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The immunosuppressive tumor microenvironment (TME) is a formidable barrier to the success of adoptive cell therapies for solid tumors. Oncolytic immunotherapy with engineered adenoviruses (OAd) may disrupt the TME by infecting tumor cells, as well as surrounding stroma, to improve the functionality of tumor-directed chimeric antigen receptor (CAR)-T cells, yet efficient delivery of OAds to solid tumors has been challenging. Here we describe how mesenchymal stromal cells (MSCs) can be used to systemically deliver a binary vector containing an OAd together with a helper-dependent Ad (HDAd; combinatorial Ad vector [CAd]) that expresses interleukin-12 (IL-12) and checkpoint PD-L1 (programmed death-ligand 1) blocker. CAd-infected MSCs deliver and produce functional virus to infect and lyse lung tumor cells while stimulating CAR-T cell anti-tumor activity by release of IL-12 and PD-L1 blocker. The combination of this approach with administration of HER.2-specific CAR-T cells eliminates 3D tumor spheroids in vitro and suppresses tumor growth in two orthotopic lung cancer models in vivo. Treatment with CAd MSCs increases the overall numbers of human T cells in vivo compared to CAR-T cell only treatment and enhances their polyfunctional cytokine secretion. These studies combine the predictable targeting of CAR-T cells with the advantages of cancer cell lysis and TME disruption by systemic MSC delivery of oncolytic virotherapy: incorporation of immunostimulation by cytokine and checkpoint inhibitor production through the HDAd further enhances anti-tumor activity.

The ancient Greek novel introduced to the history of literature a new topos: the “complex of emotions.” This became a staple of storytelling and remains widely in use across a variety of genres to the present day. The Hellenistic Jewish text Joseph and Aseneth employs this topos in at least three passages, where it draws attention to the cognitive-emotional aspect of the heroine’s conversion. This is interesting for what it contributes to our understanding of the genre of Aseneth, but it also has social-historical implications. In particular, it supports the idea that Aseneth reflects concerns about Gentile partners in Jewish-Gentile marriages, that Gentile partners might convert out of expedience or that they might be less than fully committed to abandoning “idolatrous” attachments. The representations of deep, grievous, and complex emotions in Aseneth’s transformational turn from idolatry to monolatry, then, might play a psychagogic role for the Gentile reader interested in marrying a Jewish person.

Heparin-induced thrombocytopenia (HIT) is a highly thrombogenic condition. Cancer patients are already at high risk of thrombosis. The treatment and outcomes of HIT in cancer patients are not well established. We retrospectively identified patients with active cancer who were diagnosed with HIT at our institution. Only patients with a positive HIT assay and intermediate to high 4Ts score were included. We assessed patients for baseline characteristics, HIT characteristics, non-heparin agent usage, and outcomes (recurrent thrombosis, bleeding, and death) up to 180 days after diagnosis of HIT. Between November 1, 2006 and December 31, 2016, 39 patients with active cancer received a diagnosis of HIT. Of these, 35.9% had thrombotic complications at diagnosis. Gastrointestinal cancer was the most common solid organ malignancy while myeloproliferative neoplasm (MPN) was the most common hematological malignancy. Fondaparinux was the most often used parenteral agent at any point of follow-up (87.2%), followed by argatroban (41.0%). Less than half the patients transitioned to an oral agent. The recurrent thrombosis rate was 17.9%, the bleeding rate was 20.5%, the major bleeding rate was 10.3%, and the mortality rate was 15.4% in the entire cohort. HIT in cancer patients is associated with poor outcomes.

Purpose To critically review the literature reporting biomechanical outcomes of superior capsular reconstruction (SCR) for the treatment of massive and/or irreparable rotator cuff tears. Methods A systematic review was performed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines using the PubMed, MEDLINE, and Cochrane Library databases in August 2020. Cadaveric studies were assessed for glenohumeral translation, subacromial contact pressure, and superior humeral translation comparing SCR with an intact cuff with reference to a torn control state. Results A total of 15 studies (142 shoulders) were included in our data analysis. SCR showed improvements in superior humeral translation, subacromial contact force, and glenohumeral contact force when biomechanically compared with the massive and/or irreparably torn rotator cuff. No statistically significant differences were found between SCR and the intact rotator cuff regarding superior humeral translation (standard mean difference [SMD], 2.09 mm vs 2.50 mm; P = .54) or subacromial contact force (SMD, 2.85 mPa vs 2.83 mPa; P = .99). Significant differences were observed between SCR and the intact cuff for glenohumeral contact force only, in favor of the intact cuff (SMD, 1.73 N vs 5.45 N; P = .03). Conclusions SCR may largely restore static restraints to superior humeral translation in irreparable rotator cuff tears, although active glenohumeral compression is diminished relative to the intact rotator cuff. Clinical Relevance Investigating the biomechanical outcomes of SCR will help surgeons better understand the effectiveness of this treatment option.

BACKGROUND Same-day bilateral total knee arthroplasty (BiTKA) is a controversial topic in orthopedics, prompting a consensus statement to be released by national experts. To date, no studies have evaluated the trends of this method since these recommendations. This study utilized a national database to evaluate: 1) incidence; 2) patient characteristics; 3) hospital characteristics; and 4) inpatient course for same-day BiTKAs in the United States from 2009 to 2016. METHOD The National Inpatient Sample database was queried for individuals undergoing same-day BiTKAs, yielding 245,138 patients. Patient demographics included age, sex, race, obesity status and Charlson Comorbidity Index (CCI) score. Hospital characteristics consisted of location/teaching status, geographic region, charges, and costs. Inpatient course included length of stay, discharge disposition, and complications. RESULTS Same-day BiTKA incidence decreased from 5.6% to 4.0% over the study (p

Engineered T cells are effective therapies against a range of malignancies, but current approaches rely on autologous T cells, which are difficult and expensive to manufacture. Efforts to develop potent allogeneic T cells that are not rejected by the recipient's immune system require abrogating both T- and natural killer (NK)-cell responses, which eliminate foreign cells through various mechanisms. In the present study, we engineered a receptor that mediates deletion of activated host T and NK cells, preventing rejection of allogeneic T cells. Our alloimmune defense receptor (ADR) selectively recognizes 4-1BB, a cell surface receptor temporarily upregulated by activated lymphocytes. ADR-expressing T cells resist cellular rejection by targeting alloreactive lymphocytes in vitro and in vivo, while sparing resting lymphocytes. Cells co-expressing chimeric antigen receptors and ADRs persisted in mice and produced sustained tumor eradication in two mouse models of allogeneic T-cell therapy of hematopoietic and solid cancers. This approach enables generation of rejection-resistant, 'off-the-shelf', allogeneic T-cell products to produce long-term therapeutic benefit in immunocompetent recipients.

PURPOSE The Affordable Care Act (ACA), enacted in 2010, created the Expansion of Physician Assistant Training (EPAT) grant with the goal of increasing the number of physician assistants (PAs) entering primary care. There has been no analysis regarding the practice patterns of students graduating from EPAT-funded programs. This study aimed to describe the workforce impact of federal investment in PA education through the EPAT program. METHODS In 2018 the authors administered an anonymous electronic survey to all 27 EPAT PA programs funded from 2010 to 2015. The goal was to assess program and graduate characteristics, practice patterns, and intention to apply to similar future opportunities. The survey was IRB exempt. RESULTS There was a 59.30% response rate representing 366 total graduates, which reflected 62.46% of the 586 Health Resources and Services Administration (HRSA)-reported total EPAT-funded students. Of the respondents, 16.41% of EPAT recipients self-identified as non-White, 4.54% indicated Hispanic ethnicity, 53.65% identified as being of disadvantaged status, and 32.92% reported coming from rural backgrounds. Sixty-three percent entered primary care immediately following graduation, while 87.88% reported practicing primary care immediately after graduation or at the last point of contact. Fifty-two percent of EPAT graduates practiced in medically underserved areas (MUAs). CONCLUSION Recipients of HRSA EPAT funding practiced in primary care specialties immediately following graduation at a rate that was 2.5 times higher than the national PA average. This specialty choice was durable for several years post-graduation. The EPAT program funded over 140 PA graduates who immediately practiced in MUAs. This funding supported a more racially and ethnically diverse student population and higher number of students coming from rural areas than the national average for PA students.

Humans expanded out of Africa 50,000-70,000 years ago, but many details of this migration are poorly understood. Here, Haber et al. sequence Y chromosomes belonging to a rare African lineage and analyze..., Present-day humans outside Africa descend mainly from a single expansion out ∼50,000–70,000 years ago, but many details of this expansion remain unclear, including the history of the male-specific Y chromosome at this time. Here, we reinvestigate a rare deep-rooting African Y-chromosomal lineage by sequencing the whole genomes of three Nigerian men described in 2003 as carrying haplogroup DE* Y chromosomes, and analyzing them in the context of a calibrated worldwide Y-chromosomal phylogeny. We confirm that these three chromosomes do represent a deep-rooting DE lineage, branching close to the DE bifurcation, but place them on the D branch as an outgroup to all other known D chromosomes, and designate the new lineage D0. We consider three models for the expansion of Y lineages out of Africa ∼50,000–100,000 years ago, incorporating migration back to Africa where necessary to explain present-day Y-lineage distributions. Considering both the Y-chromosomal phylogenetic structure incorporating the D0 lineage, and published evidence for modern humans outside Africa, the most favored model involves an origin of the DE lineage within Africa with D0 and E remaining there, and migration out of the three lineages (C, D, and FT) that now form the vast majority of non-African Y chromosomes. The exit took place 50,300–81,000 years ago (latest date for FT lineage expansion outside Africa – earliest date for the D/D0 lineage split inside Africa), and most likely 50,300–59,400 years ago (considering Neanderthal admixture). This work resolves a long-running debate about Y-chromosomal out-of-Africa/back-to-Africa migrations, and provides insights into the out-of-Africa expansion more generally.

RESEARCH SUMMARY: In addition to outsourcing the management of correctional facilities, many local and state authorities contract with private companies to provide a variety of services and processes within U.S. courthouses, jails, and prisons. In this article, we explore the various “cost points” at which individuals who make contact with public systems of justice are charged by private entities. We provide two case studies with an in-depth look at how private companies make money within U.S. justice facilities—court-ordered programs and prison services. POLICY IMPLICATIONS: Through our examples, we show the extent to which private companies generate profits within U.S. systems of justice and the potential impacts of justice “cost points” on those involved in these systems. We end by suggesting policy makers more thoroughly explore the reasons for the privatization of justice system practices and services and develop transparent oversight to ensure private arrangements do not impose undue burdens on justice-involved individuals and their families.

Objective To determine outcomes of COVID-19 in patients with Multiple Sclerosis (MS) and related conditions, and to determine predictors of these outcomes. Methods This was a multicenter, observational cohort study of patients with MS or related CNS autoimmune disorders who developed confirmed or highly suspected COVID-19 infection from 2/1/2020 to 12/31/2020. Main Outcome and Measure The primary outcome measure was hospitalization status due to COVID-19. Severity of infection was measured using a 4-point ordinal scale: 1. home care; 2. hospitalization without mechanical ventilation; 3. hospitalization and mechanical ventilation, and 4. death. Results Of 474 patients in the study, 63.3% had confirmed COVID-19 infection and 93.9% were diagnosed with an MS phenotype. Mean age was 45±13 (mean±SD) years, 72% were female, and 86% were treated with a DMT at the time of infection. 58 patients (12.2%) were hospitalized. 24 patients (5.1%) were critically ill (requiring ICU care or outcome of death), of which 15 patients (3.2%) died. Higher neurological disability and older age independently predicted hospitalization. 85% (102/120) of patients with known antibody results not treated with anti-CD20 therapies were seropositive while only 39.5% (17/43) of patients treated with anti-CD20 demonstrated seropositivity (p

Approximately 1-3% of all trauma patients have a renal injury. Eighty percent of renal trauma is due to blunt injury, with the remainder due to penetrating trauma which is most often iatrogenic. Contrast enhanced computed tomography is used to triage patients and offers a quick and accurate assessment of any potential organ injury. If injury is present, The American Association for the Surgery of Trauma grading system can both grade renal injuries and be used to help guide management and intervention. Grades are assigned based on imaging and clinical features of renal trauma, and have prognostic and treatment implications for patients. The objective of this narrative review is to identify optimal management of patients with renal trauma, specifically which patients can be treated with endovascular interventions following renal trauma, which can be observed, and which would be best managed surgically. For hemodynamically stable patients with renal trauma, endovascular angiography and embolization is a non-invasive approach that can be used to control bleeding and potentially avoid surgery or nephrectomy in select cases. Future research is needed to determine if a specific antibiotic regimen is needed prior to or following embolization. Further research is needed to evaluate the effectiveness of endovascular management of high-grade renal trauma (grade V). Complications of renal embolization include short-term hypertension, long term hypertension in cases of significant ischemia, acute kidney injury, and infection.

Objectives Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy (TMA) caused by ADAMTS13 deficiency with mortality of up to 90% in the absence of treatment, typically therapeutic plasma exchange (TPE). TTP presents similarly to other TMAs in which TPE is ineffective and associated with morbidity and additional costs. Thus, we sought to assess clinical and laboratory parameters differentiating TTP from other TMAs in our institution’s catchment population. Methods We reviewed 8 years of data from a Canadian provincial apheresis center, including 100 patients with suspected TMA who underwent ADAMTS13 testing, 35 of whom were diagnosed with TTP. We assessed clinical and laboratory parameters to identify discriminators of TTP and assigned PLASMIC TTP prediction scores. Results We observed a higher frequency of neurologic symptoms, more severe thrombocytopenia, and less creatinine elevation in TTP relative to other TMAs. High PLASMIC scores (6-7 points) had 83% sensitivity and 88% specificity for TTP diagnoses; however, ADAMTS13 activity testing was required for correct diagnoses in 14 cases. Conclusions Clinical and laboratory parameters including PLASMIC scoring may lead to misdiagnosis in some cases of TMA. ADAMST13 activity testing provides definitive diagnosis of TTP, supporting the role of rapid turnaround ADAMTS13 testing for appropriate treatment of TMAs.

Background Despite the well-known clinical effects of midazolam and ketamine, including sedation and memory impairment, the neural mechanisms of these distinct drugs in humans are incompletely understood. The authors hypothesized that both drugs would decrease recollection memory, task-related brain activity, and long-range connectivity between components of the brain systems for memory encoding, pain processing, and fear learning. Methods In this randomized within-subject crossover study of 26 healthy adults, the authors used behavioral measures and functional magnetic resonance imaging to study these two anesthetics, at sedative doses, in an experimental memory paradigm using periodic pain. The primary outcome, recollection memory performance, was quantified with d′ (a difference of z scores between successful recognition versus false identifications). Secondary outcomes were familiarity memory performance, serial task response times, task-related brain responses, and underlying brain connectivity from 17 preselected anatomical seed regions. All measures were determined under saline and steady-state concentrations of the drugs. Results Recollection memory was reduced under midazolam (median [95% CI], d′ = 0.73 [0.43 to 1.02]) compared with saline (d′ = 1.78 [1.61 to 1.96]) and ketamine (d′ = 1.55 [1.12 to 1.97]; P < 0.0001). Task-related brain activity was detected under saline in areas involved in memory, pain, and fear, particularly the hippocampus, insula, and amygdala. Compared with saline, midazolam increased functional connectivity to 20 brain areas and decreased to 8, from seed regions in the precuneus, posterior cingulate, and left insula. Compared with saline, ketamine decreased connectivity to 17 brain areas and increased to 2, from 8 seed regions including the hippocampus, parahippocampus, amygdala, and anterior and primary somatosensory cortex. Conclusions Painful stimulation during light sedation with midazolam, but not ketamine, can be accompanied by increased coherence in brain connectivity, even though details are less likely to be recollected as explicit memories. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Purpose To investigate clinical outcomes after superior capsular reconstruction (SCR) for the treatment of massive and/or irreparable rotator cuff tears treated with either allograft or autograft. Methods Using the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines, in April 2020 a systematic review was performed using PubMed, MEDLINE, EMBASE, and Cochrane databases. Clinical studies were assessed for patient-reported outcomes and range of motion, comparing dermal allografts to fascia lata autografts, with a minimum follow-up of 12 months. Results A total of 16 clinical studies involving 598 patients (606 shoulders) were included for data analysis, with a weighted mean follow-up of 36.9 months (range 12 to 60). Visual analogue scale (VAS) pain scores decreased from 4.0 to 6.9 mm preoperatively to 0 to 2.5 mm postoperatively. American Shoulder & Elbow Surgeons score increased from 20.3 to 54.5 preoperatively to 73.7 to 97.0 postoperatively. Forward flexion increased from 27.0° to 142.7° preoperatively to 134.5° to 167.0° postoperatively. External rotation increased from 13.2° to 41.0° preoperatively to 30.0° to 59.0° postoperatively. Acromiohumeral distance increased from 3.4 to 7.1 mm preoperatively to 6.0 to 9.7 mm postoperatively. The total rates of complications, graft failure, and revision surgery were 5.6%, 13.9%, and 6.9%, respectively. Conclusions Irrespective of tissue source, SCR serves as a reasonable joint-preserving option for massive, irreparable rotator cuff tears, with favorable short- to midterm improvements in patient-reported outcomes and range of motion. Level of Evidence IV, systematic review of level III and IV studies.

Background Use of computer-assisted navigation (CAN) and robotic-assisted (RA) surgery in total knee arthroplasty (TKA) and unicompartmental knee arthroplasty (UKA) both necessitate the use of tracking pins rigidly fixed to the femur and tibia. Although periprosthetic fractures through tracking pin sites are rare, there is a paucity of literature on this potential complication. Therefore, the purpose of this study was to perform a systematic review of the current literature to assess the incidence and clinical outcomes of periprosthetic fractures through tracking pin sites following CAN and RA TKA and UKA. Methods A systematic review was performed following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines using the PubMed, MEDLINE, and Cochrane databases in April 2020. Studies were assessed for the presence of pin site fractures, fracture characteristics, and clinical outcomes. Results Seventeen clinical studies (5 case series, 1 cohort study, and 11 case reports) involving 29 pin-related fractures were included for review. The overall incidence ranged from 0.06% to 4.8%. The mean time from index arthroplasty to fracture was 9.5 weeks (range, 0 to 40 weeks). The majority of fractures occurred in the femoral diaphysis (59%). Nineteen fractures (66%) were displaced and 10 (34%) were nondisplaced or occult. The majority of cases were atraumatic in nature or involved minor trauma and were typically preceded by persistent leg pain. A transcortical pin trajectory, large pin diameter (>4 mm), diaphyseal fixation, multiple placement attempts, and the use of non-self-drilling, non-self-tapping pins were the most commonly reported risk factors for pin-related periprosthetic fractures following CAN or RA TKA. Conclusions Surgeons should maintain a high index of suspicion for pin-related fractures in patients with ongoing leg or thigh pain after CAN or RA TKA in order to avoid fracture displacement and additional morbidity. As CAN and RA TKA have unique complication risks, the debate regarding the value of technology-assisted TKA and its cost-effectiveness continues. Level of evidence Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The COVID-19 global pandemic has had considerable health impact, including sub-Saharan Africa. In Malawi, a resource-limited setting in Africa, gaining access to data to inform the COVID-19 response is challenging. Information on adherence to physical distancing guidelines and reducing contacts are nonexistent, but critical to understanding and communicating risk, as well as allocating scarce resources. We present a case study which leverages aggregated call detail records into a daily data pipeline which summarize population density and mobility in an easy-to-use dashboard for public health officials and emergency operations. From March to April 2021, we have aggregated 6-billion calls and text messages and continue to process 12 million more daily. These data are summarized into reports which describe, quantify, and locate mass gatherings and travel between subdistricts. These reports are accessible via web dashboards for policymakers within the Ministry of Health and Emergency Operations Center to inform COVID-19 response efforts and resource allocation.

Male infertility is a prevalent condition, concerning 5-10% of men. So far, only some recurrent genetic factors have been described as confident contributors to spermatogenic failure. Here, we report the first re-sequencing study of the Y-chromosomal Azoospermia Factor c (AZFc) region combined with gene dosage and Y-haplogroup determination. In analysing 2,324 Estonian men, we uncovered a novel structural variant as a high-penetrant risk factor to male infertility. The Y lineage R1a1-M458, reported at >20% frequency in several European populations, carries a fixed ∼1.6 Mb long r2/r3 inversion destabilizing the AZFc region and predisposing to recurrent microdeletions. Such complex rearrangements were significantly enriched among severe oligozoospermia cases. The carrier vs non-carrier risk to spermatogenic failure was increased 8.6-fold (p = 6.0 × 10−4). The finding contributes to improved molecular diagnostics and clinical management of infertility. Carrier identification in young age will facilitate timely counselling and reproductive decision-making.

Background INR is traditionally used as a marker of clinical coagulopathy, but is suboptimal in liver disease patients due to rebalanced hemostasis and its ineffectiveness to predict bleeding. Rotational thromboelastometry (ROTEM) testing evaluates whole blood hemostasis, which may provide more accurate assessments with the EXTEM CT parameter than INR. Thus, in end-stage liver disease (ESLD) patients, we hypothesized that elevated INRs are associated with normal EXTEM CT values. Methods A retrospective study assessing adult (>18) patients with ESLD and elevated INRs undergoing liver transplantation, was performed to assess correlations between INR and EXTEM CT. This included patients post-ROTEM implementation where all had pre-operative ROTEM testing; and patients up to one year pre-ROTEM implementation to compare transfusion utilization. Data abstracted also included patient demographics, coagulation testing results, liver disease etiology, and MELD score. Results The study included 138 patients in the post-ROTEM group and 59 patients in the pre-ROTEM group. Normal EXTEM CT was observed in 95.3 % and 93 % of patients with INR of 1.3–1.8 and up to 3 respectively. There was no correlation between INR of 1.3–1.8 and EXTEM CT (⍴ = 0.239), and only moderate correlation was observed with higher INRs (⍴ = 0.617 with INRs >1.8). ROTEM-guided transfusion in liver transplant surgeries was associated with reduced plasma transfusion (OR 0.27, 95 % CI 0.12−0.58, p = 0.001) after adjusting for red cell utilization and coagulation testing. Conclusion Our study suggests ROTEM may be advantageous for evaluating coagulopathy in patients with liver disease and ROTEM-guided transfusion reduces plasma transfusion.

Objectives: Despite substantial research linking adverse childhood experiences (ACEs) and health, it is unclear how associations differ by veteran status and military service era (draft, volunteer era). The current study evaluated differences in ACEs and health by veteran status and era, increasing understanding important for service provision as the volunteer era veteran population increases. Methods: Behavioral Risk Factor Surveillance System 2012 data were used in univariate and weighted multivariable logistic regression models to assess associations among veteran status, service era, ACEs, and health. Results: Volunteer era veterans experienced the most ACEs (M = 2.42); draft era veterans experienced the fewest (M = 1.04). Individuals reporting 3 or more ACEs were 3.67 times (95% CI = 3.22-4.19) more likely to endorse depression, 1.32 times (95% CI = 1.17-1.48) more likely to report poorer general health, and 1.77 times (95% CI = 1.58-1.97) more likely to endorse poorer physical health, compared to those reporting none. Volunteer era veterans were 2.43 times more likely to report poorer physical health (95% CI = 1.49-3.97) than draft era veterans, adjusting for ACEs. Conclusions: ACEs were associated with poorer health independent of veteran status and service era. Volunteer era veterans experienced more ACEs; need for trauma-informed services supporting whole health may increase.

Background The niche surgery of same-day bilateral total knee arthroplasty (sd-BTKA) continues to create debate amongst specialists in arthroplasty. To date, there is a significant lack of literature on obese patients undergoing sd-BTKA, and no study has evaluated outcomes of this procedure when compared to non-obese patients. Therefore, this study will perform a retrospective analysis to compare (I) incidence, (II) demographics, and (III) complications of sd-BTKA in non-obese, obese, and morbidly obese patients in the United States from 2009 to 2016. Methods The National Inpatient Sample (NIS) database was queried for all individuals that underwent sd-BTKA from 2009 to 2016. This returned 184,844 non-obese patients, 39,901 obese patients, and 20,394 morbidly obese patients. Analyzed variables included mean age, mean length of stay (LOS), race, payer, age-adjusted Charlson Comorbidity Index score, discharge disposition, hospital charges, hospital costs, and complications. Chi-square analyses and analyses of variance were utilized to assess categorical and continuous variables, respectively. Results Non-obese patients most commonly underwent sd-BTKA over the course of the study. As weight status increased, mean age decreased and the proportion of females, LOS, hospital charges and costs, and proportion of discharges to skilled nursing facilities increased. Regression analysis demonstrated obese and morbidly obese cohorts were at an overall increased odds for experiencing complications. Specifically, obese patients were at increased risk for pulmonary emboli, periprosthetic joint infections, and respiratory failures, while morbidly obese patients are at increased risk for pulmonary emboli, respiratory failures, and urinary tract infections. Conclusions Surgeons should thoroughly evaluate the risks and benefits of performing sd-BTKA on obese and morbidly obese patients, as both confer higher overall complication rates and increased length of stay. More research is necessary to characterize the cost analysis of this procedure, as health care models continue to transition to more cost-effective procedures.

Case A 33-year-old man presented with a closed distal humerus fracture after a fall from scaffolding. Computed tomography demonstrated intra-articular gas, despite the lack of arthrotomy, open fracture, or skin defects. The "vacuum phenomenon" (VP), or the presence of intra-articular gas in closed injuries, has primarily been described in the axial skeleton. To our knowledge, there are no reports in fractures of the elbow. Conclusion The incidence of the VP is under-reported and represents a lack of physician awareness. The VP should remain a diagnosis of exclusion; however, physicians should be aware of this phenomenon to prevent unnecessary patient harm.

Case. Two elderly males presented with traumatic shoulder dislocation and bony Bankart fracture consisting of greater than 25% of the glenoid width. Due to several concomitant factors such as polytrauma, activity level, rotator cuff pathology, optimization of comorbidities, risk of complications, and potential for revision surgery, the patients were treated with reverse shoulder arthroplasty (RSA). Conclusion. RSA may be a satisfactory treatment option for isolated, large glenoid fractures associated with anterior glenohumeral instability in the elderly. These patients are susceptible to rapid deconditioning with prolonged immobilization and may not be medically suited to undergo the prolonged recovery period associated with open reduction internal fixation or potentially undergo revision operations.

Annually, approximately 65,000 inferior vena cava (IVC) filters are placed in the United States (Ahmed et al., J Am Coll Radiol 15:1553–1557, 2018). Approximately 35% of filters are eventually retrieved (Angel et al., J Vasc Interv Radiol 22: 1522–1530 e1523, 2011). Complications during filter retrieval depend heavily on technique and filter position. In this paper, we review risk factors and incidence of complications during IVC filter removal. We also discuss ways these complications could be avoided and the appropriate management if they occur.

OBJECTIVE. Abdominal aortic aneurysm is a significant cause of morbidity and mortality in the United States. Endovascular aneurysm repair (EVAR) is the preferred treatment modality. Surveillance imaging after EVAR detects potential complications. The most common complication is endoleak, which can predispose the aorta to rupture. This article provides a comprehensive and evidence-based review regarding surveillance imaging after EVAR to help readers understand current societal guidelines, guide institutional protocols, and provide a framework to facilitate safe, cost-effective, and clinically relevant imaging of patients after EVAR. CONCLUSION. Lifelong surveillance is necessary for patients who have undergone EVAR. Triple-phase CT angiography (CTA) within 30 days after EVAR is necessary to triage patients appropriately and guide future imaging. Patients without endoleak on initial CTA can be monitored with annual duplex ultrasound. Patients with type I or type III endoleaks should be referred for intervention. Patients with type II and type V endoleaks should be referred for intervention only if the sac diameter grows by more than 1 cm. MR angiography should be used primarily as a problem-solving modality or in patients with contraindications to contrast media or radiation. Strong consideration should be given to more frequent surveillance in patients who have undergone EVAR who have aneurysms with a hostile neck anatomy compared with those patients with favorable neck anatomy.

Waldenström macroglobulinemia is a rare disorder affecting about 1400 people annually in the United States. This case report reviews from a primary care provider’s perspective the initial presentation of a patient who complained of fatigue and dizziness that ultimately led to hospital admission with a diagnosis of Waldenström macroglobulinemia. The referral to hematology/oncology prompting the bone marrow biopsy that led to the diagnosis highlights the important role of the primary care provider in the initial workup, coordination among specialists, and overall management of patients with rare disorders.

Introduction The COVID-19 pandemic has caused widespread disruptions including to health services. In the early response to the pandemic many countries restricted population movements and some health services were suspended or limited. In late 2020 and early 2021 some countries re-imposed restrictions. Health authorities need to balance the potential harms of additional SARS-CoV-2 transmission due to contacts associated with health services against the benefits of those services, including fewer new HIV infections and deaths. This paper examines these trade-offs for select HIV services. Methods We used four HIV simulation models (Goals, HIV Synthesis, Optima HIV and EMOD) to estimate the benefits of continuing HIV services in terms of fewer new HIV infections and deaths. We used three COVID-19 transmission models (Covasim, Cooper/Smith and a simple contact model) to estimate the additional deaths due to SARS-CoV-2 transmission among health workers and clients. We examined four HIV services: voluntary medical male circumcision, HIV diagnostic testing, viral load testing and programs to prevent mother-to-child transmission. We compared COVID-19 deaths in 2020 and 2021 with HIV deaths occurring now and over the next 50 years discounted to present value. The models were applied to countries with a range of HIV and COVID-19 epidemics. Results Maintaining these HIV services could lead to additional COVID-19 deaths of 0.002 to 0.15 per 10,000 clients. HIV-related deaths averted are estimated to be much larger, 19–146 discounted deaths per 10,000 clients. Discussion While there is some additional short-term risk of SARS-CoV-2 transmission associated with providing HIV services, the risk of additional COVID-19 deaths is at least 100 times less than the HIV deaths averted by those services. Ministries of Health need to take into account many factors in deciding when and how to offer essential health services during the COVID-19 pandemic. This work shows that the benefits of continuing key HIV services are far larger than the risks of additional SARS-CoV-2 transmission.

Thyroid nodules are extremely prevalent among older adults, and pose a challenge due to the frequency in which they are incidentally encountered. Approximately 5% of all nodules are malignant. Ultrasound is the first line tool to evaluate thyroid nodules, and can help identify nodules that are high-risk for malignancy. Fine needle aspiration (FNA) is an excellent low-risk procedure used to evaluate suspicious thyroid nodules and identify thyroid malignancy. It is performed with a 22-27-gauge needle under ultrasound guidance. Core needle biopsy (CNB) is usually not required; however, it can be helpful if FNA is non-diagnostic or inconclusive. On-site pathologist evaluation can help determine which patients need additional sampling. CNB is usually performed with a trocar technique using an 18-gauge biopsy device under ultrasound guidance. Complications from thyroid biopsy are rare, and the most common complications are discomfort, small to moderate hematoma, and insufficient sampling. Although rare, a rapidly expanding large hematoma can cause airway compression requiring intubation and surgery to preserve the airway and achieve hemostasis. Following biopsy, approximately 10.8% of thyroid nodules will require surgical excision.

Throughout the Appalachian Mountain chain, entrepreneurs have capitalized on the outdoor sporting experience. Both summer and winter sports such as fly fishing, hiking, skiing and snowboarding are very popular. One popular emerging activity is skeet, trap, and sporting clays shooting. Major tourist enterprises are developing this opportunity for both tourists and the local residents. To meet the increasing demand, ranges are being constructed throughout the region from Alabama to Maine. Within North Carolina that are approximately 12 ranges, with an additional 10 in east Tennessee. Although these activities have had few opponents, sporting clays establishments have received an insignificant number of complaints that the noise level is above the noxious level. A research experiment was designed to test noise levels at one sporting clays course situated near a vacation resort. The first phase of this experiment determined that the noise levels at the source from 12 and 20 gauge shotguns were insignificant. The allowable rounds used are the standard reduced load target load. At the source there was a significant difference between trap (85.85 dBA) and skeet (74.95 dBA). At the closest guest location (second phase) 333 samples were taken between August 2015 and March 2016. The noise level averaged 53.7 dBA (σ = 7.43dBA). During the third phase (January to March 2016) 44 samples were obtained at the main resort lodging site. At Site 2 the noise level averaged 31.9 dBA (σ = 5.45). The fourth and final phase of this study was to determine the noise levels at the closest guest location for each of the 12 sporting clays stations. Ninety-six samples (8 per station) were collected in October 2016. The average noise level was 53.0 dBA (σ 4.19 dBA). An analysis at the statistical confidence level of 97.5% was conducted. First all stations were analyzed in a pairwise comparison analysis. Stations that were not significantly different from one another were combined. Thus the 12 stations were reduced to three combined stations. The analysis determined that the noise level from stations 1 through 5 (48.9dBA, σ =1.50 dBA) was significantly lower than from the other stations. Next loudest was the combinations of stations 6, 7, 10, and 11 (54.1 dBA, σ = 1.69). The last loudest combination was stations 8, 9, and 12 (58.6 dBA, σ = 1.50 dDA). Thus there was a difference of 9.7 dBA between the lowest and the loudest station. Since every 5 dBA difference equates to 2 to 3 times louder, depending on frequency, the loudest station is approximately 4 to 6 times louder that the lowest noise level. However, all stations are below the OSHA Standard. With an annoyance level (60.0 dBA) for the guest activity, the gunshots are less than the nuisance level and significantly less than the permissible level. The few complaints about the noise levels are not supported by the noise level data. A logical conclusion is that the objection is the act of shooting and not the noise level of the shotgun’s sharp or impact report. Potential solutions might be to examine stations 8, 9, and 12 and considering possible relocation, orientation, or emplacement of a thick tree barrier to absorb the reports. Regression analysis was used to develop a highly significant model to predict noise levels with the variables collected. However, this will not solve the complaints from those who object to reports under any circumstance.

Vaccinations are considered one of public health’s greatest accomplishments. Despite evidence for vaccine effectiveness, uptake levels are still well below the Centers for Disease Control and Prevention’s guidelines. The immunization decision-making process for parents is complex and depends on factors associated with knowledge and experiences. This qualitative study sought to expand on a previous decision-making model for immunizations by examining how individuals receive vaccination information, determining the role of experience in influencing decisions, and understanding how young adults might locate vaccination information in the future. Three focus groups were conducted with 29 undergraduate students without children. Results suggest that young adults exhibit an awareness of information regarding vaccine use and effectiveness, value doctor opinions and recommendations, and desire more robust research on vaccinations. Implications of these results include the importance of (1) disseminating vaccination education to young adults, (2) enhancing consistency/trust between medical professionals and youth, and (3) expanding public policy to increase vaccine uptake.

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy (TMA) resulting from severe ADAMTS13 deficiency, which is generally treated with therapeutic plasma exchange (PLEX). Although ADAMTS13 activity is often assayed to differentiate TTP from TMAs not requiring PLEX, technical and logistical constraints often limit rapid turnaround of results, with PLEX initiated based on clinical suspicion of TTP while awaiting ADAMTS13 activity results. We estimated the potential reduction in plasma product use if rapid turnaround ADAMTS13 activity testing were available in our centre. Methods: We reviewed medical records for all Vancouver General Hospital patients with ADAMTS13 activity testing since assay implementation. Patients receiving PLEX but ultimately diagnosed with a disease not requiring PLEX were identified as "potentially avoidable PLEX" (paPLEX), and their plasma product exposures and related blood product costs were estimated. Laboratory results, ADAMTS13 activity, and PLASMIC scores (a validated clinical tool for TTP diagnosis) of this group were compared to those of newly diagnosed TTP patients (N=35). Results: We identified 16 paPLEX patients, including TMAs secondary to malignant hypertension, infection, hemolytic uremic syndrome, illicit drug use, autoimmune renal disease, and malignancy (Table 1). These patients underwent 104 total PLEX cycles (3-12 per patient, median 6), involving 1,428 plasma units (28-199 per patient, median 71.5) and estimated product-associated costs of $187,759 CAD ($140,889 USD). Median platelet counts were significantly lower in TTP than the paPLEX group (7x109/L versus 38x109/L), as was serum creatinine (98µmol/L versus 224µmol/L). PLASMIC scores indicating low or intermediate likelihood of TTP were observed in 63% of patients receiving paPLEX and 17% of patients with TTP. All patients with TTP had ADAMTS13 activity < 10%, while all patients receiving paPLEX had ADAMTS13 activity ≥ 30%. Conclusions: Unnecessary PLEX carries significant patient blood product exposure risks and system costs that may be circumvented if TTP can be reliably distinguished from other TMAs at the time of initial presentation. In our cohort, ADAMTS13 activity results provided clear separation of these groups and improved upon TTP diagnosis by clinical judgement and PLASMIC scores. Rapid turnaround of ADAMTS13 activity testing results has the potential to reduce the unnecessary costs and blood product exposures resulting from PLEX administration to patients with non-TTP TMAs. Figure 1 Disclosures Smith: Alexion: Other: Participated in an advisory board without receiving financial compensation.

INTRODUCTION Activated partial thromboplastin time (PTT) coagulation waveforms produced by optical detection system coagulation analyzers provide additional potentially useful and routinely underutilized information for the evaluation of a patient's coagulation system. We aimed to identify features of PTT coagulation waveforms, available for all PTT assays performed in our hospital laboratories, that may prove useful in directing early investigations in patients with unexplained prolonged PTT. METHODS We retrospectively reviewed 211 PTT coagulation waveforms from patient testing and categorized them based on the underlying hemostatic abnormality: normal, therapeutic anticoagulation, lupus anticoagulant, congenital factor deficiency, or acquired factor VIII inhibitor. We compared quantitative waveform parameters and the frequency of qualitatively abnormal double-peaked first derivative waveform curves between these groups. RESULTS Partial thromboplastin time and derivative curve maxima and minima differed significantly between acquired factor VIII inhibitors and other diagnostic categories, and the second derivative curve minimum demonstrated the highest area under the receiver operator characteristic curve for identification of acquired factor VIII inhibitors (0.860; maximum accuracy: 79.5% for 2Dmin> -39.3 mAbs/s2 [sensitivity 90.5%; specificity 77.2%]). The presence of an abnormal double-peaked first derivative curve had a sensitivity of 83.3% and specificity of 81.6% for identification of acquired factor VIII inhibitors in cases with PTT >50 seconds. CONCLUSION Partial thromboplastin time coagulation waveform analysis can aid in identification of patients with acquired factor VIII inhibitors and may be of clinical utility in directing early laboratory investigations to identify patients at risk of severe bleeding without prompt intervention.

Partial anterior cruciate ligament (ACL) tears are often difficult to diagnose and treat. Recent interest in the literature has focused on performing selective-bundle ACL reconstruction in patients with symptomatic partial ACL tears when one of the ACL bundles is intact. However, the clinical examination, magnetic resonance imaging, and arthroscopic evaluation of partial ACL tears may not correlate, and proper assessment of the integrity of the intact portion of the ACL continues to be a challenge. If a selective-bundle ACL reconstruction is performed in a patient with an apparently intact but structurally damaged individual bundle, the outcome would be compromised by leaving the damaged bundle in place. This technical note provides a description of a simple and reliable arthroscopic method to aid in the diagnosis of a partial ACL tear. The use of this method to assess remaining ligamentous tissue will assist surgeons in deciding for or against selective-bundle ACL reconstruction.

The genomes of present-day humans outside Africa originated almost entirely from a single migration out ~50,000-70,000 years ago[1, 2], followed by mixture with Neanderthals contributing ~2% to all non-Africans [3, 4]. However, the details of this initial migration remain poorly-understood because no ancient DNA analyses are available from this key time period, and interpretation of present-day autosomal data is complicated due to subsequent population movements/reshaping [5]. One locus, however, does retain male-specific information from this early period: the Y-chromosome, where a detailed calibrated phylogeny has been constructed [6]. Three present-day Y lineages were carried by the initial migration: the rare haplogroup D, the moderately rare C, and the very common FT lineage which now dominates most non-African populations [6, 7]. We show that phylogenetic analyses of haplogroup C, D and FT sequences, including very rare deep-rooting lineages, together with phylogeographic analyses of ancient and present-day non-African Y-chromosomes, all point to East/South-east Asia as the origin 50,000-55,000 years ago of all known non-African male lineages (apart from recent migrants). This observation contrasts with the expectation of a West Eurasian origin predicted by a simple model of expansion from a source near Africa [8, 9], and can be interpreted as resulting from extensive genetic drift in the initial population or replacement of early western lineages from the east, thus informing and constraining models of the initial expansion.

Purpose (1) To determine whether examination under anesthesia (EUA) and/or magnetic resonance imaging (MRI) is an accurate means for determining patient selection for a selective-bundle reconstruction, (2) to determine whether the preoperative clinical assessment correlates with the arthroscopic examination, and (3) to examine histologically whether a partial anterior cruciate ligament (ACL) tear is truly partial in terms of vascular insult. Methods This prospective, nonrandomized cohort study included 95 patients who underwent primary ACL reconstruction from January 2013 through May 2014. All patients underwent an EUA, MRI, and arthroscopic evaluation. In patients with partial ACL tears, the intact bundle was resected and underwent histologic examination. The χ2 test was used to compare EUA and MRI in the detection of partial tears. Results Of the 95 patients included, 40 (42%) had EUA findings consistent with a partial ACL tear whereas 22 (23%) had MRI findings interpreted as showing a partial ACL tear. Arthroscopic examination confirmed a partial ACL tear in only 11 patients (12%). The sensitivity of EUA and MRI in the detection of partial ACL tears was 100% and 90.9%, and the specificity was 65% and 85.7%, respectively. The χ2 test suggested statistically significant associations between the method of evaluation and diagnostic outcome [χ2(1) = 7.83, P = .005]. MRI was 1.24 times more likely to correctly identify a partial tear (95% confidence interval, 1.06-1.45). EUA was 2.23 times as likely to incorrectly identify a partial tear (95% confidence interval, 1.24-4.02). The histologic analysis showed increased numbers of lymphocytes, absent polymorphonuclear leukocytes, predominant fibroblasts, neovascularization, and variable collagen orientation. Conclusions There is a disparity between EUA, MRI, and arthroscopic findings in the evaluation of partial ACL tears. Arthroscopy remains the gold standard for diagnosing the macroscopic integrity of the intact bundle. Microscopic analysis reveals that the integrity of the remaining intact ligament material is altered and may show a histologic response similar to a complete ACL rupture. Level of Evidence Level III, prospective, nonrandomized cohort study.

Iatrogenic injury is unfortunately a leading cause of morbidity and mortality for patients worldwide. The etiology of iatrogenic injury is broad, and can be seen with both diagnostic and therapeutic interventions. While steps can be taken to reduce the occurrence of iatrogenic injury, it is often not completely avoidable. Once iatrogenic injury has occurred, prompt recognition and appropriate management can help reduce further harm. The objective of this narrative review it to help reader better understand the risk factors associated with, and treatment options for a broad range of potential iatrogenic injuries by presenting a series of iatrogenic injury cases. This review also discusses rates, risk factors, as well as imaging and clinical signs of iatrogenic injury with an emphasis on endovascular and minimally invasive treatments. While iatrogenic vascular injury once required surgical intervention, now minimally invasive endovascular treatment is a potential option for certain patients. Further research is needed to help identify patients that are at the highest risk for iatrogenic injury, allowing patients and providers to reconsider or avoid interventions where the risk of iatrogenic injury may outweigh the benefit. Further research is also needed to better define outcomes for patients with iatrogenic vascular injury treated with minimally invasive endovascular techniques verses conservative management or surgical intervention.

Background Patients with heart failure (HF) can be affected by disabling symptoms and low quality of life. Furthermore, they may frequently need to visit the emergency department or be hospitalized due to their condition deteriorating. Home telemonitoring can play a role in tracking symptoms, reducing hospital visits, and improving quality of life. Objective Our objective was to conduct a feasibility study of a home health monitoring (HHM) solution for patients with HF in British Columbia, Canada, to prepare for conducting a randomized controlled trial. Methods Patients with HF were recruited from 3 urban hospitals and provided with HHM technology for 60 days of monitoring postdischarge. Participants were asked to monitor their weight, blood pressure, and heart rate and to answer symptomology questions via Bluetooth sensors and a tablet computer each day. A monitoring nurse received this data and monitored the patient’s condition. In our evaluation, the primary outcome was the combination of unscheduled emergency department revisits of discharged participants or death within 90 days. Secondary outcomes included 90-day hospital readmissions, patient quality of life (as measured by Veterans Rand 12-Item Health Survey and Kansas City Cardiomyopathy Scale), self-efficacy (as measured by European Heart Failure Self-Care Behaviour Scale 9), end-user experience, and health system cost-effectiveness including cost reduction and hospital bed capacity. In this feasibility study, we also tested the recruitment strategy, clinical protocols, evaluation framework, and data collection methods. Results Seventy participants were enrolled into this trial. Participant engagement to monitoring was measured at 94% (N=70; ie, data submitted 56/60 days on average). Our evaluation framework allowed us to collect sound data, which also showed encouraging trends: a 79% reduction of emergency department revisits post monitoring, an 87% reduction in hospital readmissions, and a 60% reduction in the median hospital length of stay (n=36). Cost of hospitalization for participants decreased by 71%, and emergency department visit costs decreased by 58% (n=30). Overall health system costs for our participants showed a 56% reduction post monitoring (n=30). HF-specific quality of life (Kansas City Cardiomyopathy Scale) scores showed a significant increase of 101% (n=35) post monitoring (P Conclusions Results from this small-sample feasibility study suggested that our HHM intervention can be beneficial in supporting patients post discharge. Additionally, key insights from the trial allowed us to refine our methods and procedures, such as shifting our recruitment methods to in-patient wards and increasing our scope of data collection. Although these findings are promising, a more rigorous trial design is required to test the true efficacy of the intervention. The results from this feasibility trial will inform our next step as we proceed with a randomized controlled trial across British Columbia. Trial Registration ClinicalTrials.gov NCT03439384; https://clinicaltrials.gov/ct2/show/NCT03439384

A survey conducted at six Florida regions examines participants’ perceptions of public archaeology outreach programs on cultural heritage preservation. The findings for participants’ perceptions showed that the Florida Public Archaeology Network is reaching the organizational goal in creating appreciation and awareness for cultural heritage. Statistical analysis demonstrated a correlation between the programs being educational and changing participants’ perceptions in archaeology, and participants’ perceptions being changed and creating a love for cultural heritage and archaeology. These responses will information how public archaeology programs are impacting Florida’s cultural heritage through citizen science programs focused on preserving the past.

The spleen is the most commonly injured organ in blunt abdominal trauma. Unstable patients undergo laparotomy and splenectomy. Stable patients with lower grade injuries are treated conservatively; those stable patients with moderate to severe splenic injuries (grade III-V) benefit from endovascular splenic artery embolization. Two widely used embolization approaches are proximal and distal splenic artery embolization. Proximal splenic artery embolization decreases the perfusion pressure in the spleen but allows for viability of the spleen to be maintained via collateral pathways. Distal embolization can be used in cases of focal injury. In this article we review relevant literature on splenic embolization indication, and technique, comparing and contrasting proximal and distal embolization. Additionally, we review relevant anatomy and discuss collateral perfusion pathways following proximal embolization. Finally, we review potential complications of splenic artery embolization.

We describe a Phase I dose escalation study (NCT03081910) of autologous CD5-directed CAR T cells as treatment of relapsed or refractory (r/r) T cell malignancies. CD5 is a pan-T cell marker present in ∼85% of T cell malignancies. Establishing a CAR T platform to target neoplasms of T cell origin has been hindered by shared expression of targetable antigens on both malignant and normal T cells promoting CAR T cell fratricide. We developed a second-generation CD5-specific CAR with CD28 co-stimulation that produces minimal and transient fratricide in T cells. The study was designed to evaluate the safety and feasibility of CD5 CAR T cells in patients with r/r T-cell malignancies as a bridge to allogeneic HSCT. Here we present our findings in patients with r/r non-Hodgkin T cell lymphoma (T-NHL). We have treated 5 patients (62-71 yrs) with CD5+ r/r T-NHL on dose levels 1 and 2 (1 × 107 and 5 × 107 CAR T cells/m2). All patients were heavily pretreated, with a median of 4 (range 2 -18) prior lines of therapy. One patient had previously failed allo-HSCT. All patients were transplant-eligible with an identified donor. Patients received cytoreductive chemotherapy with Cy/Flu followed by infusion of CD5 CAR T cells. We evaluated adverse events, clinical responses, and expansion/persistence of CAR T cells post-infusion. Two patients received CD5 CAR T cells on dose level 1 and 3 on dose level 2. CAR T cells reached peak expansion in peripheral blood (PB) 1-4 weeks after infusion. CD5 CAR T cells were detected in lymph nodes in 2 patients who underwent biopsies following treatment. PB CD3+ cell numbers were transiently reduced after cytoreduction and CAR T cell infusion, but ablation was never complete. CRS occurred in 3/5 patients (all at DL2). Grade 1 CRS was observed in 2 patients, and 1 patient had Grade 2 CRS and Grade 2 neurotoxicity, which resolved after treatment with tocilizumab and supportive care, respectively. Two patients experienced prolonged cytopenias at 6 weeks, one of whom also had reactivations of CMV and BK virus requiring antiviral therapy. On disease re-evaluation 4-8 weeks post-CD5 CAR T cell infusion, 3 of 5 evaluable patients obtained an objective response (1 on DL1 and 2 on DL2). Complete responses (CR) were achieved in 1 patient with angioimmunoblastic T cell lymphoma (AITL) and 1 with peripheral T cell lymphoma (PTCL) (Figure 1). Another patient with extensive AITL was classified as a mixed response due to the appearance of a new PET-avid lesion with resolution of remaining lesions (Figure 2). This patient received a 2nd infusion, proceeded to HSCT and remains in CR 6 mons post-transplant. These results demonstrate that CD5 CAR T cells are safe and can induce clinical responses in heavily treated patients with r/r CD5+ T-NHL without inducing complete T-cell aplasia. Importantly, elimination of malignant T cells by CD5 CAR T cells may allow previously ineligible patients to proceed to HSCT.

Pain is a hallmark of almost all bodily ailments and can be modulated by agents, including analgesics and anesthetics that suppress pain signals in the central nervous system. Defects in the modulatory systems, including the endogenous pain-inhibitory pathways, are a major factor in the initiation and chronicity of pain. Thus, pain modulation is particularly applicable to the practice of medicine. This review summarizes the existing literature on pain modulation. Here, we critically reviewed the literature from PubMed on pain modulation published primarily within the past 5 years in high impact journals. Specifically, we have discussed important anatomical landmarks of pain modulation and outlined the endogenous networks and underlying mechanisms of clinically relevant pain modulatory methods. The Gate Control Theory is briefly presented with discussion on the capacity of pain modulation to cause both hyper- and hypoalgesia. An emphasis has been given to highlight key areas in pain research that, because of unanswered questions or therapeutic potential, merit additional scientific scrutiny. The information presented in this paper would be helpful in developing novel therapies, metrics, and interventions for improved patient management.

Medical imaging has become a central component of patient care to ensure early and accurate diagnosis. Unfortunately, many imaging modalities use ionizing radiation to generate images. Ionizing radiation even in low doses can cause direct DNA damage and generate reactive oxygen species and free radicals, leading to DNA, protein, and lipid membrane damage. This cell damage can lead to apoptosis, necrosis, teratogenesis, or carcinogenesis. As many as 2% of cancers (and an associated 15,000 deaths annually) can be linked to computed tomography exposure alone. Radioprotective agents have been investigated using various models including cells, animals, and recently humans. The data suggest that radioprotective agents working through a variety of mechanisms have the potential to decrease free radical damage produced by ionizing radiation. Radioprotective agents may be useful as an adjunct to medical imaging to reduced patient morbidity and mortality due to ionizing radiation exposure. Some radioprotective agents can be found in high quantities in antioxidant rich foods, suggesting that a specific diet recommendation could be beneficial in radioprotection.

Background Direct-acting oral anticoagulants (DOACs), which have gained approval for stroke prevention in nonvalvular atrial fibrillation and treatment of venous thromboembolism, have become increasingly preferred over warfarin given their predictable pharmacodynamics, lack of required monitoring, and superior outcomes. Direct-acting oral anticoagulants have been shown to be associated with an increased frequency of gastrointestinal bleeding compared with warfarin, but the severity and characteristics of gastrointestinal bleeding in these patients is poorly understood. Methods We retrospectively evaluated electronic medical records of patients with gastrointestinal bleeding (n = 8496) from 2010-2016. We identified 61 patients with gastrointestinal bleeding episodes while treated with DOACs (rivaroxaban, dabigatran, or apixaban) and 123 patients with gastrointestinal bleeding while taking warfarin. We randomly selected a control group of 296 patients with gastrointestinal bleeding who were not receiving anticoagulation treatment from the same sample. Outcomes included the need for hospitalization, blood transfusion, endoscopic or surgical intervention, and 30-day mortality. Results The DOAC and warfarin groups were similar in terms of age and underlying comorbidity (assessed using the Charlson Comorbidity Index), but the DOAC group had greater concomitant aspirin use. Gastrointestinal bleeding was classified as upper (n = 186), lower (n = 88), anorectal (n = 183), small bowel (n = 9), and indeterminate (n = 14). After adjusting for differences in baseline variables, the DOAC group had fewer hospitalizations and required fewer transfusions than the warfarin group. The DOAC and control groups were not statistically different for all outcomes. There were no significant mortality differences among groups. Conclusion Although prior studies have shown a higher frequency of gastrointestinal bleeding in patients treated with DOACs compared with warfarin, our data suggest that gastrointestinal bleeding in patients taking DOACs may be less severe. These differences occurred despite significantly greater concomitant aspirin use in the DOAC group compared with warfarin users.