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Competing Interests: Competing interests The authors have no competing interests.

No study has investigated the length of time it takes to diagnose multiple sclerosis (MS) or neuromyelitis optic spectrum disorder (NMOSD, aquaporin 4 antibody disease or myelin oligodendrocyte glycoprotein antibody disease, MOGAD) following the onset of de novo optic neuritis (ON). Minimizing the time between ON and downstream diagnoses needs urgency since early diagnosis equals early treatment. The time elapsed from ON to a subsequent diagnosis of MS/NMOSD was estimated through analysis of retrospective data collected from the Axon Registry (AR) of the American Academy of Neurology (AAN) and from the University of Kentucky (UK), Lexington. The time to diagnose MS/NMOSD was arbitrarily set as occurring < 6 months (early) or > 6 months (delayed) following ON. Data was collected between 2007 and 2021 (AR) and 2012 to 2022, for UK, respectively. Of the 4015 ON patients from the AR dataset, 1069 (26.6 %) were diagnosed with MS, with 857 (80.2 %) diagnosed < 6 months (early) and 212 (19.8 %) diagnosed after > 6 months (delayed). Secondly, 420/4015 (10.4 %) were diagnosed with NMOSD (either MOGAD or AQP4 antibody disease), of which 340/420 (80.9 %) were diagnosed < 6 months (early) and 80/420 (19 %) diagnosed > 6 months (delayed). In the UK dataset, a total of 90/1464 individuals (6.14 %) were diagnosed with MS; of these, 69 patients (76.7 %) were diagnosed at < 6 months (early) and included a sub-group of 25 (27.8 %) diagnosed < 4 weeks; 21 (23.3 %) were diagnosed > 6 months (delayed) following ON. In either dataset (AR or UK, between 20 % - 23 % of MS diagnoses occurred > 6 months (delayed) after a diagnosis of ON. An accelerated diagnosis (4 weeks or less) of MS/NMOSD following ON in the UK data suggests that it is possible to minimize the time to a downstream diagnosis if a 'test bundle' of MRI of orbits, brain, C-spine, cerebrospinal fluid (CSF) analysis, and serum testing for NMOSD is used. Additional studies using prospective, larger datasets are required to confirm our findings., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: American College of Surgeons Commission on Cancer (CoC) quality measures are used to monitor and evaluate metrics among their CoC-accredited programs, which include seven of Delaware's hospitals. The Delaware Department of Health and Social Services, Division of Public Health (DPH) also utilizes these metrics to monitor and evaluate Delaware's overall performance on these standards of care as it relates to the health care provided to cancer patients., Methods: Delaware Cancer Registry (DCR) cases diagnosed in 2018 and 2019 were selected and were analyzed separately to calculate results for each selected measure by year: HT, nBX, LNoSurg, and RECRTCT., Results: Results of the analysis showed that three out of the four CoC quality measures evaluated met the CoC standard of care for both 2018 and 2019 data. The three measures that met the CoC standards for 2018 were HT (90.4%), nBX (87.6%), and LNoSurg (93.3%). The RECRTCT measure did not meet the CoC standard for 2018 data with 71.4%. All four measures evaluated met the CoC standards for 2019 (HT - 91.6%; nBX - 85.2%; LNoSurg - 92.7%; RECRTCT - 92.3%)., Discussion: A majority of cases assessed met the CoC quality measure standards, meeting standards of cancer care and treatment. More discovery work needs to be done to assess the RECRTCT metric to explore reasons why cases did not meet the CoC quality measure standards. There was notable improvement seen for the HT measure over time, where cases had not met the CoC standard in previous years., Public Health Implications: When CoC quality measures are met, medical providers can ensure patients receive effective and targeted cancer care. This practice ultimately saves resources, reduces cancer burden, impacts survival, and improves public health outcomes., (2024 The journal and its content is copyrighted by the Delaware Academy of Medicine / Delaware Public Health Association (Academy/DPHA).)

Introduction: Surgery (oesophagectomy), with neoadjuvant chemo(radio)therapy, is the main curative treatment for patients with oesophageal cancer. Several surgical approaches can be used to remove an oesophageal tumour. The Ivor Lewis (two-phase procedure) is usually used in the UK. This can be performed as an open oesophagectomy (OO), a laparoscopically assisted oesophagectomy (LAO) or a totally minimally invasive oesophagectomy (TMIO). All three are performed in the National Health Service, with LAO and OO the most common. However, there is limited evidence about which surgical approach is best for patients in terms of survival and postoperative health-related quality of life., Methods and Analysis: We will undertake a UK multicentre randomised controlled trial to compare LAO with OO in adult patients with oesophageal cancer. The primary outcome is patient-reported physical function at 3 and 6 weeks postoperatively and 3 months after randomisation. Secondary outcomes include: postoperative complications, survival, disease recurrence, other measures of quality of life, spirometry, success of patient blinding and quality assurance measures. A cost-effectiveness analysis will be performed comparing LAO with OO. We will embed a randomised substudy to evaluate the safety and evolution of the TMIO procedure and a qualitative recruitment intervention to optimise patient recruitment. We will analyse the primary outcome using a multi-level regression model. Patients will be monitored for up to 3 years after their surgery., Ethics and Dissemination: This study received ethical approval from the South-West Franchay Research Ethics Committee. We will submit the results for publication in a peer-reviewed journal., Trial Registration Number: ISRCTN10386621., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: An important parameter for survival in patients with esophageal carcinoma is lymph node status. The distribution of lymph node metastases depends on tumor characteristics such as tumor location, histology, invasion depth, and on neoadjuvant treatment. The exact distribution is unknown. Neoadjuvant treatment and surgical strategy depends on the distribution pattern of nodal metastases but consensus on the extent of lymphadenectomy has not been reached. The aim of this study is to determine the distribution of lymph node metastases in patients with resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed. This can be the foundation for a uniform worldwide staging system and establishment of the optimal surgical strategy for esophageal cancer patients., Methods: The TIGER study is an international observational cohort study with 50 participating centers. Patients with a resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed in participating centers will be included. All lymph node stations will be excised and separately individually analyzed by pathological examination. The aim is to include 5000 patients. The primary endpoint is the distribution of lymph node metastases in esophageal and esophago-gastric junction carcinoma specimens following transthoracic esophagectomy with at least 2-field lymphadenectomy in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and (disease free) survival., Discussion: The TIGER study will provide a roadmap of the location of lymph node metastases in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and survival. Patient-tailored treatment can be developed based on these results, such as the optimal radiation field and extent of lymphadenectomy based on the primary tumor characteristics., Trial Registration: NCT03222895 , date of registration: July 19th, 2017.

Wildfires are a natural part of most forest ecosystems, but due to changing climatic and environmental conditions, they have become larger, more severe, and potentially more damaging. Forested watersheds vulnerable to wildfire serve as drinking water supplies for many urban and rural communities. The highly variable nature of wildfire behavior combined with spatially complex patterns in vegetation, landscape, and hydrologic factors create uncertainty surrounding the postfire effects on water supplies. Wildfires often cause dramatic changes in forest vegetation structure and soil conditions, and alter the watershed processes that control streamflow, soil erosion, nutrient export, and downstream water chemistry. The authors' work centers on field and laboratory studies to advance knowledge of postfire changes in soil and water chemical composition that influence drinking water treatment. High intensity postfire rainstorms typically increase runoff that erodes ash and soil from burned landscapes and dramatically elevates turbidity, nutrient, and dissolved organic carbon (DOC) levels in surface waters, which can cause short-term challenges for water providers. There is also growing evidence that water quality impacts can persist after high severity fires due to slow vegetative recovery, and nitrogen and DOC have remained elevated for 15 years following high severity fire. Low-moderate temperatures during wildfire may also influence water quality. Research by the authors showed that the solubility of organic matter, and C and N released from soils increased following soil heating at temperatures ≤ 350 °C. Further, the water extracted organic matter from soils heated at 225-350 °C included higher proportions of condensed aromatic structures, such as black carbon and black nitrogen. Short-term postfire water quality degradation following high intensity rainstorms can force water treatment plants to shut down or can significantly challenge treatment process performance. Extreme turbidity and high DOC in poststorm water, coupled with compositional organic matter changes, reduced the coagulation efficiency of postfire water supplies. Field and lab-based studies documented the formation of small, aromatic soluble compounds during wildfire that contribute to inefficient DOC removal from postfire stormwater. Due to increased postfire DOC concentrations, and poor treatability of poststorm runoff, toxic disinfection byproduct (DBP) formation increased during water treatment. Exceedance of drinking water standards for the carbonaceous DBPs, trihalomethanes and haloacetic acids, may present a critical management concern for water providers following wildfires. Further, postfire formation of nitrogen compounds and increased nitrogenous DBP precursors for haloacetonitriles and chloropicrin were discovered. N-DBPs pose a public health concern due to their toxicity, and water providers should be aware of potential increases in N-DBP formation following fire. Evidence from the authors' studies demonstrates that even partially burned watersheds and wildfires burning at moderate temperature can have significant, lasting effects on C and N exports, source water quality, drinking water treatability, and DBP formation. Both short- and long-term postfire water quality impacts can create challenges for drinking water providers as they confront variability in supply and treatability. Communities, forest managers, and potable water providers will need to adapt to more frequent, destructive wildfires and anticipate greater variability in water quality.

Objective: Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited., Design: To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations. We also interrogated recently described RNA interference screen data for these tumour cell lines to identify candidate genetic dependencies or vulnerabilities that could be exploited as therapeutic targets., Results: By integrating the genomic features of oesophageal tumour cell lines with siRNA and drug screening data, we identified a series of candidate targets in oesophageal cancer, including a sensitivity to inhibition of the kinase BTK in MYC amplified oesophageal tumour cell lines. We found that this genetic dependency could be elicited with the clinical BTK/ERBB2 kinase inhibitor, ibrutinib. In both MYC and ERBB2 amplified tumour cells, ibrutinib downregulated ERK-mediated signal transduction, cMYC Ser-62 phosphorylation and levels of MYC protein, and elicited G 1 cell cycle arrest and apoptosis, suggesting that this drug could be used to treat biomarker-selected groups of patients with oesophageal cancer., Conclusions: BTK represents a novel candidate therapeutic target in oesophageal cancer that can be targeted with ibrutinib. On the basis of this work, a proof-of-concept phase II clinical trial evaluating the efficacy of ibrutinib in patients with MYC and/or ERBB2 amplified advanced oesophageal cancer is currently underway (NCT02884453)., Trial Registration Number: NCT02884453; Pre-results., Competing Interests: Competing interests: IYC has received research funding from Janssen and Pharmacyclics as part of a sponsored research agreement. IC accepts research funding from Janssen-Cilag., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Introduction: Biomedical research has traditionally been the domain of developed countries. We aim to study the effects of the increased focus on biomedical and medical research on level 1-4 publications in several industrialised and newly industrialised countries endowed with petroleum and gas resources., Methods: We identified all level 1-4 publications from 01/01/1994 to 31/12/2013 via PubMed using advanced options. The population and GDP (current US$) data from 1994-2013 were obtained through data provided by the World Bank and the raw data was normalised based on these two indicators., Results: From 1994-2013, Saudi Arabia and Malaysia were responsible for the highest absolute number of level 1 to 4 biomedical and medical research publications with 2551 and 1951 publications respectively. When normalised to population, Kuwait and Qatar had the highest publication rates, with 7.84 and 3.99 publications per 100,000 inhabitants respectively in a five yearly average. Kuwait produced the largest number of publications per billion (current US$) of GDP, at 2.92 publications, followed by Malaysia at 2.82 publications in a five yearly average., Conclusion: The population size of a country as well as GDP can influence the number of level 1-4 publications in some countries. More importantly, effective government policy which stimulates research as well as a culture which actively promotes research as shown by Malaysia have proven to have a larger influence on the amount of level 1-4 biomedical and medical publications.

Importance: Preventing tuberculosis among the homeless has emerged as an especially difficult challenge., Objectives: We assessed a 2008-2009 tuberculosis (TB) outbreak ad subsequent prevention strategies among homeless persons in metropolitan Jackson, Hinds County, Mississippi., Design, Setting and Participants: We compared data about cases and subclinical TB infections (LTBI) among homeless persons during the outbreak and post-outbreak years, interviewed involved homeless persons, compiled observations from visits to Jackson homeless shelters and conducted literature reviews on homelessness and infectious diseases. We reviewed homeless shelter TB prevention methods adopted by other municipalities, guidelines developed by the Centers for Disease Control and Prevention (CDC), and recommendations from other official and ad hoc groups and considered their applicability to metropolitan Jackson., Main Outcomes and Measures: The Mississippi State Department of Health TB Program assisted by the CDC and other agencies, contained the Jackson-area outbreak by the end of 2009 as reflected by progressively lower TB rates among homeless persons thereafter. However, some follow-up activities and enforcement of shelter preventive measures have not been consistently maintained. Resources to prevent further outbreaks continue to be inadequate, and over-reliance on private organizations has continued. In the process, appreciation of the dynamic interaction enhancing TB risk among the homeless and incarcerated persons has emerged., Results: Major outbreak contributors were lack of periodic TB screening among homeless shelter clients, preventive treatment compliance and follow-up difficulties among those with subclinical tuberculosis infections, interrupted preventive measures among infected persons incarcerated in local correctional facilities who disproportionately re-join Jackson's homeless community when released, inadequate attention to shelter environmental preventive strategies such as ultraviolet light germicidal irradiators and proper air-exchange/ventilation, costs of isolation housing for homeless people with full-blown tuberculosis (especially those co-infected with HIV and other infections and those with alcohol and/or other chemical dependencies), lack of adequate transportation which impacts access to evaluation and care, lack of mandated ongoing training among shelter and correctional facility staff, and inadequate attention to the societal problem of homelessness itself., Conclusions: Sustained adherence to local shelter and correctional facility TB prevention measures based on standards and policies proved effective in other settings is most crucial. These include requirements for periodic tuberculosis prevention and awareness training for shelter and correctional facility staff, ongoing tuberculosis screening and follow-up among homeless shelter clients and inmates of local correctional facilities, and attention to shelter and correctional facility environmental sanitation, proper ventilation, ultraviolet light fixtures and capacity/bed alignment standards.

Combinatorial approaches that integrate conventional pathology with genomic profiling and functional genomics have begun to enhance our understanding of the genetic basis of breast cancer. These methods have identified key genotypic-phenotypic correlations in different breast cancer subtypes that have led to the discovery of genetic dependencies that drive their behavior. Moreover, this knowledge has been applied to define novel tailored therapies for these groups of patients with cancer. With the current emphasis on characterizing the mutational repertoire of breast cancers by next-generation sequencing, the question remains as to what constitutes a driver event. By focusing efforts on homogenous subgroups of breast cancer and integrating orthogonal data-types combined with functional approaches, we can begin to unravel the heterogeneity and identify aberrations that can be therapeutically targeted., (©2013 AACR.)

Amplification of 11q13 is found in approximately 15% of breast cancers. Cyclin D1 (CCND1) has been reported to be the 'driver' of this amplicon, however, multiple genes map to the smallest region of amplification of 11q13. Out of these genes, cortactin (CTTN) has been shown to be consistently overexpressed at the mRNA level in tumours harbouring 11q13 amplification. The aims of this study are to define whether CTTN is consistently co-amplified with the main core of the 11q13 amplicon, whether it is consistently overexpressed when amplified and to determine correlations between CTTN amplification and overexpression with clinicopathological features of breast cancers and survival of breast cancer patients. CTTN and CCND1 chromogenic in situ hybridisation (CISH) probes and a validated monoclonal antibody against CTTN were applied to a tissue microarray of a cohort of breast cancers from patients treated with anthracycline-based chemotherapy. CTTN and CCND1 amplifications were found in 12.3 and 12.4% of cases, respectively. All cases harbouring CTTN amplification also displayed CCND1 amplification. High expression of CTTN was found in 10.8% of cases and was associated with CTTN amplification, expression of 'basal' markers and topoisomerase IIα. Exploratory subgroup analysis of tumours devoid of 11q13 amplification revealed that high expression of CTTN in the absence of CTTN gene amplification was associated with lymph node negative disease, lack of hormone receptors and FOXA1, expression of 'basal' markers, high Ki-67 indices, p53 nuclear expression, and basal-like and triple negative phenotypes. CTTN expression and CTTN gene amplification were not associated with disease-, metastasis-free and overall survival. In conclusion, CTTN is consistently co-amplified with CCND1 and expressed at higher levels in breast cancers harbouring 11q13 amplification, suggesting that CTTN may also constitute one of the drivers of this amplicon. CTTN expression is not associated with the outcome of breast cancer patients treated with anthracycline-based chemotherapy.

Objective: Conventional Milligan-Morgan haemorrhoidectomy is associated with significant pain and potentially hazardous complications. Doppler-Guided Haemorrhoidal Artery Ligation (DGHAL) may offer a lower risk, pain-free alternative. We present our early and long-term outcome experience with DGHAL, combined with patient views and satisfaction with the procedure., Method: One hundred and thirteen DGHALs were performed over a 13 month period by two surgeons in a single centre. Patients graded the severity of postoperative pain on visual-analogue scales. Clinical follow-up was at 6 weeks (n = 103), with long-term follow-up (n = 90) by postal questionnaire at median of 30 months., Results: Seven out of one hundred and three (6%) patients reported postoperative discomfort requiring analgesia. Ninety-three out of one hundred and three (90%) patients reported complete relief or significant improvement in their symptoms at 6 weeks, dropping to 77/90 (86%) at 30 months. Anal fissures developed in 2/103 (2%) patients, both treated with Diltiazem ointment. Further surgery was required in 8/90 (9%) patients. Eighty-two out of ninety (91%) patients said they would undergo DGHAL again., Conclusion: DGHAL is a relatively painless, safe, and effective procedure for symptomatic stage I-III haemorrhoids, for which we have demonstrated long-term durability and acceptability. Its role lies between office based procedures and more invasive operative interventions.

Background: We aimed to determine if a poor response to proton pump inhibitors (PPIs) can predict a poor outcome following laparoscopic antireflux surgery (LARS) in our surgically treated population., Methods: A total of 324 patients undergoing LARS were included in this study. Following standardized assessment, patients recorded the efficacy of their medication on visual analogue scales. Pre- and postoperative symptom scores were recorded, with outcomes measured by modified Visick scores., Results: There were 233 good responders (>50% relief) and 91 poor responders (<49% relief). Both groups demonstrated a significant decline in postoperative symptom scores. Ninety-four percent of good responders had an excellent or good outcome, compared to 87% of poor responders. Twenty-seven patients reported a fair or poor outcome, despite improved postoperative symptom scores. Fifteen of these patients reported continuing heartburn; five had positive pH tests., Conclusion: Our results do not support the assumption that a poor response to PPIs equates to a poor outcome after LARS.

To date, studies on the mitral flow convergence method have used rigid, circular, or slit orifices to represent the regurgitant orifice. In this study, explanted porcine mitral valves, with the entire mitral apparatus preserved, were mounted in an in vitro model to reproduce the three-dimensional regurgitant orifice geometry while permitting close control and measurement of the experimental conditions. This experimental setup permitted the evaluation of the hemispheric and hemielliptic formulas under realistic physiologic conditions. In this study, a heart rate of 70 beats/min was used with cardiac outputs between 1.5 and 6 L/min. Peak regurgitant flow rates ranged from 7 to 16 L/min (regurgitant jet velocities ranged from 2 to 5.5 m/sec); peak aortic flow rates ranged from 9 to 30 L/min. Four native mitral valves were used for these studies for a total of 28 stages. Although the hemielliptic modification has previously shown success in vitro and computationally, it has not been used clinically because of difficulty imaging the flow convergence region in three orthogonal planes. A curve-fitting algorithm was developed to extract the hemielliptic dimensions from two standard ultrasound views by rotating the transducer 90 degrees. Improved agreement was obtained between true and calculated flow rates by the hemielliptic formula (y = 1.02 x + 0.29; r = 0.91) compared with the hemispheric formula (y = 1.18 x - 2.2; r = 0.66). This method provides accurate results with a realistic three-dimensional regurgitant orifice geometry and has the capability of being incorporated as a function key on an ultrasound machine for clinical application.

The noninvasive quantification of mitral regurgitation remains an important clinical goal. Recently, the flow convergence method was developed to estimate the regurgitant flow rate. This study used three-dimensional pulsatile flow computational simulations to evaluate the accuracy of the flow convergence method in the presence of complicating factors such as ventricular confinement, noncircular orifice shape, and the presence of aortic outflow. Results showed that in the absence of aortic outflow and ventricular confinement, there was a plateau zone where the calculated flow rate by the hemispheric formula approximated the true flow rate, independent of the orifice shape. In the presence of aortic outflow and in chambers of physiologic dimensions, there was no longer a clear zone where the hemispheric formula was valid. The hemi-elliptic modification of the flow convergence method worked in all cases, independent of the degree of ventricular confinement or the presence of aortic outflow. Therefore, application of the hemi-elliptic formula should be considered in future clinical studies.

Two weeks of binocular lid suture in adult cats caused selective cell loss in lamina A1 of the lateral geniculate nucleus. The loss was manifested as a shift in the latency distribution of LGN cell responses to optic chiasm shock. Proportionately fewer LGN cells with slowly conducting retinal afferents (X-cell range) were in evidence following binocular suture. This change was observed only in lamina A1 while laminae A and C retained normal latency distributions. These observations confirm and extend recent reports of the susceptibility of adult cat visual system to environmental modification.

Adult cats with chronic (two weeks) monocular paralysis had lateral geniculates with diminished numbers of cells characterized by long latency responses to optic chiasm shock. This diminution was unexpectedly more prominent among lamina A1 cells, driven by the mobile and presumably normal eye, than among cells receiving inputs from the paralyzed eye. These results confirm reports suggesting that a hitherto unrecognized degree of plasticity exists in the central nervous system of the adult cat.