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Introduction: There are no standard targeted treatment options for advanced KRAS-mutant NSCLC beyond KRAS G12C inhibitors. A computational model identified regorafenib and low-dose methotrexate as synergistic in preclinical models of KRAS-mutant NSCLC. This study evaluated the efficacy and safety of the combination in previously treated advanced KRAS-mutant NSCLC. Methods: This single-arm phase II study included regorafenib 80 to 120 mg oral daily and oral methotrexate dose escalated to tolerability from 10 to 20 mg twice weekly during the first cycle. Both agents were administered on weeks 1 to 3 of each 4-week cycle. The primary end point was progression-free survival. Results: In total, 18 patients with KRAS-mutant NSCLC were enrolled. Five patients received regorafenib at a 120 mg starting dose with four discontinuing due to toxicity; subsequently, 13 patients were treated at an 80 mg starting dose, with eight dose-escalating to 120 mg after the first cycle. Median progression-free survival was 3.7 months (95% confidence interval 1.8–8.6) and median overall survival was 10.4 months (95% confidence interval 5.2–30.3). The objective response rate was 16.7% and the 8-week disease control rate was 66.7%. Grade 3 treatment-related adverse events occurred in 11 patients, most often oral mucositis (n = 2) and asymptomatic lipase increase (n = 2). One patient developed asymptomatic grade 4 lipase increase. Conclusions: Combination treatment of regorafenib and oral methotrexate in patients with KRAS-mutant NSCLC was limited due to toxicity, and the study did not meet its primary end point. Computational modeling may aid in repurposing therapeutic options though caution must be exercised with tolerability.

Background: Cerebral palsy (CP) is a group of nonprogressive disorders of movement and posture caused by abnormal development of, or damage to, motor control centers of the brain. A single nucleotide polymorphism (SNP), rs1800795, in the promoter region of

BackgroundPediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions.Objectives and methodsThe objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array.Results and discussionWe identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS.ConclusionsThis is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient's disease course and prognosis.

Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by complex genetics and multifaceted gene-environment interactions. Compared to whites, African Americans have a lower risk for developing MS, but African Americans with MS have a greater risk of disability. These differences between African Americans and whites may represent differences in genetic susceptibility and/or environmental factors. SNPs from 12 candidate genes have recently been identified and validated with MS risk in white populations. We performed a replication study using 918 cases and 656 unrelated controls to test whether these candidate genes are also associated with MS risk in African Americans. CD6, CLEC16a, EVI5, GPC5, and TYK2 contained SNPs that are associated with MS risk in the African American data set. EVI5 showed the strongest association outside the major histocompatibility complex (rs10735781, OR=1.233, 95% CI=1.06-1.43, P-value=0.006). In addition, RGS1 seems to affect age of onset whereas TNFRSF1A seems to be associated with disease progression. None of the tested variants showed results that were statistically inconsistent with the effects established in whites. The results are consistent with shared disease genetic mechanisms among individuals of European and African ancestry.

EXECUTIVE SUMMARY- Iowa was a tobacco control leader in the 19th Century. In 1897 the General Assembly completely prohibited the use, sale, and possession of tobacco products in the state. When the law was repealed in 1921, the General Assembly enacted strong measures to prevent tobacco use by minors. In 1921 Iowa passed the first state cigarette excise tax (2 cents).- Tobacco control reemerged in the 1970s, however a coalition of health groups were consistently outmaneuvered by tobacco industry lobbyists.- In 1990 health groups attempted to strengthen Iowa’s Clean Indoor Air Act (passed in 1987), however the tobacco industry, represented primarily by Charles Wasker, co-opted the bill, stripping meaningful tobacco control provisions and using it to include ambiguous language to preempt localities from passing clean indoor air laws, which chilled local clean indoor air action for a decade.- In 1993 the voluntary health organizations founded Tobacco Free Iowa (TFI), a dedicated statewide tobacco control coalition to advocate for tobacco control policy change. In 1995 TFI hired Serge Garrison, a former R.J. Reynolds (RJR) lobbyist, to lobby to repeal clean indoor air preemption. Garrison, who helped draft the preemption clause when working for RJR, questioned whether Iowa’s ambiguously worded clause actually preempted local clean indoor air action.- Iowa, represented by Attorney General Tom Miller (D), was a party in the 1998 Master Settlement Agreement. Miller and the Iowa Attorney General’s Office, have been strong allies to tobacco control in Iowa.- After the MSA, in 2000, Iowa created the Division of Tobacco Use Prevention and Control within the Iowa Department of Public Health to implement a state tobacco control program funded with MSA revenue.- In 2001 the General Assembly passed legislation to securitize the MSA revenue stream to receive an upfront lump sum in lieu of most future MSA payments. Politicians framed MSA securitization as a way to create stable funding for health programs, including tobacco, but the vast majority of the money went to infrastructure projects.- The Health Iowans Tobacco Trust created through securitization to fund tobacco and other health programs was continually raided by the General Assembly from 2001 to 2008, and zeroed out in 2009.- The Iowa Tobacco Division has never been funded at or near the CDC recommended best practices for tobacco control and tobacco control advocates have not mobilized enough political pressure to demand and protect funding for the Tobacco Division.- From 1998 to 2008, $44,577 in campaign contributions were given to Iowa legislative candidates and party committees by five tobacco companies: Altria/Philip Morris, Farner-Bocken (an Iowa-based distributor), Myers-Cox Company (an Iowa-based distributor),R.J. Reynolds, and US Smokeless Tobacco.- Tobacco industry contributions spiked in 2000 when the Iowa General Assembly was considering legislation to create the Iowa Tobacco Division and deciding the use of their MSA payments. Contributions dropped in 2004 after the General Assembly mandated that the Tobacco Division have a youth focus (a pro-industry position) and securitized most of their MSA revenue. In 2004, industry contributions jumped back up (and steadily increased though 2008) concurrent with an increase in the introduction of tobacco control initiatives (which were repeatedly killed until 2007).- The tobacco industry focused contributions on legislative leaders. Rep. Christopher Rants(R-Woodbury) former Iowa House Majority Leader (1999-2003) and Speaker of the House (2003-2006) received the most industry money from 1998-2008 ($7,397). Rants was a key player in killing tobacco tax and local control bills throughout the 2000s. Representative Jamie Van Fossen (R- Scott) who served as the Chair of the House Ways and Means Committee received the second greatest amount ($6,050), followed by Sen. Stewart Iverson, Jr. (R-Wright), Senate Majority Leader from 1997-2006 ($2,220).- From 1998 to 2008, tobacco industry contributions to Republican candidates and the Republican party ($27,947) far outweighed contributions to their Democratic counterparts($15,130). From 1998 to 2007, Republicans controlled both houses (except in 2006 when the Senate was tied).- Republican legislators were significantly more pro-tobacco than Democrats.- Legislators who accepted campaign contributions from the tobacco industry were significantly more pro-tobacco than those who did not, controlling for party.- The tobacco industry maintains a significant lobbying presence, between 2003 and 2008 the tobacco industry reported $667,875 in lobbying expenditures in Iowa.- After an inquiry prompted by Serge Garrison in the late 1990s, Attorney General Tom Miller (D) issued an opinion in November 2000 stating that state law did not preempt local clean indoor air ordinances.- From 1999 to 2003 there was a tide of local clean indoor air action. In March 2002, Ames passed Iowa’s first clean indoor air ordinance. Ames’ ordinance included a tobacco industry inspired “hours” provision that allowed smoking after 8:30pm, advocated for by hospitality interests, making the ordinance weak. Its passage created momentum for other localities to pass clean indoor air measures.- In January 2002, Iowa City passed Iowa’s first 100% smokefree restaurant ordinance. Other localities, aided by the Iowa Attorney General’s Office and TFI, began considering ordinances and enactment of voluntary clean indoor air policies.- Local clean indoor air progress was blocked in 2003, after a group of Ames business owners, funded by Philip Morris, challenged the Ames ordinance in court. In May 2003, the Iowa Supreme Court ruled that the 1990 Clean Indoor Air Act was preemptive.- In 2003, TFI collapsed, leaving Iowa without a functioning tobacco control coalition until 2006. In 2003 some advocates reorganized to create CAFE Iowa and CAFE Iowa CAN, primarily to repeal preemption.- Beginning in 2005, under the direction of Iowa Tobacco Division Director Bonnie Mapes, Iowa advocates reorganized and created a strategic plan. In 2006 the Iowa Tobacco Prevention Alliance was created to assume the role of Iowa’s statewide tobacco control coalition.- The combination Democrats taking control of the legislature in 2007 and the reorganization of tobacco control advocates in 2006 led to substantial tobacco control policy changes.- In 2007 the Iowa General Assembly passed a $1 increase in the cigarette tax, the first increase in 16 years.- In 2008 the General Assembly passed the strong Iowa Smokefree Air Act that extended smokefree environments to 99 percent of Iowa employees and repealed preemption.- Following the 2007 tax increase, adult smoking rates in Iowa fell from 18 to 14% in two years (2006 to 2008).- Youth smoking rates increased from 2004 to 2006 following a substantial cut in allocations to the Tobacco Division in 2002, leading to a substantial decrease in expenditures for Just Eliminate Lies, Iowa’s youth counter-marketing campaign.- Tobacco control advocates must make securing and maintain adequate funding for Iowa’s Tobacco Division a top priority. The CDC recommends that tobacco control programs in Iowa be funded at $36.7 million per year. In FY 2009, the Tobacco Division received only $11.0 million, less than a third of the CDC recommended level. An increase in funding is particularly important because of the increase in youth smoking rates since JEL’s 2002 funding cut.- Given the Tobacco Division’s limited budget and the increasing levels of youth and young adult smoking, the Tobacco Division should focus less on funding individual level cessation services (other than the Quitline, which is a public health intervention) and instead increase its emphasis on media and community-based programs that are more cost effective public health interventions to reduce tobacco use.- Advocates should work to require health insurance to provide cessation services through the medical services budget, not public health.- Advocates need to expand their base beyond major cities to rural areas of Iowa to broaden the base of support for smokefree environments and expand the political base to maintain and expand funding for tobacco control efforts.

Satellite monitoring of icebergs in the Arctic region is paramount for the safety of shipping and maritime activities. The potential of polarimetric synthetic aperture radar data in enhancing detection capabilities of icebergs under interchangeable and challenging conditions is explored in this work. We introduce RADARSAT-2 quad-pol C-band data to detect icebergs in Kongsfjorden, Svalbard. The location contains two tidewater glaciers and is chosen because multiple processes are present in this region, such as ice formation and its relationship with the glaciers, freshwater discharge. Six state-of-the-art detectors are tested for detection performance. These are the dual-intensity polarization ratio anomaly detector, polarimetric notch filter, polarimetric match filter, symmetry, polarimetric whitening filter (PWF), and optimal polarimetric detector (OPD). In addition, we also tested the parameters of the Cloude–Pottier decomposition. In this study, we make use of a ground-based radar for validation and comparison with satellite images. We show that in calm sea-state conditions, the OPD and PWF detectors give high probability of detection (PD) values of 0.7–0.8 when the probability of false alarm (PF) value is 0.01–0.05, compared with choppy sea conditions where the same detectors have degraded performance (PD = 0.5–0.7). Target-to-clutter ratio (TCR) values for each polarization channel is also extracted and compared to the icebergs’ dimensions. The ground-based radar shows higher values in TCR, compared with satellite images. These findings corroborate previous work and show that sea-ice activity, surface roughness, incidence angle, weather, and sea-state conditions all affect the sensitivity of the detectors for this task.

This study evaluated the influence of acute water ingestion and maintaining an upright posture on raw bioimpedance and subsequent estimates of body fluids and composition. Twenty healthy adults participated in a randomized crossover study. In both conditions, an overnight food and fluid fast was followed by an initial multi-frequency bioimpedance assessment (InBody 770). Participants then ingested 11 mL/kg of water (water condition) or did not (control condition) during a 5-minute period. Thereafter, bioimpedance assessments were performed every 10 minutes for one hour with participants remaining upright throughout. Linear mixed effects models were used to examine the influence of condition and time on raw bioimpedance, body fluids, and body composition. Water consumption increased impedance of the arms but not trunk or legs. However, drift in leg impedance was observed, with decreasing values over time in both conditions. No effects of condition on body fluids were detected, but total body water and intracellular water decreased by ~0.5 kg over time in both conditions. Correspondingly, lean body mass did not differ between conditions but decreased over the measurement duration. The increase in body mass in the water condition was detected exclusively as fat mass, with final fat mass values ~1.3 kg higher than baseline and also higher than the control condition. Acute water ingestion and prolonged standing exert practically meaningful effects on relevant bioimpedance variables quantified by a modern, vertical multi-frequency analyzer. These findings have implications for pre-assessment standardization, methodological reporting, and interpretation of assessments.

We consider estimation and variable selection in the partial linear model for censored data. The partial linear model for censored data is a direct extension of the accelerated failure time model, the latter of which is a very important alternative model to the proportional hazards model. We extend rank-based lasso-type estimators to a model that may contain nonlinear effects. Variable selection in such partial linear model has direct application to high-dimensional survival analyses that attempt to adjust for clinical predictors. In the microarray setting, previous methods can adjust for other clinical predictors by assuming that clinical and gene expression data enter the model linearly in the same fashion. Here, we select important variables after adjusting for prognostic clinical variables but the clinical effects are assumed nonlinear. Our estimator is based on stratification and can be extended naturally to account for multiple nonlinear effects. We illustrate the utility of our method through simulation studies and application to the Wisconsin prognostic breast cancer data set. [ABSTRACT FROM AUTHOR]

The intrauterine device (IUD) is an effective contraceptive for many women. The copper-releasing IUD can be used for 10 years before replacement and is a good choice for women who cannot, or choose not to, use hormone-releasing contraceptives. However, some women experience an increase in menstrual blood loss and dysmenorrhea. The progestin-releasing IUD can be used for five years. It may reduce menorrhagia and dysmenorrhea, although some women have increased spotting and bleeding during the first months after insertion. The ideal candidates for IUD use are parous women in stable, monogamous relationships. Pregnancy, unexplained vaginal bleeding, and a lifestyle placing the woman at risk for sexually transmitted diseases are contraindications to IUD use. Insertion of the IUD can take place at any time during the menstrual cycle provided the woman is not pregnant. Before insertion, a bimanual examination and a sounding of the uterus are necessary to determine the uterus position and the depth of the uterine cavity. The IUD is inserted into the uterus according to individual protocols, with the threads cut at a length to allow the patient to check the device's position. Expulsion may occur with both types of IUDs. [ABSTRACT FROM AUTHOR]

The family physician often provides the first and only medical intervention for fingertip injuries. Proper diagnosis and management of fingertip injuries are vital to maintaining proper function of the hand and preventing permanent disability. A subungual hematoma is a painful condition that involves bleeding beneath the nail, usually after trauma. Treatment requires subungual decompression, which is achieved by creating small holes in the nail. A nail bed laceration is treated by removing the nail and suturing the injured nail bed. Closed fractures of the distal phalanx may require reduction but usually are minimally displaced and stable, and can be splinted. Open or intra-articular fractures of the distal phalanx may warrant referral. Patients with mallet finger cannot extend the distal interphalangeal joint because of a disruption of the extensor mechanism. Radiographs help to differentiate between tendinous and bony mallet types. Most mallet finger injuries heal with six to eight weeks of splinting, but some require referral. Flexor digitorum profundus avulsion always requires referral. Dislocations of the distal interphalangeal joint are rare and usually occur dorsally. [ABSTRACT FROM AUTHOR]

Effective treatment of acne vulgaris can prevent emotional and physical scarring. Therapy varies according to the severity of the disease. Topical medication is generally adequate in clearing comedonal acne, while inflammatory acne usually requires the addition of oral medication. Systemic antibiotics are used most frequently and can be highly effective. Newer formulations of combined oral contraceptives are also helpful in modulating sebum production in the female patient. Severe nodulocystic acne that does not respond to topical retinoids and systemic antibiotics may be treated with isotretinoin. However, the side effect profile of this medication is extensive, and physicians should be well-versed in its potential adverse effects. [ABSTRACT FROM AUTHOR]

Seborrheic dermatitis is a chronic inflammatory disorder affecting areas of the head and trunk where sebaceous glands are most prominent. Lipophilic yeasts of the Malassezia genus, as well as genetic, environmental and general health factors, contribute to this disorder. Scalp seborrhea varies from mild dandruff to dense, diffuse, adherent scale. Facial and trunk seborrhea is characterized by powdery or greasy scale in skin folds and along hair margins. Treatment options include application of selenium sulfide, pyrithione zinc or ketoconazole-containing shampoos, topical ketoconazole cream or terbinafine solution, topical sodium sulfacetamide and topical corticosteroids. [ABSTRACT FROM AUTHOR]

Icebergs represent hazards to ships and maritime activities and therefore their detection is essential. Synthetic Aperture Radar (SAR) satellites are very useful for this, due to their capability to acquire data under cloud cover and during day and night passes. In this work, we compared six state-of-the-art polarimetric target detectors to test their performance and ability to detect small-sized icebergs HH and HV. We also compared these detectors with single-polarimetric intensity channels and we tested using two scenarios: open ocean and sea ice. Our results show that the multi-look polarimetric whitening filter (MPWF) and the optimal polarimetric detector (OPD) provide the most optimal performance in quad- and dual-polarimetric mode detection. The analysis shows that, overall, quad-polarimetric detectors provide the best detection performance. When the false alarm rate (PF) is fixed to 10−5, the probabilities of detection (PD) are 0.99 in open ocean and 0.90 in sea ice. Dual-polarimetric or single-polarimetric detectors show an overall reduction in performance (the ROC curves show a decrease), but this degradation is not very large (120 m, as they are easier to detect). However, the differences between quad- and dual- or single-polarimetric detectors became much more evident when the PF value was fixed to low detection probabilities 10−6 (i.e., smaller icebergs). In the single-polarimetric mode, the HV channel showed PD values of 0.62 for open ocean and 0.26 for sea ice, compared to values of 0.81 (open ocean) and 0.77 (sea ice) obtained with quad-polarimetric detectors.

Advances in neurobiology support the development of medications to treat alcoholism by modifying the activity of specific chemical messengers (i.e., neurotransmitters) in the brain. Among the most promising new medications is acamprosate, which appears to decrease the intensity of craving after a person has stopped drinking. Naltrexone (ReVia) has been shown to decrease alcohol consumption, although its practical effectiveness may be compromised by poor patient compliance and other factors. Ondansetron shows promise for decreasing drinking and increasing abstinence rates among early onset alcoholics, who respond poorly to psychosocial treatment alone. Researchers are investigating whether the use of specific medications in combination can further enhance their effectiveness. Additional research is needed to determine how medications interact with different psychosocial factors and treatments. [ABSTRACT FROM AUTHOR]

Flexible sigmoidoscopy is an important screening procedure because of its ability to detect early changes in the distal colon. The 60-cm flexible sigmoidoscope provides excellent visualization with minimal discomfort to patients. Successful sigmoidoscopy requires adequate patient preparation, proper equipment and an experienced examiner who can recognize both normal and abnormal findings. Complications arising from sigmoidoscopy are rare, but patients may experience some cramping, gas or watery stools. Screening and primary preventive measures, including regular exercise and increased dietary fiber intake, can lower the morbidity and mortality associated with colorectal cancer. [ABSTRACT FROM AUTHOR]

Icebergs are ocean hazards which require extensive monitoring. Synthetic Aperture Radar (SAR) satellites can help with this, however, SAR backscattering is strongly influenced by the properties of icebergs, together with meteorological and environmental conditions. In this work, we used five images of quad-pol ALOS-2/PALSAR-2 SAR data to analyse 1332 icebergs in five locations in west and east Greenland. We investigate the backscatter and polarimetric behaviour, by using several observables and decompositions such as the Cloude–Pottier eigenvalue/eigenvector and Yamaguchi model-based decompositions. Our results show that those icebergs can contain a variety of scattering mechanisms at L-band. However, the most common scattering mechanism for icebergs is surface scattering, with the second most dominant volume scattering (or more generally, clouds of dipoles). In some cases, we observed a double bounce dominance, but this is not as common. Interestingly, we identified that different locations (e.g., glaciers) produce icebergs with different polarimetric characteristics. We also performed a multi-scale analysis using boxcar 5 × 5 and 11 × 11 window sizes and this revealed that depending on locations (and therefore, characteristics) icebergs can be a collection of strong scatterers that are packed in a denser or less dense way. This gives hope for using quad-pol polarimetry to provide some iceberg classifications in the future.

An investigation of the microbial diversity of the extremely acidic, metal-rich Lake Robule was carried out using culture-dependant and culture-independent (T-RFLP) methods, and the ability of indigenous bacteria from the lake water to leach copper from a mineral concentrate was tested. T-RFLP analysis revealed that the dominant bacteria in lake water samples were the obligate heterotroph Acidiphilium cryptum (~50% of total bacteria) and the iron-oxidizing autotroph Leptospirillum ferrooxidans (~40%) The iron/sulfur-oxidizing autotroph Acidithiobacillus ferrooxidans had been reported to be the most abundant bacteria in the lake in an earlier study by other authors, but it was not detected in the present study using T-RFLP. Although it was isolated on solid media and detected in enrichment (bioleaching) cultures. The presence of the two bacterial species detected by T-RFLP (L. ferrooxidans and A. cryptum) was also confirmed by cultivation on solid media. The presence and relative abundance of bacteria inhabiting Lake Robule was explained by the physiological characteristics of the bacteria and the physico-chemical characteristics of the lake water. [Projekat Ministarstva nauke Republike Srbije, br. 176016 i br.173048]

Abstract Background The recently approved anti-AIDS drug rilpivirine (TMC278, Edurant) is a nonnucleoside inhibitor (NNRTI) that binds to reverse transcriptase (RT) and allosterically blocks the chemical step of DNA synthesis. In contrast to earlier NNRTIs, rilpivirine retains potency against well-characterized, clinically relevant RT mutants. Many structural analogues of rilpivirine are described in the patent literature, but detailed analyses of their antiviral activities have not been published. This work addresses the ability of several of these analogues to inhibit the replication of wild-type (WT) and drug-resistant HIV-1. Results We used a combination of structure activity relationships and X-ray crystallography to examine NNRTIs that are structurally related to rilpivirine to determine their ability to inhibit WT RT and several clinically relevant RT mutants. Several analogues showed broad activity with only modest losses of potency when challenged with drug-resistant viruses. Structural analyses (crystallography or modeling) of several analogues whose potencies were reduced by RT mutations provide insight into why these compounds were less effective. Conclusions Subtle variations between compounds can lead to profound differences in their activities and resistance profiles. Compounds with larger substitutions replacing the pyrimidine and benzonitrile groups of rilpivirine, which reorient pocket residues, tend to lose more activity against the mutants we tested. These results provide a deeper understanding of how rilpivirine and related compounds interact with the NNRTI binding pocket and should facilitate development of novel inhibitors.

Abstract Background The goal of this research was to compare the demographics, clinical characteristics and treatment patterns for newly diagnosed multiple sclerosis (MS) patients in a commercial managed care population who received disease-modifying drug (DMD) therapy versus those not receiving DMD therapy. Methods A retrospective cohort study using US administrative healthcare claims identified individuals newly diagnosed with MS (no prior MS diagnosis 12 months prior using ICD-9-CM 340) and ≥ 18 years old during 2001-2007 to characterize them based on demographics, clinical characteristics, and pharmacologic therapy for one year prior to and a minimum of one year post-index. The index date was the first MS diagnosis occurring in the study period. Follow-up of subjects was done by ICD-9-CM code identification and not by actual chart review. Multivariate analyses were conducted to adjust for confounding variables. Results Patients were followed for an average of 35.7 ± 17.5 months after their index diagnosis. Forty-three percent (n = 4,462) of incident patients received treatment with at least one of the DMDs during the post-index period. Treated patients were primarily in the younger age categories of 18-44 years of age, with DMD therapy initiated an average of 5.3 ± 9.1 months after the index diagnosis. Once treatment was initiated, 27.7% discontinued DMD therapy after an average of 17.6 ± 14.6 months, and 16.5% had treatment gaps in excess of 60 days. Conclusions Nearly 60% of newly-diagnosed MS patients in this commercial managed care population remained untreated while over a quarter of treated patients stopped therapy and one-sixth experienced treatment gaps despite the risk of disease progression or a return of pre-treatment disease activity.

Abstract Background Catheter-related bacteraemias (CRBs) contribute significantly to morbidity, mortality and health care costs in dialysis populations. Despite international guidelines recommending avoidance of catheters for haemodialysis access, hospital admissions for CRBs have doubled in the last decade. The primary aim of the study is to determine whether weekly instillation of 70% ethanol prevents CRBs compared with standard heparin saline. Methods/design The study will follow a prospective, open-label, randomized controlled design. Inclusion criteria are adult patients with incident or prevalent tunneled intravenous dialysis catheters on three times weekly haemodialysis, with no current evidence of catheter infection and no personal, cultural or religious objection to ethanol use, who are on adequate contraception and are able to give informed consent. Patients will be randomized 1:1 to receive 3 mL of intravenous-grade 70% ethanol into each lumen of the catheter once a week and standard heparin locks for other dialysis days, or to receive heparin locks only. The primary outcome measure will be time to the first episode of CRB, which will be defined using standard objective criteria. Secondary outcomes will include adverse reactions, incidence of CRB caused by different pathogens, time to infection-related catheter removal, time to exit site infections and costs. Prospective power calculations indicate that the study will have 80% statistical power to detect a clinically significant increase in median infection-free survival from 200 days to 400 days if 56 patients are recruited into each arm. Discussion This investigator-initiated study has been designed to provide evidence to help nephrologists reduce the incidence of CRBs in haemodialysis patients with tunnelled intravenous catheters. Trial Registration Australian New Zealand Clinical Trials Registry Number: ACTRN12609000493246

Background: The goal of hip labral reconstruction is to restore the suction seal, requiring the labral graft to be precisely secured along the acetabular rim. When performed arthroscopically, controlling the graft as it is suspended in the hip joint between 2 cannulas can be challenging, making fixation in the optimal position to restore the suction seal difficult to achieve. Indications: Labral reconstruction/augmentation is indicated for patients with a deficient/dysfunctional labrum when repair alone cannot restore/maintain the suction seal. Technique Description: Following diagnostic arthroscopy, debridement, and measurement of the labral deficiency (30 mm), 70 mm tibialis anterior allograft was tubularized with a whipstitch and prepared with long suture tails at both ends and a single mattress stitch placed through the graft at the medial end. Holes for the anchors were pre-drilled. Viewing from the anterolateral portal, the graft was introduced down a sled through the modified anterior portal, pulled through the joint, and guided into the posterolateral portal cannula via instrumentation through the distal anterolateral accessory portal. With initial fixation achieved medially with the mattress stitch, directing the graft into position while achieving optimal coverage of the deficient area was facilitated by the excess graft length pulled into the posterolateral portal cannula. Results: Labral reconstruction can restore the suction seal of the hip joint when repair alone is not sufficient. Comparative studies with matched repair cohorts have demonstrated comparable survivorship and patient-reported outcomes between groups, with similar rates of patient acceptable symptomatic state and minimal clinically important difference between groups, and similar rates of return to sport in high-level athletes. Recent systematic reviews have largely corroborated these findings. Discussion/Conclusions: Arthroscopic labral reconstruction is an effective treatment option when repair alone cannot restore the suction seal when the graft is secured in an optimal position, but controlling the graft during passage and fixation while achieving a final length spanning the segmental deficiency in continuity with native tissue at both ends can present technical challenges. The labral pull-through technique greatly facilitates this process. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

Background: Locked posterior glenohumeral dislocations are a rare but often missed injury when it occurs. In these dislocations, patients may have a reverse Hill–Sachs lesion, which are associated with high rates of recurrent posterior glenohumeral instability. Open reduction with allograft reconstruction to reconstruct the defect can be used to treat chronic locked posterior glenohumeral dislocations. Indications: Osteochondral allograft reconstruction is indicated when patients have a large defect affecting less than 50% of the articular surface and if the humeral head has been dislocated for less than 6 months. Technique Description: With the patient in beach chair position, exposure is obtained through deltopectoral approach. An open reduction is performed, and the defect is debrided down to healthy bleeding bone. The defect is templated, and the allograft is harvested and prepared. The allograft is securely fixed using cannulated cancellous screws. The patient undergoes a postoperative rehabilitation protocol. Results: There have been several case series following allograft reconstruction for locked posterior dislocations that have demonstrated good results. Riff et al found favorable results in his series of 20 patients with isolated humeral head lesions, with significant improvement in patient-outcome measures. There are several potential complications though. A systematic review by Saltzman et al found allograft resorption to occur in 36% and glenohumeral arthritic changes to occur in 35% with frozen allografts. These rates appear to be improved with fresh allografts. Discussion/Conclusion: In conclusion, osteochondral allograft is an effective surgical treatment for large Hill–Sachs defects in chronic locked posterior dislocations.

Introduction: Somatic KRAS mutations occur in 25% of patients with NSCLC. Treatment with MEK inhibitor monotherapy has not been successful in clinical trials to date. Compensatory activation of FGFR1 was identified as a mechanism of trametinib resistance in KRAS-mutant NSCLC, and combination therapy with trametinib and ponatinib was synergistic in in vitro and in vivo models. This study sought to evaluate this drug combination in patients with KRAS-mutant NSCLC. Methods: A phase 1 dose escalation study of trametinib and ponatinib was conducted in patients with advanced NSCLC with KRAS mutations. A standard 3-plus-3 dose escalation was done. Patients were treated with the study therapy until intolerable toxicity or disease progression. Results: A total of 12 patients with KRAS-mutant NSCLC were treated (seven at trametinib 2 mg and ponatinib 15 mg, five at trametinib 2 mg and ponatinib 30 mg). Common toxicities observed were rash, diarrhea, and fever. Serious adverse events potentially related to therapy were reported in five patients, including one death in the study and four cardiovascular events. Serious events were observed at both dose levels. Of note, 75% (9 of 12) were assessable for radiographic response and no confirmed partial responses were observed. The median time on study was 43 days. Conclusions: In this phase 1 study, in patients with KRAS-mutant advanced NSCLC, combined treatment with trametinib and ponatinib was associated with cardiovascular and bleeding toxicities. Exploring the combination of MEK and FGFR1 inhibition in future studies is potentially warranted but alternative agents should be considered to improve safety and tolerability.

Objective:. To compare outcomes after bariatric surgery between Medicaid and non-Medicaid patients and assess whether differences in social determinants of health were associated with postoperative weight loss. Background:. The literature remains mixed on weight loss outcomes and healthcare utilization for Medicaid patients after bariatric surgery. It is unclear if social determinants of health geocoded at the neighborhood level are associated with outcomes. Methods:. Patients who underwent laparoscopic sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) from 2008 to 2017 and had ≥1 year of follow-up within a large health system were included. Baseline characteristics, 90-day and 1-year outcomes, and weight loss were compared between Medicaid and non-Medicaid patients. Area deprivation index (ADI), urbanicity, and walkability were analyzed at the neighborhood level. Median regression with percent total body weight (TBW) loss as the outcome was used to assess predictors of weight loss after surgery. Results:. Six hundred forty-seven patients met study criteria (191 Medicaid and 456 non-Medicaid). Medicaid patients had a higher 90-day readmission rate compared to non-Medicaid patients (19.9% vs 12.3%, P < 0.016). Weight loss was similar between Medicaid and non-Medicaid patients (23.1% vs 21.9% TBW loss, respectively; P = 0.266) at a median follow-up of 3.1 years. In adjusted analyses, Medicaid status, ADI, urbanicity, and walkability were not associated with weight loss outcomes. Conclusions:. Medicaid status and social determinants of health at the neighborhood level were not associated with weight loss outcomes after bariatric surgery. These findings suggest that if Medicaid patients are appropriately selected for bariatric surgery, they can achieve equivalent outcomes as non-Medicaid patients.

The unequal discussion of Black males’ health is a pressing social problem. This study addressed Black males’ lay perspectives regarding their health, illness, and mortality, with attention to the determinants of men’s health, prevention, lifestyle, and opportunities for health promotion using an exploratory/qualitative research methodology. Participants were 68 Black males aged 15 to 68 years, with an average age of 44 years ( SD = 14.5). The narratives represented a complex interplay of biopsychosocial factors, ranging from intrapersonal attitudes, interpersonal experiences to discussions about community and public policy injustices. Five prominent themes emerged: (a) lack of chronic disease awareness, (b) fatalism, (c) fear and anxiety of academic–medical settings, (d) hyperactive masculinity fatigue, and (e) the gay–straight divide. The term Tired Black Male Health syndrome was coined in the forum. Implications of these findings are discussed in the context of culturally relevant strategies for improving Black male community health engagement.

Early reperfusion of ischemic cardiac tissue remains the most effective intervention for improving clinical outcome following myocardial infarction. However, abnormal increases in intracellular Ca²⁺ during myocardial reperfusion can cause cardiomyocyte death and consequent loss of cardiac function, referred to as ischemia/reperfusion (IR) injury. Therapeutic modulation of Ca²⁺ handling provides some cardioprotection against the paradoxical effects of restoring blood flow to the heart, highlighting the significance of Ca²⁺ overload to IR injury. Cardiac IR is also accompanied by dynamic changes in the expression of microRNAs (miRNAs); for example, miR-214 is upregulated during ischemic injury and heart failure, but its potential role in these processes is unknown. Here, we show that genetic deletion of miR-214 in mice causes loss of cardiac contractility, increased apoptosis, and excessive fibrosis in response to IR injury. The cardioprotective roles of miR-214 during IR injury were attributed to repression of the mRNA encoding sodium/calcium exchanger 1 (Ncx1), a key regulator of Ca²⁺ influx; and to repression of several downstream effectors of Ca²⁺ signaling that mediate cell death. These findings reveal a pivotal role for miR-214 as a regulator of cardiomyocyte Ca²⁺ homeostasis and survival during cardiac injury. [ABSTRACT FROM AUTHOR]

Alcoholism and nicotine dependence share many neurobiological underpinnings; the presence of one drug can cause a person to crave the other. Depressive illness can complicate comorbid alcohol and nicotine dependence by exacerbating the negative affect encountered during attempts to abstain from one or both drugs. Given the morbidity and mortality associated with cigarette smoking, it is imperative to identify treatments to promote smoking cessation and address comorbid psychiatric conditions contemporaneously. Pharmacotherapeutic options demonstrating varying degrees of efficacy and promise in preclinical and clinical studies include nicotine replacement therapy (NRT), selective serotonin reuptake inhibitors (SSRIs), bupropion, varenicline, tricyclic antidepressants, and bupropion plus NRT. Topiramate has shown potential for promoting smoking cessation in alcoholics, although its safety in depressed patients has not been fully explored. The efficacy of medications for treating nicotine dependence is generally enhanced by the inclusion of behavioral interventions such as cognitive behavioral therapy. When group cohesion and social support are stressed, success rates increase among depressed smokers undergoing smoking cessation treatment. Additional treatment strategies targeting dually dependent individuals with comorbid psychiatric disorders, including special populations such as women and adolescents, await further investigation. [ABSTRACT FROM AUTHOR]

Coronaviruses (CoVs) maintain large RNA genomes that frequently undergoes mutations and recombination, contributing to their evolution and emergence. In this study, we find that SARS-CoV-2 has greater RNA recombination frequency than other human CoVs. In addition, coronavirus RNA recombination primarily occurs at uridine (U)-enriched RNA sequences. Therefore, we next evaluated the role of SARS-CoV-2 NSP15, a viral endonuclease that targets uridines (EndoU), in RNA recombination and virus infection. Using a catalytically inactivated EndoU mutant (NSP15 H234A ), we observed attenuated viral replication in vitro and in vivo . However, the loss of EndoU activity also dysregulated inflammation resulting in similar disease in vivo despite reduced viral loads. Next-generation sequencing (NGS) demonstrated that loss of EndoU activity disrupts SARS-CoV-2 RNA recombination by reducing viral sub-genomic message but increasing recombination events that contribute to defective viral genomes (DVGs). Overall, the study demonstrates that NSP15 plays a critical role in regulating RNA recombination and SARS-CoV-2 pathogenesis., Competing Interests: Competing Interests A.L.R. is a co-founder and co-owner of “ClickSeq Technologies LLC.”, a next-generation sequencing service provider of ClickSeq protocols and downstream analyses such as those presented in this manuscript. VDM have filed a patent on the reverse genetic system for SARS-CoV-2. All other authors declare no conflicts of interest.

Introduction: Nadofaragene firadenovec (Ad-IFNα/Syn3) is now approved for BCG-unresponsive bladder cancer (BLCA). IFNα is a pleiotropic cytokine that causes direct tumor cell killing via TRAIL-mediated apoptosis, angiogenesis inhibition, and activation of the innate and adaptive immune system. We established an immunocompetent murine BLCA model to study the effects of murine adenoviral IFNα (muAd-Ifnα) gene therapy on cancer cells and the tumor microenvironment using a novel murine equivalent of Nadofaragene firadenovec (muAd-Ifnα)., Methods: Tumors were induced by instilling MB49 cells into the bladders of mice; luciferase imaging confirmed tumor development. Mice were treated with adenovirus control (Ad-Ctrl; empty vector), or muAd-Ifnα (3x10 11 VP/mL), and survival analysis was performed. For single-cell sequencing (scRNAseq) analysis (72h), bladders were harvested and treated with collagenase/hyaluronidase and TrypLE for cell dissociation. Single cells were suspended in PBS/1% FBS buffer; viability was assessed with Vicell cell counter. scRNAseq analysis was performed using 10X genomics 3' sequencing. Raw RNAseq data were pre-processed using Cell Ranger single-cell software. Seurat (R package) was used to normalize and cluster the scRNA data. Pooled differential gene expression analysis in specific cell clusters was performed with DESeq2., Results: We identified 16 cell clusters based on marker expression which were grouped into epithelial (tumor), uroplakin-enriched, endothelial, T-cells, neutrophils, and macrophage clusters. Top differentially expressed genes between muAd-Ifnα and Ad-Ctrl were identified. Within the specific cell clusters, IPA analysis revealed significant differences between muAd-Ifnα and control. IFNα signaling and hypercytokinemia/chemokinemia were upregulated in all clusters. Cell death pathways were upregulated in tumor and endothelial clusters. T-cells demonstrated upregulation of the immunogenic cell death signaling pathway and a decrease in the Th2 pathway genes. Macrophages showed upregulation of PD1/PD-L1 pathways along with downregulation of macrophage activation pathways (alternate and classical). Multiplex immunofluorescence confirmed increased infiltration with macrophages in muAd-Ifnα treated tumors compared to controls. PD1/PD-L1 expression was reduced at 72h., Discussion: This single-cell analysis builds upon our understanding of the impact of Ad-IFNα on tumor cells and other compartments of the microenvironment. These data will help identify mechanisms to improve patient selection and therapeutic efficacy of Nadofaragene firadenovec., Competing Interests: DM: Grants or funding: AstraZeneca; honoraria: Janssen. CD: Consulting for AstraZeneca. Consulting and stock options for CG Oncology. Research support: Shared resources covered by the Cancer Center Support Grant funding from NIH/NCI award number P30CA016672. Creator of intellectual property owned by UT/MDACC related to the use of genetic alterations as a predictive biomarker for response to Nadofaragene firadenovec. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Steinmetz, Pierce, Martini, Tholomier, Manyam, Chen, Sood, Duplisea, Johnson, Czerniak, Lee, Jagannath, Yla-Herttuala, Parker, McConkey, Dinney and Mokkapati.)

Deuterium ( 2 H) spin relaxation of 13 CH 2 D methyl groups has been widely applied to investigate picosecond-to-nanosecond conformational dynamics in proteins by solution-state NMR spectroscopy. The B 0 dependence of the 2 H spin relaxation rates is represented by a linear relationship between the spectral density function at three discrete frequencies J(0), J(ω D ) and J(2ω D ). In this study, the linear relation between 2 H relaxation rates at B 0 fields separated by a factor of two and the interpolation of rates at intermediate frequencies are combined for a more robust approach for spectral density mapping. The general usefulness of the approach is demonstrated on a fractionally deuterated (55%) and alternate 13 C- 12 C labeled sample of E. coli RNase H. Deuterium relaxation rate constants (R 1 , R 1ρ , R Q , R AP ) were measured for 57 well-resolved 13 CH 2 D moieties in RNase H at 1 H frequencies of 475 MHz, 500 MHz, 900 MHz, and 950 MHz. The spectral density mapping of the 475/950 MHz data combination was performed independently and jointly to validate the expected relationship between data recorded at B 0 fields separated by a factor of two. The final analysis was performed by jointly analyzing 475/950 MHz rates with 700 MHz rates interpolated from 500/900 MHz data to yield six J(ω D ) values for each methyl peak. The J(ω) profile for each peak was fit to the original (τ M , S f 2 , τ f ) or extended model-free function (τ M , S f 2 , S s 2 , τ f , τ s ) to obtain optimized dynamic parameters., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Significance: Minimally invasive surgery (MIS) has shown vast improvement over open surgery by reducing post-operative stays, intraoperative blood loss, and infection rates. However, in spite of these improvements, there are still prevalent issues surrounding MIS that may be addressed through hyperspectral imaging (HSI). We present a laparoscopic HSI system to further advance the field of MIS., Aim: We present an imaging system that integrates high-speed HSI technology with a clinical laparoscopic setup and validate the system's accuracy and functionality. Different configurations that cover the visible (VIS) to near-infrared (NIR) range of electromagnetism are assessed by gauging the spectral fidelity and spatial resolution of each hyperspectral camera., Approach: Standard Spectralon reflectance tiles were used to provide ground truth spectral footprints to compare with those acquired by our system using the root mean squared error (RMSE). Demosaicing techniques were investigated and used to measure and improve spatial resolution, which was assessed with a USAF resolution test target. A perception-based image quality evaluator was used to assess the demosaicing techniques we developed. Two configurations of the system were developed for evaluation. The functionality of the system was investigated in a phantom study and by imaging ex vivo tissues., Results: Multiple configurations of our system were tested, each covering different spectral ranges, including VIS (460 to 600 nm), red/NIR (RNIR) (610 to 850 nm), and NIR (665 to 950 nm). Each configuration is capable of achieving real-time imaging speeds of up to 20 frames per second. RMSE values of 3.51 ± 2.03 % , 3.43 ± 0.84 % , and 3.47% were achieved for the VIS, RNIR, and NIR systems, respectively. We obtained sub-millimeter resolution using our demosaicing techniques., Conclusions: We developed and validated a high-speed hyperspectral laparoscopic imaging system. The HSI system can be used as an intraoperative imaging tool for tissue classification during laparoscopic surgery., (© 2024 The Authors.)

Aneuploidy is nearly ubiquitous in tumor genomes, but the role of aneuploidy in the early stages of cancer evolution remains unclear. Here, by inducing heterogeneous aneuploidy in non-transformed human colon organoids (colonoids), we investigated how the effects of aneuploidy on cell growth and differentiation may promote malignant transformation. Previous work implicated p53 activation as a downstream response to aneuploidy induction. We found that simple aneuploidy, characterized by 1-3 gained or lost chromosomes, resulted in little or modest p53 activation and cell cycle arrest when compared with more complex aneuploid cells. Single-cell RNA sequencing analysis revealed that the degree of p53 activation was strongly correlated with karyotype complexity. Single-cell tracking showed that cells could continue to divide despite the observation of one to a few lagging chromosomes. Unexpectedly, colonoids with simple aneuploidy exhibited impaired differentiation after niche factor withdrawal. These findings demonstrate that simple aneuploid cells can escape p53 surveillance and may contribute to niche factor-independent growth of cancer-initiating colon stem cells.

Background/objectives: Stroke damage to the primary visual cortex induces large, homonymous visual field defects that impair daily living. Here, we asked if vision-related quality of life (VR-QoL) is impacted by time since stroke., Subjects/methods: We conducted a retrospective meta-analysis of 95 occipital stroke patients (female/male = 26/69, 27-78 years old, 0.5-373.5 months poststroke) in whom VR-QoL was estimated using the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ) and its 10-item neuro-ophthalmic supplement (Neuro10). Visual deficit severity was represented by the perimetric mean deviation (PMD) calculated from 24-2 Humphrey visual fields. Data were compared with published cohorts of visually intact controls. The relationship between VR-QoL and time poststroke was assessed across participants, adjusting for deficit severity and age with a multiple linear regression analysis., Results: Occipital stroke patients had significantly lower NEI-VFQ and Neuro10 composite scores than controls. All subscale scores describing specific aspects of visual ability and functioning were impaired except for ocular pain and general health, which did not differ significantly from controls. Surprisingly, visual deficit severity was not correlated with either composite score, both of which increased with time poststroke, even when adjusting for PMD and age., Conclusions: VR-QoL appears to improve with time postoccipital stroke, irrespective of visual deficit size or patient age at insult. This may reflect the natural development of compensatory strategies and lifestyle adjustments. Thus, future studies examining the impact of rehabilitation on daily living in this patient population should consider the possibility that their VR-QoL may change gradually over time, even without therapeutic intervention., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Despite the major roles of choroid plexus epithelial cells (CPECs) in brain homeostasis and repair, their developmental lineage and diversity remain undefined. In simplified differentiations from human pluripotent stem cells, derived CPECs (dCPECs) displayed canonical properties and dynamic multiciliated phenotypes that interacted with Aβ uptake. Single dCPEC transcriptomes over time correlated well with human organoid and fetal CPECs, while pseudotemporal and cell cycle analyses highlighted the direct CPEC origin from neuroepithelial cells. In addition, time series analyses defined metabolic (type 1) and ciliogenic dCPECs (type 2) at early timepoints, followed by type 1 diversification into anabolic-secretory (type 1a) and catabolic-absorptive subtypes (type 1b) as type 2 cells contracted. These temporal patterns were then confirmed in independent derivations and mapped to prenatal stages using human tissues. In addition to defining the prenatal lineage of human CPECs, these findings suggest new dynamic models of ChP support for the developing human brain.

Introduction: Enfortumab vedotin (EV) is an antibody drug conjugate approved for advanced urothelial cancer, consisting of a monomethyl auristatin E payload linked to a human monoclonal antibody targeting nectin-4. No validated biomarker predictive of or correlated with response exists for EV. Cutaneous toxicity is among the most common EV-related toxicities and typically emerges in early cycles. This retrospective experience of patients with urothelial cancer treated with EV monotherapy evaluated whether EV-related cutaneous toxicity correlated with improved outcomes including progression-free (PFS) and overall (OS) survival and overall response rate (ORR)., Patients and Methods: Patients treated with EV monotherapy at Johns Hopkins were identified, and baseline characteristics, treatment, and toxicity details were extracted through chart review. Univariable Cox hazard ratios (HRs) were calculated for assessing the effect of baseline patient characteristics and cutaneous toxicity in PFS and OS. Based on the univariable analysis and known risk factors, all subsequent analyses were adjusted for: Eastern Cooperative Oncology Group performance status, visceral metastases at baseline, gender as well as EV dose, and weight to account for dosing differences. Multivariable Cox proportional HRs were used for comparing PFS and OS between patients with and without cutaneous toxicity, assessing toxicity and EV dose as a time-dependent variables. Adjusted p-values were calculated to compare ORR and disease control rate (DCR) between groups using the Poisson regression model., Results: Of the 78 patients analyzed, 42 (53.8%) experienced EV-related cutaneous toxicity that appeared early during treatment (median time to occurrence 0.5 months from EV initiation). Cutaneous toxicity correlated with significantly improved OS [HR, 0.48; 95% confidence interval (CI), 0.25, 0.9; P = 0.0235], ORR (68.3% vs. 20.7%, P = 0.0033) and DCR (82.9% vs. 48.3%, P = 0.0122). Median PFS was numerically longer in the cutaneous toxicity group (6.3 vs. 1.7 months), although no significance was achieved in the multivariable analysis (HR, 0.62; 95% CI: 0.35, 0.108; P = 0.0925)., Conclusion: In this retrospective study, EV-related cutaneous toxicity was associated with improved patient outcomes. Confirming this observation and understanding its mechanism could lead to discovery of a new clinical biomarker of EV response that can emerge in the first cycle., Competing Interests: BJ: Seagen Emerging Thought Leader Advisory Board. NH discloses consulting compensation from AstraZeneca, Merck, Genentech, GlaxoSmithKline, Ferring, Champions Oncology, Health Advances, Keyquest Health, Guidepoint Global, Seattle Genetics, Mirati, Incyte, TransMed, CicloMed, Janssen, Pfizer, Boehringer Ingelheim, Pfizer, and EMD Serono; research support to the institution from HTG Molecular Diagnostics, AstraZeneca, Bristol Myers-Squibb, Genentech, Seattle Genetics, OncoGenex, Pieris, Inovio, Principia Biopharm; speaking honorarium from Creative Educational Concepts, and Large Urology Group Practice Association. JH-C: Seagen Consultant May 2021, Genentech research support, Gilead Sciences, EMD Serono. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Vlachou, Johnson, McConkey, Jing, Matoso, Hahn and Hoffman-Censits.)

Research on transformers in remote sensing (RS), which started to increase after 2021, is facing the problem of a relative lack of review. To understand the trends of transformers in RS, we undertook a quantitative analysis of the major research on transformers over the past two years by dividing the application of transformers into eight domains: land use/land cover (LULC) classification, segmentation, fusion, change detection, object detection, object recognition, registration, and others. Quantitative results show that transformers achieve a higher accuracy in LULC classification and fusion, with more stable performance in segmentation and object detection. Combining the analysis results on LULC classification and segmentation, we have found that transformers need more parameters than convolutional neural networks (CNNs). Additionally, further research is also needed regarding inference speed to improve transformers' performance. It was determined that the most common application scenes for transformers in our database are urban, farmland, and water bodies. We also found that transformers are employed in the natural sciences such as agriculture and environmental protection rather than the humanities or economics. Finally, this work summarizes the analysis results of transformers in remote sensing obtained during the research process and provides a perspective on future directions of development.

Accurate segmentation of retinal layers in optical coherence tomography (OCT) images is critical for assessing diseases that affect the optic nerve, but existing automated algorithms often fail when pathology causes irregular layer topology, such as extreme thinning of the ganglion cell-inner plexiform layer (GCIPL). Deep LOGISMOS, a hybrid approach that combines the strengths of deep learning and 3D graph search to overcome their limitations, was developed to improve the accuracy, robustness and generalizability of retinal layer segmentation. The method was trained on 124 OCT volumes from both eyes of 31 non-arteritic anterior ischemic optic neuropathy (NAION) patients and tested on three cross-sectional datasets with available reference tracings: Test-NAION (40 volumes from both eyes of 20 NAION subjects), Test-G (29 volumes from 29 glaucoma subjects/eyes), and Test-JHU (35 volumes from 21 multiple sclerosis and 14 control subjects/eyes) and one longitudinal dataset without reference tracings: Test-G-L (155 volumes from 15 glaucoma patients/eyes). In the three test datasets with reference tracings (Test-NAION, Test-G, and Test-JHU), Deep LOGISMOS achieved very high Dice similarity coefficients (%) on GCIPL: 89.97±3.59, 90.63±2.56, and 94.06±1.76, respectively. In the same context, Deep LOGISMOS outperformed the Iowa reference algorithms by improving the Dice score by 17.5, 5.4, and 7.5, and also surpassed the deep learning framework nnU-Net with improvements of 4.4, 3.7, and 1.0. For the 15 severe glaucoma eyes with marked GCIPL thinning (Test-G-L), it demonstrated reliable regional GCIPL thickness measurement over five years. The proposed Deep LOGISMOS approach has potential to enhance precise quantification of retinal structures, aiding diagnosis and treatment management of optic nerve diseases., Competing Interests: Z. Chen, None; H. Zhang, None; E.F. Linton, None; B.A. Johnson, None; Y.J. Choi, None; M.J. Kupersmith, None; M. Sonka, University of Iowa (Patents), Medical Imaging Applications, LLC (Co-Founder), VIDA Diagnostics, Inc. (Co-Founder); M.K. Garvin, University of Iowa (Patent); R.H. Kardon, FaceX, LLC (Co-Founder), J-K Wang, None., (© 2024 Optica Publishing Group.)

Introduction: Chronic workplace stress and burnout are impediments to physicians' professional fulfillment, healthcare organizations' efficiency, and patient care quality/safety. General surgery residents are especially at risk due to the complexity of their training. We report the protocol of a metaanalysis of chronic stress and burnout among Accreditation Council for Graduate Medical Education (ACGME)-affiliated general surgery residents in the era after duty-hour reforms, plus downstream effects on their health and clinical performance., Methods: The proposed systematic review and metaanalysis (PROSPERO registration CRD42021277626) will synthesize/pool data from studies of chronic stress and burnout among general surgery residents at ACGME-affiliated programs. The timeframe under review is subdivided into three intervals: (a) after the 2003 duty-hour restrictions but before 2011 reforms, (b) after the 2011 reforms but before the coronavirus pandemic, and (c) the first 3 years after the pandemic's outbreak. Only studies reporting outcomes based on validated instruments will be included. Qualitative studies, commentaries/editorials, narrative reviews, and studies not published in English will be excluded. Multivariable analyses will adjust for sample characteristics and the methodological quality of included studies., Conclusions: The metaanalysis will yield evidence reflecting experiences of North American-based general surgery residents in the years after ACGME-mandated duty-hour restructuring., Competing Interests: The authors report no funding or conflicts of interests., (Copyright © 2024 Baylor University Medical Center.)

Inflammation-associated fibroblasts (IAFs) are associated with progression and drug resistance of chronic inflammatory diseases such as inflammatory bowel disease (IBD), but their direct impact on epithelial cells is unknown. Here, we developed an in vitro model whereby human colon fibroblasts are induced by specific cytokines and recapitulate key features of IAFs in vivo. When cocultured with patient-derived colon organoids (colonoids), IAFs induced rapid colonoid expansion and barrier disruption due to swelling and rupture of individual epithelial cells. Colonoids cocultured with IAFs also show increased DNA damage, mitotic errors, and proliferation arrest. These IAF-induced epithelial defects are mediated by a paracrine pathway involving prostaglandin E 2 and its receptor EP4, leading to protein kinase A -dependent activation of the cystic fibrosis transmembrane conductance regulator. EP4-specific chemical inhibitors effectively prevented IAF-induced colonoid swelling and restored normal proliferation and genome stability. These findings reveal a mechanism by which IAFs could promote and perpetuate IBD and suggest a therapeutic avenue to mitigate inflammation-associated epithelial injury.

Objective: To determine the long-term outcomes, including mortality and recurrent seizures, among children living with HIV (CLWH) who present with new onset seizure., Methods: Zambian CLWH and new onset seizure were enrolled prospectively to determine the risk of and risk factors for recurrent seizures. Demographic data, clinical profiles, index seizure etiology, and 30-day mortality outcomes were previously reported. After discharge, children were followed quarterly to identify recurrent seizures and death. Given the high risk of early death, risk factors for recurrent seizure were evaluated using a model that adjusted for mortality., Results: Among 73 children enrolled, 28 died (38%), 22 within 30-days of the index seizure. Median follow-up was 533 days (IQR 18-957) with 5% (4/73) lost to follow-up. Seizure recurrence was 19% among the entire cohort. Among children surviving at least 30-days after the index seizure, 27% had a recurrent seizure. Median time from index seizure to recurrent seizure was 161 days (IQR 86-269). Central nervous system opportunistic infection (CNS OI), as the cause for the index seizure was protective against recurrent seizures and higher functional status was a risk factor for seizure recurrence., Significance: Among CLWH presenting with new onset seizure, mortality risks remain elevated beyond the acute illness period. Recurrent seizures are common and are more likely in children with higher level of functioning even after adjusting for the outcome of death. Newer antiseizure medications appropriate for co-usage with antiretroviral therapies are needed for the care of these children. CNS OI may represent a potentially reversible provocation for the index seizure, while seizures in high functioning CLWH without a CNS OI may be the result of a prior brain injury or susceptibility to seizures unrelated to HIV and thus represent an ongoing predisposition to seizures., Plain Language Summary: This study followed CLWH who experienced a new onset seizure to find out how many go on to have more seizures and identify any patient characteristics associated with having more seizures. The study found that mortality rates continue to be high beyond the acute clinical presentation with new onset seizure. Children with a CNS OI causing the new onset seizure had a lower risk of later seizures, possibly because the trigger for the seizure can be treated. In contrast, high functioning children without a CNS OI were at higher risk of future seizures., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Purpose: Damage to the adult primary visual cortex (V1) causes vision loss in the contralateral hemifield, initiating a process of transsynaptic retrograde degeneration (TRD). Here, we examined retinal correlates of TRD using a new metric to account for global changes in inner retinal thickness and asked if perceptual training in the intact or blind field impacts its progression., Methods: We performed a meta-analysis of optical coherence tomography data in 48 participants with unilateral V1 stroke and homonymous visual defects who completed clinical trial NCT03350919. After measuring the thickness of the macular ganglion cell and inner plexiform layer (GCL-IPL) and the peripapillary retinal nerve fiber layer (RNFL), we computed individual laterality indices (LI) at baseline and after ∼6 months of daily motion discrimination training in the intact or blind field. Increasingly positive LI denoted greater layer thinning in retinal regions affected versus unaffected by the cortical damage., Results: Pretraining, the affected GCL-IPL and RNFL were thinner than their unaffected counterparts, generating LI values positively correlated with time since stroke. Participants trained in their intact field exhibited increased LIGCL-IPL. Those trained in their blind field had no significant change in LIGCL-IPL. LIRNFL did not change in either group., Conclusions: Relative shrinkage of the affected versus unaffected macular GCL-IPL can be reliably measured at an individual level and increases with time post-V1 stroke. Relative thinning progressed during intact-field training but appeared to be halted by training within the blind field, suggesting a potentially neuroprotective effect of this simple behavioral intervention.

G3BP1/2 are paralogous proteins that promote stress granule formation in response to cellular stresses, including viral infection. The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inhibits stress granule assembly and interacts with G3BP1/2 via an ITFG motif, including residue F17, in the N protein. Prior studies examining the impact of the G3PB1-N interaction on SARS-CoV-2 replication have produced inconsistent findings, and the role of this interaction in pathogenesis is unknown. Here, we use structural and biochemical analyses to define the residues required for G3BP1-N interaction and structure-guided mutagenesis to selectively disrupt this interaction. We find that N-F17A mutation causes highly specific loss of interaction with G3BP1/2. SARS-CoV-2 N-F17A fails to inhibit stress granule assembly in cells, has decreased viral replication, and causes decreased pathology in vivo. Further mechanistic studies indicate that the N-F17-mediated G3BP1-N interaction promotes infection by limiting sequestration of viral genomic RNA (gRNA) into stress granules., Competing Interests: Declaration of interests J.P.T. is a consultant for Nido Biosciences. V.D.M. has filed a patent on the reverse genetic system and reporter SARS-CoV-2., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Viruses interact with numerous host factors to facilitate viral replication and to dampen antiviral defense mechanisms. We currently have a limited mechanistic understanding of how SARS-CoV-2 binds host factors and the functional role of these interactions. Here, we uncover a novel interaction between the viral NSP3 protein and the fragile X mental retardation proteins (FMRPs: FMR1, FXR1-2). SARS-CoV-2 NSP3 mutant viruses preventing FMRP binding have attenuated replication in vitro and reduced levels of viral antigen in lungs during the early stages of infection. We show that a unique peptide motif in NSP3 binds directly to the two central KH domains of FMRPs and that this interaction is disrupted by the I304N mutation found in a patient with fragile X syndrome. NSP3 binding to FMRPs disrupts their interaction with the stress granule component UBAP2L through direct competition with a peptide motif in UBAP2L to prevent FMRP incorporation into stress granules. Collectively, our results provide novel insight into how SARS-CoV-2 hijacks host cell proteins and provides molecular insight into the possible underlying molecular defects in fragile X syndrome., (© 2024. The Author(s).)

Purpose: To visualize and quantify structural patterns of optic nerve edema encountered in papilledema during treatment., Methods: A novel bi-channel deep-learning variational autoencoder (biVAE) model was trained using 1498 optical coherence tomography (OCT) scans of 125 subjects over time from the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) and 791 OCT scans of 96 control subjects from the University of Iowa. An independent test dataset of 70 eyes from 70 papilledema subjects was used to evaluate the ability of the biVAE model to quantify and reconstruct the papilledema spatial patterns from input OCT scans using only two variables., Results: The montage color maps of the retinal nerve fiber layer (RNFL) and total retinal thickness (TRT) produced by the biVAE model provided an organized visualization of the variety of morphological patterns of optic disc edema (including differing patterns at similar thickness levels). Treatment effects of acetazolamide versus placebo in the IIHTT were also demonstrated in the latent space. In image reconstruction, the mean signed peripapillary retinal nerve fiber layer thickness (pRNFLT) difference ± SD was -0.12 ± 17.34 µm, the absolute pRNFLT difference was 13.68 ± 10.65 µm, and the RNFL structural similarity index reached 0.91 ± 0.05., Conclusions: A wide array of structural patterns of papilledema, integrating the magnitude of disc edema with underlying disc and retinal morphology, can be quantified by just two latent variables., Translational Relevance: A biVAE model encodes structural patterns, as well as the correlation between channels, and may be applied to visualize individuals or populations with papilledema throughout treatment.