffuse p40/p63 expression sparing ducts. SOX10 and S100 were positive to varying extents in all, while SMA/SMMS was positive in 4 of 5. MYB IHC/RNA ISH were positive in all cases. Neuroendocrine markers were negative. Sequencing demonstrated SCC-like genetics with TP53 mutations (4 of 4), 11q13 amplification (3 of 4), and structural variants of unknown significance in 2 of 5 (Case 4 GLI3::ZNF804B, Case 5 ZNF521::AC090403.1 and CYLD::FSTL1). We demonstrate SCCs with basaloid features, non-diffuse p40/p63, as well as ductal and often myoepithelial differentiation. Despite features which traditionally point to a salivary-type carcinoma, especially high-grade AdCC, they exhibited squamous dysplasia/conventional SCC, SCC-like mutational profiles, and absence of MYB/MYBL1/NFIB fusions, strongly supporting squamous derivation. We propose the term basaloid ASC mimicking AdCC (BAC MAC). Recognition of this new SCC variant is important to avoid misdiagnosis and mismanagement.
The optimal surgical margin width for intrahepatic cholangiocarcinoma (ICC) remains uncertain. We hypothesized that the oncologic benefit of a wide margin may be modulated by tumor-related factors. Patients who underwent curative-intent liver resection for solitary ICC were identified from a large international multi-institutional database. A novel metric, the margin-to-size ratio (MSR), was defined as the ratio of surgical margin width (mm) to tumor size (mm), integrating both parameters into a single variable. Multivariable Cox regression models were used to evaluate the association between MSR and recurrence-free survival (RFS). Among 1,172 patients, the median tumor size was 57.0 mm, median margin width was 4.0 mm (IQR, 1.0-10.0), and median MSR was 0.07 (IQR, 0.02-0.20). On multivariable analysis, a higher MSR was independently associated with improved RFS (HR 0.59; 95% CI, 0.36-0.96; p = 0.033), whereas neither absolute margin width nor R1 resection status was associated with RFS. Using maximally selected rank statistics, an MSR threshold of 0.142 was identified. Patients with a high MSR (≥ 0.142) had superior 3-year RFS compared with individuals with a low MSR (< 0.142) (55.7% [95% CI, 46.0-67.6] vs. 45.2% [95% CI, 38.0-53.8]; p = 0.016). MSR was independently associated with RFS following ICC resection, whereas conventional margin metrics, including absolute margin width and R1 resection status, were not associated with RFS. MSR may provide a clinically interpretable framework to contextualize margin adequacy relative to tumor size and inform individualized decision-making.
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The multimodal direct inversion (MMDI) algorithm is widely used in magnetic resonance elastography (MRE) to estimate tissue shear stiffness but relies on the Helmholtz equation, which assumes a uniform, homogeneous, and infinite medium. Its use of the Laplacian operator also makes it highly sensitive to noise. This study proposes a deep-learning-driven inversion framework for shear modulus estimation in MRE (DIME) to improve the robustness and accuracy of inversion. DIME was trained on displacement-stiffness pairs generated through finite element modeling (FEM), using small image patches to capture local wave behavior and enhance robustness to global variations. Validation was performed on homogeneous and heterogeneous FEM-simulated datasets. The method was further evaluated using an anatomy-informed simulated liver dataset with known ground truth (GT) and directly compared with MMDI. Finally, DIME was tested on in vivo liver MRE data from eight healthy and seven fibrotic subjects. In FEM simulations, DIME produced stiffness maps with low inter-pixel variability, accurate boundary delineation, and higher correlation with GT than MMDI. In anatomy-informed liver simulations, DIME reproduced stiffness patterns with high fidelity (r = 0.99, R2 = 0.98), while MMDI showed greater underestimation. In in vivo liver data, DIME preserved physiologically consistent stiffness patterns and closely matched MMDI, while MMDI demonstrated systematic over- or underestimation depending on the acquisition and filtering configuration. DIME demonstrated higher correlation with ground truth in simulations and visually similar stiffness maps in vivo, while MMDI displayed a larger bias that may be attributed to directional filtering. These results highlight the feasibility of DIME for clinical MRE applications.
Neglected tropical diseases (NTDs), particularly those with prominent cutaneous manifestations such as leishmaniasis, leprosy, and Buruli ulcer, represent a substantial global health burden, affecting hundreds of millions of people and perpetuating cycles of poverty and disability. Despite the current availability of treatment strategies, vaccines remain the most sustainable and cost-effective intervention that can reduce reliance on chemotherapeutics. However, vaccine research and development (R&D) for these diseases face considerable challenges that cannot be overcome without a strategic shift in response by national and international health programmes and organisations, research funders, and the pharmaceutical industry. This paper draws on collective insights from the VALIDATE Network workshop on "Vaccines for Skin Neglected Tropical Diseases-Progress and Challenges" (Bogotá, Colombia, 5-8 May 2025). We advocate for a multisectoral shift across three critical pillars: i) an increase in funding for NTD vaccine R&D, ii) integration of NTD vaccine R&D into the preparedness and response policies by international agencies and local governments, and iii) fostering patient and public engagement and advocacy for NTD vaccine R&D and implementation. Coordinated efforts across these three pillars will unlock the transformative potential of vaccines and substantially reduce the health, societal, and economic burdens from these diseases.
To evaluate the accuracy of 3 femoral craniocaudal radiographic techniques in assessment of femoral morphology using CT scans as the imaging modality of choice. Candidates were assessed from September 2024 through October 2025, and those with a normal orthopedic examination were enrolled. Extended limb, sitting position, and horizontal beam radiographs and CT scans were evaluated for frontal plane alignment, with the following measurements completed by 2 investigators independently: anatomic lateral distal femoral angle (aLDFA), mechanical lateral distal femoral angle, anatomic lateral proximal femoral angle, and mechanical lateral proximal femoral angle. Angles were statistically compared (P < .05) between groups, and interobserver variability was evaluated. Femoral morphology of 25 dogs (50 femora) with body weights ranging from 14 to 45 kg was assessed. Horizontal beam was most accurate for anatomic lateral proximal femoral angle, mechanical lateral proximal femoral angle, and aLDFA, whereas extended limb was most accurate for mechanical lateral distal femoral angle, with each showing no significant difference from CT. Sitting position was not the most accurate for any measurement. All measurements demonstrated high interobserver agreement (intraclass correlation coefficient > 0.8 for all parameters). Proximal and distal canine femoral morphology can be reliably measured by specific radiographic views in the absence of CT. In the absence of a CT scan, horizontal beam is recommended for accurate assessment of proximal femoral morphology in planning of total hip replacement and also demonstrated superiority when considering aLDFA measurements used for patellar luxation surgery planning.
The properties of functional brain networks are an important determinant of cognitive function in aging and dementia. Despite this, few studies have comprehensively examined demographic and biopsychosocial predictors of functional brain networks, and none have attempted to do so across the adult lifespan while accounting for collinearity among these predictors. The current study used data from 525 individuals between the ages of 35 and 100 years from the Human Connectome Project 2.0 Lifespan Release, which includes task-based functional neuroimaging, physical and emotional health, and demographic information. Two functional brain network properties previously identified as moderators of cognitive functioning across the lifespan, entropy (regional specialization) and modularity (network segregation)-were used as outcome metrics in elastic net regression models that identified and ranked predictors of these metrics as well as their age-interaction terms. Our models ranked and established generalizability of key biopsychosocial health determinants of brain network properties across the lifespan using methodology allowing for high collinearity among predictors, differing notably from correlational findings. Derived models ranked biological sex, sleep duration, instrumental support, visual acuity, education, social isolation, diastolic blood pressure, and vigorous physical activity as the strongest generalizable factors. Biological sex exhibited a significant moderation effect such that males demonstrated greater age-related differences in entropy and modularity compared to females. Given that these brain network properties have previously been linked to cognitive functioning, understanding the complex interplay between these biopsychosocial determinants is crucial for informing intervention targets with the greatest potential for maintaining or improving cognitive functioning in aging.
Therapeutic strategies that manipulate the host response to infection to reduce inflammation and host driven tissue damage may reduce disease pathogenesis. However, therapeutic approaches that have dual host-modulatory and antimicrobial therapeutic effects remain limited. Mammalian targeting MEK1/2 inhibitor compounds represent one class of small molecules that have now been recognized to have anti-viral effects through disruption of viral replication in epithelial cells and have direct anti-bacterial effects on gram-positive bacteria. MEK1/2 inhibitors elicit anti-inflammatory effects during in vivo infection and injury models that also include models of infection with gram-negative bacteria and parasites. This review aims to summarize progress made in understanding the effects of MEK1/2 inhibitor compounds on host innate immune cells and will highlight experimental models of infection or injury in which MEK1/2 inhibitors have been evaluated. The direct and indirect antimicrobial effects of MEK1/2 inhibitor compounds and the emerging recognition of different roles of MEK1 and MEK2 in programming cellular responses will be identified and discussed.