Implementation of a cardiogenic shock team in a tertiary academic center.

OBJECTIVE: Observational studies have shown that the management of patients with cardiogenic shock (CS) by dedicated multidisciplinary teams improves clinical outcomes. Nevertheless, these studies reflect a specific organizational setting with most patients being transferred from referring hospitals, hospitalized in cardiac intensive care units (ICU), or treated with mechanical circulatory support (MCS) devices. The purpose of this study was to document the organization and outcomes of a CS team offering acute care in an all-comer population. METHODS: A CS team was developed in a large academic tertiary institution. The team consisted of emergency care physicians, critical care cardiologists, interventional cardiologists, cardiac surgeons, ICU physicians, and heart failure specialists and was supported by a predefined operating protocol, a dedicated communication platform, and regular team meetings. RESULTS: Over 12 months, 70 CS patients (69 ± 13 years old, 67% males) were included. Acute myocardial infarction (AMI-CS) was the most common cause (64%); 31% of the patients presented post-resuscitated cardiac arrest and 56% needed invasive mechanical ventilation (IMV). Coronary angiography was performed in 70% and 53% had percutaneous coronary intervention. MCS was used in 10% and 6% were referred for urgent cardiac surgery. The in-hospital mortality in our center was 40% with 39% of the patients dying within 24 h from presentation. Overall, 76% of the live patients were discharged home. CONCLUSION: Across an all-comer population, AMI was the most common cause of CS. A significant number of patients presented post-cardiac arrest, and the majority required IMV. Mortality was high with a significant number dying within hours of presentation.

Topical sirolimus in dermatology: a systematic review.

CONTEXT: Topical sirolimus is increasingly utilised off-license to manage various dermatological conditions whilst avoiding typical adverse effects associated with systemic sirolimus. However, widespread use is limited by a highly heterogeneous evidence base of mixed quality. OBJECTIVE: to evaluate the current evidence base for the indications, efficacy and safety profile for topical sirolimus in dermatology. DATA SOURCES: A literature search was conducted from 2005 to July 4th, 2023, of English language studies, with the following databases consulted: MEDLINE, PubMed, Embase, CENTRAL and EBSCO. Key words included 'topical', 'rapamycin', 'sirolimus' and 'dermatology'. DATA EXTRACTION: Data on drug efficacy, concentration, side effects, co-interventions and follow up were extracted. RESULTS: The search identified 202 studies; 71 studies met the inclusion criteria. Efficacy of topical sirolimus was demonstrated in facial angiofibromas (799 patients) compared to placebo across multiple randomised controlled trials with a predominant concentration of 0.1%. Evidence was mixed for sirolimus use in port-wine stains (61 patients), with evidence of effectiveness in combined sirolimus and pulsed-dye laser. Multiple case reports demonstrated clinical improvement with topical sirolimus use in cutaneous vascular abnormalities (33 patients) at a higher concentration of 1%. Other applications of topical sirolimus were predominantly case reports demonstrating generally favourable outcomes. Topical sirolimus was generally well tolerated - most reported adverse effects were localised irritation and pruritus. Ointment-based preparations and once-daily dosing appeared to confer a better side effect profile. CONCLUSION: Most high-quality data pertain to the efficacy of topical sirolimus in treating facial angiofibromas in tuberous sclerosis. Outcomes are generally promising in other indications and good tolerability, but data quality is mixed.

Vibrio alginolyticus: A Rare Cause of Otitis Externa off the Coast of Florida.

Vibrio alginolyticus, a gram-negative marine bacterium, poses significant health risks through various infections transmitted via contaminated seawater or seafood consumption. This case report details a 42-year-old male presenting with chronic seropurulent discharge from his ear, ultimately diagnosed with otitis externa caused by V. alginolyticus. Examination findings and antibiotic sensitivity testing informed the treatment strategy, leading to a successful resolution. The increasing incidence of V. alginolyticus infections, particularly in warm coastal water, necessitated heightened clinical awareness and appropriate management. As global temperatures rise, proactive measures including patient education and accurate diagnosis become crucial in preventing disease progression and complications associated with V. alginolyticus infections.

Evolutionary déjà vu? A case of convergent evolution in an ant-plant association.

Obligatory ant-plant symbioses often appear to be single evolutionary shifts within particular ant lineages; however, convergence can be revealed once natural history observations are complemented with molecular phylogenetics. Here, we describe a remarkable example of convergent evolution in an ant-plant symbiotic system. Exclusively arboreal, Myrmelachista species can be generalized opportunists nesting in several plant species or obligately symbiotic, live-stem nesters of a narrow set of plant species. Instances of specialization within Myrmelachista are known from northern South America and throughout Middle America. In Middle America, a diverse radiation of specialists occupies understory treelets of lowland rainforests. The morphological and behavioural uniformity of specialists suggests that they form a monophyletic assemblage, diversifying after a single origin of specialization. Using ultraconserved element phylogenomics and ancestral state reconstructions, we show that shifts from opportunistic to obligately symbiotic evolved independently in South and Middle America. Furthermore, our analyses support a remarkable case of convergence within the Middle American radiation, with two independently evolved specialist clades, arising nearly simultaneously from putative opportunistic ancestors during the late Pliocene. This repeated evolution of a complex phenotype suggests similar mechanisms behind trait shifts from opportunists to specialists, generating further questions about the selective forces driving specialization.

Sentinel lymph node positivity in melanoma: Which risk prediction tool is most accurate?

BACKGROUND: Sentinel lymph node biopsy for melanoma determines treatment and prognostic factors and improves disease-specific survival. To risk-stratify patients for sentinel lymph node biopsy consideration, Memorial Sloan Kettering Cancer Center and Melanoma Institute Australia developed nomograms to predict sentinel lymph node positivity. We aimed to compare the accuracy of these 2 nomograms. METHODS: A multi-institutional study of patients with melanoma receiving sentinel lymph node biopsy between September 2018 and December 2022 was performed. The accuracy of the 2 risk prediction tools in determining a positive sentinel lymph node biopsy was analyzed using receiver operating characteristic curves and area under the curve. RESULTS: In total, 532 patients underwent sentinel lymph node biopsy for melanoma; 98 (18.4%) had positive sentinel lymph node. Increasing age was inversely related to sentinel lymph node positivity (P < .01); 35.7% of patients ≤30 years had positive sentinel lymph node compared with 9.7% of patients ≥75 years. When we analyzed the entire study population, accuracy of the 2 risk prediction tools was equal (area under the curveMemorial Sloan Kettering Cancer Center: 0.693; area under the curveMIA: 0.699). However, Memorial Sloan Kettering Cancer Center tool was a better predictor in patients aged ≥75 years (area under the curveMemorial Sloan Kettering Cancer Center: 0.801; area under the curveMelanoma Institute Australia: 0.712, P < .01) but Melanoma Institute Australia tool performed better in patients with a higher mitotic index (mitoses/mm2 ≥2; area under the curveMemorial Sloan Kettering Cancer Center: 0.659; area under the curveMelanoma Institute Australia: 0.717, P = .027). Both models were poor predictors of sentinel lymph node positivity in young patients (age ≤30 years; area under the curveMemorial Sloan Kettering Cancer Center: 0.456; area under the curveMelanoma Institute Australia: 0.589, P = .283). CONCLUSION: The current study suggests that the 2 risk stratification tools differ in their abilities to predict sentinel lymph node positivity in specific populations: Memorial Sloan Kettering Cancer Center tool is a better predictor for older patients, whereas Melanoma Institute Australia tool is more accurate in patients with a higher mitotic index. Both nomograms performed poorly in predicting sentinel lymph node positivity in young patients.

Developing a curriculum for advanced fellowship training in complex cancer for the UK.

AIM: Surgery for complex colorectal cancer is elaborate: preoperative assessment, patient selection, radiological interpretation, operative strategy, operative technical skills, operative standardization, postoperative care and management of complications are all critical components. Given this complexity, training that encompasses all these crucial aspects to generate suitably edified surgeons is essential. To date, no curriculum exists to guide training in advanced and recurrent pelvic malignancy, particularly for complex colorectal cancer. Such a curriculum would potentially offer numerous advantages, not only for individual surgeons but also for research, governance, international collaboration and benchmarking. The aim of this study was to design and develop a framework for a curriculum for fellowship training in complex colorectal cancer that encompasses pelvic exenteration surgery. METHOD: Kern described a six-step method for curriculum design that is now widely adopted in medical education. Our study utilizes steps 1-4 of Kern's method to develop a syllabus and assessment framework for curriculum development for fellowship training in complex colorectal cancer encompassing pelvic exenteration. A literature review was conducted to address step 1, followed by targeted needs assessment in step 2 by conducting focus groups with trainees, fellows and experts to identify learning needs and goals with objective setting for step 3. An expert consensus group then voted on these recommendations and developed educational strategy recommendations as step 4. For the purposes of brevity, 'pelvic exenteration' in the text is taken to also encompass extended and multivisceral resections that fall under the remit of complex [colorectal] cancer. RESULTS: Step 1 of Kern's method identified a gap in the literature on curricula in complex cancer surgery. Step 2 identified key areas regarded as learning needs by trainees, including anatomy, hands-on experience and case volume. Step 3 defined the goals and objectives of a fellowship curriculum, defined in six domains including theoretical knowledge, decision-making, technical skills, postoperative management and continuing professional development. Finally, as a prelude to stages 5 and 6, a strategy for implementation and for feedback and assessment was agreed by an expert consensus meeting that defined case volume (a minimum of 20 pelvic exenteration operations within a fellowship period) and coverage of this syllabus with derived metrics. CONCLUSIONS: Our working group has developed a curriculum framework for advanced fellowship training in complex cancer in the UK. Validation is needed through implementation, and affirmation of its utility, both nationally and internationally, must be sought.

The COMPASS complex maintains the metastatic capacity imparted by a subpopulation of cells in UPS.

Intratumoral heterogeneity is common in cancer, particularly in sarcomas like undifferentiated pleomorphic sarcoma (UPS), where individual cells demonstrate a high degree of cytogenic diversity. Previous studies showed that a small subset of cells within UPS, known as the metastatic clone (MC), as responsible for metastasis. Using a CRISPR-based genomic screen in-vivo, we identified the COMPASS complex member Setd1a as a key regulator maintaining the metastatic phenotype of the MC in murine UPS. Depletion of Setd1a inhibited metastasis development in the MC. Transcriptome and chromatin sequencing revealed COMPASS complex target genes in UPS, such as Cxcl10, downregulated in the MC. Deleting Cxcl10 in non-MC cells increased their metastatic potential. Treating mice with human UPS xenografts with a COMPASS complex inhibitor suppressed metastasis without affecting tumor growth in the primary tumor. Our data identified an epigenetic program in a subpopulation of sarcoma cells that maintains metastatic potential.

Patient satisfaction with women vs men surgical interns and senior residents.

BACKGROUND: Patient satisfaction is critical for referrals and reimbursement of surgical faculty but remains poorly characterized for residents. We investigated whether patient evaluations of surgical trainees vary by resident gender. METHODS: Surgical inpatients evaluated surgical resident care postoperatively after positively identifying trainees. Evaluations (Consumer Assessment of Healthcare Providers and Systems Surgical Care Surveys (S-CAHPS)) were scored by the "top-box" method, stratified by training level, and compared between women and men residents. RESULTS: Ninety-one percent of patients participated (n â€‹= â€‹324/357). Patients recognized women interns less than men (75.0 â€‹% vs 87.2 â€‹%, p â€‹= â€‹0.01). S-CAHPS scores for women vs men interns were equivalent except for spending sufficient time with patients (75.6 â€‹% vs 88.0 â€‹%, p â€‹= â€‹0.02). For senior residents, there was no difference in patient recognition of women vs men (83.9 â€‹% vs 85.2 â€‹%, p â€‹= â€‹0.91) or in any S-CAHPS scores (p â€‹> â€‹0.05). CONCLUSIONS: Gendered differences in patient evaluations of surgical trainees exist for interns but resolve by senior years. Future work should explore how patient evaluations can support trainee development while ensuring patients recognize the role of surgical residents regardless of gender.

Multispecies pasture diet and cow breed impacts on milk composition and quality in a seasonal spring-calving dairy production system.

In recent years, there has been significant emphasis on the composition of pasture-based cow feed and the potential benefits of incorporating multispecies swards to improve sustainability and biodiversity. This study compared the effects of a conventional perennial ryegrass (PRG) monoculture supported by high chemical nitrogen (N) usage with a low chemical N application multispecies sward system (MSS) on the composition and quality of milk across lactation using spring-calving Holstein-Friesian (HF) and Jersey Holstein-Friesian (JFX) cows. Bulk milk samples (n = 144) were collected from each group at morning and evening milking on a weekly basis (n = 36) throughout lactation and analyzed for gross composition and physico-chemical properties. Cow breed had a significant impact on milk profile, with milk from HF cows having significantly smaller milk fat globule (MFG) size, higher instability index values, higher yield, and lower total solids levels, compared with JFX cows. Notably, HF cows had increased milk total solids and fat levels when fed on MSS, as opposed to the PRG-fed HF cows. Feeding MSS pasture increased creaming velocity values in mid and late lactation, and resulted in similar milk gross composition to PRG. In comparison to PRG, MSS-fed groups showed significantly increased total solids yield, including higher levels of protein and fat yield. In late lactation, MSS feeding was associated with reduced MFG size. All physicochemical properties studied (MFG size, creaming velocity, instability index) showed decreasing values from early to late lactation stage. Overall, these findings demonstrate the significant effects of cow diet, breed and stage of lactation on compositional and physico-chemical characteristics of milk, with important implications for milk processing and dairy product quality.

Meeting report: Considerations for trial design and endpoints in licensing therapeutic HPV16/18 vaccines to prevent cervical cancer.

Cervical cancer is a major cause of morbidity and mortality globally with a disproportionate impact on women in low- and middle-income countries. In 2021, the World Health Organization (WHO) called for increased vaccination, screening, and treatment to eliminate cervical cancer. However, even with widespread rollout of human papillomavirus (HPV) prophylactic vaccines, millions of women who previously acquired HPV infections will remain at risk for progression to cancer for decades to come. The development and licensing of an affordable, accessible therapeutic HPV vaccine, designed to clear or control carcinogenic HPV and/or to induce regression precancer could significantly contribute to the elimination efforts, particularly benefiting those who missed out on the prophylactic vaccine. One barrier to development of such vaccines is clarity around the regulatory pathway for licensure. In Washington, D.C. on September 12-13, 2023, a meeting was convened to provide input and guidance on trial design with associated ethical and regulatory considerations. This report summarizes the discussion and conclusions from the meeting. Expert presentation topics included the current state of research, potential regulatory challenges, WHO preferred product characteristics, modeling results of impact of vaccine implementation, epidemiology and natural history of HPV infection, immune responses related to viral clearance and/or precancer regression including potential biomarkers, and ethical considerations. Panel discussions were held to explore specific trial design recommendations to support the licensure process for two vaccine indications: (1) treatment of prevalent HPV infection or (2) treatment of cervical precancers. Discussion covered inclusion/exclusion criteria, study endpoints, sample size and power, safety, study length, and additional data needed, which are reported here. Further research of HPV natural history is needed to address identified gaps in regulatory guidance, especially for therapeutic vaccines intended to treat existing HPV infections.

Primary Closure of External Fixator Pin Sites Is Safe After Orthopaedic Trauma Surgery.

OBJECTIVES: To determine if rates of pin site infection and surgical site infection among patients managed with primary closure after external fixator removal were similar to those allowed to heal secondarily. DESIGN: Retrospective cohort. SETTING: Urban/Suburban Academic Level I Trauma Center. PATIENT SELECTION CRITERIA: Patients who had received a lower extremity external fixator for provisional management before definitive fixation of lower extremity fractures were included with pin site wounds closed primarily or allowed to heal by secondary intention. OUTCOME MEASURES AND COMPARISONS: The rate of pin tract infection and surgical site infection following primary closure of external fixator pin sites relative to patients whose pin sites were allowed to heal through secondary intention. RESULTS: In total, 256 patients were evaluated: 143 patients (406 pin sites) in the primary closure group and 113 patients (340 in sites) in the secondary closure group. The average age was 49 ± 16 years. Sixty-five percent of included patients were male. There was no difference in pin tract infections between cohorts (primary = 0.5%, secondary = 1.5%, P = 0.26). External fixator duration in the primary closure group was 11.5 ± 8.4 days and 13.0 ± 8.1 days in the secondary closure group (P = 0.15). There was a greater rate of surgical site infections in the secondary intention cohort (15.9% vs. 7.7%, P = 0.047). CONCLUSIONS: There was no difference in pin site infection rate after primary pin site closure relative to patients who were allowed to heal through secondary intention. Furthermore, there was a lower rate of surgical site infection after primary closure. These results challenge the dogma of secondary closure for ex fix pin sites, suggesting that debridement and primary closure is a safe option for management of external fixator pin sites and may impart benefit in decreasing infection risk. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumours of the lung and prostate: a phase 1/2, first-in-human trial.

BACKGROUND: Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [89Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer. METHODS: We conducted an open-label, first-in-human study of immunoPET-CT imaging with [89Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [89Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [89Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [89Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741. FINDINGS: Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [89Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [89Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort. INTERPRETATION: DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies. FUNDING: National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.

Deuterium Metabolic Imaging of Alzheimer Disease at 3-T Magnetic Field Strength: A Pilot Case-Control Study.

Background Impaired glucose metabolism is characteristic of several types of dementia, preceding cognitive symptoms and structural brain changes. Reduced glucose uptake in specific brain regions, detected using fluorine 18 (18F) fluorodeoxyglucose (FDG) PET, is a valuable diagnostic marker in Alzheimer disease (AD). However, the use of 18F-FDG PET in clinical practice may be limited by equipment availability and high cost. Purpose To test the feasibility of using MRI-based deuterium (2H) metabolic imaging (DMI) at a clinical magnetic field strength (3 T) to detect and localize changes in the concentration of glucose and its metabolites in the brains of patients with a clinical diagnosis of AD. Materials and Methods Participants were recruited for this prospective case-control pilot study between March 2021 and February 2023. DMI was performed at 3 T using a custom birdcage head coil following oral administration of deuterium-labeled glucose (0.75 g/kg). Unlocalized whole-brain MR spectroscopy (MRS) and three-dimensional MR spectroscopic imaging (MRSI) (voxel size, 3.2 cm cubic) were performed. Ratios of 2H-glucose, 2H-glutamate and 2H-glutamine (2H-Glx), and 2H-lactate spectroscopic peak signals to 2H-water peak signal were calculated for the whole-brain MR spectra and for individual MRSI voxels. Results A total of 19 participants, including 10 participants with AD (mean age, 68 years ± 5 [SD]; eight males) and nine cognitively healthy control participants (mean age, 70 years ± 6; six males) were evaluated. Whole-brain spectra demonstrated a reduced ratio of 2H-Glx to 2H-glucose peak signals in participants with AD compared with control participants (0.41 ± 0.09 vs 0.58 ± 0.20, respectively; P = .04), suggesting an impairment of oxidative glucose metabolism in AD. However, there was no evidence of localization of these changes to the expected regions of metabolic impairment at MRSI, presumably due to insufficient spatial resolution. Conclusion DMI at 3 T demonstrated impairment of oxidative glucose metabolism in the brains of patients with AD but no evidence of regional signal differences. © RSNA, 2024 Supplemental material is available for this article.

Adenosine A2A receptor as a potential regulator of Mycobacterium leprae survival mechanisms: new insights into leprosy neural damage.

Background: Leprosy is a chronic infectious disease caused by Mycobacterium leprae, which can lead to a disabling neurodegenerative condition. M. leprae preferentially infects skin macrophages and Schwann cells-glial cells of the peripheral nervous system. The infection modifies the host cell lipid metabolism, subverting it in favor of the formation of cholesterol-rich lipid droplets (LD) that are essential for bacterial survival. Although researchers have made progress in understanding leprosy pathogenesis, many aspects of the molecular and cellular mechanisms of host-pathogen interaction still require clarification. The purinergic system utilizes extracellular ATP and adenosine as critical signaling molecules and plays several roles in pathophysiological processes. Furthermore, nucleoside surface receptors such as the adenosine receptor A2AR involved in neuroimmune response, lipid metabolism, and neuron-glia interaction are targets for the treatment of different diseases. Despite the importance of this system, nothing has been described about its role in leprosy, particularly adenosinergic signaling (AdoS) during M. leprae-Schwann cell interaction. Methods: M. leprae was purified from the hind footpad of athymic nu/nu mice. ST88-14 human cells were infected with M. leprae in the presence or absence of specific agonists or antagonists of AdoS. Enzymatic activity assays, fluorescence microscopy, Western blotting, and RT-qPCR analysis were performed. M. leprae viability was investigated by RT-qPCR, and cytokines were evaluated by enzyme-linked immunosorbent assay. Results: We demonstrated that M. leprae-infected Schwann cells upregulated CD73 and ADA and downregulated A2AR expression and the phosphorylation of the transcription factor CREB (p-CREB). On the other hand, activation of A2AR with its selective agonist, CGS21680, resulted in: 1) reduced lipid droplets accumulation and pro-lipogenic gene expression; 2) reduced production of IL-6 and IL-8; 3) reduced intracellular M. leprae viability; 4) increased levels of p-CREB. Conclusion: These findings suggest the involvement of the AdoS in leprosy neuropathogenesis and support the idea that M. leprae, by downmodulating the expression and activity of A2AR in Schwann cells, decreases A2AR downstream signaling, contributing to the maintenance of LD accumulation and intracellular viability of the bacillus.

Human fascioliasis emergence in southern Asia: Complete nuclear rDNA spacer and mtDNA gene sequences prove Indian patient infection related to fluke hybridization in northeastern India and Bangladesh.

Fascioliasis is a snail-borne zoonotic disease with impact on the development of human subjects and communities. It is caused by two liver-infecting fasciolid trematode species, the globally-distributed Fasciola hepatica and the Africa/Asia-restricted but more pathogenic, larger F. gigantica. Fasciola gigantica is the cause of endemicity in livestock throughout the warm lowlands from Pakistan to southeastern Asia since old times. Human fascioliasis is emerging in this region at present, with an increase of patient reports. Complete sequences of rDNA ITS-1 and ITS-2 spacers and mtDNA nad1 and cox1 genes were obtained from fasciolid eggs found in the endoscopic bile aspirate from a patient of Arunachal Pradesh, northeastern India. Egg measurements, pronounced ITS heterozygosity, and pure F. gigantica mtDNA haplotypes demonstrate an infection by a recent F. gigantica-like hybrid. Sequence identities and similarities with the same DNA markers found in livestock from Bangladesh prove the human-infecting fasciolid to present identical ITSs and nad1 haplotypes and only one silent transversion in cox1 when compared to a widely-spread combined haplotype in animals. In northeastern India and Bangladesh, human fascioliasis emergence appears linked to increasing livestock prevalences due to: ruminant importation from other countries because of the increasing demand of rapidly growing human populations; numerous livestock movements, including transborder corridors, due to the uncontrolled small-scale household farming practices; and man-made introduction of F. hepatica with imported livestock into an area originally endemic for F. gigantica leading to frequent hybridization. Sequences, phylogenetic trees, and networks indicate that the origins of intermediate/hybrid fasciolids and factors underlying human infection risk differ in eastern and western South Asia. The emergence scenario in southern China and Vietnam resembles the aforementioned of northeastern India and Bangladesh, whereas in Pakistan it is linked to increasing monsoon rainfall within climate change combined with an impact of an extensive irrigation system. Past human-guided movements of pack animals along the western Grand Trunk Road and the eastern Tea-Horse Road explain the F. gigantica mtDNA results obtained. Physicians should be aware about these emerging scenarios, clinical pictures, diagnostic techniques and treatment. Government authorities must appropriately warn health professionals, ensure drug availability and improve livestock control.

Osteoporotic Fractures: Diagnosis, Evaluation, and Significance From the International Working Group on DXA Best Practices.

Osteoporotic fractures, also known as fragility fractures, are reflective of compromised bone strength and are associated with significant morbidity and mortality. Such fractures may be clinically silent, and others may present clinically with pain and deformity at the time of the injury. Unfortunately, and even at the time of detection, most individuals sustaining fragility fractures are not identified as having underlying metabolic bone disease and are not evaluated or treated to reduce the incidence of future fractures. A multidisciplinary international working group with representation from international societies dedicated to advancing the care of patients with metabolic bone disease has developed best practice recommendations for the diagnosis and evaluation of individuals with fragility fractures. A comprehensive narrative review was conducted to identify key articles on fragility fractures and their impact on the incidence of further fractures, morbidity, and mortality. This document represents consensus among the supporting societies and harmonizes best practice recommendations consistent with advances in research. A fragility fracture in an adult is an important predictor of future fractures and requires further evaluation and treatment of the underlying osteoporosis. It is important to recognize that most fragility fractures occur in patients with bone mineral density T scores higher than -2.5, and these fractures confirm the presence of skeletal fragility even in the presence of a well-maintained bone mineral density. Fragility fractures require further evaluation with exclusion of contributing factors for osteoporosis and assessment of clinical risk factors for fracture followed by appropriate pharmacological intervention designed to reduce the risk of future fracture. Because most low-trauma vertebral fractures do not present with pain, dedicated vertebral imaging and review of past imaging is useful in identifying fractures in patients at high risk for vertebral fractures. Given the importance of fractures in confirming skeletal fragility and predicting future events, it is recommended that an established classification system be used for fracture identification and reporting.

Longitudinal Increases in Time to Surgery for Patients with Breast Cancer: A National Cohort Study.

BACKGROUND: Longer time to surgery (TTS) is associated with worse survival in patients with breast cancer. Whether this association has encouraged more prompt care delivery remains unknown. METHODS: The National Cancer Database was used to identify patients ≥18 years of age diagnosed with clinical stage 0-III breast cancer between 2006 and 2019 for whom surgery was the first mode of treatment. A linear-by-linear test for trend assessed median TTS across the interval. Adjusted linear regression modeling was used to examine TTS trends across patient subgroups. RESULTS: Overall, 1,435,584 patients met the inclusion criteria. The median age was 63 years (interquartile range [IQR] 53-72), 84.3% of patients were White, 91.1% were non-Hispanic, and 99.2% were female. The median TTS in 2006 was 26 days (IQR 16-39) versus 39 days in 2019 (IQR 27-56) [p < 0.001]. In a multivariable linear regression model, TTS increased significantly, with an annual increase of 0.83 days (95% confidence interval 0.82-0.85; p < 0.001). A consistent, significant increase in TTS was observed on subgroup analyses by surgery type, reconstruction, patient race, hospital type, and disease stage. Black race, Hispanic ethnicity, and having either Medicaid or being uninsured were significantly associated with prolonged TTS, as were mastectomy and reconstructive surgery. CONCLUSIONS: Despite evidence that longer TTS is associated with poorer outcomes in patients with breast cancer, TTS has steadily increased, which may be particularly detrimental to marginalized patients. Further studies are needed to ensure the delivery of timely care to all patients.

Unraveling iron oxides as abiotic catalysts of organic phosphorus recycling in soil and sediment matrices.

In biogeochemical phosphorus cycling, iron oxide minerals are acknowledged as strong adsorbents of inorganic and organic phosphorus. Dephosphorylation of organic phosphorus is attributed only to biological processes, but iron oxides could also catalyze this reaction. Evidence of this abiotic catalysis has relied on monitoring products in solution, thereby ignoring iron oxides as both catalysts and adsorbents. Here we apply high-resolution mass spectrometry and X-ray absorption spectroscopy to characterize dissolved and particulate phosphorus species, respectively. In soil and sediment samples reacted with ribonucleotides, we uncover the abiotic production of particulate inorganic phosphate associated specifically with iron oxides. Reactions of various organic phosphorus compounds with the different minerals identified in the environmental samples reveal up to ten-fold greater catalytic reactivities with iron oxides than with silicate and aluminosilicate minerals. Importantly, accounting for inorganic phosphate both in solution and mineral-bound, the dephosphorylarion rates of iron oxides were within reported enzymatic rates in soils. Our findings thus imply a missing abiotic axiom for organic phosphorus mineralization in phosphorus cycling.