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Increasing rates of simultaneous heart-kidney (SHK) transplant in the United States exacerbate the overall shortage of deceased donor kidneys (DDK). Current allocation policy does not impose constraints on SHK eligibility, and how best to do so remains unknown. We apply a decision-analytic model to evaluate options for heart transplant (HT) candidates with comorbid kidney dysfunction. We compare SHK with a "Safety Net" strategy, in which DDK transplant is performed 6 months after HT, only if native kidneys do not recover. We identify patient subsets for whom SHK using a DDK is efficient, considering the quality-adjusted life year (QALY) gains from DDKs instead allocated for kidney transplant-only. For an average-aged candidate with a 50% probability of kidney recovery after HT-only, SHK produces 0.64 more QALYs than Safety Net at a cost of 0.58 more kidneys used. SHK is inefficient in this scenario, producing fewer QALYs per DDK used (1.1) than a DDK allocated for KT-only (2.2). SHK is preferred to Safety Net only for candidates with a lower probability of native kidney recovery (24%-38%, varying by recipient age). This finding favors the implementation of a Safety Net provision and should inform the establishment of objective criteria for SHK transplant eligibility.

A potential solution to the deceased donor organ shortage is to expand donor acceptability criteria. The procurement cost implications of using nonstandard donors is unknown. Using 5 years of US organ procurement organization (OPO) data, we built a cost function model to make cost projections: the total cost was the dependent variable; production outputs, including the number of donors and organs procured, were the independent variables. In the model, procuring one kidney or procuring both kidneys from double/en bloc transplantation from a single-organ donor resulted in a marginal cost of $55 k (95% confidence interval [CI] $28 k, $99 k) per kidney, and procuring only the liver from a single-organ donor results in a marginal cost of $41 k (95% CI $12 k, $69 k) per liver. Procuring two kidneys for two candidates from a donor lowered the marginal cost to $36 k (95% CI $22 k, $66 k) per kidney, and procuring two kidneys and a liver lowers the marginal cost to $24 k (95% CI $17 k, $45 k) per organ. Economies of scale were observed, where high OPO volume was correlated with lower costs. Despite higher cost per organ than for standard donors, kidney transplantation from nonstandard donors remained cost-effective based on contemporary US data.

OBJECTIVE The present systematic review and pooled analysis aims to assess the incidence and risk factors for the development of retrograde ejaculation (RE) following first-time open anterior lumbar surgery. METHODS A systematic MEDLINE review via PubMed was performed, identifying 130 clinical papers relating to the topic. Eighteen publications were selected according to predetermined inclusion and exclusion criteria and were used to determine the incidence of RE. Only the publications that provided data on surgical risk factors present specifically in the men in the study were included in the analysis of risk factors. RESULTS Of the 2503 men included, there were 57 reported events of RE (2.3%). Of the cases for which long-term data were provided, 45.8% had resolved by final follow-up. There was a statistically significant increased risk associated with a transperitoneal as opposed to a retroperitoneal approach (8.6% vs 3.2%), as well as with the use of recombinant human bone morphogenetic protein–2 (rhBMP-2) in anterior lumbar interbody fusion (ALIF) as opposed to ALIF with bone graft or arthroplasty in controls (5.0% vs 1.8%). However, when excluding from analysis the patients operated on prior to the FDA’s 2008 warning that commented on the drug’s neuroinflammatory properties, there was no significant difference in rates of RE in patients receiving rhBMP-2 versus the control group (2.4% vs 2.5%). There was no significant difference in risk based on single- versus multilevel procedure or on ALIF versus arthroplasty. CONCLUSIONS In a pooled analysis of currently published data on men undergoing first-time open anterior lumbar surgery, this study found an overall incidence of RE of 2.3%. Nearly half of these patients recovered, reporting resolution of symptoms anywhere between 3 months and 48 months. Analysis of risk factors was limited by a paucity of published literature segregating data by sex. However, there was an increased risk associated with rhBMP-2 only when including data collected prior to the FDA warning on its detrimental properties. The authors therefore posit that the risk of RE is probably overestimated in the literature, given that the vast majority of the data available were collected prior to this warning and given the subsequent implementation of precautions when handling rhBMP-2.

The coronavirus disease 2019 (COVID-19) pandemic has changed health care delivery across the United States. Few analyses have specifically looked at quantifying the financial impact of the pandemic on practicing neurosurgeons. A survey analysis was performed to address this need.A 19-question survey was distributed to practicing neurosurgeons in the United States and its territories. The questions evaluated respondents' assessments of changes in patient and procedural volume, salary and benefits, practice expenses, staffing, applications for government assistance, and stroke management. Responses were stratified by geographic region.The response rate was 5.1% (267/5224). Most respondents from each region noted a50% decrease in clinic volume. Respondents from the Northeast observed a 76% decrease in procedure volume, which was significantly greater than that of other regions (P = 0.003). Northeast respondents were also significantly more likely to have been reassigned to nonneurosurgical clinical duties during the pandemic (P0.001). Most respondents also noted decreased salary and benefits but experienced no changes in overall practice expenses. Most respondents did not experience significant reductions in nursing or midlevel staffing. These trends were not significantly different between regions.The COVID-19 pandemic has led to decreases in patient and procedural volume and physician compensation despite stable practice expenses. Significantly more respondents in the Northeast region noted decreases in procedural volume and reassignment to nonneurosurgical COVID-related medical duties. Future analysis is necessary as the pandemic evolves and the long-term clinical and economic implications become clear.

Objective: Vascular smooth muscle cell (VSMC) plasticity plays a critical role in the development of atherosclerosis. Long noncoding RNAs (lncRNAs) are emerging as important regulators in the vessel wall and impact cellular function through diverse interactors. However, the role of lncRNAs in regulating VSMCs plasticity and atherosclerosis remains unclear. Approach and Results: We identified a VSMC-enriched lncRNA cardiac mesoderm enhancer-associated noncoding RNA (CARMN) that is dynamically regulated with progression of atherosclerosis. In both mouse and human atherosclerotic plaques, CARMN colocalized with VSMCs and was expressed in the nucleus. Knockdown of CARMN using antisense oligonucleotides in Ldlr −/− mice significantly reduced atherosclerotic lesion formation by 38% and suppressed VSMCs proliferation by 45% without affecting apoptosis. In vitro CARMN gain- and loss-of-function studies verified effects on VSMC proliferation, migration, and differentiation. TGF-β1 (transforming growth factor-beta) induced CARMN expression in a Smad2/3-dependent manner. CARMN regulated VSMC plasticity independent of the miR143/145 cluster, which is located in close proximity to the CARMN locus. Mechanistically, lncRNA pulldown in combination with mass spectrometry analysis showed that the nuclear-localized CARMN interacted with SRF (serum response factor) through a specific 600–1197 nucleotide domain. CARMN enhanced SRF occupancy on the promoter regions of its downstream VSMC targets. Finally, knockdown of SRF abolished the regulatory role of CARMN in VSMC plasticity. Conclusions: The lncRNA CARMN is a critical regulator of VSMC plasticity and atherosclerosis. These findings highlight the role of a lncRNA in SRF-dependent signaling and provide implications for a range of chronic vascular occlusive disease states.

Patient-reported outcome measures such as the Pediatric Eye Questionnaire (PedEyeQ) are increasingly recognized as important in healthcare assessment. Defining normal PedEyeQ thresholds would allow classification of individual children as having reduced versus normal domain scores. We prospectively enrolled visually normal children (aged 0-17 years; n = 310) to calculate normal PedEyeQ domain thresholds. In addition, 48 children with bilateral visual impairment (VI; best-eye acuity worse than 20/70 or 20/70 or better with limited visual fields) were enrolled for validation. The Child PedEyeQ (four domains) was completed by 5- to 17-year-olds. Parents completed Proxy (five domains) and Parent PedEyeQ (four domains). Each domain was Rasch scored (converted to 0-100); normal thresholds were defined as the 5th percentile of scores in visually normal controls. For Child 5-11 PedEyeQ, 39%-78% of VI children had reduced domain scores, and 88%-100% for 12- to 17-year-olds. For Proxy PedEyeQ, proportions ranged from 55% to 100% and for Parent PedEyeQ ≥83% had reduced scores. High prevalence of reduced PedEyeQ domain scores in the VI cohort, validates the use of normal thresholds. Nevertheless, variability in child self-reporting creates challenges for identifying individual 5- to 11-year-olds with reduced scores.

ObjectiveTo evaluate the efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with active ankylosing spondylitis (AS).MethodsThis phase III, multicenter, double-blind, placebo-controlled study (ClinicalTrials.gov: NCT01583374) randomized patients with active AS (1:1:1) to placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily for 24 weeks, followed by a long-term extension phase (up to 5 yrs). The primary endpoint was Assessment of the Spondyloarthritis international Society 20 (ASAS20) response at Week 16. The effect of treatment on radiographic outcomes after 104 weeks was assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS).ResultsIn total, 490 patients with active AS were randomized in the study (placebo: n = 164; apremilast 20 mg twice daily: n = 163; apremilast 30 mg twice daily: n = 163). The primary endpoint of ASAS20 response at Week 16 was not met (placebo: 37%; apremilast 20 mg twice daily: 35%; apremilast 30 mg twice daily: 33%; P = 0.44 vs placebo). At Week 104, mean (SD) changes from baseline in mSASSS were 0.83 (3.6), 0.98 (2.2), and 0.57 (1.9) in patients initially randomized to placebo, apremilast 20 mg twice daily, and apremilast 30 mg twice daily, respectively. The most frequently reported adverse events through Week 104 were diarrhea, nasopharyngitis, upper respiratory infection, and nausea.ConclusionNo clinical benefit was observed with apremilast treatment in patients with active AS. The safety and tolerability of apremilast were consistent with its known profile.

Vasoconstrictors are the treatment of choice for hepatorenal syndrome (HRS). We evaluate the real-life effectiveness of a sequential vasoconstrictor regimen of midodrine-octreotide followed by norepinephrine in a nonintensive care unit (non-ICU) setting in the United States, where terlipressin is not available. The diagnosis of HRS and definitions of response to therapy were based on 2015 guidelines from the International Club of Ascites. In adult patients with HRS without partial or full response to oral midodrine and subcutaneous octreotide, norepinephrine was administered at a starting dose of 5 mcg/minute, with a goal to achieve a mean arterial pressure (MAP) of 10 mm Hg above baseline. We assessed predictors of response and treatment outcomes. A total of 61 patients were administered midodrine and octreotide for the treatment of HRS, with a 28% response rate. The median MELD-Na (Model for End-Stage Liver Disease-sodium) score was 30 (interquartile range [IQR] 24-35). Responders were more likely to have alcohol-related liver disease and lower Acute-on-Chronic Liver Failure (ACLF) grade. Of the nonresponders, 20 were then administered norepinephrine, of whom 45% achieved full or partial response. Achieving an MAP increase of ≥10 mm Hg was associated with a greater probability of response. Patients who responded to norepinephrine experienced improved transplant-free survival at 90 days (88% versus 27%; P = 0.02); 5 of 20 patients experienced norepinephrine treatment-related adverse events, namely arrhythmias. Norepinephrine can be effectively used in a non-ICU setting as rescue therapy in patients who have not responded to midodrine and octreotide. Based on these data, we propose a practical stepwise algorithm for vasoconstrictor therapy to manage HRS in situations where terlipressin is not an option.

Background In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed–platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed–platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed–platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab. Patients and methods Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators’ choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed–platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS. Results After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed–platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed–platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed–platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed–platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed–platinum and 66.8% of patients receiving placebo plus pemetrexed–platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off. Conclusions Pembrolizumab plus pemetrexed–platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed–platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed–platinum in patients with previously untreated metastatic nonsquamous NSCLC.

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Pancreatic angiosarcoma is an exceedingly rare malignancy accounting for

There is a lack of normative data for children tested with the electronic Early Treatment for Diabetic Retinopathy Study (E-ETDRS) protocol. In the current cross-sectional study, the mean best-corrected normal and 95% lower tolerance limit for E-ETDRS visual acuity by year in children 7-12 years of age was measured. Our objective was to provide a large normative data set for E-ETDRS visual acuity in children for use in clinical management and clinical trials.

Objective:Peripheral artery disease (PAD) is an atherothrombotic disease of the lower limbs with substantial morbidity and mortality. We used next-generation sequencing to identify genome-wide expression signatures associated with prevalent PAD and its outcomes.Approach and Results:We performed whole blood RNA sequencing among patients with severe symptomatic PAD undergoing lower extremity revascularization and controls. Dysregulated pathways and blood transcriptional modules were identified by comparing patients with PAD (n=42) to age- and sex-matched controls (N=29). The identified signature was compared in patients with PAD before LER with or without incident major adverse cardiac or limb events (MACLE). A novel microRNA associated with prevalent PAD and incident MACLE was then evaluated in a mouse hindlimb ischemia model. One hundred twenty-seven transcripts were differentially expressed (77 upregulated and 50 downregulated; adjustedP0.5) and analyzed using weighted gene co-expression network analysis. Weighted gene co-expression network analysis revealed blood modules enriched for immune activation, secretory granules, and coagulation in patients with PAD. Of these 127 differentially expressed transcripts, 40 were significantly associated with MACLE (log-rank false discovery rate Conclusions:A whole blood transcript signature identified patients with symptomatic PAD and PAD patients at increased risk of MACLE. A previously uncharacterized transcript microRNA-4477b was overexpressed in prevalent PAD, incident MACLE, and in a mouse hindlimb ischemia model. Our novel transcriptomic signature provides insight into potential mechanisms of patients with severe symptomatic PAD.

ObjectiveDetermine the effectiveness of intraosseous basivertebral nerve radiofrequency neurotomy for the treatment of chronic low back pain with type 1 or 2 Modic changes.DesignSystematic review.PopulationPersons aged ≥18 years with chronic low back pain with type 1 or 2 Modic changes.InterventionIntraosseous basivertebral nerve radiofrequency neurotomyComparisonSham, placebo procedure, active standard care treatment, or none.OutcomesThe primary outcome of interest was the proportion of individuals with ≥50% pain reduction. Secondary outcomes included ≥10-point improvement in function as measured by Oswestry Disability Index as well as ≥2-point reduction in pain score on the Visual Analog Scale or Numeric Rating Scale, and decreased use of pain medication.MethodsThree reviewers independently assessed publications before May 15, 2020, in MEDLINE and Embase and the quality of evidence was evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation framework.ResultsOf the 725 publications screened, seven publications with 321 participants were ultimately included. The reported 3-month success rate for ≥50% pain reduction ranged from 45% to 63%. Rates of functional improvement (≥10-point Oswestry Disability Index improvement threshold) ranged from 75% to 93%. For comparison to sham treatment, the relative risk of treatment success defined by ≥50% pain reduction and ≥10-point Oswestry Disability Index improvement was 1.25 (95% confidence interval [CI]: .88—1.77) and 1.38 (95% CI: 1.10—1.73), respectively. For comparison to continued standard care treatment the relative risk of treatment success defined by ≥50% pain reduction and ≥10-point Oswestry Disability Index improvement was 4.16 (95% CI: 2.12–8.14) and 2.32 (95% CI: 1.52–3.55), respectively.ConclusionsThere is moderate-quality evidence that suggests this procedure is effective in reducing pain and disability in patients with chronic low back pain who are selected based on type 1 or 2 Modic changes, among other inclusion and exclusion criteria used in the published literature to date. Success of the procedure appears to be dependent on effective targeting of the BVN. Non-industry funded high-quality, large prospective studies are needed to confirm these findings.

BACKGROUND CONTEXT Positive psychosocial factors early after surgery, such as resilience and self-efficacy, may be important characteristics for informing individualized postoperative care. PURPOSE To examine the association of early postoperative resilience and self-efficacy on 12-month physical function, pain interference, social participation, disability, pain intensity, and physical activity after lumbar spine surgery. STUDY DESIGN/SETTING Pooled secondary analysis of prospectively collected trial data from two academic medical centers. PATIENT SAMPLE Two hundred and forty-eight patients who underwent laminectomy with or without fusion for a degenerative lumbar condition. OUTCOME MEASURES Physical function, pain inference, and social participation (ability to participate in social roles and activities) were measured using the Patient Reported Outcomes Measurement Information System. The Oswestry Disability Index, Numeric Rating Scale, and accelerometer activity counts were used to measure disability, pain intensity, and physical activity, respectively. METHODS Participants completed validated outcome questionnaires at 6 weeks (baseline) and 12 months after surgery. Baseline positive psychosocial factors included resilience (Brief Resilience Scale) and self-efficacy (Pain Self-Efficacy Questionnaire). Multivariable linear regression analyses were used to assess the associations between early postoperative psychosocial factors and 12-month outcomes adjusting for age, sex, study site, randomized group, fusion status, fear of movement (Tampa Scale for Kinesiophobia), and outcome score at baseline. This study was funded by Patient-Centered Outcomes Research Institute and Foundation for Physical Therapy Research. There are no conflicts of interest. RESULTS Resilience at 6 weeks after surgery was associated with 12-month physical function (unstandardized beta=1.85 [95% confidence interval [CI]: 0.29; 3.40]), pain interference (unstandardized beta=−1.80 [95% CI: −3.48; −0.12]), social participation (unstandardized beta=2.69 [95% CI: 0.97; 4.41]), and disability (unstandardized beta=−3.03 [95% CI: −6.04; −0.02]). Self-efficacy was associated with 12-month disability (unstandardized beta=−0.21 [95% CI: −0.37; −0.04]. CONCLUSIONS Postoperative resilience and pain self-efficacy were associated with improved 12-month patient-reported outcomes after spine surgery. Future work should consider how early postoperative screening for positive psychosocial characteristics can enhance risk stratification and targeted rehabilitation management in patients undergoing spine surgery.

With the outbreak of Coronavirus Disease 2019 (COVID-19), came struggles and hardships that were not foreseen. One of these struggles was to maintain an adequate supply of medical equipment, medications, and other necessities to help protect individuals and communities. Proper hand hygiene is an important part of the response to COVID-19. Sanitizing and taking steps to prevent contraction of COVID-19 was a high priority and with the high demand, the availability of hand sanitizer was scare. In March 2020, the US Food and Drug Administration (FDA) released a policy allowing pharmacists to temporarily compound alcohol-based hand sanitizer during the public health emergency. This provided the Purdue University Pharmacy the opportunity to provide this essential service to the Purdue and local community. In collaboration with the Purdue University Pharmacy, four pharmacists, two pharmacy technicians, and five pharmacy students compounded a total of 831.36 liters of hand sanitizer (approximately 220 gallons) during March and April 2020. They packaged the product into smaller bottles (i.e., two ounces) and labeled them according to FDA guidelines. This resulted in over 13,000 bottles of hand sanitizer that was safe for human use. Many of the bottles were donated to campus and community agencies including food pantries and transitional housing and shelters to assist those most in need. While the remaining bottles were sold (at cost) to campus and community members, police departments, fire departments, sanitation departments, funeral homes, libraries, and childcare centers, to name just a few. Pharmacy students reflected on the experience and commented that the initiative impacted them both personally and professionally and provided a way to work together and give back to the community during this challenging time. This community outreach initiative helped to protect community members and allowed the pharmacy students to continue to learn during this uncertain time.

Introduction: Coronary computed tomography angiography (CCTA) is emerging as an important noninvasive testing modality for coronary angiography. The performance characteristic of CCTA in patients with advanced kidney disease is unknown. Methods: We performed a systematic review and meta-analysis of studies specifically investigating the sensitivity and specificity of CCTA compared to coronary angiogram as a reference standard in patients with advanced kidney disease, defined as dialysis dependence or nearing kidney transplantation. Two independent investigators assessed studies for inclusion/exclusion, quality, and characteristics, while a third investigator adjudicated. Results: We identified 4 studies including a total of 217 patients, of whom 159 were dialysis dependent. Three of the 4 studies had a high risk of bias in patient selection and study flow, while 1 study rated low in all areas of bias. The studies were heterogeneous in their patient selection and CCTA protocol but consistent in their definition of obstructive coronary artery disease. The pooled sensitivity and specificity for CCTA were 0.96 (0.87–0.99) and 0.66 (0.57–0.74), respectively. When we restricted the analysis to dialysis-dependent patients, the pooled sensitivity and specificity for CCTA were 0.99 (0.74–1.00) and 0.67 (0.49–0.82), respectively. Conclusions: Based on limited data, CCTA appears to have comparable sensitivity but lower specificity relative to the non-kidney disease population.

Snitching is the act of providing information to the authorities in exchange for rewards. Although snitching is, strictly speaking, a taboo among street offenders and prison inmates worldwide, offenders regard some types of snitching as relatively more acceptable than others. Studies regarding the social meaning of snitching have mostly been conducted with reference to American and European contexts, while the situation in the Asian or Chinese context has not been thoroughly explored. This paper helps to fill a research gap by examining the characteristics of the social meaning of snitching in a severely under-researched context—the inmate culture within Chinese drug detention centers. Our discussion is based on data collected from semi-structured interviews with 28 former inmates of drug detention centers, and it endeavors to explore how offenders conceptualize snitching and why they perceive snitching in the way they do. Our findings show that, while inmates in Chinese drug detention centers generally despise snitching, they see some specific forms of snitching as normal or even necessary. We analyze how inmates rationalize snitching behavior in these specific cases, and argue that this process is shaped by the collective control system implemented in the detention centers: (1) the collective merit system that connects each person’s well-being to the collective well-being, and (2) the informant mechanism that divides inmates into competing factions. Finally, theoretical implications are provided.

Purpose of review Simultaneous heart-liver (SHL) transplants are only a small proportion of overall heart and liver transplantation, they have been increasing in frequency and thus challenge the equitable allocation of organs. Recent findings The incidence of SHL transplants is reviewed along with the outcomes of SHL transplants and their impact on the waitlist, particularly in the context of solitary heart and liver transplantation. The ethical implications, most importantly the principles of utility and equity, of SHL transplant are addressed. In the context of utility, the distinction of a transplant being life-saving versus life-enhancing is investigated. The risk of hepatic decompensation for those awaiting both solitary and combined organ transplantation is an important consideration for the principle of equity. Lastly, the lack of standardization of programmatic approaches to SHL transplant candidates, the national approach to allocation, and the criteria by which programs are evaluated are reviewed. Summary As with all multiorgan transplantation, SHL transplantation raises ethical issues of utility and equity. Given the unique patient population, good outcomes, lack of alternatives, and overall small numbers, we feel there is continued ethical justification for SHL, but a more standardized nationwide approach to the evaluation, listing, and allocation of organs is warranted.

STUDY DESIGN Secondary analysis of randomized controlled trial data. OBJECTIVE The aim of this study was to examine whether preoperative physical performance is an independent predictor of patient-reported disability and pain at 12 months after lumbar spine surgery. SUMMARY OF BACKGROUND DATA Patient-reported outcome measures (PROMs) are commonly used to assess clinical improvement after lumbar spine surgery. However, there is evidence in the orthopedic literature to suggest that PROMs should be supplemented with physical performance tests to accurately evaluate long-term outcomes. METHODS A total of 248 patients undergoing surgery for degenerative lumbar spine conditions were recruited from two institutions. Physical performance tests (5-Chair Stand and Timed Up and Go) and PROMs of disability (Oswestry Disability Index: ODI) and back and leg pain (Brief Pain Inventory) were assessed preoperatively and at 12 months after surgery. RESULTS Physical performance tests and PROMs significantly improved over 12 months following lumbar spine surgery (P

Endometrial carcinoma, the most common gynaecological cancer, develops from endometrial epithelium which is composed of secretory and ciliated cells. Pathologic classification is unreliable and there is a need for prognostic tools. We used single cell sequencing to study organoid model systems derived from normal endometrial endometrium to discover novel markers specific for endometrial ciliated or secretory cells. A marker of secretory cells (MPST) and several markers of ciliated cells (FAM92B, WDR16, and DYDC2) were validated by immunohistochemistry on organoids and tissue sections. We performed single cell sequencing on endometrial and ovarian tumours and found both secretory-like and ciliated-like tumour cells. We found that ciliated cell markers (DYDC2, CTH, FOXJ1, and p73) and the secretory cell marker MPST were expressed in endometrial tumours and positively correlated with disease-specific and overall survival of endometrial cancer patients. These findings suggest that expression of differentiation markers in tumours correlates with less aggressive disease, as would be expected for tumours that retain differentiation capacity, albeit cryptic in the case of ciliated cells. These markers could be used to improve the risk stratification of endometrial cancer patients, thereby improving their management. We further assessed whether consideration of MPST expression could refine the ProMiSE molecular classification system for endometrial tumours. We found that higher expression levels of MPST could be used to refine stratification of three of the four ProMiSE molecular subgroups, and that any level of MPST expression was able to significantly refine risk stratification of the copy number high subgroup which has the worst prognosis. Taken together, this shows that single cell sequencing of putative cells of origin has the potential to uncover novel biomarkers that could be used to guide management of cancers. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The current World Health Organization classification does not distinguish transitional cell carcinoma of the ovary (TCC) from conventional tubo-ovarian high-grade serous carcinoma (HGSC), despite evidence suggesting improved prognosis for patients with TCC; instead, it is considered a morphologic variant of HGSC. The immunohistochemical (IHC) markers applied to date do not distinguish between TCC and HGSC. Therefore, we sought to compare the proteomic profiles of TCC and conventional HGSC to identify proteins enriched in TCC. Prognostic biomarkers in HGSC have proven to be elusive, and our aim was to identify biomarkers of TCC as a way of reliably and reproducibly identifying patients with a favorable prognosis and better response to chemotherapy compared with those with conventional HGSC. Quantitative global proteome analysis was performed on archival material of 12 cases of TCC and 16 cases of HGSC using SP3 (single-pot, solid phase—enhanced, sample preparation)-Clinical Tissue Proteomics, a recently described protocol for full-proteome analysis from formalin-fixed paraffin-embedded tissues. We identified 430 proteins that were significantly enriched in TCC over HGSC. Unsupervised co-clustering perfectly distinguished TCC from HGSC based on protein expression. Pathway analysis showed that proteins associated with cell death, necrosis, and apoptosis were highly expressed in TCCs, whereas proteins associated with DNA homologous recombination, cell mitosis, proliferation and survival, and cell cycle progression pathways had reduced expression. From the proteomic analysis, three potential biomarkers for TCC were identified, claudin-4 (CLDN4), ubiquitin carboxyl-terminal esterase L1 (UCHL1), and minichromosome maintenance protein 7 (MCM7), and tested by IHC analysis on tissue microarrays. In agreement with the proteomic analysis, IHC expression of those proteins was stronger in TCC than in HGSC (p < 0.0001). Using global proteomic analysis, we are able to distinguish TCC from conventional HGSC. Follow-up studies will be necessary to confirm that these molecular and morphologic differences are clinically significant.

Background context The North American Spine Society's (NASS) Evidence Based Clinical Guideline for the Diagnosis and Treatment of Low Back Pain features evidence-based recommendations for diagnosing and treating adult patients with nonspecific low back pain. The guideline is intended to reflect contemporary treatment concepts for nonspecific low back pain as reflected in the highest quality clinical literature available on this subject as of February 2016. PURPOSE The purpose of the guideline is to provide an evidence-based educational tool to assist spine specialists when making clinical decisions for adult patients with nonspecific low back pain. This article provides a brief summary of the evidence-based guideline recommendations for diagnosing and treating patients with this condition. Study design This is a guideline summary review. Methods This guideline is the product of the Low Back Pain Work Group of NASS’ Evidence-Based Clinical Guideline Development Committee. The methods used to develop this guideline are detailed in the complete guideline and technical report available on the NASS website. In brief, a multidisciplinary work group of spine care specialists convened to identify clinical questions to address in the guideline. The literature search strategy was developed in consultation with medical librarians. Upon completion of the systematic literature search, evidence relevant to the clinical questions posed in the guideline was reviewed. Work group members utilized NASS evidentiary table templates to summarize study conclusions, identify study strengths and weaknesses, and assign levels of evidence. Work group members participated in webcasts and in-person recommendation meetings to update and formulate evidence-based recommendations and incorporate expert opinion when necessary. The draft guideline was submitted to an internal and external peer review process and ultimately approved by the NASS Board of Directors. Results Eighty-two clinical questions were addressed, and the answers are summarized in this article. The respective recommendations were graded according to the levels of evidence of the supporting literature. Conclusions The evidence-based clinical guideline has been created using techniques of evidence-based medicine and best available evidence to aid practitioners in the diagnosis and treatment of adult patients with nonspecific low back pain. The entire guideline document, including the evidentiary tables, literature search parameters, literature attrition flowchart, suggestions for future research, and all of the references, is available electronically on the NASS website at https://www.spine.org/ResearchClinicalCare/QualityImprovement/ClinicalGuidelines.aspx

Background Chin-on-chest kyphotic cervical deformity can be debilitating. Surgical deformity correction serves to decompress neural elements and restore lordosis. This can be achieved through multiple osteotomies with instrumentation and fusion, sometimes requiring a staged approach. Such procedures carry a high risk of neurologic injury. Here we present examples of transient neurologic dysfunction not previously reported in the common literature. Case Description The authors present 3 patients who underwent extreme cervical deformity correction for chin-on-chest deformity. Deformity correction in all cases was obtained through multiple osteotomies with multilevel cervicothoracic posterior instrumentation and arthrodesis. On postoperative examination, all 3 patients developed transient ataxia, dysmetria, and decreased proprioception in all 4 extremities—examination findings consistent with dorsal column dysfunction. All symptoms resolved within 2–3 weeks postoperatively. Conclusions Incomplete spinal cord syndromes such as posterior cord syndrome can be caused by compression or stretching of the ascending dorsal spinal tracts. Considering the large degree of correction obtained, we hypothesize the resulting shortening of the dorsal columns as the pathomechanism. Providers should be aware, and patients should be counseled preoperatively that these symptoms may occur. If these symptoms are present postoperatively, appropriate diligence is warranted with the understanding that these deficits may be transient.

Background: Debate on whether to stop fusion at L5 or to extend fusion to S1 in a long spinal construct has been a controversial topic in spine surgery. Fewer data are available to support whether to include a prior solid fusion at L4–L5 or to extend to S1 during a proximal extension of fusion to T10. The purpose of this review is to report and discuss 2 cases of L5 vertebra fracture after proximal extension of solid L4–L5 fusion to T10 and to provide a guideline to surgeons based on the available literature. Methods: Case report and literature review. Results: Literature review identified multiple publications with levels of evidence from level 2 to level 4. Advanced L5–S1 degeneration with long-segment fusion to L5 is reported to be greater than 60% with a new rate of symptom development approaching 20%–25%. There is no prior literature specific to L5 fracture development after thoracic lumbar fusion with the lowest instrumented level at a fused L4–L5 segment. Reoperation rate is not consistently affected by the lowest instrumented vertebral level L5 versus sacrum/ilium. Conclusions: Literature review is inconclusive as to the need to include the lumbosacral junction when performing a proximal extension of fusion from L5 to the thoracic spine, especially during a revision adult deformity surgery. Stress of the long lever arm of a long-segment thoracolumbar fusion above a prior solid L4–L5 fusion could cause the L5 vertebra to split in the coronal plane, resulting in vertebral body fracture even with a mildly degenerated disc at L5–S1 prior to surgery. Level of Evidence: 4.

Chronic opioid usage not only causes addiction behavior through the central nervous system, but also modulates the peripheral immune system. However, how opioid impacts the immune system is still barely characterized systematically. In order to understand the immune modulatory effect of opioids in an unbiased way, here we perform single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from opioid-dependent individuals and controls to show that chronic opioid usage evokes widespread suppression of antiviral gene program in naive monocytes, as well as in multiple immune cell types upon stimulation with the pathogen component lipopolysaccharide. Furthermore, scRNA-seq reveals the same phenomenon after a short in vitro morphine treatment. These findings indicate that both acute and chronic opioid exposure may be harmful to our immune system by suppressing the antiviral gene program. Our results suggest that further characterization of the immune modulatory effects of opioid is critical to ensure the safety of clinical opioids., Over 100 million of opioid prescriptions are issued yearly in the USA alone, but the impact of opioid use on the immune system is barely characterized. Here the authors report antiviral immune response is blunted in several types of blood cells from opioid-dependent individuals, and when healthy donor cells are exposed to morphine in a dish.

Introduction Immune-complex deposition in the transplanted kidney can present as well-phenotyped recurrent or de novo glomerular disease. However, a subset, herein termed immune-complex glomerulopathy not otherwise specified (ICG-NOS), defies classification. We quantified, categorized, and characterized cases of transplant ICG-NOS occurring at a single US academic medical center. Methods We retrospectively reviewed our single-institution pathology database (July 2007–July 2018) to identify and categorize all cases of immune-complex deposition in kidney allografts (based on immunofluorescence microscopy). We extracted clinicopathologic and outcome data for ICG-NOS (i.e., immune complex deposition not conforming to any well-characterized glomerular disease entity). Results Of 104 patients with significant immune deposits, 28 (27%) were classified as ICG-NOS. We created 5 mutually exclusive ICG-NOS categories: Full-house, Quasi-full-house, IgA-rich, C1q-rich, and C1q-poor. Overall, 16 (57%) patients met criteria for definite or possible allograft rejection, including 9 (32%) with antibody-mediated rejection (ABMR), 3 (11%) suspicious for ABMR, 1 (4%) with T-cell–mediated rejection (TCMR), and 9 (32%) with borderline TCMR. After a median follow-up of 2.3 (range, 0.1–14.0) years after biopsy, 7 (25%) allografts had failed and an additional 8 (29%) had persistent renal dysfunction (hematuria, 14%; proteinuria, 21%; and estimated glomerular filtration rate, Graphical abstract

Background The Centers for Disease Control and Prevention have declared that the United States is amidst a continuing opioid epidemic, with drug overdose–related death tripling between 1999 and 2014. Among the 47,055 overdose-related deaths that occurred in 2014, 28,647 (60.9%) of them involved an opioid. Methods To determine if there are specific trends in opioid prescribing practices of specific groups of surgeons to better describe any regional or subspecialty trends that exist, the Part D Prescriber Public Use File was used to evaluate all prescription drug orders for Medicare beneficiaries with a Part D prescription drug plan for the 2015 calendar year. Only those providers with the specialty description corresponding to a surgical specialty were included in this study, using the provider's Part B claims. Results A total of 65,277,932 claims made to Part D by 90,253 surgeons in the 2015 service year were analyzed in this study, demonstrating statistically significant differences in the opioid prescribing practices of surgeons from different states, cities, practice settings, and subspecialties (P, Highlights • A total of 47,055 overdose deaths occurred in 2014; 28,647 (60.9%) of them involved an opioid. • Medicare Part D was queried for information on prescription drug events. • A total of 65,277,932 claims by 90,253 surgeons in the 2015 service year were analyzed. • Prescribing practices differed from surgeons based on states and subspecialties. • Opioid medication claims cost the health care system $133,091,997.81 in benefits.

The construct of frailty was first developed in gerontology to help identify older adults with increased vulnerability when confronted with a health stressor. This article is a review of studies in which frailty has been applied to pre- and post-kidney transplantation (KT) populations. Although KT is the optimal treatment for end-stage kidney disease (ESKD), KT candidates often must overcome numerous health challenges associated with ESKD before receiving KT. After KT, the impacts of surgery and immunosuppression represent additional health stressors that disproportionately impact individuals with frailty. Frailty metrics could improve the ability to identify KT candidates and recipients at risk for adverse health outcomes and those who could potentially benefit from interventions to improve their frail status. The Physical Frailty Phenotype (PFP) is the most commonly used frailty metric in ESKD research, and KT recipients who are frail at KT (~20% of recipients) are twice as likely to die as nonfrail recipients. In addition to the PFP, many other metrics are currently used to assess pre- and post-KT vulnerability in research and clinical practice, underscoring the need for a disease-specific frailty metric that can be used to monitor KT candidates and recipients. Although frailty is an independent risk factor for post-transplant adverse outcomes, it is not factored into the current transplant program risk-adjustment equations. Future studies are needed to explore pre- and post-KT interventions to improve or prevent frailty.

BACKGROUND: Organ scarcity continues in solid organ transplantation, such that the availability of organs limits the number of people able to benefit from transplantation. Medical advancements in managing end-stage organ disease have led to an increasing demand for multi-organ transplant, wherein a patient with multi-organ disease receives more than one organ from the same donor. Current allocation schemes give priority to multi-organ recipients over single-organ transplant recipients, which raises ethical questions regarding equity and utility. METHODS: We use simultaneous liver-kidney (SLK) transplant, a type of multi-organ transplant, as a case study to examine the tension between equity and utility in multi-organ allocation. We adapt the health economics willingness-to-pay threshold to a solid organ transplant setting by coining a new metric: the willingness-to-transplant (WTT) threshold. RESULTS: We demonstrate how the WTT threshold can be used to evaluate different SLK allocation strategies by synthesizing utility and equity perspectives. CONCLUSIONS: We submit that this new framework enables us to distill the question of SLK allocation down to: what is the minimum amount of benefit we require from a deceased donor kidney to allocate it for a particular indication? Addressing the above question will prove helpful to devising a rational system of SLK allocation and is applicable to other transplant settings.

PURPOSE: To evaluate the recently developed Pediatric Eye Questionnaire (PedEyeQ) in visually impaired and visually normal children, as an initial validation of the PedEyeQ. DESIGN: Questionnaire validation study METHODS: 48 children with visual impairment (retinal, cortical, and corneal conditions) and 59 visually normal controls were enrolled at two centers. Five- to 17-year-old children completed the Child PedEyeQ (5–11 and 12–17 year-old versions), and parents completed the Proxy PedEyeQ (0–4, 5–11, 12–17 year-old versions) and the Parent PedEyeQ. Rasch scores were calculated, by age group, for each distinct domain within each age-specific PedEyeQ (converted to 0–100 for interpretation). Domains for the Child PedEyeQ are functional vision, bothered by eyes/vision, social, frustration/worry. Proxy PedEyeQ domains are: functional vision, bothered by eyes/vision, social, frustration/worry, eye-care. Parent PedEyeQ domains are: impact on parent and family, worry about child’s eye condition, worry about child’s self-perception/interactions, worry about child’s functional vision. For each domain, median PedEyeQ scores were compared between visually impaired and visually normal cohorts. RESULTS: Child 5–11 and 12–17 PedEyeQ scores were significantly lower (worse) for visually impaired children than for controls for each domain (P

Retrospective cohort study.The purpose of this investigation was to evaluate the regional variations in the use of nonoperative therapies in patients diagnosed with a lumbar intervertebral disc herniation 3 months prior to undergoing microdiscectomy surgery.Regional variations in the management of chronic pain conditions have been previously identified. Patients suffering from a lumbar intervertebral disc herniation are typically treated with a brief course of conservative management prior to attempting microdiscectomy surgery. Whether regional differences exist in the utilization or costs of maximum nonoperative therapy (MNT) remains unknown.Medical records from patients diagnosed with a lumbar intervertebral disc herniation undergoing 1, 2, or 3-level index microdiscectomy operations between 2007 and 2017 were gathered from the HORTHO insurance database consisting of private/commercially insured and Medicare Advantage beneficiaries. Patient regional designation was divided into Midwest, Northeast, South, and West territories and was derived from the insurance claim location. The utilization of MNT within 3 months after initial lumbar herniation diagnosis in adult patients was analyzed.Our population consisted of 13,106 patients who underwent primary index microdiscectomy surgery. Significant regional variation was identified in the nonoperative therapy failure rate (P0.0001), with the highest proportion of Midwest patients failing (2.7%). There were statistical differences in the regional distribution of patients utilizing NSAIDs (P0.0001), muscle relaxants (P0.0001), lumbar epidural steroid injections (P0.0001), physical therapy and occupational therapy sessions (P0.0001), chiropractor treatments (P0.0001), and emergency department services (P = 0.0049). The total direct cost associated with all MNT prior to microdiscectomy was $13,205,924, with 59.6% from the South, 31.1% from the Midwest, 8.3% from the West, and 1.1% from the Northeast.These findings indicate that regional differences exist in the utilization and costs of MNT of a lumbar intervertebral herniated disc prior to microdiscectomy surgery.3.

The tumor microenvironment (TME), including infiltrated immune cells, is known to play an important role in tumor growth; however, the mechanisms underlying tumor immunogenicity have not been fully elucidated. Here, we discovered an unexpected role for the transcription factor SIX1 in regulating the tumor immune microenvironment. Based on analyses of patient datasets, we found that SIX1 was upregulated in human tumor tissues and that its expression levels were negatively correlated with immune cell infiltration in the TME and the overall survival rates of cancer patients. Deletion of Six1 in cancer cells significantly reduced tumor growth in an immune-dependent manner with enhanced antitumor immunity in the TME. Mechanistically, SIX1 was required for the expression of multiple collagen genes via the TGFBR2-dependent Smad2/3 activation pathway, and collagen deposition in the TME hampered immune cell infiltration and activation. Thus, our study uncovers a crucial role for SIX1 in modulating tumor immunogenicity and provides proof-of-concept evidence for targeting SIX1 in cancer immunotherapy.

BACKGROUND AND OBJECTIVES: In December 2014, the Kidney Allocation System (KAS) was implemented to improve equity in access to transplantation, but preliminary studies in children show mixed results. Thus, we aimed to assess how the 2014 KAS policy change affected racial and ethnic disparities in pediatric kidney transplantation access and related outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a retrospective cohort study of children