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IntroductionOnline patient educational materials (OPEMs) help patients engage in their health care. The American Medical Association (AMA) recommends OPEM be written at or below the 6th grade reading level. This study assessed the readability of deep venous thrombosis OPEM in English and Spanish.MethodsGoogle searches were conducted in English and Spanish using "deep venous thrombosis" and "trombosis venosa profunda," respectively. The top 25 patient-facing results were recorded for each, and categorized into source type (hospital, professional society, other). Readability of English OPEM was measured using several scales including the Flesch Reading Ease Readability Formula and Flesch-Kincaid Grade Level. Readability of Spanish OPEM was measured using the Fernández-Huerta Index and INFLESZ Scale. Readability was compared to the AMA recommendation, between languages, and across source types.ResultsOnly one (4%) Spanish OPEM was written at an easy level, compared to 7 (28%) English OPEM (P = 0.04). More English (28%) OPEM were easy to read compared to Spanish (4%), with a significant difference in reading difficulty breakdown between languages (P = 0.04). The average readability scores for English and Spanish OPEM across all scales were significantly greater than the recommended level (P

ObjectiveDiabetic foot ulcers (DFUs) present a significant global health challenge, resulting in high morbidity and economic costs. Current available treatments often fail to achieve satisfactory healing rates, highlighting the need for novel therapies. This study evaluated the safety and efficacy of a novel autologous whole blood clot (AWBC)-a blood-based, biodegradable provisional matrix-in conjunction with standard of care (SoC) when compared to SoC alone in the treatment of hard-to-heal DFUs.MethodA multicentre, prospective, blinded assessor, randomised controlled trial was conducted at 16 sites across the US, South Africa and Turkey. A cohort of patients with hard-to-heal DFUs was enrolled and randomised to either the AWBC group or the control group. The primary endpoint was complete wound closure at 12 weeks, while secondary endpoints included time to heal and percentage area reduction (PAR) at four and eight weeks. Data were analysed using both intention-to-treat (ITT) and per-protocol (PP) populations.ResultsThe cohort included 119 patients. AWBC treatment resulted in a significantly higher healing rate compared to the control in both ITT (41% versus 15%, respectively; p=0.002) and PP populations (51% versus 18%, respectively; p=0.0075). AWBC treatment also resulted in a shorter mean time to heal and higher durability of wound closure. Safety analysis showed a similar incidence of adverse events (AEs) between groups, with no device-related AEs.ConclusionThe AWBC system, by modulating the wound microenvironment and providing a functional extracellular matrix, offered a promising new approach to treating hard-to-heal DFUs, demonstrating superior healing outcomes compared to SoC alone in this study.

BackgroundDeeper insights into ERBB2-driven cancers are essential to develop new treatment approaches for ERBB2+ breast cancers (BCs). We employed the Collaborative Cross (CC) mouse model to unearth genetic factors underpinning Erbb2-driven mammary tumour development and metastasis.Methods732 F1 hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains were monitored for mammary tumour phenotypes. GWAS pinpointed SNPs that influence various tumour phenotypes. Multivariate analyses and models were used to construct the polygenic score and to develop a mouse tumour susceptibility gene signature (mTSGS), where the corresponding human ortholog was identified and designated as hTSGS. The importance and clinical value of hTSGS in human BC was evaluated using public datasets, encompassing TCGA, METABRIC, GSE96058, and I-SPY2 cohorts. The predictive power of mTSGS for response to chemotherapy was validated in vivo using genetically diverse MMTV-Erbb2 mice.FindingsDistinct variances in tumour onset, multiplicity, and metastatic patterns were observed in F1-hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains. Besides lung metastasis, liver and kidney metastases emerged in specific CC strains. GWAS identified specific SNPs significantly associated with tumour onset, multiplicity, lung metastasis, and liver metastasis. Multivariate analyses flagged SNPs in 20 genes (Stx6, Ramp1, Traf3ip1, Nckap5, Pfkfb2, Trmt1l, Rprd1b, Rer1, Sepsecs, Rhobtb1, Tsen15, Abcc3, Arid5b, Tnr, Dock2, Tti1, Fam81a, Oxr1, Plxna2, and Tbc1d31) independently tied to various tumour characteristics, designated as a mTSGS. hTSGS scores (hTSGSS) based on their transcriptional level showed prognostic values, superseding clinical factors and PAM50 subtype across multiple human BC cohorts, and predicted pathological complete response independent of and superior to MammaPrint score in I-SPY2 study. The power of mTSGS score for predicting chemotherapy response was further validated in an in vivo mouse MMTV-Erbb2 model, showing that, like findings in human patients, mouse tumours with low mTSGS scores were most likely to respond to treatment.InterpretationOur investigation has unveiled many new genes predisposing individuals to ERBB2-driven cancer. Translational findings indicate that hTSGS holds promise as a biomarker for refining treatment strategies for patients with BC.FundingThe U.S. Department of Defense (DoD) Breast Cancer Research Program (BCRP) (BC190820), United States; MCIN/AEI/10.13039/501100011039 (PID2020-118527RB-I00, PDC2021-121735-I00), the "European Union Next Generation EU/PRTR," the Regional Government of Castile and León (CSI144P20), European Union.

PurposeWe previously demonstrated the clinical significance of circulating tumor DNA (ctDNA) in patients with HER2-negative breast cancer receiving neoadjuvant chemotherapy (NAC). Here, we compared its predictive and prognostic value with cell-free DNA (cfDNA) concentration measured in the same samples from the same patients.Experimental design145 patients with hormone receptor (HR)-positive/HER2-negative and 138 triple-negative breast cancer (TNBC) with ctDNA data from a previous study were included in the analysis. Associations of serial cfDNA concentration with residual cancer burden (RCB) and distant recurrence-free survival (DRFS) were examined.ResultsIn TNBC, we observed a modest negative correlation between cfDNA concentration 3 weeks after treatment initiation and RCB, but none of the other timepoints showed significant correlation. In contrast, ctDNA was significantly positively correlated with RCB at all timepoints (all R > 0.3 and P < 0.05). In the HR-positive/HER2-negative group, cfDNA concentration did not associate with response to NAC, but survival analysis showed that high cfDNA shedders at pretreatment had a significantly worse DRFS than low shedders (hazard ratio, 2.12; P = 0.037). In TNBC, the difference in survival between high versus low cfDNA shedders at all timepoints was not statistically significant. In contrast, as previously reported, ctDNA at all timepoints was significantly correlated with DRFS in both subtypes.ConclusionsIn TNBC, cfDNA concentrations during therapy were not strongly correlated with response or prognosis. In the HR-positive/HER2-negative group, pretreatment cfDNA concentration was prognostic for DRFS. Overall, the predictive and prognostic value of cfDNA concentration was more limited than that of ctDNA.

ObjectiveThoracic outlet syndrome (TOS) has life-changing impacts on young athletes. As the level of competition increases between the high school (HS) and collegiate (CO) stage of athletics, the impact of TOS may differ. Our objective is to compare surgical outcomes of TOS in HS and CO athletes.MethodsThis was a retrospective review of HS and CO athletes within a prospective surgical TOS database. The primary outcome was postoperative return to sport. Secondary outcomes were resolution of symptoms assessed with somatic pain scale (SPS), QuickDASH, and Derkash scores. Categorical and continuous variables were compared using χ2 and analysis of variance, respectively. Significance was defined as P < .05.ResultsThirty-two HS and 52 CO athletes were identified. Females comprised 82.9% HS and 61.5% CO athletes (P = .08). Primary diagnoses were similar between groups (venous TOS: HS 50.0% vs CO 42.3%; neurogenic TOS: 43.9% vs 57.7%; pectoralis minor syndrome: 6.3% vs 0.0%) (P = .12). Pectoralis minor syndrome was a secondary diagnosis in 3.1% and 3.8% of HS and CO athletes, respectively (P = 1.00). The most common sports were those with overhead motion, specifically baseball/softball (39.3%), volleyball (12.4%), and water polo (10.1%), and did not differ between groups (P = .145). Distribution of TOS operations were similar in HS and CO (First rib resection: 94.3% vs 98.1%; scalenectomy: 0.0% vs 1.9%, pectoralis minor tenotomy: 6.3% vs 0.0%) (P = .15). Operating room time was 90.0 vs 105.3 minutes for HS and CO athletes, respectively (P = .14). Mean length of stay was 2.0 vs 1.9 days for HS and CO athletes (P = .91). Mean follow-up was 6.9 months for HS athletes and 10.5 months for CO athletes (P = .39). The majority of patients experienced symptom resolution (HS 80.0% vs CO 77.8%; P = 1.00), as well as improvement in SPS, QuickDASH, and Derkash scores. Return to sport was similar between HS and CO athletes (72.4% vs 73.3%; P = .93). Medical disability was reported in 100% HS athletes and 58.3% CO athletes who did not return to sport (P = .035).ConclusionsDespite increased level of competition, HS and CO athletes demonstrate similar rates of symptom resolution and return to competition. Of those that did not return to their sport, HS athletes reported higher rates of medical disability as a reason for not returning to sport compared with CO athletes.

Biomarkers for evaluating tumor response to therapy and estimating the risk of disease relapse represent tremendous areas of clinical need. To evaluate treatment efficacy, tumor response is routinely assessed using different imaging modalities like positron emission tomography/computed tomography or magnetic resonance imaging. More recently, the development of circulating tumor DNA detection assays has provided a minimally invasive approach to evaluate tumor response and prognosis through a blood test (liquid biopsy). Integrating imaging- and circulating tumor DNA-based biomarkers may lead to improvements in the prediction of patient outcomes. For this mini-review, we searched the scientific literature to find original articles that combined quantitative imaging and circulating tumor DNA biomarkers to build prediction models. Seven studies reported building prognostic models to predict distant recurrence-free, progression-free, or overall survival. Three discussed building models to predict treatment response using tumor volume, pathologic complete response, or objective response as endpoints. The limited number of articles and the modest cohort sizes reported in these studies attest to the infancy of this field of study. Nonetheless, these studies demonstrate the feasibility of developing multivariable response-predictive and prognostic models using regression and machine learning approaches. Larger studies are warranted to facilitate the building of highly accurate response-predictive and prognostic models that are generalizable to other datasets and clinical settings.

In people living with HIV, Kaposi Sarcoma (KS), a vascular neoplasm caused by KS herpesvirus (KSHV/HHV-8), remains one of the most common malignancies worldwide. Individuals living with HIV, receiving otherwise effective antiretroviral therapy, may present with extensive disease requiring chemotherapy. Hence, new therapeutic approaches are needed. The Wilms' tumor 1 (WT1) protein is overexpressed and associated with poor prognosis in several hematologic and solid malignancies and has shown promise as an immunotherapeutic target. We found that WT1 was overexpressed in >90% of a total 333 KS biopsies, as determined by immunohistochemistry and image analysis. Our largest cohort from ACTG, consisting of 294 cases was further analyzed demonstrating higher WT1 expression was associated with more advanced histopathologic subtypes. There was a positive correlation between the proportion of infected cells within KS tissues, assessed by expression of the KSHV-encoded latency-associated nuclear antigen (LANA), and WT1 positivity. Areas with high WT1 expression showed sparse T-cell infiltrates, consistent with an immune evasive tumor microenvironment. We show that major oncogenic isoforms of WT1 are overexpressed in primary KS tissue and observed WT1 upregulation upon de novo infection of endothelial cells with KSHV. KSHV latent viral FLICE-inhibitory protein (vFLIP) upregulated total and major isoforms of WT1, but upregulation was not seen after expression of mutant vFLIP that is unable to bind IKKƴ and induce NFκB. siRNA targeting of WT1 in latent KSHV infection resulted in decreased total cell number and pAKT, BCL2 and LANA protein expression. Finally, we show that ESK-1, a T cell receptor-like monoclonal antibody that recognizes WT1 peptides presented on MHC HLA-A0201, demonstrates increased binding to endothelial cells after KSHV infection or induction of vFLIP expression. We propose that oncogenic isoforms of WT1 are upregulated by KSHV to promote tumorigenesis and immunotherapy directed against WT1 may be an approach for KS treatment.

Life-threatening "breakthrough" cases of critical COVID-19 are attributed to poor or waning antibody (Ab) response to SARS-CoV-2 vaccines in individuals already at risk. Preexisting auto-Abs neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; their contribution to hypoxemic breakthrough cases in vaccinated people is unknown. We studied a cohort of 48 individuals (aged 20 to 86 years) who received two doses of a messenger RNA (mRNA) vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Ab levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal Ab response to the vaccine. Among them, 10 (24%) had auto-Abs neutralizing type I IFNs (aged 43 to 86 years). Eight of these 10 patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, whereas two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized type I IFNs at 10 ng/ml and three at 100 pg/ml only. Seven patients neutralized SARS-CoV-2 D614G and Delta efficiently, whereas one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only type I IFNs at 100 pg/ml neutralized both D614G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating Abs capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a notable proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.

BackgroundOnline resources are a valuable source of information for patients and have been reported to improve engagement and adherence to medical care. However, readability of online patient educational materials (OPEMs) is crucial for them to serve their intended purpose. The American Medical Association (AMA) recommends that OPEM be written at or below the sixth grade reading level. To avoid disparities in access to comprehensible health information on peripheral artery disease (PAD), it is imperative that the readability of PAD OPEM is appropriate for both English-speaking and Spanish-speaking patients. The aim of this study is to evaluate the readability of PAD OPEM in Spanish and compare to English-language OPEM.MethodsWe conducted a Google search in English and Spanish using "peripheral arterial disease" and "enfermedad arterial periferica", respectively, and the top 25 patient-accessible articles were collected for each. Articles were categorized by source type: hospital, professional society, or other. Readability of English-language OPEM was measured using the Flesch Reading Ease Readability Formula, Automated Readability Index, Coleman-Liau Index, Flesch-Kincaid Grade Level, Gunning Fog, Linsear Write Formula, and the Simple Measure of Gobbledygook Index. Readability of Spanish OPEM was measured using the Fernández-Huerta Index and Índice Flesch-Szigriszt Scale. Readability of the articles was compared to the AMA recommendation, between English- and Spanish-language, and across sources using statistical tests appropriate to the data.ResultsOPEM from professional societies represented the fewest number of English- (n = 7, 28%) and Spanish-language (n = 6, 24%) articles. Most English-speaking (n = 18, 72%) and Spanish-language (n = 20, 80%) OPEM were considered difficult as measured by the Flesch Reading Ease Readability Formula and Fernández-Huerta Index, respectively, but did not significantly differ between languages (P = 0.59). There were no significant differences in the average readability of all readability measurements across sources (hospital, professional society, or other). All the average readability grade levels for English-speaking and Spanish-language OPEM was significantly higher than the sixth grade reading level (P

Todd Lewis and co-authors discuss development and use of the People's Voice Survey for health system assessment.

BackgroundPerioperative care after surgery for thoracic outlet syndrome (TOS) involves multimodal pain control. Pain catheters with bupivacaine infusion are a modality to minimize perioperative narcotic use. Our study aims to compare surgically placed pain catheters (SP) with erector spinae pain catheters (ESP) placed by the anesthesia pain service.MethodsRetrospective review of a prospectively maintained surgical TOS database identified patients undergoing transaxillary first rib resection (FRR) who had either SP or ESP placed for pain control. Patients were matched for age and gender. Data collected included demographics, operative details, and perioperative pain medication use. Narcotic pain medication doses were converted to milligram morphine equivalents (MME) for comparison between groups. Pain medications were collected for several time points: intraoperatively, for each post-operative day (POD), and for the entire hospital stay.ResultsEighty-eight total patients were selected for comparison: 44 patients in the SP and ESP groups. Patients in each group did not differ with regards to age, BMI, gender, diagnosis, or comorbidities. There were no differences in preoperative narcotic use, preoperative pain score, or QuickDASH score. All patients underwent FRR. Concurrent cervical rib resection was performed in 6.8% SP and 6.8% ESP patients (p=1.00), pectoralis minor tenotomy in 34.1% SP and 29.5% ESP patients (p=0.65), and venogram in 31.8% SP and 31.8% ESP patients (p=1.00). Mean OR time was 90.0 minutes in SP and 105.3 minute in ESP cases (p=0.15). Mean length of stay was 1.9 days for SP and 1.8 days for ESP patients (p=0.56). There were no significant differences in intraoperative narcotics dosing in MME (SC: 22.1 vs ESP: 25.3, p=0.018). On POD 0, there were no differences in total narcotics dosing (MME) (SC: 112.0 vs ESP: 100.7, p=0.59), or in the use of acetaminophen, NSAIDS, or muscle relaxants. A similar trend in narcotics dosing was observed on POD 1 (SP: 58.6 vs ESP: 69.7, p=0.43), and POD 2 (SP: 23.5 vs ESP: 71.3, p=0.23). On POD 1, there was a higher percentage of SP patients taking NSAIDs (63.6% vs 40.9%, p=0.024), however, this difference was not observed on POD 2. There were no differences in acetaminophen or muscle relaxant use on POD 1 or 2. Total hospital stay MME was similar between groups (SC: 215.9 vs ESP: 250.9, p=0.23) CONCLUSION: Pain catheters with bupivacaine infusions are helpful adjuncts in postoperative pain control after FRR for TOS. This study compares SP to ESP, and demonstrates no difference in narcotics use between SP and ESP groups. SC should be used for pain control in facilities which do not have an anesthesia pain service available for ESP placement.

BackgroundThe influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA level and presence of infectious virus on symptom occurrence is poorly understood, particularly among nonhospitalized individuals.MethodsThe study included 85 nonhospitalized, symptomatic adults, who were enrolled from September 2020 to November 2021. Data from a longitudinal cohort studied over 28 days was used to analyze the association of individual symptoms with SARS-CoV-2 viral RNA load, or the presence or level of infectious (culturable) virus. Presence of infectious virus and viral RNA load were assessed daily, depending on specimen availability, and amount of infectious virus was assessed on the day of maximum RNA load. Participants were surveyed for the start and end dates of 31 symptoms at enrollment and at days 9, 14, 21, and 28; daily symptom presence was determined analytically. We describe symptoms and investigate their possible association with viral determinants through a series of single or pooled (multiple days across acute period) cross-sectional analyses.ResultsThere was an association between viral RNA load and the same-day presence of many individual symptoms. Additionally, individuals with infectious virus were more than three times as likely to have a concurrent fever than individuals without infectious virus, and more than two times as likely to have concurrent myalgia, chills, headache, or sore throat.ConclusionsWe found evidence to support the association of viral RNA load and infectious virus on some, but not all symptoms. Fever was most strongly associated with the presence of infectious virus; this may support the potential for symptom-based isolation guidance for COVID-19.

BackgroundTo identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections.MethodsChildren presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39).ResultsIn the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV.ConclusionsMIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.

From 2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) household transmission studies (enrolling April 2020 to January 2022) with rapid enrollment and specimen collection for 14 days, 61% (43/70) of primary cases had culturable virus detected ≥6 days post-onset. Risk of secondary infection among household contacts tended to be greater when primary cases had culturable virus detected after onset. Regardless of duration of culturable virus, most secondary infections (70%, 28/40) had serial intervals

Circulating tumor DNA (ctDNA) analysis may improve early-stage breast cancer treatment via non-invasive tumor burden assessment. To investigate subtype-specific differences in the clinical significance and biology of ctDNA shedding, we perform serial personalized ctDNA analysis in hormone receptor (HR)-positive/HER2-negative breast cancer and triple-negative breast cancer (TNBC) patients receiving neoadjuvant chemotherapy (NAC) in the I-SPY2 trial. ctDNA positivity rates before, during, and after NAC are higher in TNBC than in HR-positive/HER2-negative breast cancer patients. Early clearance of ctDNA 3 weeks after treatment initiation predicts a favorable response to NAC in TNBC only. Whereas ctDNA positivity associates with reduced distant recurrence-free survival in both subtypes. Conversely, ctDNA negativity after NAC correlates with improved outcomes, even in patients with extensive residual cancer. Pretreatment tumor mRNA profiling reveals associations between ctDNA shedding and cell cycle and immune-associated signaling. On the basis of these findings, the I-SPY2 trial will prospectively test ctDNA for utility in redirecting therapy to improve response and prognosis.

BackgroundFrailty is a known risk factor for adverse outcomes following surgery and affects at least 3 of every 10 US Veterans aged 65 years and older. We designed a study to characterize the association between frailty and complications after endovascular aneurysm repair (EVAR) compared to open aneurysm repair (OAR) at our regional Veterans Affairs Medical Center.MethodsVeterans who underwent either OAR or EVAR at our institution between January 1, 2000 and December 31, 2020 were identified. We examined medical history, procedure characteristics, perioperative complications, and frailty as measured by the 5-factor modified frailty index (mFI-5). Frailty was defined as an mFI-5 score ≥2. Primary endpoints were postoperative complications, duration of surgery, and length of hospital stay. Tests of association were performed with t-test and chi-squared analysis.ResultsOver the 21-year period, we identified 314 patients that underwent abdominal aortic aneurysm (AAA) repair with 115 (36.6%) OAR and 199 EVAR (63.4%) procedures. Patients undergoing EVAR were older on average (72.1 years vs. 70.2 years) and had a higher average mFI-5 compared to the open repair group (1.49 vs. 1.23, P = 0.036). When comparing EVAR and OAR cohorts, patients undergoing OAR had a larger AAA diameter (6.5 cm, standard deviation [SD]: 1.5) compared to EVAR (5.5 cm, SD: 1.1 P

ObjectivesTo develop alginate nanoparticles functionalized with polysorbate 80 (P80) as miltefosine carriers for brain targeting in the oral treatment of cryptococcal meningitis.MethodsMiltefosine-loaded alginate nanoparticles functionalized or not with P80 were produced by an emulsification/external gelation method and the physicochemical characteristics were determined. The haemolytic activity and cytotoxic and antifungal effects of nanoparticles were assessed in an in vitro model of the blood-brain barrier (BBB). A murine model of disseminated cryptococcosis was used for testing the efficacy of oral treatment with the nanoparticles. In addition, serum biomarkers were measured for toxicity evaluation and the nanoparticle biodistribution was analysed.ResultsP80-functionalized nanoparticles had a mean size of ∼300 nm, a polydispersity index of ∼0.4 and zeta potential around -50 mV, and they promoted a sustained drug release. Both nanoparticles were effective in decreasing the infection process across the BBB model and reduced drug cytotoxicity and haemolysis. In in vivo cryptococcosis, the oral treatment with two doses of P80 nanoparticles reduced the fungal burden in the brain and lungs, while the non-functionalized nanoparticles reduced fungal amount only in the lungs, and the free miltefosine was not effective. In addition, the P80-functionalization improved the nanoparticle distribution in several organs, especially in the brain. Finally, treatment with nanoparticles did not cause any toxicity in animals.ConclusionsThese results support the potential use of P80-functionalized alginate nanoparticles as miltefosine carriers for non-toxic and effective alternative oral treatment, enabling BBB translocation and reduction of fungal infection in the brain.

Catheter-associated urinary tract infections (CAUTIs) account for 40% of hospital-acquired infections (HAIs). As 20 to 50% of hospitalized patients receive catheters, CAUTIs are one of the most common HAIs, resulting in increased morbidity, mortality, and health care costs. Candida albicans is the second most common CAUTI uropathogen, yet relative to its bacterial counterparts, little is known about how fungal CAUTIs are established. Here, we show that the catheterized bladder environment induces Efg1- and fibrinogen (Fg)-dependent biofilm formation that results in CAUTI. In addition, we identify the adhesin Als1 as the critical fungal factor for C. albicans Fg-urine biofilm formation. Furthermore, we show that in the catheterized bladder, a dynamic and open system, both filamentation and attachment are required, but each by themselves are not sufficient for infection. Our study unveils the mechanisms required for fungal CAUTI establishment, which may aid in the development of future therapies to prevent these infections.

BackgroundVeterans are disproportionately affected by housing insecurity (HI), which can lead to adverse health outcomes and reduced life expectancy. We sought to examine the impact of HI on the outcomes of veterans who underwent abdominal aortic aneurysm (AAA) repair at our regional Veterans Affairs medical center.MethodsRetrospective chart review was performed on patients who underwent AAA repair at our institution between January 1, 2000, and December 31, 2020. We examined medical history, procedure details, hospitalization course, and postoperative outcomes. Primary endpoints were a 30-day mortality and median survival. Secondary endpoints were hospital length of stay, readmission rate, and perioperative complications. Hypothesis testing was performed with t-test and chi-squared analysis. Survival analysis was conducted using Kaplan-Meier estimation.ResultsOf the 314 veterans that underwent AAA repair (mean age of 71.4 ± 7.8 years, 99.7% male) over the 21-year period, we identified 39 (12.4%) patients with a history of HI. The HI was associated with a positive smoking history (100% vs. 88.0%, P = 0.022), lower rate of hypertension diagnosis (69.2% vs. 84.0%, P = 0.024), and increased rate of surgical site infections (SSI) (10.3% vs. 1.8%, P = 0.016). The median postoperative survival was lower in the HI group (7.6 years [CI 6.0-11.2] vs. 8.9 [CI 6.9-10.3]).ConclusionsHI was associated with reduced median postoperative survival, greater readmission rate, and increased risk of SSI following AAA repair.

ObjectiveWe compared the functional outcomes among adolescent athletes with venous thoracic outlet syndrome (VTOS) and neurogenic TOS (NTOS) after thoracic outlet decompression.MethodsWe performed a single-institution retrospective review of a prospective database of adolescent athletes (aged 13-19 years) from June 1, 1996 to December 31, 2021 who had undergone operative decompression for TOS. The demographic data, preoperative symptoms, operative details, and postoperative outcomes were compared. The primary outcome was the postoperative return to sport. The secondary outcomes included symptom resolution and assessment of the somatic pain scale, QuickDASH, and Derkash scores. The Fisher exact test and t test were used to evaluate the categorical and continuous variables, respectively. A logistic regression model was constructed to adjust for the influence of preoperative factors and return to sport.ResultsA total of 60 patients (40.0% with VTOS and 60.0% with NTOS) were included. The average age of the VTOS patients was 17.2 years vs 16.6 years for the NTOS patients (P = .265). The NTOS patients were more likely to be female (88.9% vs 62.5%; P = .024). The NTOS patients had more frequently presented with pain (97.2% vs 70.8%; P = .005), paresthesia (94.4% vs 29.1%; P = .021), and weakness (67.7% vs 12.5%; P = .004) but had less often reported swelling (25.0% vs 95.8%; P < .001). At presentation, the NTOS patients had also reported a longer symptom duration (17.7 months vs 3.1 months; P < .001). Transaxillary first rib resection with subtotal scalenectomy was performed for 100% of the VTOS patients and 94.4% of the NTOS patients undergoing cervical rib resection (2.8%) or scalenectomy alone (2.8%). Additionally, 11.1% of the NTOS patients had undergone combined first rib resection and cervical rib resection. For the VTOS patients, postoperative venography showed patent subclavian veins in 27.8%. In addition, 44.4% had required venoplasty, 16.8% had required thrombolysis, and 11% were chronically occluded. No significant differences were found in blood loss, operative time, or length of stay between the groups. No surgical complications occurred. The average follow-up was 6.3 months. Significant differences were found between the VTOS and NTOS groups for the pre- and postoperative somatic pain scale, QuickDASH, and Derkash scores. Complete symptom resolution had occurred in 83.3% of the VTOS and 75% of the NTOS patients (P = .074). No statistically significant difference in the return to sport was observed between the two groups (VTOS, 94.4%; vs NTOS, 73.9%; P = .123). Of the NTOS patients, 10.0% had had other concomitant injuries and 5.0% had had medical conditions that had precluded their return to sport. Logistic regression found no significant relationship between the preoperative somatic pain scale score, QuickDASH score, or duration of symptoms and the return to sport.ConclusionsAdolescent athletes with VTOS and NTOS can have good functional outcomes, and most will be able to return to sport after surgery. Greater initial symptom severity and concomitant injuries were observed in adolescents with NTOS. Of those who had not returned to sport postoperatively, three of seven had had unrelated health issues that had prevented their return to sport.

BackgroundKawasaki disease (KD) is a systemic vasculitis that mainly affects children under 5 years of age. Up to 30% of patients develop coronary artery abnormalities, which are reduced with early treatment. Timely diagnosis of KD is challenging but may become more straightforward with the recent discovery of a whole-blood host response classifier that discriminates KD patients from patients with other febrile conditions. Here, we bridged this microarray-based classifier to a clinically applicable quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay: the Kawasaki Disease Gene Expression Profiling (KiDs-GEP) classifier.MethodsWe designed and optimized a qRT-PCR assay and applied it to a subset of samples previously used for the classifier discovery to reweight the original classifier.ResultsThe performance of the KiDs-GEP classifier was comparable to the original classifier with a cross-validated area under the ROC curve of 0.964 [95% CI: 0.924-1.00] vs 0.992 [95% CI: 0.978-1.00], respectively. Both classifiers demonstrated similar trends over various disease conditions, with the clearest distinction between individuals diagnosed with KD vs viral infections.ConclusionWe successfully bridged the microarray-based classifier into the KiDs-GEP classifier, a more rapid and more cost-efficient qRT-PCR assay, bringing a diagnostic test for KD closer to the hospital clinical laboratory.ImpactA diagnostic test is needed for Kawasaki disease and is currently not available. We describe the development of a One-Step multiplex qRT-PCR assay and the subsequent modification (i.e., bridging) of the microarray-based host response classifier previously described by Wright et al. The bridged KiDs-GEP classifier performs well in discriminating Kawasaki disease patients from febrile controls. This host response clinical test for Kawasaki disease can be adapted to the hospital clinical laboratory.

BackgroundThoracic outlet syndrome (TOS) is an infrequent condition which results in disability in use of upper extremity. While TOS is often associated with manual labor, industrial workers, and accidents, it has not been reported in a physician (MD) population. Given the investment of time and effort in training to become a MD, the impact of TOS may be devastating. Our objective is to report the presentation and outcome of TOS in MDs.MethodsA prospectively surgical database was reviewed for MDs who sought care of disabling TOS between 1997 and 2022. Demographic, clinical, outcome and pathological data were reviewed. Outcomes were assessed based on Somatic Pain Scale (SPS), Quick Disabilities of Arm, Shoulder and Hand (DASH) scores, and Derkash scores. Results were also assessed based on return to employment.ResultsA total of 19 MDs were identified, from 1,687 TOS cases. The group included 13 (63%) men, 6 (31%) women, average age 45 years (range 27-57). Presentations included 1 (5.3%) arterial TOS (ATOS), 9 (47.4%) venous TOS (VTOS), and 9 (47.4) neurogenic TOS (NTOS). All patients were right-handed, and symptomatic side was dominant hand in 7 (37%) patients. Etiologies included repetitive motion injury, athletic injury, and congenital bony abnormalities. Repetitive motion was associated with 3/9 (33%) NTOS. Significant athletic activities were noted in 12 of 19 (63%) MDs, including 8/9 (89%) VTOS and 4/9 (44%) NTOS. Athletic activities associated with VTOS included triathletes (2), rock climbing (1), long distance swimming (2), and weightlifting (3). Of the 9 NTOS cases, 3 were associated with weightlifting and 1 with skiing. Congenital causes included 1 (5%) abnormal first rib and 1 (5%) cervical rib. Time from symptom onset to consultation varied significantly according to diagnosis: ATOS 6 days, VTOS 97 days, and NTOS 2,335 days (P

Highly pathogenic avian influenza (HPAI) A/H5N1 viruses (lineage 2.3.4.4b) are rapidly invading the Americas, threatening wildlife, poultry, and potentially evolving into the next global pandemic. In November 2022 HPAI arrived in Peru, triggering massive pelican and sea lion die-offs. We report genomic characterization of HPAI/H5N1 in five species of marine mammals and seabirds (dolphins, sea lions, sanderlings, pelicans and cormorants). Peruvian viruses belong to lineage 2.3.4.4b, but they are 4:4 reassortants where 4 genomic segments (PA, HA, NA and MP) position within the Eurasian lineage that initially entered North America from Eurasia, while the other 4 genomic segments (PB2, PB1, NP and NS) position within the American lineage (clade C) that circulated in North America. These viruses are rapidly accruing mutations, including mutations of concern, that warrant further examination and highlight an urgent need for active local surveillance to manage outbreaks and limit spillover into other species, including humans.

Increased mitotic activity is associated with the genesis and aggressiveness of many cancers. To assess the clinical value of mitotic activity as prognostic biomarker, we performed a pan-cancer study on the mitotic network activity index (MNAI) constructed based on 54-gene mitotic apparatus network. Our pan-cancer assessment on TCGA (33 tumor types, 10,061 patients) and validation on other publicly available cohorts (23 tumor types, 9,209 patients) confirmed the significant association of MNAI with overall survival, progression-free survival, and other prognostic endpoints in multiple cancer types, including lower-grade gliomas (LGG), breast invasive carcinoma (BRCA), as well as many others. We also showed significant association between MNAI and genetic instability, which provides a biological explanation of its prognostic impact at pan-cancer landscape. Our association analysis revealed that patients with high MNAI benefitted more from anti-PD-1 and Anti-CTLA-4 treatment. In addition, we demonstrated that multimodal integration of MNAI and the AI-empowered Cellular Morphometric Subtypes (CMS) significantly improved the predictive power of prognosis compared to using MNAI and CMS alone. Our results suggest that MNAI can be used as a potential prognostic biomarker for different tumor types toward different clinical endpoints, and multimodal integration of MNAI and CMS exceeds individual biomarker for precision prognosis.

BackgroundYoghurt can modify gastrointestinal disease risk, possibly acting on gut microbiota. Our study aimed at exploring the under-investigated association between yoghurt and gastric cancer (GC).MethodsWe pooled data from 16 studies from the Stomach Cancer Pooling (StoP) Project. Total yoghurt intake was derived from food frequency questionnaires. We calculated study-specific odds ratios (ORs) of GC and the corresponding 95% confidence intervals (CIs) for increasing categories of yoghurt consumption using univariate and multivariable unconditional logistic regression models. A two-stage analysis, with a meta-analysis of the pooled adjusted data, was conducted.ResultsThe analysis included 6278 GC cases and 14,181 controls, including 1179 cardia and 3463 non-cardia, 1191 diffuse and 1717 intestinal cases. The overall meta-analysis revealed no association between increasing portions of yoghurt intake (continuous) and GC (OR = 0.98, 95% CI = 0.94-1.02). When restricting to cohort studies, a borderline inverse relationship was found (OR = 0.93, 95% CI = 0.88-0.99). The adjusted and unadjusted OR were 0.92 (95% CI = 0.85-0.99) and 0.78 (95% CI = 0.73-0.84) for any vs. no yoghurt consumption and GC risk. The OR for 1 category of increase in yoghurt intake was 0.96 (95% CI = 0.91-1.02) for cardia, 1.03 (95% CI = 1.00-1.07) for non-cardia, 1.12 (95% CI = 1.07-1.19) for diffuse and 1.02 (95% CI = 0.97-1.06) for intestinal GC. No effect was seen within hospital-based and population-based studies, nor in men or women.ConclusionsWe found no association between yoghurt and GC in the main adjusted models, despite sensitivity analyses suggesting a protective effect. Additional studies should further address this association.

BackgroundAccurate and repeatable measurement of high-grade glioma (HGG) enhancing (Enh.) and T2/FLAIR hyperintensity/edema (Ed.) is required for monitoring treatment response. 3D measurements can be used to inform the modified Response Assessment in Neuro-oncology criteria. We aim to develop an HGG volumetric measurement and visualization AI algorithm that is generalizable and repeatable.MethodsA single 3D-Convoluted Neural Network, NS-HGlio, to analyze HGG on MRIs using 5-fold cross validation was developed using retrospective (557 MRIs), multicentre (38 sites) and multivendor (32 scanners) dataset divided into training (70%), validation (20%), and testing (10%). Six neuroradiologists created the ground truth (GT). Additional Internal validation (IV, three institutions) using 70 MRIs, and External validation (EV, single institution) using 40 MRIs through measuring the Dice Similarity Coefficient (DSC) of Enh., Ed. ,and Enh. + Ed. (WholeLesion/WL) tumor tissue and repeatability testing on 14 subjects from the TCIA MGH-QIN-GBM dataset using volume correlations between timepoints were performed.ResultsIV Preoperative median DSC Enh. 0.89 (SD 0.11), Ed. 0.88 (0.28), WL 0.88 (0.11). EV Preoperative median DSC Enh. 0.82 (0.09), Ed. 0.83 (0.11), WL 0.86 (0.06). IV Postoperative median DSC Enh. 0.77 (SD 0.20), Ed 0.78. (SD 0.09), WL 0.78 (SD 0.11). EV Postoperative median DSC Enh. 0.75 (0.21), Ed 0.74 (0.12), WL 0.79 (0.07). Repeatability testing; Intraclass Correlation Coefficient of 0.95 Enh. and 0.92 Ed.ConclusionNS-HGlio is accurate, repeatable, and generalizable. The output can be used for visualization, documentation, treatment response monitoring, radiation planning, intra-operative targeting, and estimation of Residual Tumor Volume among others.

BackgroundDespite advances in early detection and therapies, cancer is still one of the most common causes of death worldwide. Since each tumor is unique, there is a need to implement personalized care and develop robust tools for monitoring treatment response to assess drug efficacy and prevent disease relapse.Main bodyRecent developments in liquid biopsies have enabled real-time noninvasive monitoring of tumor burden through the detection of molecules shed by tumors in the blood. These molecules include circulating tumor nucleic acids (ctNAs), comprising cell-free DNA or RNA molecules passively and/or actively released from tumor cells. Often highlighted for their diagnostic, predictive, and prognostic potential, these biomarkers possess valuable information about tumor characteristics and evolution. While circulating tumor DNA (ctDNA) has been in the spotlight for the last decade, less is known about circulating tumor RNA (ctRNA). There are unanswered questions about why some tumors shed high amounts of ctNAs while others have undetectable levels. Also, there are gaps in our understanding of associations between tumor evolution and ctNA characteristics and shedding kinetics. In this review, we summarize current knowledge about ctNA biology and release mechanisms and put this information into the context of tumor evolution and clinical utility.ConclusionsA deeper understanding of the biology of ctDNA and ctRNA may inform the use of liquid biopsies in personalized medicine to improve cancer patient outcomes.

BackgroundElectronic cigarettes (eC) may not be entirely benign. There is a lack of data on the effect of a single acute exposure of eC vapor using various heating sources and power settings upon lung injury. The purpose of this study was to determine if an acute exposure with eC vapor heated with different heating elements and power levels induced inflammatory changes in the lungs and heart.MethodsRats were exposed to pure air or received a single, 4-h exposure to eC vapor. The devices used either a stainless steel (SS) or nichrome (NC) heating element randomized to a low or high atomization power (45 versus 70 W). Rats were euthanized within 48 h of exposure.ResultsThe eC groups showed accumulation of inflammatory cells in bronchial lumen, near the pleura, and within the alveolar spaces. The numbers of inflammatory cells per field in the lung parenchyma were significantly greater in the rats exposed to eC groups vs. the air group. There were significantly higher inflammatory gene expression changes in the lungs of animals assigned to 70 W power. We observed that eC vapor generated using burnt coils were toxic and could cause acute respiratory distress and myocarditis.ConclusionIn conclusion, one 4-h exposure to eC vapor, in the absence of vitamin E oil or nicotine, significantly increased lung inflammation. Effects were seen after exposures to vapor generated using SS and NC heating elements at either high or low power. Vapor from devices with burnt coils can negatively affect the heart and lung.

ObjectiveOnline resources can be a valuable source of information for patients and have been shown to result in more inquiry during medical office visits, following physician medical recommendation more closely, and making self-directed lifestyle changes. The accessibility to these resources is limited by the readability level of the article and the literacy level of the population. Peripheral artery disease (PAD) is estimated to affect between 8 and 12 million people in the United States with greater disease severity among under insured or uninsured populations. As PAD continues to increase in prevalence, it is imperative that patients have access to comprehensible patient-centered health information. This study aims to evaluate the readability of online PAD patient education materials.MethodsThe search engine Google was used to collect the first 25 patient-accessible online articles pertaining to the search term "peripheral artery disease." Articles were then categorized by source type: hospital, professional society, or other. Readability was measured using the following tests: Automated Readability Index, Coleman-Liau Index, Flesch-Kincaid Grade Level, Gunning Fog, Linsear Write Formula, and the SMOG Index. Statistical analyses were performed using Statistical Analysis Software, with P values less than .05 being statistically significant.ResultsTwenty-five articles were categorized by source and statistically analyzed. The average readability of PAD patient education materials was 10.8 and significantly above the American Medical Association, National Institutes of Health, and US Department of Health and Human Services recommended reading level of sixth grade. Readability scores among source categories were not significantly different.ConclusionsCommonly available online PAD resources are written at a grade level above that currently recommended by medical societies. Hospitals, professional societies, and other stakeholders in PAD patient education should take into consideration the readability of their materials to make medicine more accessible. Readable articles may combat the historic and structural racism often found in our health care system that marginalizes those with lower health literacy. It is imperative to develop patient education at an appropriate level to enrich patient autonomy.

Stem-cell derived in vitro cardiac models have provided profound insights into mechanisms in cardiac development and disease. Efficient differentiation of specific cardiac cell types from human pluripotent stem cells using a three-step Wnt signaling modulation has been one of the major discoveries that has enabled personalized cardiovascular disease modeling approaches. Generation of cardiac cell types follow key development stages during embryogenesis, they intuitively are excellent models to study cardiac tissue patterning in primitive cardiac structures. Here, we provide a brief overview of protocols that have laid the foundation for derivation of stem-cell derived three-dimensional cardiac models. Further this article highlights features and utility of the models to distinguish the advantages and trade-offs in modeling embryonic development and disease processes. Finally, we discuss the challenges in improving robustness in the current models and utilizing developmental principles to bring higher physiological relevance. In vitro human cardiac models are complimentary tools that allow mechanistic interrogation in a reductionist way. The unique advantage of utilizing patient specific stem cells and continued improvements in generating reliable organoid mimics of the heart will boost predictive power of these tools in basic and translational research.

BackgroundAs of early 2022, the Omicron variants are the predominant circulating lineages globally. Understanding neutralizing antibody responses against Omicron BA.1 and BA.2 after vaccine breakthrough infections will provide insights into BA.2 infectivity and susceptibility to subsequent reinfection.MethodsLive virus neutralization assays were used to study immunity against Delta and Omicron BA.1 and BA.2 variants in samples from 86 individuals, 24 unvaccinated (27.9%) and 62 vaccinated (72.1%), who were infected with Delta (n = 42, 48.8%) or BA.1 (n = 44, 51.2%). Among the 62 vaccinated individuals, 39 were unboosted (62.9%), whereas 23 were boosted (37.1%).ResultsIn unvaccinated infections, neutralizing antibodies (nAbs) against the three variants were weak or undetectable, except against Delta for Delta-infected individuals. Both Delta and BA.1 breakthrough infections resulted in strong nAb responses against ancestral wild-type and Delta lineages, but moderate nAb responses against BA.1 and BA.2, with similar titers between unboosted and boosted individuals. Antibody titers against BA.2 were generally higher than those against BA.1 in breakthrough infections.ConclusionsThese results underscore the decreased immunogenicity of BA.1 compared to BA.2, insufficient neutralizing immunity against BA.2 in unvaccinated individuals, and moderate to strong neutralizing immunity induced against BA.2 in Delta and BA.1 breakthrough infections.

BackgroundSARS-CoV-2 nucleocapsid antigen can be detected in plasma, but little is known about its performance as a diagnostic test for acute SARS-CoV-2 infection or infectious viral shedding among nonhospitalized individuals.MethodsWe used data generated from anterior nasal and blood samples collected in a longitudinal household cohort of SARS-CoV-2 cases and contacts. Participants were classified as true positives if polymerase chain reaction (PCR) positive for SARS-CoV-2 and as true negatives if PCR negative and seronegative. Infectious viral shedding was determined by the cytopathic effect from viral culture. Stratified by 7 days after symptom onset, we constructed receiver operating characteristic (ROC) curves to describe optimized accuracy (Youden index), optimized sensitivity, and specificity.ResultsOf 80 participants, 58 (73%) were true positives while 22 (27%) were true negatives. Using the manufacturer's cutoff of 1.25 pg/mL for evaluating infection, sensitivity was higher from 0 to 7 days (77.6% [95% confidence interval {CI}, 64%-88.2%]) than from 8 to 14 days (43.2% [95% CI, 31.1%-54.5%]) after symptom onset; specificity was unchanged at 100% (95% CI, 88.1%-100%). This test had higher sensitivity (100% [95% CI, 88.4%-100%]) and lower specificity (65% [95% CI, 40.8%-84.6%]) for infectious viral shedding as compared with infection, particularly within the first week of symptom onset. Although the presence of N-antigen correlated with infectious viral shedding (r = 0.63; P < .01), sensitivity still declined over time. Additional cutoffs from ROC curves were identified to optimize sensitivity and specificity.ConclusionsWe found that this SARS-CoV-2 N-antigen test was highly sensitive for detecting early but not late infectious viral shedding, making it a viable screening test for community-dwelling individuals to inform isolation practices.

BackgroundWe hypothesize among patients undergoing lower extremity amputation, access to pre-, and post operative rehabilitation services; as well as improved medical care, have led to higher rates of postoperative ambulation, and improved survival.MethodsRetrospective single center review of all major lower extremity amputations performed at the Greater Los Angeles Veterans Affairs Healthcare System from 2000-2020 stratified into multiyear cohorts. We abstracted demographics, operative indication, comorbidities, preoperative medical management, perioperative complications, discharge location, and pre and postoperative ambulatory status. Odds of ambulation after amputation were analyzed using multivariate logistic regression. Survival was analyzed using multivariate logistic regression and Kaplan-Meier survival analysis. Multivariate logistic predictors were selected based on prior literature and clinical experience.ResultsWe identified 654 operations in our study, noting fewer amputations performed in the latest 3 cohort years as compared to the initial cohort (2000-2004). Patients undergoing below-knee amputations (BKA) had 2.7 times (P

ObjectiveManagement of Paget-Schroetter syndrome (PSS) with first rib resection (FRR) and venoplasty is successful in re-establishing subclavian vein (SCV) patency in most cases. However, in cases with subacute or chronic venous occlusion, SCV patency may not be achieved. Thus, the role for FRR remains controversial in cases of subacute or chronic SCV occlusion. Our goal is to determine whether FRR is beneficial in PSS patients with subacute or chronic SCV occlusion.MethodsA prospectively maintained thoracic outlet syndrome (TOS) database was searched for patients undergoing FRR who were identified as having SCV occlusion on preoperative venography between 2012 and 2021. Preoperative and postoperative venous patency were determined by venography. Standardized functional outcomes were assessed using the Quick Disability Arm, Shoulder, Hand (QuickDASH-QDS) and Somatic Pain Scale (SPS) before and after FRR. The Derkash outcome score was recorded after FRR.ResultsOver the study period, 966 TOS operations were performed; of these, 401 were for venous TOS, and 33 patients were identified with subacute or chronic preoperative SCV occlusion verified by venography. The median age was 29 years, with 73% men. Eighteen patients had attempted thrombolysis; eight were performed at our institution, and ten performed at a referring facility. The median time from the symptom onset of SCV occlusion to FRR was 78 days for all patients. For the group that achieved venous patency after FRR, the time from SCV occlusion to FRR was 71 days, and it was 106 days for the group that remained occluded after FRR. All underwent postoperative venography and percutaneous attempt at SCV recanalization. Recanalization was successful in 64% (21) and unsuccessful in 36% (12). All patients experienced improvement in SPS and QDS. For all patients, the average SPS improved from 1.69 preoperatively to 0.25 postoperatively and the average QDS improved from 27.63 preoperatively to 10.19 postoperatively (P > .05). For patients who were successfully recanalized, the final SPS was 0.18 and the final QDS was 11.22 (P > .05). In patients who failed to achieve recanalization, the final SPS was 0.40 and the final QDS was 9.06 (P > .05). All postoperative Derkash outcome scores were excellent and good, with none fair or poor.ConclusionsIn patients with subacute or chronic preoperative SCV occlusion, surgical decompression and postoperative angioplasty resulted in re-establishing SCV patency in 64% of patients. Symptomatic patients clinically improve after surgical decompression regardless of whether venous patency is successfully re-established. These results indicate that symptomatic patients with PSS should be considered for TOS decompression even if their SCV is occluded in the subacute or chronic presentation.

BackgroundHouseholds have emerged as important venues for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. Little is known, however, regarding the magnitude and determinants of household transmission in increasingly vaccinated populations.MethodsFrom September 2020 to January 2022, symptomatic nonhospitalized individuals with SARS-CoV-2 infection by RNA detection were identified within 5 days of symptom onset; all individuals resided with at least 1 other SARS-CoV-2-uninfected household member. These infected persons (cases) and their household members (contacts) were subsequently followed with questionnaire-based measurement and serial nasal specimen collection. The primary outcome was SARS-CoV-2 infection among contacts.ResultsWe evaluated 42 cases and their 74 household contacts. Among the contacts, 32 (43%) became infected, of whom 5 (16%) were asymptomatic; 81% of transmissions occurred by 5 days after the case's symptom onset. From 21 unvaccinated cases, 14-day cumulative incidence of SARS-CoV-2 infection among contacts was 18/40 (45% [95% confidence interval {CI}, 29%-62%]), most of whom were unvaccinated. From 21 vaccinated cases, 14-day cumulative incidence of SARS-CoV-2 infection was 14/34 (41% [95% CI, 25%-59%]) among all contacts and 12/29 (41% [95% CI, 24%-61%]) among vaccinated contacts. At least 1 comorbid condition among cases and 10 or more days of RNA detection in cases were associated with increased risk of infection among contacts.ConclusionsAmong households including individuals with symptomatic SARS-CoV-2 infection, both vaccinated-to-vaccinated and unvaccinated-to-unvaccinated transmission of SARS-CoV-2 to household contacts was common. Because vaccination alone did not notably reduce risk of infection, household contacts will need to employ additional interventions to avoid infection.

Background and aimsWe previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors.Approach and resultsWe analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. The percent of patients with NASH and fibrosis was comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared with subtypes B and C. Subtype A VLDL-TG and VLDL-apolipoprotein B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL5,6 , and remnant lipoprotein cholesterol were lower among subtype A compared with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 NAFLD risk allele were lower in subtype A.ConclusionsMetabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors, with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic versus cardiovascular outcomes, offering clinically relevant risk stratification.

IntroductionAccess to surgical service is limited by provider availability and geographic barriers. Telemedicine ensures that patients can access medical care.ObjectiveThe objective is to describe our use of telemedicine in delivering vascular surgery services to remote locations before and during the COVID-19 pandemic.MethodsWe conducted a retrospective chart review analyzing care delivered at six vascular surgery telemedicine clinics over a 22-month period. We examined vascular diagnoses, recommended interventions, referrals placed, and emergency department visits within 30 days of evaluation. We calculated travel distance saved for patients between their local clinic and our main hospital.ResultsWe identified 94 patients and 144 telemedicine visits, with an average of 1.5 visits per patient (SD = 0.73). The most common referrals were for peripheral artery disease (20.2%) and abdominal aortic aneurysm (14.9%). Three patients were immediately referred to the emergency department due to concern for acute limb ischemia (2) or questionable symptomatic AAA (1). Telemedicine visit recommendations were distributed between no intervention (n = 30, 31.9%), medical management (n = 41, 43.6%), and surgical intervention (n = 23, 24.5%).The surgical intervention cohort was most commonly referred to arterial revascularization (n = 4), venous ablation (n = 4), and arteriovenous fistula procedures (n = 4). Fourteen patients came to our main hospital for surgery and four to local providers. Average travel distance saved per telemedicine visit was 104 miles (SD = 43.7).ConclusionsTelemedicine provided safe, efficient care during the COVID-19 pandemic and saved patients an average of 104 travel miles per visit.

BackgroundEvidence from epidemiological studies on the role of tea drinking in gastric cancer risk remains inconsistent. We aimed to investigate and quantify the relationship between tea consumption and gastric cancer in the Stomach cancer Pooling (StoP) Project consortium.MethodsA total of 9438 cases and 20,451 controls from 22 studies worldwide were included. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) of gastric cancer for regular versus non-regular tea drinkers were estimated by one and two-stage modelling analyses, including terms for sex, age and the main recognised risk factors for gastric cancer.ResultsCompared to non-regular drinkers, the estimated adjusted pooled OR for regular tea drinkers was 0.91 (95% CI: 0.85-0.97). When the amount of tea consumed was considered, the OR for consumption of 1-2 cups/day was 1.01 (95% CI: 0.94-1.09) and for >3 cups/day was 0.91 (95% CI: 0.80-1.03). Stronger inverse associations emerged among regular drinkers in China and Japan (OR: 0.67, 95% CI: 0.49-0.91) where green tea is consumed, in subjects with H. pylori infection (OR: 0.68, 95% CI: 0.58-0.80), and for gastric cardia cancer (OR: 0.64, 95% CI: 0.49-0.84).ConclusionOur results indicate a weak inverse association between tea consumption and gastric cancer.

BackgroundThe causal pathway between high education and reduced risk of gastric cancer (GC) has not been explained. The study aimed at evaluating the mediating role of lifestyle factors on the relationship between education and GC METHODS: Ten studies with complete data on education and five lifestyle factors (smoking, alcohol drinking, fruit and vegetable intake, processed meat intake and salt consumption) were selected from a consortium of studies on GC including 4349 GC cases and 8441 controls. We created an a priori score based on the five lifestyle factors, and we carried out a counterfactual-based mediation analysis to decompose the total effect of education on GC into natural direct effect and natural indirect effect mediated by the combined lifestyle factors. Effects were expressed as odds ratios (ORs) with a low level of education as the reference category.ResultsThe natural direct and indirect effects of high versus low education were 0.69 (95% CI: 0.62-0.77) and 0.96 (95% CI: 0.95-0.97), respectively, corresponding to a mediated percentage of 10.1% (95% CI: 7.1-15.4%). The mediation effect was limited to men.ConclusionsThe mediation effect of the combined lifestyle factors on the relationship between education and GC is modest. Other potential pathways explaining that relationship warrants further investigation.

Steven-Johnson syndrome (SJS) is a rare condition commonly associated with exposure to antibiotics. We have presented the case of a 76-year-old man with end-stage renal disease who had developed SJS after endovascular thrombectomy of hemodialysis access. He had developed epithelial erosions of the mucosal membranes, hemorrhagic bullae to the palmar and plantar surfaces, and erosions of the genitalia. The findings from biopsies of the lip and palm were suggestive of a drug reaction. He developed SJS three times after exposure to iodinated contrast. The one time he did not develop SJS, he had undergone open thrombectomy with no contrast exposure.

Integrating HIV-related care with treatment for substance use disorder provides an opportunity to better meet the needs of people living with these conditions. People with substance use disorder are rendered especially vulnerable by prevailing policies, structural inequalities, and stigmatisation. In this Series paper we analyse existing literature and empirical evidence from scoping reviews on integration designs for the treatment of HIV and substance use disorder, to understand barriers to and facilitators of care integration and to map ways forward. We discuss how approaches to integration address two core gaps in current models: a failure to consider human rights when incorporating the perspectives of people living with HIV and people who use drugs, and a failure to reflect critically on structural factors that determine risk, vulnerability, health-care seeking, and health equity. We argue that successful integration requires a person-centred approach, which is grounded in human rights, treats both concerns holistically, and reconnects with underlying social, economic, and political inequalities.

Introduction and hypothesisThe aims of this study were to evaluate the effectiveness of gelatin methacryloyl as an adjunct to anterior vaginal wall injury with or without vaginal mesh compared with traditional repair with suture.MethodsVirginal cycling Hartley strain guinea pigs (n = 60) were randomized to undergo surgical injury and repair using either polyglactin 910 suture or gelatin methacryloyl for epithelium re-approximation or anterior colporrhaphy with mesh augmentation using either polyglactin 910 suture or gelatin methacryloyl for mesh fixation and epithelium re-approximation. Noninjured controls (n = 5) were also evaluated. After 4 days, 4 weeks, or 3 months, tissues were analyzed by hematoxylin & eosin in addition to immunolabeling for macrophages, leukocytes, smooth muscle, and fibroblasts.ResultsSurgical injury repaired with suture was associated with increased inflammation and vessel density compared with gelatin methacryloyl. Vimentin and α-smooth muscle actin expression were increased with gelatin methacryloyl at 4 days (p = 0.0026, p = 0.0272). There were no differences in changes in smooth muscle or overall histomorphology after 3 months between the two closure techniques. Mesh repair with suture was also associated with increased inflammation and vessel density relative to gelatin methacryloyl. Quantification of collagen content by picrosirius red staining revealed increased thick collagen fibers throughout the implanted mesh with gelatin methacryloyl compared with suture at 4 weeks (0.62 ± 0.01 μm2 vs 0.55 ± 0.01, p = 0.018). Even at the long-term time point of 3 months, mesh repair with suture resulted in a profibrotic encapsulation of the mesh fibers, which was minimal with gelatin methacryloyl. Smooth muscle density was suppressed after mesh implantation returning to baseline levels at 3 months regardless of fixation with suture or gelatin methacryloyl.ConclusionsThese results suggest that gelatin methacryloyl might be a safe alternative to suture for epithelium re-approximation and anchoring of prolapse meshes to the vagina and may improve chronic inflammation in the vaginal wall associated with mesh complications.

BackgroundThe development of precision medicine is essential for personalized treatment and improved clinical outcome, whereas biomarkers are critical for the success of precision therapies.AimTo investigate whether iCEMIGE (integration of CEll-morphometrics, MIcro biome, and GEne biomarker signatures) improves risk stratification of breast cancer (BC) patients.MethodsWe used our recently developed machine learning technique to identify cellular morphometric biomarkers (CMBs) from the whole histological slide images in The Cancer Genome Atlas (TCGA) breast cancer (TCGA-BRCA) cohort. Multivariate Cox regression was used to assess whether cell-morphometrics prognosis score (CMPS) and our previously reported 12-gene expression prognosis score (GEPS) and 15-microbe abundance prognosis score (MAPS) were independent prognostic factors. iCEMIGE was built upon the sparse representation learning technique. The iCEMIGE scoring model performance was measured by the area under the receiver operating characteristic curve compared to CMPS, GEPS, or MAPS alone. Nomogram models were created to predict overall survival (OS) and progress-free survival (PFS) rates at 5- and 10-year in the TCGA-BRCA cohort.ResultsWe identified 39 CMBs that were used to create a CMPS system in BCs. CMPS, GEPS, and MAPS were found to be significantly independently associated with OS. We then established an iCEMIGE scoring system for risk stratification of BC patients. The iGEMIGE score has a significant prognostic value for OS and PFS independent of clinical factors (age, stage, and estrogen and progesterone receptor status) and PAM50-based molecular subtype. Importantly, the iCEMIGE score significantly increased the power to predict OS and PFS compared to CMPS, GEPS, or MAPS alone.ConclusionOur study demonstrates a novel and generic artificial intelligence framework for multimodal data integration toward improving prognosis risk stratification of BC patients, which can be extended to other types of cancer.

ObjectivesCongenital abnormalities of the first rib (ABNFR) are a rare cause of thoracic outlet syndrome (TOS). The range of abnormalities have not been clearly documented in the literature. Surgical decompression in these patients presents with increased complexity secondary to anomalous anatomy. Our goal is to review an institutional experience of first rib resection (FRR) performed for ABNFRs, to present a novel classification system, and to analyze outcomes according to clinical presentation.MethodsA prospectively collected database was used to identify individuals with ABNFRs who underwent FRR for TOS between 1990-2021. These individuals were identified both by preoperative imaging and intraoperative descriptions of the first rib after resection. Demographic, clinical, perioperative and pathological data were reviewed. ABNFRs were classified into 3 categories according to anatomical criteria: (I) Hypoplastic, (II) Fused, and (III) Hyperplastic. Outcomes were rated using the standardized Quick Disability of Arm Shoulder and Hand Scores (QDS), Somatic Pain Scores (SPS) and Derkash Scores (DkS).ResultsAmong the 2200 cases of TOS, there were 19 patients (0.8%) with ABNFR who underwent FRR. Average age at surgery was 30.5 (range 11-74), including 13 men and 6 women. Presentations included 9 arterial (ATOS), 6 neurogenic (NTOS), and 4 venous (VTOS) cases. There were 6 class I, 6 class II, and 7 class III ABNFRs. Among 6 NTOS patients there were 4 abnormal nerve conduction tests and 5 positive anterior scalene muscle blocks. Among the 9 patients with ATOS, thrombolysis was attempted in 5 patients, and of these, 3 ultimately required surgical thrombectomy. Of 4 VTOS cases, 2 were managed with thrombolysis, and 2 with anticoagulation alone. The approach for FRR was transaxillary in all patients. Secondary procedures included 1 pectoralis minor tenotomy, 1 scalenectomy, and 1 contralateral rib resection. No major neurological or vascular complications occurred. There was 1 patient who required surgical evacuation of a hematoma. Intraoperative chest tube placement was required in 5 patients secondary to pleural entry during dissection. There was an overall improvement in symptoms over an average follow-up of 7.4 months. QDS reduced from 49.7 pre-op to 22.1 (P < 0.05). SPS improved from 3.4 pre-op to 1.8. DkS scores were good to excellent in 79% of patients. Residual symptoms were noted in 7, and ATOS accounted for 5 (70%) of these. All patients were able to return to work.ConclusionsDespite increased complexity, ABNFRs may be safely resected via transaxillary approach with low incidence of complications, very good symptom relief, and excellent outcomes. Congenital ABNFRs may by classified into 3 categories (hypoplastic, fused, and hyperplastic) with a variety of presentations, including ATOS, NTOS, and VTOS. Classification of ABNFRs allows concise description of abnormal anatomy which facilitates comparison between series and provides direction for surgical management to ultimately optimize patient outcomes.

BackgroundThe role of allium vegetables on gastric cancer (GC) risk remains unclear.MethodsWe evaluated whether higher intakes of allium vegetables reduce GC risk using individual participant data from 17 studies participating in the "Stomach cancer Pooling (StoP) Project", including 6097 GC cases and 13,017 controls. Study-specific odds ratios (ORs) were pooled using a two-stage modelling approach.ResultsTotal allium vegetables intake was inversely associated with GC risk. The pooled OR for the highest versus the lowest study-specific tertile of consumption was 0.71 (95% confidence interval, CI, 0.56-0.90), with substantial heterogeneity across studies (I2 > 50%). Pooled ORs for high versus low consumption were 0.69 (95% CI, 0.55-0.86) for onions and 0.83 (95% CI, 0.75-0.93) for garlic. The inverse association with allium vegetables was evident in Asian (OR 0.50, 95% CI, 0.29-0.86) but not European (OR 0.96, 95% CI, 0.81-1.13) and American (OR 0.66, 95% CI, 0.39-1.11) studies. Results were consistent across all other strata.ConclusionsIn a worldwide consortium of epidemiological studies, we found an inverse association between allium vegetables and GC, with a stronger association seen in Asian studies. The heterogeneity of results across geographic regions and possible residual confounding suggest caution in results interpretation.

BackgroundHelicobacter pylori is the most important risk factor for non-cardia gastric cancer (NCGC); however, the magnitude of the association varies across epidemiological studies. This study aimed to quantify the association between H. pylori infection and NCGC, using different criteria to define infection status.MethodsA pooled analysis of individual-level H. pylori serology data from eight international studies (1325 NCGC and 3121 controls) from the Stomach Cancer Pooling (StoP) Consortium was performed. Cases and controls with a negative H. pylori infection status were reclassified as positive considering the presence of anti-Cag A antibodies, gastric atrophy, or advanced stage at diagnosis, as available and applicable. A two-stage approach was used to pool study-specific adjusted odds ratios (OR), and 95% confidence intervals (95% CI). A meta-analysis of published prospective studies assessing H. pylori seropositivity in NCGCs was conducted.ResultsThe OR for the association between serology-defined H. pylori and NCGC was 1.45 (95% CI: 0.87-2.42), which increased to 4.79 (95% CI: 2.39-9.60) following the reclassification of negative H. pylori infection. The results were consistent across strata of sociodemographic characteristics, clinical features and lifestyle factors, though significant differences were observed according to geographic region-a stronger association in Asian studies. The pooled risk estimates from the literature were 3.01 (95% CI: 2.22-4.07) for ELISA or EIA and 9.22 (95% CI: 3.12-27.21) for immunoblot or multiplex serology.ConclusionThe NCGC risk estimate from StoP based on the reclassification of H. pylori seronegative individuals is consistent with the risk estimates obtained from the literature. Our classification algorithm may be useful for future studies.

BackgroundEndovenous ablation techniques have replaced greater saphenous vein (GSV) ligation and stripping for treatment of venous insufficiency. Our objective was to investigate our initial procedural experience and clinical presentation of patients undergoing mechanochemical ablation (MOCA) at a single institution. We hypothesized that closure level and success rate improved over time and were comparable to other endovenous ablation techniques.MethodsWe retrospectively reviewed all MOCA procedures performed at the Greater Los Angeles Veterans Affairs Hospital from 2015 - 2020. Variables included CEAP and VCSS scores, patient symptoms, post procedure duplex ultrasound, closure level, and need for anticoagulation. Success was defined as GSV thrombosis on initial post procedure duplex ultrasound. Procedure associated extension of thrombus into the deep veins was defined using the American Venous Forum (AVF) endothermal heat induced thrombosis (EHIT) classification.Results104 venous ablation procedures were performed on 86 patients. Eleven (12.8%) patients received bilateral interventions, and six (7%) patients had asynchronous interventions on the same leg. The average age was 58.4 years (SD 12) and 93% were male. Pre-procedural symptoms included pain (102, 98.1%), varicose veins (87, 83.7%), edema (58, 55.8%), and active ulcers (19, 18.3%). A CEAP category of C2 was the most common indication (34.6%), followed by C3 (22.1%) and C6 (21.2%). Forty-five (43.2%) patients had deep system reflux, and 53% had concomitant phlebectomies. Average VCSS score was 7.5 (SD 3.5).We observed a GSV ablation rate of 92.7% (n = 89) in the 96 procedures which had post-procedure follow up, with no temporal evidence of a learning curve. On post procedure duplex of the 89 technically successful ablations, 77 (86.5%) patients had AVF EHIT level 1 closure, three (3.4%) had level 2 closure, eight (8.9%) had level 3 closure, and one had a level 4 closure. Fourteen (15.7%) patients were newly started on anticoagulation for an average of 33.2 days (SD 34.1). Of the 19 legs treated for active venous ulcers, 13 (68.4%) had improvement or resolution of their venous ulcers. No pulmonary embolic complications were reported.ConclusionsWe observed a successful GSV thrombosis rate of 92.7% using MOCA without evidence of a learning curve and comparable to that reported in the literature. The rate of thrombus extension into the deep veins was 14.6%, with no adverse effects associated with anticoagulation or clinically significant sequelae of AVF EHIT level 2 or greater. Comparisons with MOCA associated thrombus extension into deep veins in the literature are limited as post procedure screening duplex are not standard of care. However, we demonstrated that MOCA ablation of the GSV is a safe procedure that may be performed with good technical success.

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.