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An occluded external iliac venous stent was found eroding through the thigh six years after placement to maintain lower extremity arteriovenous patency. Open retroperitoneal removal was advised, but the patient was too frail for open surgery and was lost to follow-up. She returned three years later with persistent, purulent drainage from the eroded tract. A tine-by-tine excision procedure was chosen and performed under moderate sedation to great success. Appropriate wound healing was confirmed one month postoperatively. This case demonstrates an uncommon lower extremity venous stent removal approach in the context of foreign body migration within a chronic wound.

Background: In recent years, blockchain technology has made great strides in diverse industries but has fallen behind within the pharmaceutical industry. The pharmaceutical industry is complex and would benefit greatly from the distributed database and emphasis of information privacy promoted by blockchain technology. This paper identifies the potential best application for blockchain technology in the United States pharmaceutical industry by identifying current trends, companies exploring the possibilities of blockchain technology, and industry concerns with opportunities for improvement. Methods: We utilized a 4D framework using ease of implementation, novelty, necessity, and fit of the overall industry to examine the adoption of blockchain technology in the pharmaceutical industry. Based on the 2D framework of difficulty and novelty as driving factors for the development of foundational technologies in the world of business by Iansiti and Lakhani in The Harvard Business Review, each application was ranked and scored for the best potential implementation. The potential applications proposed in this paper can be grouped into two main categories. The first category, management, includes best use cases such as health records, clinical trials, and inventory systems. The second category, monitoring, highlights cases such as pharmaceutical products, preventing counterfeits, optimizing supply chains, and addressing prescription misuse and abuse.Results: Each application was ranked by the four metrics in the framework, giving the greatest weight to necessity and ease of implementation. Using the highlighted methodology above, the applications for best implementation include Prescription Drug Misuse and Abuse Prevention, Prevention of Counterfeits, Clinical Trial Outcomes, and Smart Contracts. Conclusion: Blockchain technology offers a new and promising solution to pharmaceutical industry needs. Each application of blockchain technology must fit within the framework of necessary, ease of implementation, familiarity amongst stakeholders, and fit of the overall industry to promote the most appropriate use. By using the extended framework proposed by Iansiti and Lakhani we show that blockchain, in all these domains, shows promise to improve pharmaceutical industry performance.

Abstract An effective human immunodeficiency virus type I (HIV-1) vaccine that robustly elicits broadly neutralizing antibodies (bnAbs) against HIV-1 envelope glycoproteins (Envs) to block viral entry is still not available. Thus, identifying triggers for elicitation of different types of anti-HIV-1 Env antibodies by vaccination could provide further guidance for immunogen design and vaccine development. Here, we studied the immune response to HIV-1 Env immunogens in rabbits. We show that sequential immunizations with conformation-specific Env immunogens can elicit low titer but broad neutralization responses against heterologous, neutralization-resistant (tier 2/3) transmitted/founder (T/F) HIV-1 strains. More importantly, an mRNA vaccine candidate that could mediate the presentation of a cytoplasmic tail-deleted (ΔCT) HIV-1AD8 Env immunogen on virus-like particles significantly increased the neutralization response. This strategy shifted the type of elicited antibodies, decreasing the level of binding to soluble Envs while significantly increasing their overall viral neutralization activity. The breadth and potency of neutralizing response against heterologous, T/F HIV-1 strains significantly increased in a subset of rabbits. Efficient neutralization activity was associated with high cellular immune responses specific to HIV-1 Envs. These results help to understand the immune response to different immunization schemes and will allow developing new approaches to selectively manipulate the type of humoral immune response by specific vaccination.

Vascular Ehlers-Danlos syndrome (VEDS) is rare, affecting an estimated 1 per 50,000 individuals, and is associated with abdominal aortic aneurysms (AAAs), among other arteriopathies. We present three patients with genetically confirmed VEDS who underwent successful open AAA surgical repair and demonstrate that elective open AAA repair with careful tissue manipulation is safe and feasible for patients with VEDS. These cases also demonstrate that the VEDS genotype is associated with the aortic tissue quality (genotype–surgical phenotype correlation), with the most friable tissue encountered in the patient with a large amino acid substitution and the least friable tissue in the patient with a null (haploinsufficiency) variant.

An 80-year-old man presented with a subacute zone 3-5 type B aortic dissection complicated by rupture and visceral and lower extremity malperfusion. He underwent emergent zone 2 repair with a Gore TAG thoracic branch endograft with inclusion of the left subclavian artery for a dominant left vertebral artery. The patient's postoperative course was uncomplicated. Type B aortic dissections can be anatomically complex, and rupture is a rare complication in the subacute phase. We report the novel use of a Gore TAG thoracic branch endograft for the management of type B aortic dissection complicated by rupture and demonstrate its feasibility for patients with type B aortic dissection complicated by rupture.

Objectives The COVID-19 pandemic has required significant modifications of hospital care. The objective of this study was to examine the operational approaches taken by US hospitals over time in response to the COVID-19 pandemic.Design, setting and participants This was a prospective observational study of 17 geographically diverse US hospitals from February 2020 to February 2021.Outcomes and analysis We identified 42 potential pandemic-related strategies and obtained week-to-week data about their use. We calculated descriptive statistics for use of each strategy and plotted percent uptake and weeks used. We assessed the relationship between strategy use and hospital type, geographic region and phase of the pandemic using generalised estimating equations (GEEs), adjusting for weekly county case counts.Results We found heterogeneity in strategy uptake over time, some of which was associated with geographic region and phase of pandemic. We identified a body of strategies that were both commonly used and sustained over time, for example, limiting staff in COVID-19 rooms and increasing telehealth capacity, as well as those that were rarely used and/or not sustained, for example, increasing hospital bed capacity.Conclusions Hospital strategies during the COVID-19 pandemic varied in resource intensity, uptake and duration of use. Such information may be valuable to health systems during the ongoing pandemic and future ones.

Determining the eruption frequency-Magnitude (f-M) relationship for data-limited volcanoes is challenging since it requires a comprehensive eruption record of the past eruptive activity. This is the case for Melimoyu, a long-dormant and data-limited volcano in the Southern Volcanic Zone (SVZ) in Chile with only two confirmed Holocene eruptions (VEI 5). To supplement the eruption records, we identified analogue volcanoes for Melimoyu (i.e., volcanoes that behave similarly and are identified through shared characteristics) using a quantitative and objective approach. Firstly, we compiled a global database containing 181 variables describing the eruptive history, tectonic setting, rock composition, and morphology of 1,428 volcanoes. This database was filtered primarily based on data availability into an input dataset comprising 37 numerical variables for 438 subduction zone volcanoes. Then, we applied Agglomerative Nesting, a bottom-up hierarchical clustering algorithm on three datasets derived from the input dataset: 1) raw data, 2) output from a Principal Component Analysis, and 3) weighted data tuned to minimise the dispersion in the absolute probability per VEI. Lastly, we identified the best set of analogues by analysing the dispersion in the absolute probability per VEI and applying a set of criteria deemed important by the local geological service, SERNAGEOMIN, and VB. Our analysis shows that the raw data generate a low dispersion and the highest number of analogues (n = 20). More than half of these analogues are in the SVZ, suggesting that the tectonic setting plays a key role in the clustering analysis. The eruption f-M relationship modelled from the analogue’s eruption data shows that if Melimoyu has an eruption, there is a 49% probability (50th percentile) of it being VEI≥4. Meanwhile, the annual absolute probability of a VEI≤1, VEI 2, VEI 3, VEI 4, and VEI≥5 eruption at Melimoyu is 4.82 × 10−4, 1.2 × 10−3, 1.45 × 10−4, 9.77 × 10−4, and 8.3 × 10−4 (50th percentile), respectively. Our work shows the importance of using numerical variables to capture the variability across volcanoes and combining quantitative approaches with expert knowledge to assess the suitability of potential analogues. Additionally, this approach allows identifying groups of analogues and can be easily applied to other cases using numerical variables from the global database. Future work will use the analogues to populate an event tree and define eruption source parameters for modelling volcanic hazards at Melimoyu.

Studies have demonstrated that socioeconomic status, insurance, race, and distance impact clinical outcomes in patients with abdominal aortic aneurysms. The purpose of this study was to assess if these factors also impact clinical outcomes in patients with thoracoabdominal aortic aneurysms (TAAAs). We conducted a retrospective review of patients with TAAAs confirmed by computed tomography imaging between 2009 and 2019 at a single institution. Patients' zip codes were mapped to American Community Survey Data to obtain geographic poverty rates. We used the standard U.S. Census definition of high-poverty concentration as >20% of the population living at 100% of the poverty rate. Our primary outcome was overall survival, stratified by whether the patient underwent repair. Of 578 patients, 575 had zip code data and were analyzed. In both the nonoperative (N = 268) and operative (N = 307) groups, there were no significant differences in age, race, comorbidities, clinical urgency, surgery utilization, or surgery modality between patients living in high-poverty areas (N = 95, 16.4%) vs not. In the nonoperative group, patients from high-poverty areas were more likely to have aneurysm due to dissection (37.5% vs 17.6%, P =.03). In multivariate analyses, patients from high-poverty zip codes had significantly worse nonoperative survival (hazard ratio [HR]: 1.9, 95% confidence interval [CI]: 1.1-3.3, P =.03). In the repair group, high poverty was also a significant predictor of reduced postoperative survival (HR: 1.65, 95% CI: 1-2.63, P =.04). Adding the Gagne Index, these differences persisted in both groups (nonoperative: HR: 1.93, 95% CI: 1.01-3.70, P =.05; operative: HR: 1.62, 95% CI: 1.03-2.56, P =.04). In Kaplan-Meier analysis, the difference in postoperative survival began approximately 1.5 years after repair. Private insurance was predictive of improved postoperative survival (HR: 0.42, 95% CI: 0.18-0.95, P =.04) but reduced nonoperative survival (HR: 2.05, 95% 1.01-4.14, P =.04). Data were insufficient to determine if race impacted survival discretely from poverty status. These results were found after adjusting for age, race, sex, maximum aortic diameter, coronary artery disease, distance from the hospital, insurance, and active smoking. Interestingly, in multivariate regression, traveling greater than 100 miles was correlated with increased surgery utilization (odds ratio: 1.58, 95% CI: 1.08-2.33, P =.02) and long-term survival (HR: 0.61, 95% CI: 0.41-0.92, P =.02). Patients with TAAAs living in high-poverty areas had significantly more dissections and suffered a nearly doubled risk of mortality compared with patients living outside such areas. These data suggest that these disparities are attributed to the overall impacts of poverty and highlight the pressing need for research into TAAA disparities. [ABSTRACT FROM AUTHOR]

Abstract This study sought to understand how the programmed death ligand 1 (PD-L1) inhibitor durvalumab and the immunomodulatory agent pomalidomide regulate immune cell activation and function in patients with relapsed/refractory (RR) multiple myeloma (MM). Immunologic changes in peripheral blood and bone marrow of patients treated with durvalumab as monotherapy or in combination with pomalidomide with/without dexamethasone were characterized by assessing subsets of immune cells and gene signatures to understand the immunomodulatory effect of the treatment. Soluble PD-L1 levels were elevated at screening in patients with RRMM but did not correlate with response to durvalumab combination therapy. Immune cell subsets were increased in peripheral blood during treatment with durvalumab and pomalidomide, and combination therapy induced significant gene expression changes in the MM tumor microenvironment versus durvalumab alone. Estimation of cell populations based on RNA sequencing data revealed increased monocytes, neutrophils, and natural killer cells with the combination therapy, but not with durvalumab alone. Additionally, multiplex immunofluorescence of bone marrow demonstrated that immune populations were different in responders versus nonresponders to durvalumab plus pomalidomide with dexamethasone therapy. Overall, durvalumab effectively blocked soluble PD-L1; however, durvalumab monotherapy was not associated with immunologic changes, which were observed with combination therapy.

Objective Determine the pharmacokinetics (PK) and exposure–response of hydroxychloroquine (HCQ) and desethylhydroxychloroquine (DHCQ) in paediatric SLE (pSLE).Methods We conducted an exploratory phase 2, direct-to-family trial. Children enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry with a diagnosis of pSLE were eligible if they were receiving HCQ as standard of care for ≥3 months. Biological samples were collected at up to four visits over a 6-month period. At each visit, plasma was obtained to measure the concentrations of HCQ and DHCQ, as well as cytokines. HCQ and DHCQ plasma PK data were analysed using a population PK modelling approach.Results Twenty-five subjects provided a total of 88 plasma concentrations for PK analysis. There was a poor linear fit between HCQ concentrations and total body weight (R2=0.03). There was a decline in both interferon (IFN)-alpha and IFN-gamma with higher concentrations of HCQ and DHCQ. Volume of distribution for HCQ in plasma was higher in children compared with published values in adults (73 000 L vs 44 000 L), but clearance values in children were similar to adults.Conclusions We report the first population PK model for HCQ and DHCQ in children using data from a novel direct-to-family clinical trial. We observed high interindividual variability in HCQ PK and found that weight-based dosing for HCQ is poorly correlated with drug concentrations, suggesting the need to use therapeutic drug monitoring to individualise dosing. Furthermore, our results suggest that the current weight-based dosing paradigm for HCQ may result in suboptimal drug exposures, particularly for children with obesity. Accordingly, additional studies of HCQ are needed in pSLE to determine the optimal drug concentration and dosing to reduce disease activity and improve outcomes.Trial registration number NCT04358302.

This is the story of a successful risk mitigation effort at Mount Pinatubo in 1991 that could easily have failed. The counterfactuals are the myriad of ways that the effort could have failed but didn’t. Forecasts for a large, VEI 6 eruption were the basis of 10, 20, 30 and, during the climactic eruption, even 40 km radius evacuations. Let’s use the metaphor of a train headed for the destination of successful mitigation, but that could have easily have been derailed or slowed and shunted off to a siding. Among the possible nodes of derailment: capability and trust between responding institutions; external distractions, both natural and man-made; early alert; scientific judgment of whether, when, and how big an eruption will occur; stochastic or unpredictable factors that can make even the best scientific judgment moot; optimal balance between caution and decisive actions, by scientists and civil defense alike; and effective communication between all parties. Potential derailments are detailed at each of these nodes for Pinatubo.

Abstract We summarize major findings and best-practice recommendations from three Volcano Observatory Best Practices (VOBP) workshops, which were held in 2011, 2013 and 2016. The workshops brought together representatives from the majority of the world’s volcano observatories for the purpose of sharing information on the operation and practice of these institutions and making best practice recommendations. The first workshop focused on eruption forecasting, the second on hazard communication, and the third on long-term hazard assessment. Subsequent VOBP workshops will address additional issues of broad interest to the international volcano observatory community. The objective of VOBP is to develop synergy among volcano hazards programs and their observatories internationally, so as to more rapidly and broadly advance the field of applied volcanology. Each of the workshop summaries presented here include best practice recommendations for consideration by the world’s volcano observatories.

Potentially traumatic experiences have been associated with chronic diseases. Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed as an explanation for this association. We examined the association of experiences of trauma with epigenome-wide DNAm among African American mothers (n = 236) and their children aged 3–5 years (n = 232; N = 500), using the Life Events Checklist-5 (LEC) and Traumatic Events Screening Inventory—Parent Report Revised (TESI-PRR). We identified no DNAm sites significantly associated with potentially traumatic experience scores in mothers. One CpG site on the ENOX1 gene was methylome-wide-significant in children (FDR-corrected q-value = 0.05) from the TESI-PRR. This protein-coding gene is associated with mental illness, including unipolar depression, bipolar, and schizophrenia. Future research should further examine the associations between childhood trauma, DNAm, and health outcomes among this understudied and high-risk group. Findings from such longitudinal research may inform clinical and translational approaches to prevent adverse health outcomes associated with epigenetic changes.

Introduction Direct-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.Methods Several design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.Discussion and dissemination Direct-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.Trial registration number ClinicalTrials.gov Registry (NCT04358302).

BackgroundThe tumor microenvironment (TME) is increasingly appreciated as an important determinant of cancer outcome, including in multiple myeloma (MM). However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases.Methods and findingsBetween 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5-29, 49-69 versus 70-82 months, χ2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI -1 to 31, 92-120 versus 113-129 months, χ2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6-36, 49-73 versus 74-90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies.ConclusionsIn this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in particular monocytes and granulocytes, which are often ignored in microenvironment studies.

This study aims to review current issues regarding the application of blockchain technology in health care. We illustrated the various ways in which blockchain can solve current health care issues in three main arenas: data exchange, contracts, and supply chain management. This paper presents several current and projected uses of blockchain technology in the health care industry. We predicted which of these applications are likely to be adopted quickly and provided a supply chain example of tracking the transportation of organs for transplantation.

Gradients of heat and salt affect the propagation of sound energy in the ocean. Anticipated changes in oceanic conditions will alter thermohaline conditions globally, thus altering sound propagation. In this context, we examine changes in shallow-​water propagation. Because these waters are close to the surface, they will be the earliest to change as the atmospheric state and radiative conditions change. We compare current and possible future propagation patterns near fronts and across fronts on continental shelves. Changes in sound pathways between the deep ocean and coastal regions are also examined, including an example from the Arctic Ocean.

IntroductionGeneral life stress has been associated with altered DNA methylation in individuals of African Ancestry, although the relationship between parenting stress and DNA methylation has not been described. The purpose of this study was to examine the relationship between maternal parenting stress and DNA methylation among African Ancestry mother-child dyads.MethodsWe evaluated epigenome-wide DNA methylation relative to parenting stress in 74 mother-child dyads using linear mixed models.ResultsSignificant variation in maternal DNA methylation at 95 CpG sites was associated with level of parenting stress. Notably, we identified a change in DNA methylation associated with poly (ADP-ribose) polymerase-1, which plays a key role in stress signaling. We did not identify any significant variation in child DNA methylation related to maternal parenting stress.ConclusionsHowever, DNA methylation patterns observed in children mirrored patterns observed in their mothers. The results suggest that differential maternal DNA methylation is associated with higher levels of parenting stress.

Guidelines recommend open revascularization (OR) over endovascular revascularization (ER) for the treatment of chronic mesenteric ischemia (CMI) for younger, healthier patients. However, little is known about the long-term costs of these recommendations with respect to patients' overall life expectancy. This study investigated whether 5-year value differs between these treatment modalities. Patient data were extracted from the Statewide Planning and Research Cooperative System, the New York statewide all-payor database containing demographics, diagnoses, treatments, and charges. The database was queried for patients with an International Classification of Diseases , ninth revision, code for CMI, with the specific exclusion of acute ischemia cases. A propensity score match was performed using the Charlson Comorbidity Index, age, sex, race, renal status, and pulmonary disease for the final cohort of patients. Multiple linear regression and mixed effects linear regression were used to determine factors associated with 5-year value, calculated as life-years/$100k in charges. Charges were gathered from the index admission and subsequent admissions for acute or CMI, mesenteric angiography, or follow-up reintervention. Kaplan-Meier estimation was performed for survival and reintervention-free survival. From 2000 to 2014, 875 patients underwent intervention for CMI. Of those meeting inclusion criteria, 209 (28.1%) underwent OR and 535 (71.9%) ER. After propensity score matching (n = 209 in each group), the ER group showed higher value at 5 years after the procedure (8.04 ± 11.42 life-years/$100k charges vs 4.89 ± 5.28 life-years/$100k charges; P <.01). More patients underwent reintervention in the ER group (37 patients vs 17 patients; P <.01), with 55 reinterventions in the ER group and 19 in the OR group (P <.01). Multiple linear regression analysis showed that age, congestive heart failure, dysrhythmia, cancer, and days spent in the intensive care unit were negatively associated with value at 5 years, whereas ER was positively associated. Survival was 59.6 ± 3.76% vs 62.3% ± 3.49% at 5 years (P =.91), and reintervention-free survival was 43.7 ± 3.86% vs 58.1 ± 3.53% (P =.04), for ER and OR respectively. Despite increased reinterventions and lower reintervention-free survival, the value for patients with CMI was higher in those who underwent ER in the largest propensity score-matched cohort to date looking at long-term value. Factors negatively associated with value were OR, age, days in intensive care, congestive heart failure, dysrhythmia, and cancer. In patients with amenable anatomy, ER is validated as the first-choice treatment for CMI based on the superior procedural value. [ABSTRACT FROM AUTHOR]