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We present a 54-year-old Caucasian woman, who presented with acute symptomatic type B aortic dissection with deteriorating renal function. She was a known smoker with a 2-year history of dysphagia. CT angiography documented the artery of lusoria arising from the mid-thoracic aorta, aneurysmal dilation of her descending aorta, and kinetic and static flaps around her visceral ostia. The patient was managed by staged hybrid single lumen reconstruction and bilateral subclavian to carotid transpositions. During follow-up, there was no aortic rupture or retrograde type A dissection. There were no renal, visceral, cardiac, pulmonary or spinal complications. The patient went off her antihypertensive medication with a normal estimated glomerular filtration rate and accelerated aortic modulation.

Background: Our group previously developed an upper extremity repositioning (Sup-ER) protocol for brachial plexus birth injuries (BPBIs) that may improve supination and external rotation (ER) at 2 years of age. Questions were raised about the potential for the protocol to cause internal rotation (IR) deficits. The goal of this study was to explore the longer-term outcomes of the Sup-ER protocol and investigate IR/ER function. Methods: This prospective cross-sectional cohort study examined 16 children older than 4 years of age with significant enough BPBI to be treated with the Sup-ER protocol. Total shoulder and elbow function were assessed, including passive and active ranges of motion and strength of IR and ER. Results: Range of motion (ROM) for most active movements was decreased in the affected compared to unaffected arm. Notably, IR passive ROM was similar in the affected (78.7°) and unaffected arm (82.8°). External rotation strength of the affected arm was weaker (42.8 N) compared to the unaffected arm (57.9 N). IR strength had a greater deficit in the affected (43.2 N) arm compared to the unaffected arm (72.2 N), but both ER and IR showed less deficit than described in the literature. Conclusions: Despite differences in ranges of motion between the affected and unaffected arms, ROMs for the affected arm were comparable to the functional limits as reported in the literature. The Sup-ER protocol shows potential to optimize long-term shoulder rotation function in children with BPBI without compromising IR.

Background Hybrid Deep Venous ARterialisation (DVAR) is offered as a last-ditch attempt for limb salvage in patients with chronic limb threatening ischemia (CLTI). It provides non-selective arterialisation independent of the angiosome, which harnesses the complex venous capillary network bed developed in the leg and foot. Technical Summary We present two elderly men who underwent DVAR to salvage limb with CLTI. DVAR was performed by creating an arteriovenous connection by anastomosis of the great saphenous vein (GSV) at the level of the distal popliteal and proximal tibio-peroneal trunk. Fasciotomy was performed over the length of the GSV. Subsequently, proximal in-situ catheter valvotomies of the GSV valves were undergone with the adjuvant on-table balloon maturation. The distal tarsal veins underwent balloon valvotomy under direct vision with subsequent proximal and distal tarsal veins valvuloplasties. Completion angiogram demonstrated restoration of the flow in the foot and both the patients were relieved of rest pain. Conclusion We successfully performed DVAR in two elderly patients. Our experience shows that DVAR is a simple and safe option that is easily reproducible without the need for complex endovascular hardware, only if a suitable GSV to the foot is available with no history of deep vein thrombosis.

Rotator cuff tears are the most likely source of shoulder pain in adults and may cause protracted disability. Management of rotator cuff tears is associated with considerable costs. Accurate diagnosis can guide surgical planning and help achieve a favorable clinical outcome. Although radiography remains the initial imaging test for shoulder injury, the roles of MRI and ultrasound (US) as first-line imaging after radiography are evolving. This article leverages current literature and the practical experience of subspecialty musculoskeletal radiologists from different institutions in describing a practical approach to imaging rotator cuff pathology. Both MRI and US are accurate for identifying rotator cuff tears, but each has advantages and shortcomings. As both modalities currently represent reasonable first-line approaches, considerable practice variation has evolved. Given the low cost of US, imagers should strive to optimize the quality of shoulder US examinations and to build referrer confidence in this modality. The roles of direct CT and MR arthrography as well as imaging evaluation of the postoperative rotator cuff are also considered. Through careful selection among the available imaging modalities and optimal performance and interpretation of such examinations, radiologists can positively contribute to the diagnosis and treatment of patients with rotator cuff injuries.

Her2 overexpression is associated with an aggressive form of breast cancer and malignant transformation. We demonstrate in this work that nanolipoprotein particles (NLPs) synthesized in a cell-free manner can be used to transfer Her2 protein into the membrane of nonmalignant cells in 3D culture in a nontoxic and facile manner. With NLP-mediated Her2 protein delivery, we observed an increased probability of nonmalignant cells forming apolar nongrowth-arrested tumor-like structures. The NLP delivery system alone or Her2-NLPs plus the Her2 inhibitor trastuzumab showed no effect on the acinar organization rate, indicating that Her2 signaling is key to this process. Transcriptomics revealed essentially no effect of empty NLPs compared to untreated cells, whereas Her2-NLPs versus either untreated or empty-NLP-treated cells revealed upregulation of several factors associated with breast cancer. Pathway analysis also suggested that known nodes downstream of Her2 were activated in response to Her2-NLP treatment. This demonstrates that Her2 protein delivery with NLPs is sufficient for the malignant transformation of nonmalignant cells. Thus, this system offers a new model for studying cell surface receptor signaling without genomic modification or transformation techniques.

Vaccine-induced thrombotic thrombocytopenia is a newly described disease process in the setting of expanding access to COVID-19 vaccination. The United States Centers for Disease Control and Prevention recommends treatment with an alternative to heparin in patients suspected of having vaccine-induced thrombotic thrombocytopenia. At this time there have been no reported outcomes from the treatment of vaccine-induced thrombotic thrombocytopenia with bivalirudin as a heparin alternative. We describe the early outcomes from the treatment of vaccine-induced thrombotic thrombocytopenia with bivalirudin as a heparin alternative. A 40-year-old Caucasian woman was found to have thrombocytopenia, cerebral venous sinus thrombosis, and pulmonary embolism following vaccination for COVID-19 with Ad26.COV2.S. She exhibited a steady rise in platelet count: 20×109/L at hospital day 0, 115×109/L at discharge on hospital day 6, and 182×109/L on outpatient follow-up on day 9. While the patient exhibited a transient drop in hemoglobin, there was no clinical evidence of bleeding. This patient did not demonstrate any clinical sequelae of thrombosis, and she reported resolution of her headache. Vaccination with Ad26.COV2.S appears to be associated with a small but significant risk for thrombotic thrombocytopenia within 13 days of receipt. The Centers for Disease Control and Prevention guidance to consider an alternative to heparin was not accompanied by specifically recommended alternatives. A single patient treated with bivalirudin for suspected vaccine-induced thrombotic thrombocytopenia subsequently experienced symptom improvement and a rise in platelet count and did not demonstrate any immediate negative outcomes. A provider may consider bivalirudin as an alternative to heparin in patients with suspected vaccine-induced thrombotic thrombocytopenia following Ad26.COV2.S vaccination, pending more definitive research.

OBJECTIVE Asthma action plans (AAP) are recommended to guide asthma management. Written AAPs (WAAPs) are under-utilized and can be difficult to understand. Our study designed and tested a simplified pictorial AAP (PAAP). We hypothesized that better outcomes would be obtained for youth with the PAAP. METHODS One hundred and sixty-nine (169) youth (aged 8-17; AAP-naive) were screened for this pilot, 2-arm randomized controlled trial. Feasibility, usability and preliminary efficacy of PAAP compared to a WAAP, for improving outcomes (inhaled corticosteroid (ICS) adherence, symptom control, AAP knowledge, AAP satisfaction) were assessed quantitatively. Youth received an AAP from their physician after completing baseline measures and completed measures at three additional time points (1-, 3-, and 6-month). RESULTS Forty-five youth were recruited (PAAP = 22; WAAP = 23). Youth AAP knowledge was higher for the PAAP group compared to the WAAP group (p = .017). ICS adherence did not differ between groups, over time, or based on prescribed dosing; however, for WAAP participants, adherence was lower with a higher daily prescription (4 puffs) relative to a lower dose (p = .006). Symptom control improved with both AAPs, but the change was not statistically significant. Lung function did not change significantly by AAP type or time, and literacy variables were not related significantly to outcomes. Youth satisfaction with AAP improved significantly for the PAAP group compared to the WAAP group (p = .03). CONCLUSIONS Higher AAP knowledge and satisfaction among youth in the PAAP group suggests that structured education from a physician using a PAAP is beneficial. Intervention and study design insights gained will guide future research.

Rationale: Much is known about the acute infective process of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of the coronavirus disease (COVID-19) pandemic. The marked inflammatory response and coagulopathic state in acute SARS-CoV-2 infection may promote pulmonary fibrosis. However, little is known about the incidence and seriousness of post–COVID-19 pulmonary pathology. Objectives: To describe the respiratory recovery and self-reported health after infection at the time of outpatient attendance. Methods: Infection severity was graded into three groups: 1) not requiring admission, 2) requiring hospital admission, and 3) requiring intensive care unit care. Participants underwent chest radiography and a 6-minute walk test (6MWT). Fatigue and subjective return to health were assessed, and concentrations of CRP (C-reactive protein), IL-6 (interleukin-6), sCD25 (soluble CD25), and D-dimer were measured. The associations between initial illness and abnormal chest X-ray findings, 6MWT distance, and perception of maximal exertion were investigated. Results: A total of 487 patients were offered an outpatient appointment, of whom 153 (31%) attended for assessment at a median of 75 days after diagnosis. A total of 74 (48%) had required hospital admission during acute infection. Persistently abnormal chest X-ray findings were seen in 4%. The median 6MWT distance covered was 460 m. A reduced distance covered was associated with frailty and length of inpatient stay. A total of 95 (62%) patients believed that they had not returned to full health, whereas 47% met the case definition for fatigue. Ongoing ill health and fatigue were associated with an increased perception of exertion. None of the measures of persistent respiratory disease were associated with initial disease severity. Conclusions: This study highlights the rates of objective respiratory disease and subjective respiratory symptoms after COVID-19 and the complex multifactorial nature of post–COVID-19 ill health.

Background: Lifestyle modification is the cornerstone of management for patients with severe and complicated obesity, but the effects of structured lifestyle programmes on quality of life, anxiety and depression scores and cardiovascular risk factors are not well-described. We sought to describe changes in self-reported quality of life and mental health-related outcomes as well as cardiovascular risk factors in patients completing a 10-week multidisciplinary lifestyle-modification programme. Methods: We conducted a prospective cohort study of all patients referred from our bariatric service who completed the programme between 2013 and 2019. In addition to weight, body mass index (BMI), blood pressure, HbA1c, lipid profile and functional capacity, we quantified health-related quality of life using the Dartmouth COOP Questionnaire and the European Quality of Life Questionnaire Visual Analogue Scale (EQVAS) and mental health using the Hospital Anxiety and Depression Scale (HADS). Results: Of 1122 patients who started the programme, 877 (78.2%) completed it and were included in per protocol analyses. Mean age was 47.3 ± 11.9 years, 66.9% were female, 34.8% were in full- or part-time employment and 69.4% were entitled to state-provided medical care. BMI decreased from 47.0 ± 7.8 to 46.2 ± 7.8 kg m−2 and weight decreased from 131.6 ± 25.5 to 129.5 ± 25.4 kg (both p < 0.001). There were significant reductions in anxiety and depression scores and improvements in all Dartmouth COOP domains. The EQVAS score increased from 52 ± 22 to 63 ± 19 (p < 0.001). Small but statistically significant reductions in LDL cholesterol, systolic blood pressure and HBA1c were also observed. Conclusions: Adults with severe and complicated obesity completing a specialised bariatric lifestyle-modification programme showed significant improvements in self-reported mental health and quality of life, in addition to reductions in cardiovascular risk factors.

The purpose of this investigation was to characterize the CMR and clinical parameters that correlate to prosthetic valve size (PVS) determined at SAVR and develop a multi-parametric model to predict PVS. Sixty-two subjects were included. Linear/area measurements of the aortic annulus were performed on cine CMR images in systole/diastole on long/short axis (SAX) views. Clinical parameters (age, habitus, valve lesion, valve morphology) were recorded. PVS determined intraoperatively was the reference value. Data were analyzed using Spearman correlation. A prediction model combining imaging and clinical parameters was generated. Imaging parameters had moderate to moderately strong correlation to PVS with the highest correlations from systolic SAX mean diameter (r = 0.73, p

Background The role of percutaneous repair of functional mitral regurgitation (MR) is evolving. Left ventricle remodeling is known to be different between men and women; however, outcomes following percutaneous repair of functional MR have not considered the impact of sex. Methods Between 2012 and 2018, 175 patients underwent percutaneous repair of functional MR with the Mitra Clip NT/NTR (Abbott, Irvine CA) at our institution. Patients were assessed in a dedicated clinic with a follow-up that averaged 0.7±1.2 years and extended to 5.7 years. Results Men had a larger body surface area than women (p3+ was 86.0±3.5% and 77.6±5.1%, respectively. After adjusting for differences between male and female patients, women were more likely to have recurrent MR >3+ (hazard ratio 4.7, 95% confidence interval 1.2-18.4, p=0.03). Upon adjusted analysis, there was also no association between gender and survival (p=0.2). One- and 2- year survival was 69.8±4.3% and 54.3±5.5%, respectively. Conclusion Women are more likely to have recurrent severe MR after percutaneous repair of functional MR. The mechanism for this remains undetermined.

Seizures are a common presentation to emergency departments in homeless patients. Seizures and epilepsy are often poorly managed in homeless patients. In this retrospective study, conducted in a large urban university hospital; we compared the number emergency department presentations and associated head computed tomography studies in a cohort of 88 homeless patients with seizures to an age and gender-matched housed cohort of patients over a five-year period. We found that homeless patients had a significantly increased number of presentations to the emergency department and a significantly higher number of head computed tomography, with a resulting increase in radiation exposure.

Lumbar lateral interbody fusion (LLIF) has been gaining popularity among the spine surgeons dealing with degenerative spinal diseases while LLIF on L5-S1 is still challenging for its technical and anatomical difficulty. OLIF51 procedure achieves effective anterior interbody fusion based on less invasive anterior interbody fusion via bifurcation of great vessels using specially designed retractors. The technique also achieves seamless anterior interbody fusion when combined with OLIF25. A thorough understanding of the procedures and anatomical features is mandatory to avoid perioperative complications.

The prevention and treatment of chronic kidney disease can be managed not only with medical therapies, but also with dietary changes. Recent studies have shown that plant-based diets can slow disease progression and improve mortality

Intravascular papillary endothelial hyperplasia (IPEH), commonly known as Masson’s tumor, is a benign lesion that manifests as an excessive proliferation of endothelial cells within a vessel wall. IPEH is extremely rare in the brain, with only 36 intracranial cases previously described in the literature. It is commonly mistaken for more malignant pathologies, such as angiosarcoma. Careful histopathological examination is required for diagnosis, as no clinical or radiographic features are characteristic of this lesion. In this first published case of intracranial IPEH presenting during pregnancy, the authors describe a 32-year-old female with a left frontal intraparenchymal hemorrhage resulting in complete expressive aphasia at 28 weeks 6 days’ gestation. An MRI scan obtained at a local hospital demonstrated an area of enhancement within the hemorrhage. The patient underwent a left frontoparietal craniotomy for hematoma evacuation and gross-total resection (GTR) of an underlying hemorrhagic mass at 29 weeks’ gestation. This case illustrates the importance of multidisciplinary patient care and the feasibility of intervention in the early third trimester with subsequent term delivery. While GTR of IPEH is typically curative, the decision to proceed with surgical treatment of any intracranial lesion in pregnancy must balance maternal stability, gestational age, and suspected pathology.

Objectives: The aim of this study was to evaluate the outcome of transcatheter mitral valve repair (TMVr) in patients with cardiogenic shock and significant mitral regurgitation (MR). Background: Patients in cardiogenic shock with severe MR have a poor prognosis in the setting of conventional medical therapy. Because of its favorable safety profile, TMVr is being increasingly used as an acute therapy in this population, though its efficacy remains unknown. Methods: A multicenter, collaborative, patient-level analysis was conducted. Patients with cardiogenic shock and moderate to severe (3+) or severe (4+) MR who were not surgical candidates were treated with TMVr. The primary outcome was in-hospital mortality. Secondary outcomes included 90-day mortality, heart failure (HF) hospitalization, and the combined event rate of 90-day mortality and HF hospitalization following dichotomization by TMVr device success. Results: Between January 2011 and February 2019, 141 patients across 14 institutions met the inclusion criteria. In-hospital mortality occurred in 22 patients (15.6%), at 90 days in 38 patients (29.5%), and at one year in 55 patients (42.6%). Median length of hospital stay following TMVr was 10 days (interquartile range: 6 to 20 days). HF hospitalization occurred in 26 patients (18.4%) at a median of 73 days (interquartile range: 26 to 546 days). When stratified by TMVr procedural results, successful TMVr reduced rates of in-hospital mortality (hazard ratio [HR]: 0.36; 95% confidence interval [CI]: 0.13 to 0.98; p = 0.04), 90-day mortality (HR: 0.36; 95% CI: 0.16 to 0.78; p = 0.01), and the composite of 90-day mortality and HF hospitalization (HR: 0.41; 95% CI: 0.19 to 0.90; p = 0.03). Conclusions: TMVr may improve short- and intermediate-term mortality in high-risk patients with cardiogenic shock and moderate to severe MR. Randomized studies are needed to definitively establish MR as a therapeutic target in patients with cardiogenic shock.

Purpose: We compared the outcomes between the total endovascular approach using a unibody bifurcated aortoiliac endograft and the gold standard aortobifemoral bypass (ABF) surgery for the management of extensive aortoiliac occlusive disease (AIOD). Materials and Methods : : This retrospective observational study compared the outcomes of endovascular technique with unibody bifurcated endograft (UBE) using the Endologix AFX unibody stent-graft and a standard surgical approach (ABF) in the management of AIOD based on patient records in Western Vascular Institute, Galway University Hospital, National University of Ireland. Procedural details and outcomes were documented to compare both groups. Results : : From January 2002 to December 2018, 67 patients underwent AIOD (20 UBE and 47 ABF). Both the ABF and UBE groups showed 100% immediate clinical and technical successes without 30-day mortality. There were no statistical differences in the overall survival and sustained clinical improvement between the bypass and the UBE groups; however, statistically significant differences were observed in 3-year freedom from re-intervention and amputation-free survival. Furthermore, the mean length of the intensive care unit (ICU) stay was significantly lower in the UBE group than that in the ABF group (0.75 days vs. 3.1 days, P=0.001). Conclusion : : Total endovascular reconstruction of AIOD is an alternative to invasive bypass procedures, with a shorter ICU stay.

Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.

Primary aortic tumors after endovascular aortic repair are rarely reported in the literature. Here, we report an elderly male with abdominal aortic leiomyosarcomas (LMS) after an endovascular aneurysm repair in 2012 for a 5-cm symptomatic abdominal aortic aneurysm using an Endurant II aortic stent graft (Medtronic, Minneapolis, Minn). The autopsy confirmed the aortic LMS after the patient rapidly deteriorated and succumbed to death. The vascular LMS are rapidly progressive and diagnostically challenging malignant soft tissue tumors with poor prognosis, which necessitates a strong clinical suspicion and attentiveness to radiologic signs for prompt diagnosis.

There is conflicting data regarding the association of pre-transplant AT1R antibody levels and long-term outcomes following kidney transplantation.We examined the association between pre-transplant antibodies and long-term graft outcome by assaying pre-transplant sera from 125 kidney transplant recipients from 1999 to 2009.The mean age at transplant was 55.7 ± 13 years; 67.2% were male, 87.2% were Caucasian, and 67.2% received a deceased donor transplant. Induction therapy included 44.8% thymoglobulin. Human leukocyte antigen (HLA) donor-specific antibodies (DSA) were present in 22 (17.6%) patients, while AT1R antibodies 17 U/mL were present in 24 (19.2%). The mean AT1R antibodies level was 13 ± 7.2 U/mL. Patients were followed-up for 7.1 ± 1.9 years after transplant. Pre-transplant AT1R antibodies were associated with rejection (p 0.0001), antibody-mediated rejection (ABMR) (p 0.0001), and death-censored graft failure (DCGF) (p = 0.01). This was confirmed by univariate Cox regression analyses for AT1R antibodies 10 U/mL (HR 2.64, 95% Cl 1.35 - 5.17, p = 0.04) and AT1R antibodies 17 U/mL (HR = 1.74, 95% Cl 1.061 - 2.98, p = 0.04). Multivariable analyses did not retain AT1R antibodies as independent predictors of DCGF; however, pre-transplant HLA, DSA, and acute rejection during the first year were associated with DCGF (HR 2.07, 95% Cl 1.13 - 3.78, p = 0.02 and HR 3.03, 95% Cl 1.13 - 3.78, p = 0.0002, respectively).Our study indicates that in patients with a functioning kidney allograft 5 years, pre-transplant AT1R antibodies may be associated with a greater risk of rejection and late graft failure.

This paper seeks to review the important musculoskeletal issues that arise for pregnant and postpartum women. It outlines the background, diagnosis, and management of these musculoskeletal issues; reviews the existing and recent literature; and offers clinical opinions from the perspective of women’s health PM&R physicians. Existing and recent literature on pelvic girdle pain, lumbosacral back pain, pubic symphysis separation, transient osteoporosis, rectus diastasis, and postpartum neuropathy offer some new insights on management, which is often context-dependent. Management requires individualized physical therapy and precautions for delivery and postpartum. Emerging alternatives like acupuncture for pelvic girdle pain (PGP) and surgical reconstruction for diastasis recti abdominis (DRA) may be considered. The various musculoskeletal pathologies that occur in the peripartum period can produce significant disability for women. With timely diagnosis and treatment, however, these musculoskeletal issues are often transient in nature and do not result in long-term functional deficits.

Bariatric surgery is known to reduce leptin and increase adiponectin levels, but the influence of sleeve gastrectomy on the leptin: adiponectin ratio (LAR), a measure of insulin sensitivity and cardiovascular risk, has not previously been described. We sought to determine the influence of sleeve gastrectomy on LAR in adults with severe obesity.In a single centre prospective cohort study of adults undergoing laparoscopic sleeve gastrectomy over a four-month period in our unit, we measured LAR preoperatively and 12 months after surgery. Of 22 patients undergoing sleeve gastrectomy, 17 (12 females, 12 with type 2 diabetes) had follow-up LAR measured at 12.1 ± 1 months. Mean body weight decreased from 130.6 ± 30.8 kg to 97.6 ± 21.6 kg, body mass index (BMI) from 46.9 ± 7.8 to 35.3 ± 7.2 kg m−2 and excess body weight from 87.5 ± 31.3 to 41.3 ± 28.8% (all p p = 0.11), but adiponectin increased from 4.49 ± 1.6 to 8.93 ± 6.36 µg/ml (p = 0.005) and LAR decreased from 8.89 ± 4.8 to 5.26 ± 6.52 ng/µg (p = 0.001), equivalent to a 70.9% increase in insulin sensitivity. The correlation with the amount of weight lost was stronger for LAR than it was for leptin or adiponectin alone. In this single-centre, interventional prospective cohort, patients undergoing laparoscopic sleeve gastrectomy had a substantial reduction in their LAR after 12 months which was proportional to the amount of weight lost. This may indicate an improvement in insulin sensitivity and a reduction in cardiovascular risk.

First Irish National Corneal Transplant Registry report. To report about current corneal transplantation practices in Ireland including patient demographics, indications and types of transplant performed and to compare the findings with other developed countries. Nationwide retrospective review of the corneal transplants performed in Ireland between 2016 and 2019. Overall, 536 keratoplasties were carried out: 256 (47.8%) Penetrating Keratoplasties (PK), 212 (39.6%) Descemet Stripping Automated Endothelial Keratoplasties (DSAEK), 30 (5.6%) Descemet Membrane Endothelial Keratoplasties (DMEK), and 25 (4.7%) Deep Anterior Lamellar Keratoplasties (DALK). The most common indication was Keratoconus (KC, 19%), followed by Fuchs endothelial dystrophy (FED, 18.8%), and Pseudophakic bullous keratopathy (PBK, 17%). KC (34%) and re-grafting (17%) were the leading indications for PK, whereas FED and PBK were the major indications for DSAEK (38% and 33%) and DMEK (67% and 20%), respectively. During the period studied, the number of transplants increased from 11.3 to 14 grafts per month. The number of PKs remained stable, whereas Endothelial Keratoplasties, DSAEK and DMEK, increased (3.8 to 5.6 and 0.2 to 1.6 per month, respectively), becoming the most commonly performed grafts since 2018. Only a small number of DALK were performed. Corneal transplantation in Ireland is following international trends as endothelial procedures have become the most common approach since 2018. However, a low overall number of transplants is performed in Ireland compared with other countries suggesting that care pathways should be implemented to improve access to corneal transplantation.

Introduction Traumatic brain injury is a leading cause of death and disability globally with an estimated African incidence of approximately 8 million cases annually. A person suffering from a TBI is often aged 20–30, contributing to sustained disability and large negative economic impacts of TBI. Effective emergency care has the potential to decrease morbidity from this multisystem trauma. Objectives Identify and summarize key recommendations for emergency care of patients with traumatic brain injuries using a resource tiered framework. Methods A literature review was conducted on clinical care of brain-injured patients in resource-limited settings, with a focus on the first 48 h of injury. Using the AfJEM resource tiered review and PRISMA guidelines, articles were identified and used to describe best practice care and management of the brain-injured patient in resource-limited settings. Key recommendations Optimal management of the brain-injured patient begins with early and appropriate triage. A complete history and physical can identify high-risk patients who present with mild or moderate TBI. Clinical decision rules can aid in the identification of low-risk patients who require no neuroimaging or only a brief period of observation. The management of the severely brain-injured patient requires a systematic approach focused on the avoidance of secondary injury, including hypotension, hypoxia, and hypoglycaemia. Most interventions to prevent secondary injury can be implemented at all facility levels. Urgent neuroimaging is recommended for patients with severe TBI followed by consultation with a neurosurgeon and transfer to an intensive care unit. The high incidence and poor outcomes of traumatic brain injury in Africa make this subject an important focus for future research and intervention to further guide optimal clinical care.

In response to the Ebola outbreak of 2014–2016, the US Office of the Assistant Secretary for Preparedness and Response (ASPR) established 10 regional treatment centers, called biocontainment units (BCUs), to prepare and provide care for patients infected with high-consequence pathogens. Many of these BCUs were among the first units to activate for coronavirus disease 2019 (COVID-19) patient care. The activities of the Johns Hopkins BCU helped prepare the Johns Hopkins Health System for COVID-19 in the 3 domains of containment care: (1) preparedness planning, education and training, (2) patient care and unit operations, and (3) research and innovation. Here, we describe the role of the JH BCU in the Hopkins COVID-19 response to illustrate the value of BCUs in the current pandemic and their potential role in preparing healthcare facilities and health systems for future infectious disease threats.

Importance Turner syndrome (TS) is one of the most common chromosomal abnormalities in women. The condition is characterized by gonadal dysgenesis and is associated with structural cardiac abnormalities. Assisted reproductive technology with oocyte donation may be successful but places women with TS at increased risk of aortic dissection and death. Objective To summarize all cases of aortic dissection associated with pregnancy in women with TS and provide guidance regarding the safety of pregnancy. Evidence acquisition Systematic review of PubMed for reports of women with TS, aortic dissection, and pregnancy. Results There are 14 total reported cases of aortic dissection associated with pregnancy in women with TS. Ten of these cases occurred during pregnancy or in the first month postpartum. The majority of affected pregnancies resulted from oocyte donation, 2 of which were multiple gestations. Two women had a documented history of hypertension, and 3 pregnancies were complicated by preeclampsia. Bicuspid aortic valve and coarctation of the aorta were the most common associated cardiac anomalies. More than half of women had some degree of aortic dilatation. Two women had no identifiable risk factors. Conclusions and relevance Women with TS who desire pregnancy must be thoroughly counseled regarding the increased risk of aortic dissection during pregnancy and postpartum. Preconception consultation with maternal-fetal medicine, reproductive endocrinology, and cardiology is necessary along with a comprehensive physical evaluation. If women with TS choose to pursue pregnancy, they require rigorous cardiac monitoring each trimester during pregnancy and postpartum.

[Image: see text] IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compounds such as 12 with improved potency and selectivity. Additionally 12 demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective 21, which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis.

The biocontainment unit at Johns Hopkins Hospital is a specially designed, inactive high-level isolation unit designated to care for patients infected with high-consequence pathogens. The unit team designed a facility-specific readiness scale and checklist that focus on infrastructure, consumable supplies, and staffing to assess activation readiness of the biocontainment unit. Over a period of 50 days and 14 days, these tools were used as part of a routine risk assessment to first identify barriers and then tier the impact of these barriers into activation categories of "Ready," "Ready with Considerations," and "Not Ready." The assessment identified the greatest risks to activation readiness were staffing and waste management capabilities. Assessing threats to activation readiness and the risk of not being ready should be a priority for maintaining facility, regional, and national capacity to safely isolate and care for patients infected with high-consequence pathogens while maintaining healthcare worker safety.

Problem Identification: This systematic review will examine the social support needs of bereaved parents in the specific context of pediatric cancer by synthesizing the qualitative evidence. Social...

Background Endovascular intervention for chronic symptomatic type B aortic dissection (CS-TBAD) induces aortic wall stress with negative hemodynamic cardiovascular consequences. CS-TBAD risks increased morbidity and mortality due to septum maturation with significant impact on false lumen modulation, and partial lumen thrombosis conveying the worst outcome. The aim of the TIGER technique is total aortic remodeling with true lumen expansion, false lumen regression and complete thrombosis, and stabilization of overall aortic diameter. Methods We report 5 cases of aortic dissection with a mean follow-up of 16 months (6–28 months). All had aneurysmal dilation, with 3 having acute pan aortic dissection and 2 having CS-TBAD. All were managed by sTaged HybrId sinGle lumEn Reconstruction (TIGER). Our first approach was to create one single lumen from the supraceliac, infradiaphragmatic aorta to both common iliac arteries with open surgical patching of the visceral arteries; then, we performed a TEVAR 3 months later. Results Three patients required a left subclavian artery chimney graft and one required bilateral subclavian to carotid artery transposition. No spinal drainage was required, and all patients had intraoperative transesophageal echo for wire guidance. We had no aortic rupture or retrograde type A dissection, and we experienced no renal, visceral, cardiac, pulmonary, or spinal complications. All patients, but one, went off their antihypertensive medication. All patients had normal estimated glomerular filtration rate postoperatively, and they all demonstrated accelerated aortic modulation. Conclusions TIGER was not only effective at the semiacute stage to initiate remodeling and prevent malperfusion, it also facilitated a straightforward TEVAR at stage 2, which was made easier by avoiding visceral branch stenting. Moreover, it decreased the length of aortic segment, which was stented, thereby avoiding critical shattering, branch dislodgment, and visceral compromise; spinal ischemia; and negative cardiovascular consequences.

The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor despite decades of effort. The abundant extracellular matrix (ECM) in PDAC comprises a major fraction of the tumor mass and plays various roles in promoting resistance to therapies. However, nonselective depletion of ECM has led to poor patient outcomes. Consistent with that observation, we previously showed that individual matrisome proteins derived from stromal cells correlate with either long or short patient survival. In marked contrast, those derived from cancer cells correlate strongly with poor survival. Here, we studied three cancer cell–derived matrisome proteins that are significantly overrepresented during PDAC progression, AGRN (agrin), SERPINB5 (serine protease inhibitor B5), and CSTB (cystatin B). Using both overexpression and knockdown experiments, we demonstrate that all three are promoters of PDAC metastasis. Furthermore, these proteins operate at different metastatic steps. AGRN promoted epithelial-to-mesenchymal transition in primary tumors, whereas SERPINB5 and CSTB enhanced late steps in the metastatic cascade by elevating invadopodia formation and in vivo extravasation. All three genes were associated with a poor prognosis in human patients and high levels of SERPINB5, secreted by cancer cells and deposited in the ECM, correlated with poor patient prognosis. This study provides strong evidence that cancer cell–derived matrisome proteins can be causal in promoting tumorigenesis and metastasis and lead to poor patient survival. Therefore, compared with the bulk matrix, mostly made by stromal cells, precise interventions targeting cancer cell–derived matrisome proteins, such as AGRN, SERPINB5, and CSTB, may represent preferred potential therapeutic targets. Significance: This study provides insights into the biological roles of cancer cell–derived matrisome proteins in PDAC and supports the notion that these proteins are protumorigenic and better therapeutic targets.

IQGAP1 is a scaffold protein involved in a range of cellular activities, including migration, invasion, adhesion and proliferation. It is also oncogenic in a variety of cancers, promoting primary tumor growth and invasiveness. However, the role of IQGAP1 in tumor progression and metastasis remains unclear. In this study, we use both knockdown and knockout of IQGAP1 to investigate its role in the metastatic cascade of both melanoma and breast cancer cells in vivo. We find that reduction of IQGAP1 expression decreases the formation of both spontaneous and experimental metastases, without limiting primary or metastatic tumor growth. Furthermore, IQGAP1 knockout significantly inhibits extravasation of tumor cells from circulation, possibly involving invadopodial function. By expressing mutant forms of IQGAP1 in a knockout context, we also determine that IQGAP1’s pro-metastatic functions are dependent on multiple domains and functions. These data demonstrate that IQGAP1 is crucial for metastasis in vivo through regulation of extravasation and suggest that it may represent a valid therapeutic target for inhibiting metastasis.

Gallstone-related disease can have significant associated morbidity and mortality worldwide. The incidence of gallstone-related disease in the Western world is on the increase. There are multiple different pathological manifestations of gallstone disease: the presentation, diagnosis and associated complications of which vary significantly depending on anatomical location. The role of imaging in gallstone-related disease is broad with radiology playing an essential role in the diagnosis, management and follow-up of gallstone-related pathologies. This paper distills the broad range of gallstone-related pathologies into an anatomical map, discussing the disease processes involved at each point along the biliary tree and reviewing the strengths and weaknesses of different imaging modalities for each distinct disease process.

Background The ability to perform visually-guided motor tasks requires the transformation of visual information into programmed motor outputs. When the guiding visual information does not align spatially with the motor output, the brain processes rules to integrate somatosensory information into an appropriate motor response. Performance on such rule-based, “cognitive-motor integration” tasks is affected in concussion. Here, we investigate the relationship between visuomotor skill performance, concussion history, and sex during the course of a post-concussion management program. Methods Fifteen acutely concussed working-aged adults, 11 adults with a history of concussion, and 17 healthy controls all completed a recovery program over the course of 4 weeks. Prior to, mid-way, and following the program, all participants were tested on their visuomotor skills. Results We observed an overall change in visuomotor behaviour in all groups, as participants completed the tasks faster and more accurately. Specifically, we observed significant visuomotor skill improvement between the first and final sessions in participants with a concussion history compared to no-concussion-history controls. Notably, we observed a stronger recovery of these skills in females. Conclusions Our findings indicate that (1) concussion impairs visuomotor skill performance, (2) the performance of complex, rule-based tasks showed improvement over the course of a recovery program, and (3) stronger recovery in females suggests sex-related differences in the brain networks controlling skilled performance, and the effect of injury on these networks.

The flow modulator is a bare-metal graft for use in aortic, peripheral, visceral, and intracranial aneurysms. When the Streamliner Multilayer Flow Modulator (SMFM) technology was first introduced, there was no compulsion to inform and to train physicians in the new technology. Surgeons used this technology according to their judgment and discretion on a compassionate and trial-and-error basis. As with all new technologies in ill-informed hands, the consequences were catastrophic. Preoperative planning and deployment technique are key when using the SMFM. Normal proximal and distal landing zones as well as proper oversizing are crucial to provide sufficient radial force and prevent migration of the device. The SMFM should not be implanted in patients with aneurysm diameters >6.5 cm because of adventitial elastolysis, or in patients with evidence of infection resulting from a previous open repair graft or endograft. During deployment, the operator should deploy the SMFM at a slow rate of 1 cm per minute, known as “endoquilting,” allowing it to adhere to the vessel wall, preventing foreshortening and malexpansion or subsequent migration. Adequate overlap must be used when multiple SMFMs are implanted, to prevent dislocation, collapse, or endoleak. Stent occlusion can be avoided by placing the patient on clopidogrel postoperatively. Because SMFM technology is in its infancy, it is essential that a diligent preoperative plan be undertaken with a close follow-up strategy be undertaken. The SMFM is proving to be a promising option in endovascular surgery, mainly dissection, and this technological advancement can only improve in the future if research and development in device porosity and permeability and deployment technology are conducted. Positive outcomes follow, providing the limitations and instructions for use of the device are appreciated. Failing to avoid deviation from instructions for use will result in a catastrophic outcome.

The extracellular matrix (ECM) is a complex meshwork of insoluble fibrillar proteins and signaling factors interacting together to provide architectural and instructional cues to the surrounding cells. Alterations in ECM organization or composition and excessive ECM deposition have been observed in diseases such as fibrosis, cardiovascular diseases, and cancer. We provide here optimized protocols to solubilize ECM proteins from normal or tumor tissues, digest the proteins into peptides, analyze ECM peptides by mass spectrometry, and interpret the mass spectrometric data. In addition, we present here two novel R-script-based web tools allowing rapid annotation and relative quantification of ECM proteins, peptides, and intensity/abundance in mass spectrometric data output files. We illustrate this protocol with ECMs obtained from two pairs of tissues, which differ in ECM content and cellularity: triple-negative breast cancer and adjacent mammary tissue, and omental metastasis from high-grade serous ovarian cancer and normal omentum. The complete proteomics data set generated in this study has been deposited to the public repository ProteomeXchange with the data set identifier: PXD005554.

Recent research has found substantial gaps in knowledge surrounding concussion assessment and management in various groups of Canadian healthcare professionals, including medical students, physiotherapists, chiropractic students, and family medicine physicians. The purpose of this project was to explore concussion knowledge in a sample of athletic therapy students and to use these findings to make practical pedagogical recommendations to improve concussion education. A sequential explanatory mixed-methods approach (initial questionnaire, student interviews, clinical educator interviews) was used to investigate the research question. The findings showed a large gap between theoretical knowledge and practical abilities to assess and manage concussions. Additionally, students felt less prepared to assist throughout the entire continuum of concussion care (from initial recognition to return-to-play). Based on these findings, educators should consider innovative pedagogical strategies that focus on true competence development in concussion assessment and management while bridging the gap between foundational theory and practical application/skill development.

Author(s): Ashdown, Brayden; Calvello Hynes, Emilie | Abstract: Introduction: Stress-induced cardiomyopathy is a rare but serious cause of chest pain, which in recent studies has been shown to carry a similar in-hospital mortality to acute ST-elevation myocardial infarction. The pathophysiology of the disease is thought to be secondary to dysregulated catecholamine effects on myocardium.Case Report: We present a case of a previously healthy female without known thyroid disease who presented to the emergency department for acute chest pain and was found to have thyroid storm- induced cardiomyopathy in a typical stress-induced cardiomyopathy pattern without evidence of coronary disease on catheterization.Conclusion: Thyrotoxicosis can cause dysregulation of catecholamines and is a rare cause of stress-induced cardiomyopathy. It requires distinct therapies and should be considered by emergency physicians in the workup of acute chest pain with concern for stress-induced cardiomyopathy.

Background: This study assessed the checkpoint kinase 1 inhibitor prexasertib in patients with extensive-stage small-cell lung cancer (ED-SCLC). Patients and Methods: This was a parallel-cohort phase II study of 105 mg/m2 prexasertib once every 14 days for patients who progressed after no more than two prior therapies and had platinum-sensitive (Cohort 1) or platinum-resistant/platinum-refractory (Cohort 2) disease. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Exploratory endpoints included biomarker identification and assessment of an alternative regimen (Cohort 3: 40 mg/m2 days 1-3, 14-day cycle). Results: In Cohort 1 (n = 58), ORR was 5.2%; DCR, 31%; median PFS, 1.41 months (95% confidence interval [CI], 1.31-1.64); and median OS, 5.42 months (95% CI, 3.75-8.51). In Cohort 2 (n = 60), ORR was 0%; DCR, 20%; median PFS, 1.36 months (95% CI, 1.25-1.45); and median OS, 3.15 months (95% CI, 2.27-5.52). The most frequent all-grade, related, treatment-emergent adverse events were decreased neutrophil count (Cohort 1, 69.6%; Cohort 2, 73.3%), decreased platelet count (Cohort 1, 51.8%; Cohort 2, 50.0%), decreased white blood cell count (Cohort 1, 28.6%; Cohort 2, 40.0%), and anemia (Cohort 1, 39.3%; Cohort 2, 28.3%). Eleven patients (19.6%) in Cohort 1 and one patient (1.7%) in Cohort 2 experienced grade ?3 febrile neutropenia. Prexasertib pharmacokinetics were consistent with prior studies. Cohort 3 outcomes were similar to those of Cohorts 1 and 2. No actionable biomarkers were identified. Conclusion: Prexasertib did not demonstrate activity to warrant future development as monotherapy in ED-SCLC. © 2021 The Authors Boehringer Ingelheim; Amgen; Bristol-Myers Squibb; Eli Lilly and Company; Pfizer; Astellas Pharma US; AstraZeneca; Merck; Novartis; Roche; AbbVie; University of Michigan; Takeda Pharmaceuticals U.S.A.; Merck Sharp and Dohme; PTC Therapeutics; TG Therapeutics; NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research; Bayer Fund; National Institute for Health Research; European Commission; Daiichi-Sankyo; Oryzon Genomics; Otsuka Pharmaceutical; UCLH Biomedical Research Centre We thank the patients who participated in this trial and the study coordinators, nurses, nurse practitioners, clinical research assistants, and doctors who assisted with the research. The authors also thank Erin Wagner from BioStat Solutions, Inc., for statistical support and Lisa Golden, Rod Decker, and Elizabeth Spoljoric for their input and contributions to the study. MDF is supported by the University College London/University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre and runs early phase studies in the NIHR UCLH Clinical Research Facility supported by the University College London Experimental Cancer Medicine Centre. Eli Lilly and Company contracted with Syneos Health for writing support provided by Andrea D. Humphries, PhD, and editing support provided by Noelle Gasco. L.A. Byers reports receiving research funding and fees as an advisor or consultant from AstraZeneca, GenMab, and Sierra Oncology; research funding from Tolero Pharmaceuticals; and fees as an advisor or consultant from Bristol Myers Squibb, Althia, Merck, Pfizer, PharmaMar, AbbVie, Jazz Pharmaceuticals, Genentech, and Debiopharm Group. A. Navarro reports receiving fees as an advisor or consultant from Pfizer and Boehringer Ingelheim; fees from Roche and AstraZeneca speakers’ bureaus; fees for expert testimony from Oryzon Genomics and MedSIR; and fees or reimbursement for travel, accommodations, or other expenses from Roche, Pfizer, and Boehringer Ingelheim. M. Johnson reports grant funding to her institution from Eli Lilly and Company, Abbvie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, EMD Serono, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Hengrui Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Merck, Mirati Therapeutics, Neovia Onclogy, Novartis, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Regeneron Pharmaceuticals, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, TMUNITY Therapeutics, University of Michigan, and WindMIL; receiving fees for consulting services from Eli Lilly and Company, Abbvie, Amgen, AstraZeneca, Atreca, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Daiichi Sankyo, EMD Serono, Genentech/Roche, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Therapeutics, Sanofi, WindMIL, Achilles Therapeutics, Bristol Myers Squibb, Eisai, G1 Therapeutics, and Association of Community Cancer Centers; and receiving fees for consulting services performed by her spouse from Astellas and Otsuka Pharmaceuticals. K.H. Dragnev reports funding to the institution for the conduct of the trial from Eli Lilly and Company and support to the institution for conduct of company-sponsored trials from Merck, Roche/Genentech, G1 Therapeutics, Io Therapeutics, and Novartis. S. McNeely reports receiving personal fees and non-financial support from Eli Lilly and Company. A.B. Lin and spouse are both employees and shareholders of Eli Lilly and Company. M. Forster reports receiving educational grants from Merck Sharp & Dohme for the EACH study and the POPPY study, from Boehringer Ingelheim for the DARWIN1 study, and from AstraZeneca for the ORCA2 study, as well as fees for advisory and consultancy work from Achilles, AstraZeneca, Bristol Myers Squibb, Merck, Nanobiotix, Novartis, Pfizer, Pharmamar, Roche, Takeda, Bayer, and Guardant Advisory. The remaining authors have stated that they have no conflicts of interest.

Background We aimed to estimate the clinical effectiveness of Community Occupational Therapy for people with dementia and family carers–UK version (Community Occupational Therapy in Dementia–UK version [COTiD-UK]) relative to treatment as usual (TAU). We hypothesised that COTiD-UK would improve the ability of people with dementia to perform activities of daily living (ADL), and family carers’ sense of competence, compared with TAU. Methods and findings The study design was a multicentre, 2-arm, parallel-group, assessor-masked, individually randomised controlled trial (RCT) with internal pilot. It was conducted in 15 sites across England from September 2014 to January 2018. People with a diagnosis of mild to moderate dementia living in their own home were recruited in pairs with a family carer who provided domestic or personal support for at least 4 hours per week. Pairs were randomised to either receive COTiD-UK, which comprised 10 hours of occupational therapy delivered over 10 weeks in the person with dementia’s home or TAU, which comprised the usual local service provision that may or may not include standard occupational therapy. The primary outcome was the Bristol Activities of Daily Living Scale (BADLS) score at 26 weeks. Secondary outcomes for the person with dementia included the following: the BADLS scores at 52 and 78 weeks, cognition, quality of life, and mood; and for the family carer: sense of competence and mood; plus the number of social contacts and leisure activities for both partners. Participants were analysed by treatment allocated. A total of 468 pairs were recruited: people with dementia ranged from 55 to 97 years with a mean age of 78.6 and family carers ranged from 29 to 94 with a mean of 69.1 years. Of the people with dementia, 74.8% were married and 19.2% lived alone. Of the family carers, 72.6% were spouses, and 22.2% were adult children. On randomisation, 249 pairs were assigned to COTiD-UK (62% people with dementia and 23% carers were male) and 219 to TAU (52% people with dementia and 32% carers were male). At the 26 weeks follow-up, data were available for 364 pairs (77.8%). The BADLS score at 26 weeks did not differ significantly between groups (adjusted mean difference estimate 0.35, 95% CI −0.81 to 1.51; p = 0.55). Secondary outcomes did not differ between the groups. In total, 91% of the activity-based goals set by the pairs taking part in the COTiD-UK intervention were fully or partially achieved by the final COTiD-UK session. Study limitations include the following: Intervention fidelity was moderate but varied across and within sites, and the reliance on primarily proxy data focused on measuring the level of functional or cognitive impairment which may not truly reflect the actual performance and views of the person living with dementia. Conclusions Providing community occupational therapy as delivered in this study did not improve ADL performance, cognition, quality of life, or mood in people with dementia nor sense of competence or mood in family carers. Future research should consider measuring person-centred outcomes that are more meaningful and closely aligned to participants’ priorities, such as goal achievement or the quantity and quality of activity engagement and participation. Trial Registration Current Controlled Trials ISRCTN10748953., Jennifer Wenborn and colleagues investigate the effectiveness of community occupational therapy program in improving activities of daily living, cognition, and mood for people with dementia., Author summary Why was this study done? Maintaining everyday and pleasurable activities can be difficult for a person with dementia, as well as their family carer who often feels increasingly stressed as they need to give more and more support. Occupational therapists assist people to improve their health and well-being through carrying on with the activities they need and want to do. It is therefore important to develop effective strategies to deliver occupational therapy to people with dementia and their family carers who support them. What did the researchers do and find? We tested the effectiveness of the Community Occupational Therapy in Dementia–UK version (COTiD-UK) programme compared to the care that people with mild to moderate dementia and their family carers usually receive, through a clinical trial. We recruited 468 pairs comprising a person with dementia and a family carer across England who were randomly allocated to either take part in the COTiD-UK programme or to continue with their usual care. We found no statistical evidence that COTiD-UK gave more benefit to people with dementia or their carers than the usual care provided in terms of the people with dementia being able to carry out activities or their mood or quality of life nor their family carers’ sense of competence or mood. The pairs who took part in the COTiD-UK intervention set an average of 4.09 goals each, of which 91% were fully or partially achieved by the final COTiD-UK session. What do these findings mean? We did not find evidence to support commissioning the COTiD-UK intervention for people with mild to moderate dementia and their family carers. Future studies need to develop more realistic methods of measuring the effectiveness of programmes such as this, particularly to focus on the outcomes that most matter to the individuals taking part and to truly reflect the actual performance, experience, and views of the person living with dementia.

Kidney disease is a common, complex, costly, and life-limiting condition. Most kidney disease registries or information systems have been limited to single institutions or regions. A national US Department of Veterans Affairs (VA) Renal Information System (VA-REINS) was recently developed. We describe its creation and present key initial findings related to chronic kidney disease (CKD) without kidney replacement therapy (KRT). Data from the VA's Corporate Data Warehouse were processed and linked with national Medicare data for patients with CKD receiving KRT. Operational definitions for VA user, CKD, acute kidney injury, and kidney failure were developed. Among 7 million VA users in fiscal year 2014, CKD was identified using either a strict or liberal operational definition in 1.1 million (16.4%) and 2.5 million (36.3%) veterans, respectively. Most were identified using an estimated glomerular filtration rate laboratory phenotype, some through proteinuria assessment, and very few through International Classification of Diseases, Ninth Revision coding. The VA spent ∼$18 billion for the care of patients with CKD without KRT, most of which was for CKD stage 3, with higher per-patient costs by CKD stage. VA-REINS can be leveraged for disease surveillance, population health management, and improving the quality and value of care, thereby enhancing VA's capacity as a patient-centered learning health system for US veterans.

Background We examined whether key sociodemographic and clinical risk factors for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and mortality changed over time in a population-based cohort study. Methods and findings In a cohort of 9,127,673 persons enrolled in the United States Veterans Affairs (VA) healthcare system, we evaluated the independent associations of sociodemographic and clinical characteristics with SARS-CoV-2 infection (n = 216,046), SARS-CoV-2–related mortality (n = 10,230), and case fatality at monthly intervals between February 1, 2020 and March 31, 2021. VA enrollees had a mean age of 61 years (SD 17.7) and were predominantly male (90.9%) and White (64.5%), with 14.6% of Black race and 6.3% of Hispanic ethnicity. Black (versus White) race was strongly associated with SARS-CoV-2 infection (adjusted odds ratio [AOR] 5.10, [95% CI 4.65 to 5.59], p-value, George Ioannou and co-workers study the distribution of SARS-CoV-2 infections and outcomes among the United States population., Author summary Why was this study done? As the Coronavirus Disease 2019 (COVID-19) pandemic continues to evolve, some risk factors for infection with COVID-19 and death due to COVID-19 that were described early in the pandemic may be changing. Recognizing such changes is important in informing population-based approaches to prevent infection and reduce mortality. What did the researchers do and find? We investigated how the associations of key sociodemographic and clinical factors with COVID-19 infection, mortality, or case fatality changed between February 2020 and March 2021 among a cohort of approximately 9.1 million persons enrolled in the national US Veterans Affairs (VA) healthcare system, including 216,046 who tested positive and 10,230 who died of COVID-19 during the study period. Black (versus White) race was strongly associated with a 5-fold higher risk of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, a 4-fold higher risk of mortality, and a 2.5-fold higher risk of case fatality in February to March 2020, but these associations attenuated over time and were no longer statistically significant by November 2020 for infection and mortality and were reversed for case fatality. American Indian/Alaska Native (AI/AN versus White) race was associated with SARS-CoV-2 infection early in the pandemic, but this association declined over time and reversed by March 2021. Urban (versus rural) residence was associated with 2-fold higher risk of infection, a 2.5-fold higher risk of mortality, and 2.2-fold higher risk of case fatality in February to April 2020, but these associations attenuated over time and reversed by September 2020. Throughout the observation period, high comorbidity burden, younger age, Hispanic ethnicity, and obesity were consistently associated with infection, while high comorbidity burden, older age, Hispanic ethnicity, and male sex were consistently associated with mortality. What do these findings mean? Early in the pandemic, there were strongly positive associations of Black and AI/AN (versus White) race and urban (versus rural) residence with SARS-CoV-2 infection, mortality, and case fatality, but these were ameliorated or even reversed by March 2021. Our results apply directly to VA enrollees who are predominantly male and have access to universal healthcare; they need to be confirmed in other populations.

Background Thoracic and abdominal aortic stent grafts are firmer and more rigid than the native aorta. Aortic implanted devices have been implicated in the development of acute systolic hypertension, elevated pulse pressure, and reduced coronary perfusion. Case summary We report four cases of staged thoracic endovascular aortic repair (TEVAR) and then endovascular aneurysm repair (EVAR). All patients had TEVAR first for thoracic aortic aneurysm and later on developed infra-renal abdominal aortic aneurysm (AAA) that required EVAR. There were three males and one female with a median age of 74.5 years (range 67.5–78.5). None of the patients developed aortic-related major clinical adverse effects or required any aortic intervention during their follow-up. However, within 2 years, all patients developed symptomatic left ventricular hypertrophy with diastolic dysfunction. All patients had bilateral lower limb oedema, with on and off chest pain and shortness of breath (SOB), necessitating coronary angiograms, which showed no evidence of coronary artery disease. Three patients died from cardiovascular-related morbidities, and the fourth patient is still complaining of SOB despite a normal coronary angiogram. Discussion Aortic-endograft compliance mismatch is an invisible enemy, with troubling consequences for the aorta proximal and distal to the endograft. Aortic stiffness due to vascular endograft could lead to cardiovascular adverse events, even in the absence of direct aortic-related complications. After combined TEVAR and EVAR, the compliance mismatch and elasticity loss are even more pronounced than with TEVAR alone, which necessitates patient monitoring for the development of cardiovascular complications.

A vascular insult occurring early in disease onset may initiate cognitive decline leading to dementia, while pharmacological and lifestyle interventions can prevent this progression. Mice with a selective, tamoxifen-inducible deletion of NF-κB essential modulator (Nemo) in brain endothelial cells were studied as a model of vascular cognitive impairment. Groups included NemoFl controls and three NemobeKO groups: One untreated, and two treated with simvastatin or exercise. Social preference and nesting were impaired in NemobeKO mice and were not countered by treatments. Cerebrovascular function was compromised in NemobeKO groups regardless of treatment, with decreased changes in sensory-evoked cerebral blood flow and total hemoglobin levels, and impaired endothelium-dependent vasodilation. NemobeKO mice had increased string vessel pathology, blood-brain barrier disruption, neuroinflammation, and reduced cortical somatostatin-containing interneurons. These alterations were reversed when endothelial function was recovered. Findings strongly suggest that damage to the cerebral endothelium can trigger pathologies associated with dementia and its functional integrity should be an effective target in future therapeutic efforts.

Simple Summary In breast cancer development, the expression of Ki-67 is strongly associated with cancer proliferation and is a known indicator of prognosis and outcome. Ki-67 expression levels are also useful to inform treatment decision making in some cases. As a result, routine measurement of Ki-67 is now widely performed during pathological tumour evaluation. However, the Ki-67 appraisal is not without its limitations and shortcomings—the aim of this study was to provide an overview of Ki-67 use in the clinical setting, the current challenges associated with its measurement, and the novel strategies that will hopefully enhance Ki-67 proliferation indices for prospective breast cancer patients. Abstract The advent of molecular medicine has transformed breast cancer management. Breast cancer is now recognised as a heterogenous disease with varied morphology, molecular features, tumour behaviour, and response to therapeutic strategies. These parameters are underpinned by a combination of genomic and immunohistochemical tumour factors, with estrogen receptor (ER) status, progesterone receptor (PgR) status, human epidermal growth factor receptor-2 (HER2) status, Ki-67 proliferation indices, and multigene panels all playing a contributive role in the substratification, prognostication and personalization of treatment modalities for each case. The expression of Ki-67 is strongly linked to tumour cell proliferation and growth and is routinely evaluated as a proliferation marker. This review will discuss the clinical utility, current pitfalls, and promising strategies to augment Ki-67 proliferation indices in future breast oncology.

Despite improvements in the diagnosis and treatment of cancers, the incidence of pituitary metastasis has increased. Prostate cancer metastasis to the pituitary, however, is rare, and these tumors usually grow rapidly. They are also more likely to be located in the posterior pituitary, and the presenting symptoms are often nonspecific, which makes early diagnosis challenging. The management of this condition is usually multidisciplinary, and requires careful assessment and decision making. We present a case of a patient who developed prostate cancer metastasis to the pituitary. In this report, we show that patients with prostate cancer on corticosteroid therapy who develop withdrawal symptoms or other endocrine symptoms should be assessed for pituitary and other brain metastasis. This case report also discusses the impact of switching from prednisone and abiraterone to dexamethasone and abiraterone. Our report shows that patients on abiraterone and prednisone whose PSA has increased, but who have no radiologic progression, may have their PSA controlled and thereby improved survival time when they are switched to abiraterone and dexamethasone.

The prevention and treatment of atrial fibrillation includes risk factor modification beyond ablation, with lifestyle modifications including treatment of obesity through diet and moderate exercise being at the top of the list. Losing 10% of body weight if obese, a plant-based diet, exercise, maintaining systolic blood pressure below 130 mm Hg, treatment of sleep disorders and obstructive sleep apnea, stress management, and treatment of depression and anxiety should all be included in treatment. Maximizing evidence-based treatment of chronic obstructive pulmonary disease and diabetes is also paramount.

Purpose: There is an unmet need for identifying novel biomarkers in Barrett's esophagus that could stratify patients with regards to neoplastic progression. We investigate the expression patterns of extracellular matrix (ECM) molecules in Barrett's esophagus and Barrett's esophagus–related neoplasia, and assess their value as biomarkers for the diagnosis of Barrett's esophagus–related neoplasia and to predict neoplastic progression. Experimental Design: Gene-expression analyses of ECM matrisome gene sets were performed using publicly available data on human Barrett's esophagus, Barrett's esophagus–related dysplasia, esophageal adenocarcinoma (ADCA) and normal esophagus. Immunohistochemical expression of basement membrane (BM) marker agrin (AGRN) and p53 was analyzed in biopsies of Barrett's esophagus–related neoplasia from 321 patients in three independent cohorts. Results: Differential gene-expression analysis revealed significant enrichment of ECM matrisome gene sets in dysplastic Barrett's esophagus and ADCA compared with controls. Loss of BM AGRN expression was observed in both Barrett's esophagus–related dysplasia and ADCA. The mean AGRN loss in Barrett's esophagus glands was significantly higher in Barrett's esophagus–related dysplasia and ADCA compared with non-dysplastic Barrett's esophagus (NDBE; P < 0.001; specificity = 82.2% and sensitivity = 96.4%). Loss of AGRN was significantly higher in NDBE samples from progressors compared with non-progressors (P < 0.001) and identified patients who progressed to advanced neoplasia with a specificity of 80.2% and sensitivity of 54.8%. Moreover, the combination of AGRN loss and abnormal p53 staining identified progression to Barrett's esophagus–related advanced neoplasia with a specificity and sensitivity of 86.5% and 58.7%. Conclusions: We highlight ECM changes during Barrett's esophagus progression to neoplasia. BM AGRN loss is a novel diagnostic biomarker that can identify patients with NDBE at increased risk of developing advanced neoplasia.