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Since the introduction of the Grammont-style reverse total shoulder arthroplasty, the humeral stem design has been modified with improved clinical outcomes. Two distinct humeral designs have been used extensively: the inlay design, in which the humeral tray is seated within the metaphysis, and the onlay design, in which the humeral tray sits on the metaphysis at the level of the humeral neck cut. The purpose of this systematic review was to determine whether there are differences in clinical outcomes and complication rates between these designs.The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were used to perform this systematic review. A search of MEDLINE, PubMed, and Embase was performed to identify all studies comparing the clinical results of both humeral designs. Primary outcomes included patient-reported outcome measures, shoulder range of motion, and incidence of complications.From the 156 identified publications, 12 studies were included in the final review. A total of 1447 patients were included, with a minimum follow-up period of 12 months. At final follow-up, both implants demonstrated significant improvements in comparison to preoperative baseline. On comparison of the inlay vs. onlay groups, the American Shoulder and Elbow Surgeons score was higher in the inlay group (mean difference, 2.53 [95% confidence interval, 0.27-4.78]; P = .03). Postoperative motion, even if statistically greater in the onlay group (differences of 5° in forward flexion [P .001], 3° in abduction [P = .003], and 4° in external rotation [P .001]), was not clinically different. On comparison of complications, the inlay group showed more instances of scapular notching (93 of 322 patients vs. 70 of 415 patients; odds ratio, 0.35; P .001) but fewer scapular spine fractures (26 of 727 patients vs. 21 of 559 patients, P = .09).Inlay and onlay humeral tray designs in reverse total shoulder arthroplasty demonstrate similar clinical improvements postoperatively. Onlay implants have a low rate of scapular notching but a higher rate of scapular spine fracture. Understanding the strengths and weaknesses of the 2 humeral tray designs is important to provide surgeons with options to tailor surgical plans for high-risk patients.

New therapies are needed for patients with relapsed/refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) who do not benefit from or are ineligible for stem cell transplant and chimeric antigen receptor therapy. The CD30-targeted, antibody-drug conjugate brentuximab vedotin (BV) and the immunomodulator lenalidomide (Len) have demonstrated promising activity as single agents in this population. We report the results of a phase 1/dose expansion trial evaluating the combination of BV/Len in rel/ref DLBCL. Thirty-seven patients received BV every 21 days, with Len administered continuously for a maximum of 16 cycles. The maximum tolerated dose of the combination was 1.2 mg/kg BV with 20 mg/d Len. BV/Len was well tolerated with a toxicity profile consistent with their use as single agents. Most patients required granulocyte colony-stimulating factor support because of neutropenia. The overall response rate was 57% (95% CI, 39.6-72.5), complete response rate, 35% (95% CI, 20.7-52.6); median duration of response, 13.1 months; median progression-free survival, 10.2 months (95% CI, 5.5-13.7); and median overall survival, 14.3 months (95% CI, 10.2-35.6). Response rates were highest in patients with CD30+ DLBCL (73%), but they did not differ according to cell of origin (P = .96). NK cell expansion and phenotypic changes in CD8+ T-cell subsets in nonresponders were identified by mass cytometry. BV/Len represents a potential treatment option for patients with rel/ref DLBCL. This combination is being further explored in a phase 3 study (registered on https://clinicaltrials.org as NCT04404283). This trial was registered on https://clinicaltrials.gov as NCT02086604.

Richter transformation (RT) refers to the development of an aggressive lymphoma in patients with pre-existing chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). It carries a poor prognosis secondary to poor response to therapy or rapid disease relapse. Currently there are no randomized trials to guide treatment. Therapeutic decisions are often influenced by the presence or absence of a clonal relationship between the underlying CLL/SLL and the new lymphoma given the poor prognosis of patients with clonally related RT. Chromosomal microarray analysis (CMA) can help to establish clonality while also detecting genomic complexity and clinically relevant genetic variants such as loss of CDKN2A and/or TP53. As a result, CMA has potential prognostic and therapeutic implications. For this study, CMA results from patients with Richter transformation were evaluated in paired CLL/SLL and transformed lymphoma samples. CMA revealed that 86% of patients had common aberrations in the two samples indicating evidence of common clonality. CMA was also useful in detecting aberrations associated with a poor prognosis in 71% of patients with RT. This study highlights the potential clinical utility of CMA to investigate the clonal relationship between CLL/SLL and RT, provide prognostic information, and possibly guide therapeutic decision making for patients with Richter transformation.

PURPOSE Diagnosis of AIDS lymphoma in low-resource settings, like South Africa, is often delayed, leaving patients with limited treatment options. In tuberculosis (TB) endemic regions, overlapping signs and symptoms often lead to diagnostic delays. Assessment of plasma cell-free DNA (cfDNA) by next-generation sequencing (NGS) may expedite the diagnosis of lymphoma but requires high-quality cfDNA. METHODS People living with HIV with newly diagnosed aggressive B-cell lymphoma and those with newly diagnosed TB seeking care at Chris Hani Baragwanath Academic Hospital and its surrounding clinics, in Soweto, South Africa, were enrolled in this study. Each participant provided a whole blood specimen collected in cell-stabilizing tubes. Quantity and quality of plasma cfDNA were assessed. NGS of the immunoglobulin heavy chain was performed. RESULTS Nine HIV+ patients with untreated lymphoma and eight HIV+ patients with TB, but without lymphoma, were enrolled. All cfDNA quantity and quality metrics were similar between the two groups, except that cfDNA accounted for a larger fraction of recovered plasma DNA in patients with lymphoma. The concentration of cfDNA in plasma also trended higher in patients with lymphoma. NGS of immunoglobulin heavy chain showed robust amplification of DNA, with large amplicons (> 250 bp) being more readily detected in patients with lymphoma. Clonal sequences were detected in five of nine patients with lymphoma, and none of the patients with TB. CONCLUSION This proof-of-principle study demonstrates that whole blood collected for cfDNA in a low-resource setting is suitable for sophisticated sequencing analyses, including clonal immunoglobulin NGS. The detection of clonal sequences in more than half of patients with lymphoma shows promise as a diagnostic marker that may be explored in future studies.

Summary Background In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort. Methods In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0–1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 108 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov , NCT02445248 , and is ongoing. Findings Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8–43·8), the overall response rate was 53·0% (95% CI 43·5–62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3–4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported. Interpretation Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk–benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy). Funding Novartis Pharmaceuticals.

This study aimed to assess the efficacy and safety of Actovegin for the treatment of patients with Fontaine stage IIB peripheral arterial disease (PAD).The study included 366 patients with Fontaine stage IIB PAD from 19 centers (Russia, Georgia, Kazakhstan). Placebo or Actovegin (1200 mg daily [QD]) were administered intravenously for two weeks, followed by a 10-week course of oral administration (placebo or Actovegin 1200 mg QD). The primary efficacy outcome was percentage change in the initial claudication distance (ICD) by week 12. Secondary outcomes included percent and absolute changes in ICD, absolute claudication distance (ACD) and changes in Quality of Life (QoL) assessed by the SF-36 Mental Health Score.The increase in ICD after 12 weeks of Actovegin treatment was 29.19% (LS mean [Actovegin vs. placebo]; 95% CI: 9.35-49.02; P=0.0041). The percentage increase in ICD at 24 weeks was 35.51% (LS mean; 95% CI: 10.96-60.05; P=0.0047), which correspond to an increase in absolute ICD of 41.22 m (LS mean; 95% CI: 16.77-65.66; P=0.0010). The percentage increase in ACD after 24 weeks was 36.47% compared with the baseline (LS mean; 95% CI: 10.07-62.88; P=0.0069), which corresponded to an absolute increase in ACD of 50.92 m (LS mean; 95% CI: 18.35-83.49; P=0.0023). A statistically significant improvement in QoL with Actovegin compared with placebo was demonstrated within 24 weeks (LS mean 2.28; 95% CI: 0.88-3.68; P=0.0015). Actovegin demonstrated an acceptable safety and tolerability profile with minor differences from placebo.The results of this 12-week course of Actovegin demonstrated its superiority over placebo in the increase in ICD and ACD at weeks 2, 12 and 24 from the start of treatment. Actovegin has an acceptable safety and tolerability profile.

Approximately 25% of all patients who sustain perilunate dislocations present in a delayed fashion.While management of acute injuries is relatively well-described, treatment of chronic injuries can be complex and there is a paucity of scientific evidence to guide management.Treatment options include open reduction internal fixation, proximal row carpectomy, scaphoid or lunate excision with or without arthrodesis, and total wrist arthrodesis, although indications vary based on chronicity of injury and patient factors.The purpose of this article was to determine the quality of evidence supporting surgical options for the treatment of these injuries.

Current guidelines lack sufficient evidence to recommend a specific blood pressure lowering strategy to prevent cardiovascular disease after preeclampsia. We conducted a double-blind cross-over trial to identify the most potent antihypertensive strategy: renin-angiotensin-aldosterone system (RAAS) inhibition (losartan), sympathoinhibition (moxonidine), low sodium diet and placebo (n = 10). Due to low inclusion rate our study stopped prematurely. Initiatory analyses showed no significant effect of antihypertensive strategy on office blood pressure and 24-hour blood pressure. However, nocturnal dipping was significantly higher on RAAS inhibition and low sodium diet compared to placebo and sympathoinhibition. Optimal cardiovascular prevention after preeclampsia should be further explored.

Background The incidence of colorectal cancer in adults younger than age 50 has increased with rates expected to continue to increase over the next decade. The objective of this study is to examine the survival benefit of surgical resection (primary and/or metastatic) versus palliative therapy in this patient population. Methods We identified 6708 young adults aged 18–45 years diagnosed with metastatic colorectal cancer (mCRC) from 2004 to 2015 from the SEER database. Overall survival (OS) was analyzed using Kaplan–Meier estimation, log rank test, and multivariate Cox proportional hazards model. Results Sixty‐three percent of patients in our study underwent primary tumor resection (PTR), with 40% undergoing PTR alone and 23% undergoing both resection of primary disease and metastasectomy. The median OS for patients who underwent both PTR and metastasectomy was 36 months, compared to 13 months for those who did not receive any surgical intervention. The multivariate analysis showed significant OS benefit of receiving both PTR and metastasectomy (HR 0.34, 95% CI: 0.31–0.37, p, The incidence of colorectal cancer in adults younger than age 50 has increased with rates expected to continue to increase over the next decade. The objective of this study is to examine the survival benefit of surgical resection (primary and/or metastatic) vs palliative therapy in this patient population. Our study provides evidence of statistically significant increase in OS for young mCRC patients who undergo surgical intervention of the primary and/or metastatic site.

SARS-CoV2 is a novel betacoronavirus that emerged in 2019 and has resulted in a global pandemic of coronavirus disease 2019 (COVID-19) [1]. COVID-19 can cause progressive respiratory failure, which...

Current protocols for the differentiation of human-induced pluripotent stem cells (hiPSC) into cardiomyocytes only generate a small amount of cardiac pacemaker cells. In previous work, we reported the generation of high amounts of cardiac pacemaker cells by co-culturing hiPSC with mouse visceral endoderm-like (END2) cells. However, potential medical applications of cardiac pacemaker cells generated according to this protocol, comprise an incalculable xenogeneic risk. We thus aimed to establish novel protocols maintaining the differentiation efficiency of the END2 cell-based protocol, yet eliminating the use of END2 cells. Three protocols were based on the activation and inhibition of the Wingless/Integrated (Wnt) signaling pathway, supplemented either with retinoic acid and the Wnt activator CHIR99021 (protocol B) or with the NODAL inhibitor SB431542 (protocol C) or with a combination of all three components (protocol D). An additional fourth protocol (protocol E) was used, which was originally developed by the manufacturer STEMCELL Technologies for the differentiation of hiPSC or hESC into atrial cardiomyocytes. All protocols (B, C, D, E) were compared to the END2 cell-based protocol A, serving as reference, in terms of their ability to differentiate hiPSC into cardiac pacemaker cells. Our analysis revealed that protocol E induced upregulation of 12 out of 15 cardiac pacemaker-specific genes. For comparison, reference protocol A upregulated 11, while protocols B, C and D upregulated 9, 10 and 8 cardiac pacemaker-specific genes, respectively. Cells differentiated according to protocol E displayed intense fluorescence signals of cardiac pacemaker-specific markers and showed excellent rate responsiveness to adrenergic and cholinergic stimulation. In conclusion, we characterized four novel and END2 cell-independent protocols for the differentiation of hiPSC into cardiac pacemaker cells, of which protocol E was the most efficient.

Abdominal aortic aneurysm (AAA) is a life-threatening disease, with an extremely high risk of death when ruptured. With the increase in life expectancy AAA is becoming more prevalent in aging patients. Elective and emergency procedures in elderly patients with AAA are becoming more common, but the indications for aortic repair and outcomes in geriatric patients are debatable. In our report, we present long-term results of a successful endovascular aortic repair (EVAR) of a ruptured juxtarenal aortic aneurysm complicated by hypovolemia and myocardial infarction in a 92-year-old patient. No endoleaks or bleedings were detected with CT angiography in the post-operative period. After two years following the procedure, the patient is doing well and can take care of himself; there was no disease progression as confirmed by ultrasonography. In conclusion, complicated abdominal aortic aneurysms in nonagenarians can be successfully treated by EVAR with fine long-term results.

Idelalisib is a phosphatidylinositol 3-kinase δ inhibitor approved for relapsed/refractory follicular lymphoma, a type of indolent non-Hodgkin lymphoma (iNHL), and chronic lymphocytic leukemia (CLL). Idelalisib-triggered adverse events (AEs) may be managed with treatment interruption and/or dose reduction, potentially extending therapy duration and increasing the likelihood of continued response.Post hoc analyses were conducted to evaluate clinical outcomes after AE-induced idelalisib interruption for 125 patients with iNHL and 283 with CLL.Progression-free survival (PFS) was longer for patients with iNHL who experienced ≥ 2 interruptions versus those with 0 interruptions who discontinued idelalisib or study because of AEs (hazard ratio 0.33; P = .0212). Both PFS and overall survival were longer for patients with CLL with ≥ 2 interruptions versus 0 interruptions in those who discontinued therapy because of an AE (hazard ratio PFS 0.50, overall survival 0.41; P .005). Clinical benefits persisted for patients with CLL who experienced treatment interruption after receiving idelalisib for ≥ 6 months. Supplementing interruption with dose reduction did not worsen clinical outcomes. However, time off therapy of ≥ 8% may diminish the clinical benefit of treatment interruption.Idelalisib interruption and dose reduction were associated with enhanced clinical outcomes for patients with relapsed/refractory iNHL or CLL who experienced an AE, supporting this management strategy when indicated.

This study aimed to describe the variety of etiologies currently identified in infants with cardiac hypertrophy (CH) and investigate whether there is a relation with hyperinsulinism, echocardiographic characteristics and prognosis. This retrospective cohort study included infants born between 2005 and 2018 with CH measured by echocardiography [interventricular septum (IVS) and/or left ventricular posterior wall (LVPW) thickness with Z-score ≥ 2.0]. Children with congenital heart disease or hypertension were excluded. Underlying diagnosis, echocardiographic and follow-up data were extracted from patient files. Seventy-one infants with CH were included. An underlying cause of CH was identified in two-thirds (n = 47). Most common etiologies of CH were malformation syndromes (n = 23, including Noonan n = 12) and maternal diabetes mellitus (n = 13). Less common causes were congenital hyperinsulinism (n = 3), metabolic- (n = 5), sarcomeric- (n = 2) and neuromuscular disease (n = 1). In half of the identified causes (n = 22) an association with hyperinsulinism was described, including maternal diabetes mellitus (n = 13), malformation syndromes with insulin resistance (n = 6) and congenital hyperinsulinism (n = 3). CH associated with hyperinsulinism was echocardiographically characterized by lower LVPW thickness, higher IVS:LVPW ratio and more frequent sole involvement of the IVS (all, p ≤ 0.02). CH associated with hyperinsulinism normalized more often (41 vs. 0%) with lower mortality rates (14 vs. 44%) compared to CH not associated with hyperinsulinism (all, p ≤ 0.03). Nowadays, an etiology of CH can be identified in the majority of infants. The development of CH is often associated with hyperinsulinism which is mainly characterized by focal hypertrophy of the IVS on echocardiography. Prognosis depends on the underlying cause and is more favorable in CH associated with hyperinsulinism.

Transplant-associated thrombotic microangiopathy (taTMA) is a systemic vascular illness associated with significant morbidity and mortality, resulting from a convergence of risk factors after allogeneic blood or marrow transplantation (alloBMT). The diagnosis of taTMA has been a challenge, but most criteria include an elevated lactate dehydrogenase (LDH), low haptoglobin, and schistocytes on peripheral blood smear. We performed a retrospective review of the 678 consecutive adults who received high-dose post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis between January 1, 2015, and August 31, 2018. In April 2016, we initiated a monitoring program of weekly LDH and haptoglobin measurements and blood smears when those 2 parameters were both abnormal on all of our adult patients undergoing alloBMT for hematologic malignancies. During the entire period, the 1-year cumulative incidence of taTMA was 1.4% (95% confidence interval, 0.5% to 2.3%). Eight patients were taking tacrolimus at the time of diagnosis, and 1 was not on any immunosuppression. Eight of 9 patients (89%) were hypertensive. Four patients had invasive infections at the time of diagnosis, 4 patients required renal replacement therapy, and 5 of 9 patients were neurologically impaired. Eculizumab was given to 6 patients (0.9%), of whom 2 died and 4 recovered with resolution of end-organ dysfunction. The paucity of events made the determination of risk factors difficult; however, the low incidence of taTMA in this cohort may be related to the limited use of myeloablative conditioning regimens, low incidence of severe GVHD, and use of PTCy. PTCy-based GVHD prophylaxis appears to be associated with a low incidence of severe taTMA.

ObjectiveCancer incidence and mortality rates in Africa are increasing, yet their geographic distribution and determinants are incompletely characterized. The present study aims to establish the spatial epidemiology of cancer burden in Africa and delineate the association between cancer burden and the country-level socioeconomic status. The study also examines the forecasts of the cancer burden for 2040 and evaluates infrastructure availability across all African countries.MethodsThe estimates of age, sex, and country-specific incidence and mortality of 34 neoplasms in 54 African countries, were procured from GLOBOCAN 2020. Mortality-to-incidence ratio (MIR) was employed as a proxy indicator of 5-year survival rates, and the socioeconomic development of each country was measured using its human development index (HDI). We regressed age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), and MIR on HDI using linear regression model to determine the relationship between cancer burden and HDI. Maps were generated for each cancer group for each country in Africa. The data about the cancer infrastructure of African countries were extracted from the WHO Cancer Country Profiles.ResultsIn Africa, an estimated 1.1 million new cases [95% uncertainty intervals (UIs) 1.0 – 1.3 million] and 711,429 [611,604 – 827,547] deaths occurred due to neoplasms in 2020. The ASIR was estimated to be 132.1/100,000, varying from 78.4/100,000 (Niger) to 212.5/100,000 (La Réunion) in 2020. The ASMR was 88.8/100,000 in Africa, ranging from 56.6/100,000 in the Republic of the Congo to 139.4/100,000 in Zimbabwe. The MIR of all cancer combined was 0.64 in Africa, varying from 0.49 in Mauritius to 0.78 in The Gambia. HDI had a significant negative correlation with MIR of all cancer groups combined and main cancer groups (prostate, breast, cervical and colorectal). HDI explained 75% of the variation in overall 5-year cancer survival (MIR). By 2040, the burden of all neoplasms combined is forecasted to increase to 2.1 million new cases and 1.4 million deaths in Africa.ConclusionHigh cancer mortality rates in Africa demand a holistic approach toward cancer control and management, including, but not limited to, boosting cancer awareness, adopting primary and secondary prevention, mitigating risk factors, improving cancer infrastructure and timely treatment.

Recent advances in the technology of producing novel cardiomyocytes from induced pluripotent stem cells (iPSC-cardiomyocytes) fuel new hope for future clinical applications. The use of iPSC-cardiomyocytes is particularly promising for the therapy of cardiac diseases such as myocardial infarction, where these cells could replace scar tissue and restore the functionality of the heart. Despite successful cardiogenic differentiation, medical applications of iPSC-cardiomyocytes are currently limited by their pronounced immature structural and functional phenotype. This review focuses on gap junction function in iPSC-cardiomyocytes and portrays our current understanding around the structural and the functional limitations of intercellular coupling and viable cardiac graft formation involving these novel cardiac muscle cells. We further highlight the role of the gap junction protein connexin 43 as a potential target for improving cell–cell communication and electrical signal propagation across cardiac tissue engineered from iPSC-cardiomyocytes. Better insight into the mechanisms that promote functional intercellular coupling is the foundation that will allow the development of novel strategies to combat the immaturity of iPSC-cardiomyocytes and pave the way toward cardiac tissue regeneration.

With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative (NMA) HLA-haploidentical (haplo) and HLA-matched blood or marrow transplantation (BMT) have comparable outcomes. Previous reports have shown that discontinuation of immunosuppression (IS) as early as day 60 after infusion of a bone marrow (BM) haplo allograft with PTCy is feasible. There are certain diseases in which peripheral blood (PB) may be favored over BM, but given the higher rates of GVHD with PB, excessive GVHD is of increased concern. We report a completed, prospective single-center trial of stopping IS at days 90 and 60 after NMA PB stem cell transplantation (PBSCT). Between 12/2015-7/2018, 117 consecutive patients with hematologic malignancies associated with higher rates of graft failure after NMA conditioned BMT and PTCy, received NMA PB allografts on trial. The primary objective of this study was to evaluate the safety and feasibility of reduced-duration IS (from day 5 through day 90 in the D90 cohort and through day 60 in the D60 cohort). Of the 117 patients (median age, 64 years; range, 22 to 78 years), the most common diagnoses were myelodysplastic syndrome (33%), acute myelogenous leukemia (with minimal residual disease or arising from an antecedent disorder) (32%), myeloproliferative neoplasms (19%), myeloma (9%), and chronic lymphoblastic leukemia (7%). Shortened IS was feasible in 75 patients (64%) overall. Ineligibility for shortened IS resulted most commonly from GVHD (17 patients), followed by early relapse (11 patients), nonrelapse mortality (NRM) (7 patients), patient/ physician preference (4 patients) or graft failure (3 patients). Of the 57 patients in the D90 cohort, 33 (58%) stopped IS early as planned, and among the 60 patients in the D60 cohort, 42 (70%) stopped IS early as planned. The graft failure rate was 2.6%. After IS cessation, the median time to diagnosis of grade II-IV acute GVHD was 21 days in the D90 cohort and 32 days in the D60 cohort, with almost all cases developing within 40 days. Approximately one-third of these patients resumed IS. All outcome measures were similar in the 2 cohorts and our historical outcomes with 180 days of IS. The cumulative incidence of grade III-IV acute GVHD was low, 2% in the D90 cohort and 7% in the D60 cohort. The incidence of severe chronic GVHD at 2 years was 9% in the D90 cohort and 5% in the D60 cohort. The 2-year overall survival was 67% for both the D90 and D60 cohorts. The 2-year progression-free survival was 47% for the D90 cohort and 52% for the D60 cohort, and the GVHD-free, relapse-free survival was35% for both cohorts. These data suggest that reduced-duration IS in patients undergoing NMA PBSCT with PTCy is feasible and has an acceptable safety profile. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Prompt diagnosis of pulmonary embolism (PE) remains challenging, which often results in a delayed or inappropriate treatment of this life-threatening condition. Mobile thrombus in the right cardiac chambers is a neglected cause of PE. It poses an immediate risk to life and is associated with an unfavorable outcome and high mortality. Thrombus residing in the right atrial appendage (RAA) is an underestimated cause of PE, especially in patients with atrial fibrillation. This article reviews achievements and challenges of detection and management of the right atrial thrombus with emphasis on RAA thrombus. The capabilities of transthoracic and transesophageal echocardiography and advantages of three-dimensional and two-dimensional echocardiography are reviewed. Strengths of cardiac magnetic resonance imaging (CMR), computed tomography, and cardiac ventriculography are summarized. We suggest that a targeted search for RAA thrombus is necessary in high-risk patients with PE and atrial fibrillation using transesophageal echocardiography and/or CMR when available independently on the duration of the disease. High-risk patients may also benefit from transthoracic echocardiography with right parasternal approach. The examination of high-risk patients should involve compression ultrasonography of lower extremity veins along with the above-mentioned technologies. Algorithms for RAA thrombus risk assessment and protocols aimed at identification of patients with RAA thrombosis, who will potentially benefit from treatment, are warranted. The development of treatment protocols specific for the diverse populations of patients with right cardiac thrombosis is important.

Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.

PURPOSE: The current project was developed to obtain natural history information regarding cisplatin-induced peripheral neuropathy in males with testicular/germ cell cancers and to compare such neuropathy data with similarly obtained data in patients receiving other chemotherapy drugs in similarly conducted clinical trials. METHODS: Patients without baseline neuropathy symptoms, who were initiating cisplatin-based chemotherapy, completed the EORTC CIPN 20 patient-reported instrument to evaluate chemotherapy-induced peripheral neuropathy (CIPN). Results were compared to EORTC CIPN 20 data obtained from independent study sets regarding patients receiving 1) paclitaxel, 2) combined paclitaxel and carboplatin, 3) oxaliplatin, or 4) a combination of doxorubicin and cyclophosphamide (AC). The last study set of patients on AC was selected to evaluate the use of EORTC CIPN 20 data in patients receiving chemotherapy not known to cause CIPN. RESULTS: Cisplatin-induced neuropathy was more similar to neuropathy in patients receiving oxaliplatin than in those receiving paclitaxel. The cisplatin and oxaliplatin groups exhibited the coasting phenomenon and more prominent upper extremity symptoms than lower extremity symptoms during chemotherapy administration weeks. In contrast, paclitaxel-treated patients did not, on average, exhibit the coasting phenomenon; additionally, lower extremity symptoms were more prominent during the weeks when paclitaxel was administered. Cisplatin-induced neuropathy was less severe than was seen in patients in the other two groups, potentially because the cisplatin-receiving patients were younger. Patients receiving AC did not report substantial EORTC CIPN 20 changes. CONCLUSION: Understanding neuropathy similarities and differences with various chemotherapy agents may help elucidate CIPN processes and facilitate means to prevent and/or treat established CIPN.

Severe aplastic anemia (SAA) is a stem cell disorder often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis. Outcomes of related HLA-haploidentical (haplo) donors after reduced-intensity conditioning with intensive graft-versus-host disease (GVHD) prophylaxis including posttransplantation cyclophosphamide are presented here from 37 SAA, 20 relapsed/refractory (R/R), and 17 treatment-naïve (TN) SAA patients. Median follow-up is 32 months (90% confidence interval [CI], 29-44). The median age was 25 (range, 4-69) years. The median time to neutrophil recovery was 17 days (range, 15-88). Four of 37 patients (11%) experienced graft failure (GF). There was 1 primary GF of 20 patients in the R/R group and 3 of 17 in the TN group at 200 cGy (1 primary, 2 secondary), but none in the 10 patients who received 400 cGy total body irradiation. Two patients with GF succumbed to infection and 2 were rescued with second haplo BMT. The overall survival for all patients is 94% (90% CI, 88-100) at 1 and 2 years. The cumulative incidence of grade II-IV acute GVHD at day 100 is 11%. The cumulative index of chronic GVHD at 2 years is 8%. Similar results were seen in 10 SAA patients who received the identical nonmyeloablative regimen with posttransplant cyclophosphamide but matched donor transplants. Haplo BMT with posttransplant cyclophosphamide represents a potential cure in SAA, with all 20 R/R currently alive, disease-free, and with no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates, but an increase in total body irradiation dose to 400 cGy was associated with durable engraftment without greater early toxicity. Nonmyeloablative haplo BMT in TN SAA could lead to a paradigm shift, such that essentially all patients can proceed quickly to safe, curative BMT. These trials were registered at www.cincialtrials.gov as #NCT02224872) and #NCT02833805.

BACKGROUND Current clinical practices are shifting towards utilizing less invasive biopsy techniques, including fine needle aspiration (FNA) and needle core biopsies. If a patient has a suspected hematologic malignancy, a portion of the FNA sample is typically submitted for flow cytometry (FC) analysis, providing valuable immunophenotypic data. METHODS FNA specimens were identified via a pathology database search. All cases were morphologic evaluated and a subset of cases were analyzed by FC. RESULTS 245 hematologic FNA specimens were identified; 84% of these cases had an adequate number of cells for FC analysis, and an unequivocal morphologic diagnosis (benign or malignant) was rendered in 85%. The percentage of cases with an unequivocal diagnosis was statistically significantly higher in those with associated FC than with those without FC (90% vs 58%). Neither FNA technique nor anatomic site affected the likelihood of obtaining an adequate sample for FC analysis and/or rendering a definitive morphologic or unequivocal FC diagnosis. Likewise, tumor subtype did not affect the likelihood of acquiring enough cells for FC analysis, but occasionally resulted in equivocal FC diagnoses or discordant FNA and FC diagnoses. Aggressive B-cell lymphomas and Hodgkin lymphomas were significantly less likely to be detected by FC as compared to low-grade B-cell lymphomas. Discrepancies between FNA and FC diagnoses occurred in 13% of cases. The majority of discrepancies (78%) included FC false negatives, while only 22% of cases had atypical or positive FC with negative FNA. CONCLUSIONS FNA with associated FC is a powerful diagnostic technique; however, lymphoma subtype may affect diagnostic sensitivity by FC, and therefore, discordant FNA and FC results should be interpreted with caution.

The anti-CD19 chimeric antigen receptor (CAR)–T cell therapy tisagenlecleucel was evaluated in the global, phase 2 JULIET study in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We correlated tisagenlecleucel cellular kinetics with clinical/product parameters in 111 patients treated in JULIET. Tisagenlecleucel persistence in responders and nonresponders, respectively, was demonstrated for 554 and 400 days maximum by flow cytometry and for 693 and 374 days maximum by quantitative polymerase chain reaction (qPCR). No relationships were identified between cellular kinetics (qPCR) and product characteristics, intrinsic/extrinsic factors, dose, or immunogenicity. Most patients with 3-month response had detectable transgene at time of response and continued persistence for ≥6 months. Expansion (maximal expansion of transgene/CAR-positive T-cell levels in vivo postinfusion [Cmax]) was potentially associated with response duration but this did not reach statistical significance (hazard ratio for a twofold increase in Cmax, 0.79; 95% confidence interval, 0.61-1.01). Tisagenlecleucel expansion was associated with cytokine-release syndrome (CRS) severity and tocilizumab use; no relationships were observed with neurologic events. Transgene levels were associated with B-cell levels. Dose was associated with CRS severity, but this was not statistically significant after adjusting for baseline tumor burden. In contrast to the results from B-cell precursor acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia, similar exposure was observed in DLBCL in this study regardless of response and expansion was lower in DLBCL than B-ALL, likely from differences in cancer location and/or T-cell intrinsic factors. Relationships between expansion and CRS severity, and lack of relationships between dose and exposure, were similar between DLBCL and B-ALL. Tisagenlecleucel cellular kinetics in adult relapsed/refractory DLBCL improve current understanding of in vivo expansion and its relationships with safety/efficacy endpoints. This trial was registered at www.clinicaltrials.gov as #NCT02445248.

Supplemental Digital Content is available in the text., Background. The incidence of pregnancy in kidney transplantation (KT) recipients is increasing. Studies report that the incidence of graft loss (GL) during pregnancy is low, but less data are available on long-term effects of pregnancy on the graft. Methods. Therefore, we performed a meta-analysis and systematic review on GL and graft function, measured by serum creatinine (SCr), after pregnancy in KT recipients, stratified in years postpartum. Furthermore, we included studies of nulliparous KT recipients. Results. Our search yielded 38 studies on GL and 18 studies on SCr. The pooled incidence of GL was 9.4% within 2 years after pregnancy, 9.2% within 2–5 years, 22.3% within 5–10 years, and 38.5% >10 years postpartum. In addition, our data show that, in case of graft survival, SCr remains stable over the years. Only within 2 years postpartum, Δ SCr was marginally higher (0.18 mg/dL, 95%CI [0.05-0.32], P = 0.01). Furthermore, no differences in GL were observed in 10 studies comparing GL after pregnancy with nulliparous controls. Systematic review of the literature showed that mainly prepregnancy proteinuria, hypertension, and high SCr are risk factors for GL. Conclusions. Overall, these data show that pregnancy after KT has no effect on long-term graft survival and only a possible effect on graft function within 2 years postpartum. This might be due to publication bias. No significant differences were observed between pre- and postpartum SCr at longer follow-up intervals.

Hypertrophic cardiomyopathy (HCM) in neonates is a rare and heterogeneous disorder which is characterized by hypertrophy of heart with histological and functional disruption of the myocardial structure/composition. The prognosis of HCM depends on the underlying diagnosis. In this review, we emphasize the importance to consider hyperinsulinism in the differential diagnosis of HCM, as hyperinsulinism is widely associated with cardiac hypertrophy (CH) which cannot be distinguished from HCM on echocardiographic examination. We supply an overview of the incidence and treatment strategies of neonatal CH in a broad spectrum of hyperinsulinemic diseases. Reviewing the literature, we found that CH is reported in 13 to 44% of infants of diabetic mothers, in approximately 40% of infants with congenital hyperinsulinism, in 61% of infants with leprechaunism and in 48 to 61% of the patients with congenital generalized lipodystrophy. The correct diagnosis is of importance since there is a large variation in prognoses and there are various strategies to treat CH in hyperinsulinemic diseases.Conclusion: The relationship between CH and hyperinsulism has implications for clinical practice as it might help to establish the correct diagnosis in neonates with cardiac hypertrophy which has both prognostic and therapeutic consequences. In addition, CH should be recognized as a potential comorbidity which might necessitate treatment in all neonates with known hyperinsulinism.What is Known:• Hyperinsulinism is currently not acknowledged as a cause of hypertrophic cardiomyopathy (HCM) in textbooks and recent Pediatric Cardiomyopathy Registry publications.What is New:• This article presents an overview of the literature of hyperinsulinism in neonates and infants showing that hyperinsulinism is associated with cardiac hypertrophy (CH) in a broad range of hyperinsulinemic diseases.• As CH cannot be distinguished from HCM on echocardiographic examination, we emphasize the importance to consider hyperinsulinism in the differential diagnosis of HCM/CH as establishing the correct diagnosis has both prognostic and therapeutic consequences.

While patients with double-hit lymphoma (DHL) are now frequently treated with intensive front-line immunochemotherapy, outcomes for those who fail these regimens and subsequently receive curative-intent second-line immunochemotherapy are unknown. We identified 55 such patients who achieved an overall/complete response rate of 29%/11%, median progression-free/overall survival (PFS/OS) of 2/5·1 months and one-year PFS/OS of 10/19% following the start of second-line therapy. These outcomes may serve as a standard against which future second-line treatment strategies for relapsed/refractory DHL can be measured and justify investigation of non-cytotoxic therapies in the second-line setting for these patients.

To investigate if any injury to the three primary branches of the popliteal artery in open tibia fractures lead to increased soft-tissue complications, particularly in the area of the affected angiosome.Retrospective cohort comparative study.Two academic level one trauma centers.Sixty-eight adult patients with open tibia fractures with a minimum one-year follow up.N/A.Soft-tissue outcomes as measured by wound healing (delayed healing, dehiscence, or skin breakdown) and fracture related infection (FRI) at time of final follow-up.Eleven (15.1%) tibia fractures had confirmed arterial injuries via CTA (7), direct intraoperative visualization (3), intraoperative angiogram (3). Ten (91.0%) were treated with ligation and 1 (9.1%) was directly repaired by vascular surgery. Ultimately, 6 (54.5%) achieved radiographic union and 4 (36.4%) required amputation performed at a mean of 2.62 ± 2.04 months, with one patient going on to nonunion diagnosed at 10 months. Patients with arterial injury had significantly higher rates of wound healing complications, FRI, nonunion, amputation rates, return to the OR, and increased time to coverage or closure. After multivariate regression, arterial injury was associated with higher odds of wound complications, FRI, and nonunion. Ten (90.9%) patients with arterial injury had open wounds in the region of the compromised angiosome, with 7 (70%) experiencing wound complications, 6 (60%) FRIs, and 3 (30%) undergoing amputation.Arterial injuries in open tibia fractures with or without repair, have significantly higher rates of wound healing complications, FRI, delayed time to final closure, and need for amputation. Arterial injuries appear to effect wound healing in the affected angiosome.Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Key Points Question Have study characteristics of studies in patients with neuroendocrine neoplasms (NENs) changed over the last 2 decades (2000-2009 vs 2010-2020)? Findings In this quality improvement study, 119 therapeutic phase II and III studies were identified after conducting a systematic survey of NEN studies completed between January 2000 and December 2020. Studies that began enrollment after 2010 were less likely to include all NENs and more likely to specify tumor differentiation or Ki-67 index in inclusion criteria compared with studies that began enrollment before 2010. Meaning These findings suggest that NEN studies enrolling over the last decade became more focused on select tumor populations and specifically distinguishing neuroendocrine tumors from neuroendocrine carcinomas., This quality improvement study assesses changes in study design, eligibility accrual, sponsorship, and outcomes between neuroendocrine neoplasm studies that began enrollment from 2000 to 2009 vs 2010 to 2020., Importance Neuroendocrine neoplasms (NENs) have historically been grouped homogenously in clinical trials, despite their heterogeneity. Given the adoption of a more advanced pathologic classification system and drug licensure of several targeted therapies over the last decade, information is needed on whether study characteristics of NEN studies have evolved. Objective To assess changes in study design, eligibility, accrual, sponsorship, and outcomes between phase II or III NEN clinical trials that began enrollment from 2000 to 2009 vs 2010 to 2020. Design, Setting, and Participants This quality improvement study used a systematic survey of completed studies published between January 1, 2000, and December 31, 2020. Therapeutic phase II and III NEN studies were identified through a database search of Medline (via PubMed), EMBASE (OvidSP), Cumulative Index of Nursing and Allied Health Literature (EBSCOhost), Web of Science (Clarivate), Cochrane Database of Systematic Reviews (Wiley), ClinicalTrials.gov (National Institutes of Health), EU Clinical Trials Register, and National Cancer Institute Clinical Trials. Data were analyzed between March and June 2021. Main Outcomes and Measures Study characteristic proportions between the 2 enrollment periods. Results Of 3243 identified studies, 119 studies met criteria for inclusion, of which 117 studies (54 studies that began enrollment between 2000-2009 and 63 studies that began enrollment between 2010-2020) included exact dates of enrollment and were compared. Studies that began enrollment after 2010, compared with studies that began enrollment from 2000 to 2009, were less likely to include all NENs (13 studies [21%] vs 34 studies [63%]; P

Idelalisib is associated with increased occurrence of immune-related adverse events (irAEs). Clinical observations suggest a correlation between immune checkpoint inhibitor–induced irAEs and survival outcomes in patients with solid tumors; however, this relationship in hematologic malignancies is not well understood. In a post hoc analysis of 3 registrational trials, we explored the relationship between Grade ≥3 diarrhea/colitis and alanine/aspartate transaminase (ALT/AST) elevation incidences and efficacy endpoints in patients with indolent non-Hodgkin’s lymphoma (iNHL), follicular lymphoma (FL), and chronic lymphocytic leukemia treated with idelalisib. Grade ≥3 diarrhea/colitis was associated with higher overall response rate (ORR) and longer progression-free survival (PFS) for all subgroups. Grade ≥3 ALT/AST elevations were associated with improved duration of response and overall survival for all subgroups and improved ORR and PFS for patients with FL or iNHL. Our analysis in hematologic malignancies showed a trend correlating idelalisib-induced Grade ≥3 irAEs with improved efficacy.

Study the impact of various combinations of comorbid original diseases in patients infected with COVID-19 later on the disease progression and outcomes of the new coronavirus infection.The ACTIV registry was created on the Eurasian Association of Therapists initiative. 5,808 patients have been included in the registry: men and women with COVID-19 treated at hospital or at home.gov ID NCT04492384.Most patients with COVID-19 have original comorbid diseases (oCDs). Polymorbidity assessed by way of simple counting of oCDs is an independent factor in negative outcomes of COVID-19. Search for most frequent combinations of 2, 3 and 4 oCDs has revealed absolute domination of cardiovascular diseases (all possible variants). The most unfavorable combination of 2 oCDs includes atrial hypertension (AH) and chronic heart failure (CHF). The most unfavorable combination of 3 oCDs includes AH, coronary heart disease (CHD) and CHF; the worst combination of 4 oCDs includes AH, CHD, CHF and diabetes mellitus. Such combinations increased the risk of lethal outcomes 3.963, 4.082 and 4.215 times respectively.Polymorbidity determined by way of simple counting of diseases may be estimated as a factor in the lethal outcome risk in the acute phase of COVID-19 in real practice. Most frequent combinations of 2, 3 and 4 diseases in patients with COVID-19 primarily include cardiovascular diseases (AH, CHD and CHF), diabetes mellitus and obesity. Combinations of such diseases increase the COVID-19 lethal outcome risk.Цель. Изучить влияние различных комбинаций сопутствующих заболеваний, существовавших у пациентов исходно, до инфицирования вирусом SARS-CoV-2, на тяжесть течения и исходы новой коронавирусной инфекции. Материалы и методы. Регистр АКТИВ создан по инициативе Евразийской ассоциации терапевтов. В регистр включены 5808 пациентов: мужчины и женщины с диагнозом COVID-19, находящиеся на лечении в стационаре или получающие лечение на дому. Регистрация регистра: идентификатор ClinicalTrials.gov: NCT04492384. Результаты. Подавляющее большинство пациентов с COVID-19 имеют исходные сопутствующие заболевания (иСЗ). Полиморбидность, оцененная методом простого подсчета иСЗ, является самостоятельным фактором негативного прогноза больных COVID-19. Поиск наиболее часто встречающихся комбинаций из 2, 3, 4 и более СЗ выявил абсолютное доминирование сердечно-сосудистых заболеваний во всех возможных вариантах. Наиболее неблагоприятной при сочетании 2 иСЗ была комбинация, включающая артериальную гипертензию (АГ) и хроническую сердечную недостаточность (ХСН), при сочетании 3 иСЗ комбинация, включающая АГ, ишемическую болезнь сердца (ИБС), ХСН, и при сочетании 4 иСЗ комбинация, включающая АГ, ИБС, ХСН и сахарный диабет. Наличие таких комбинаций приводило к росту риска летального исхода в 3,963, 4,082, 4,215 раза соответственно. Заключение. Полиморбидность, определенная методом простого подсчета заболеваний, может использоваться в реальной практике как фактор риска летальности в остром периоде COVID-19. В состав наиболее часто встречающихся комбинаций из 2, 3, 4 заболеваний у пациентов с COVID-19 входят преимущественно сердечно-сосудистые заболевания (АГ, ИБС, ХСН), сахарный диабет и ожирение. Комбинации этих заболеваний повышают риск летального исхода при COVID-19.

The aim: To determine the level of public awareness of COVID-19 and information needs, as well as level of public confidence in both official information on COVID-19 and to develop recommendations for communication policy on longer-term awareness in pandemic settings COVID-19, using principles of behavioral economics.Materials and methods: 4 focus group interviews were conducted in residents of Ukraine, with a total quantity of 48 people aged 16-70 years questioned and an anonymous questionnaire was conducted in 1,700 respondents, representing the adult population aged 18 years and older from all over Ukraine. The representative error of the study with probability of 0.95 does not exceed 4%. The processing of questionnaires was carried out by SDU Center of Social Researches (SDUCSR) employees, using the OSA program.Results: 28.5% of respondents believe that politicians and media underestimate the danger of the COVID-19 epidemic, while other 28.1% believe that politicians and media adequately assess its danger. 18.9% of respondents are sure that the danger is exaggerated. As much as 24.5% of Ukrainian respondents could not decide on such assessment. The most common sources of information about disease/treatment are Internet and social media. Traditional media and relatives/acquaints who endured the COVID-19 also gain population`s confidence. A family doctor is the least popular source of information. 42.1% of respondents do not trust official information on the number of infected people and severity of the disease, and another 40% are not sure whether they should trust or not. Only 17.9% of respondents trust official information.Conclusions: Within informing the society about public health in conditions of a COVID-19 pandemic it is better to provide communication strategy for various target audiences: for youth which is inclined to underestimate threats of epidemic and obtains information on social networks; for people of a retirement age (as risk group) who lack information because they use only traditional media (mainly TV); for women who need psychological support to decrease in level of stress in the family more often and also to overcome the negative post-stressful situations (connected with the death of the family/relatives); for men who are inclined to neglect their own health, etc.; for the people who have endured COVID-19 to prevent possible reinfection in them.

BACKGROUND Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown. METHODS Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy. RESULTS In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse

PURPOSE Alliance/CALGB 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as frontline therapy for diffuse large B-cell lymphoma. PATIENTS AND METHODS Patients received six cycles of DA-EPOCH-R or R-CHOP. The primary objective was progression-free survival (PFS); secondary clinical objectives included response rate, overall survival (OS), and safety. RESULTS Between 2005 and 2013, 524 patients were registered; 491 eligible patients were included in the final analysis. Most patients (74%) had stage III or IV disease; International Prognostic Index (IPI) risk groups included 26% IPI 0 to 1, 37% IPI 2, 25% IPI 3, and 12% IPI 4 to 5. At a median follow-up of 5 years, PFS was not statistically different between the arms (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; P = .65), with a 2-year PFS rate of 78.9% (95% CI, 73.8% to 84.2%) for DA-EPOCH-R and 75.5% (95% CI, 70.2% to 81.1%) for R-CHOP. OS was not different (hazard ratio, 1.09; 95% CI, 0.75 to 1.59; P = .64), with a 2-year OS rate of 86.5% (95% CI, 82.3% to 91%) for DA-EPOCH-R and 85.7% (95% CI, 81.4% to 90.2%) for R-CHOP. Grade 3 and 4 adverse events were more common ( P < .001) in the DA-EPOCH-R arm than the R-CHOP arm, including infection (16.9% v 10.7%, respectively), febrile neutropenia (35.0% v 17.7%, respectively), mucositis (8.4% v 2.1%, respectively), and neuropathy (18.6% v 3.3%, respectively). Five treatment-related deaths (2.1%) occurred in each arm. CONCLUSION In the 50303 study population, the more intensive, infusional DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. The more favorable results with R-CHOP compared with historical controls suggest a potential patient selection bias and may preclude generalizability of results to specific risk subgroups.

Background Four wild polio-virus cases were reported in Borno State, Nigeria 2016, 1 year after Nigeria had been removed from the list of polio endemic countries by the World Health Organization. Resulting from Nigeria’s decade long conflict with Boko Haram, health officials had been unable to access as much as 60% of the settlements in Borno, hindering vaccination and surveillance efforts. This lack of accessibility made it difficult for the government to assess the current population distribution within Borno. This study aimed to use high resolution, visible band satellite imagery to assess the habitation of inaccessible villages in Borno State. Methods Using high resolution (31–50 cm) imagery from DigitalGlobe, analysts evaluated the habitation status of settlements in Borno State identified by Nigeria’s Vaccination Tracking System. The analysts looked at imagery of each settlement and, using vegetation (overgrowth vs. cleared) as a proxy for human habitation, classified settlements into three categories: inhabited, partially abandoned, and abandoned. Analysts also classified the intact percentage of each settlement starting at 0% (totally destroyed since last assessment) and increasing in 25% intervals through 100% (completely intact but not expanded) up to 200+% (more than doubled in size) by looking for destroyed buildings. These assessments were then used to adjust previously established population estimates for each settlement. These new population distributions were compared to vaccination efforts to determine the number of children under 5 unreached by vaccination teams. Results Of the 11,927 settlements assessed 3203 were assessed as abandoned (1892 of those completely destroyed), 662 as partially abandoned, and 8062 as fully inhabited as of December of 2017. Comparing the derived population estimates from the new assessments to previous assessment and the activities of vaccination teams shows that an estimated 180,155 of the 337,411 under five children who were unreached in 2016 were reached in 2017 (70.5% through vaccination efforts in previously inaccessible areas, 29.5% through displacement to accessible areas). Conclusions This study’s methodology provides important planning and situation awareness information to health workers in Borno, Nigeria, and may serve as a model for future data gathering efforts in inaccessible regions.

PURPOSE Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger. PATIENTS AND METHODS We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score–weighted (PSW) analysis were performed. RESULTS Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2). CONCLUSION In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.

Introduction: The use of potentially inappropriate medications (PIM) is an alarming social risk factor in cardiovascular patients. PIM administration may result in iatrogenic disorders and adverse consequences may be attenuated by limiting PIM intake.Areas covered: The goal of this review article is to discuss the trends, risks, and concerns regarding PIM administration with focus on cardiovascular patients. To find data, we searched literature using electronic databases (Pubmed/Medline 1966-2021 and Web of Science 1975-2021). The data search terms were cardiovascular diseases, potentially inappropriate medication, potentially harmful drug-drug combination, potentially harmful drug-disease combination, drug interaction, deprescribing, and electronic health record.Expert opinion: Drugs for heart diseases are the most commonly prescribed medications in older individuals. Despite the availability of explicit and implicit PIM criteria, the incidence of PIM use in cardiovascular patients remains high ranging from 7 to 85% in different patient categories. Physician-induced disorders often occur when PIM is administered and adverse effects may be reduced by limiting PIM intake. Main strategies promising for addressing PIM use include deprescribing, implementation of systematic electronic records, pharmacist medication review, and collaboration among cardiologists, internists, geriatricians, clinical pharmacologists, pharmacists, and other healthcare professionals as basis of multidisciplinary assessment teams.

The phase 2 study of idelalisib monotherapy for indolent non-Hodgkin lymphomas (iNHLs) was completed in 2018; final efficacy and safety data with up to 6.7 years long-term follow-up are reported. Patients with iNHL refractory to both rituximab and an alkylating agent were enrolled and received 150 mg idelalisib twice daily (

PURPOSE Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy. PATIENTS AND METHODS Eligible patients had measurable iNHL (FL, SLL, or marginal zone B-cell lymphoma) double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy. All were treated with duvelisib 25 mg orally twice daily in 28-day cycles until progression, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) using the revised International Working Group criteria for malignant lymphoma. RESULTS This open-label, global phase II trial enrolled 129 patients (median age, 65 years; median of three prior lines of therapy) with an ORR of 47.3% (SLL, 67.9%; FL, 42.2%; MZL, 38.9%). The estimated median duration of response was 10 months, and the estimated median progression-free survival was 9.5 months. The most frequent any-grade treatment-emergent adverse events (TEAEs) were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Among the 88.4% of patients with at least one grade 3 or greater TEAE, the most common TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%). CONCLUSION In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, double-refractory iNHL, consistent with previous observations. Duvelisib may provide a new oral treatment option for this patient population of which many are elderly and in need of additional therapies.

The purpose of this study was to compare the long-term functional status of patients treated surgically for a clavicular nonunion using patients treated either op-eratively or non-operatively for an acute clavicle fracture as a comparison group.Twenty consecutive patients treated by a single surgeon for a clavicle fracture nonunion were identified. For comparison of outcomes, acute clavicle fractures were identified from an electronic medical record (EMR) query of the same orthopedic surgeon. Ninety acute clavicle fracture patients were identified and 27 (30%) patients were available for long-term follow-up. Clavicular nonunions were compared to acute clavicle fracture patients in a univariate analysis then a multivariate analysis to analyze clavicle nonunion patients against operative and non-operative acute clavicle fracture patients. The main outcome measures were time to bony union, postoperative complications, visual analog scale (VAS) pain scores, and Short Musculoskeletal Functional Assessment (SMFA) scores at long-term follow-up.There was no difference in time to healing or functional outcomes as assessed by SMFA and VAS pain scores between clavicle nonunion and acute fracture patients. Postoperative complications also did not differ between the groups.Patients who are treated surgically for clavicular nonunions ultimately regain a similar functional status as patients who are treated either operatively or non-operatively for an acute clavicle fracture and heal acutely.

Background Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued due to progression or side effects, it is unclear how successful further therapies will be. Moreover, there is no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis we investigated whether exposure to CBT could sensitize HL to subsequent therapy. Materials and methods Seventeen centers across the US and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment using the Lugano criteria. Secondary aims included progression free survival (PFS), duration of response (DOR), and overall survival (OS). Results Eighty-one patients were included. Seventy-two percent had stage 3-4 disease, and the population was heavily pretreated with a median of 4 therapies before CBT. Most patients (65%) discontinued CBT due to progression. The ORR to post-CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post-CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post-CBT regimen. Conclusion In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post-CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials. Implications for practice Relapsed and refractory (R/R) Hodgkin lymphoma (HL) presents a clinical challenge, and better treatment strategies are greatly desired to prevent these patients from ultimately succumbing to their disease. The results of this multicenter analysis concur with a smaller, earlier report that checkpoint blockade therapy usage in R/R HL may sensitize patients their subsequent treatment. This approach may potentially be used to extend the number of options patients have or to bridge them to transplant. Prospective data is warranted prior to practice implementation. As more work is done in this area, we may also be able to optimize sequencing of CBT and novel agents in the treatment paradigm to minimize treatment-related toxicity and thus improve patient quality of life.

Neuroinflammation is involved in the progression or secondary injury of multiple brain conditions, including stroke and neurodegenerative diseases. Alarmins, also known as damage-associated molecular patterns, are released in the presence of neuroinflammation and in the acute phase of ischemia. Defensins, cathelicidin, high-mobility group box protein 1, S100 proteins, heat shock proteins, nucleic acids, histones, nucleosomes, and monosodium urate microcrystals are thought to be alarmins. They are released from damaged or dying cells and activate the innate immune system by interacting with pattern recognition receptors. Being principal sterile inflammation triggering agents, alarmins are considered biomarkers and therapeutic targets. They are recognized by host cells and prime the innate immune system toward cell death and distress. In stroke, alarmins act as mediators initiating the inflammatory response after the release from the cellular components of the infarct core and penumbra. Increased c-Jun N-terminal kinase (JNK) phosphorylation may be involved in the mechanism of stress-induced release of alarmins. Putative crosstalk between the alarmin-associated pathways and JNK signaling seems to be inherently interwoven. This review outlines the role of alarmins/JNK-signaling in cerebral neurovascular inflammation and summarizes the complex response of cells to alarmins. Emerging anti-JNK and anti-alarmin drug treatment strategies are discussed.

DNA vaccines have been used as a promising strategy for delivery of immunogenic and immunomodulatory molecules into the host cells. Although, there are some obstacles involving the capability of the plasmid vector to reach the cell nucleus in great number to promote the expected benefits. In order to improve the delivery and, consequently, increase the expression levels of the target proteins carried by DNA vaccines, alternative methodologies have been explored, including the use of non-pathogenic bacteria as delivery vectors to carry, deliver, and protect the DNA from degradation, enhancing plasmid expression.

Increasingly, adolescent, young adult, and adult children are relied upon as donors for their parents undergoing blood and marrow stem cell transplant. How family functioning impacts donors' decision making and whether haploidentical donor children have unique supportive care needs is unknown. In this qualitative research study, we conducted 15 semistructured telephone interviews among individuals who underwent blood or marrow stem cell donation for their parent. Interviews explored donors' perspectives of the transplant experience across the trajectory from screening through early post-transplant follow-up and elicited unmet needs. Major themes included: (1) perception of choice, (2) act of giving back, (3) burdens of donation, (4) anticipated health benefit to parent, and (5) impact of donation on parent/child relationship. The majority of participants described high family functioning, but strain was also evident. Family functioning rarely was reported as affecting the decision to donate, with all donors expressing a sense of obligation. Participants were overwhelmingly satisfied with their decision and the ability to give back to their parent. Suggestions for the health care team to improve the donation experience focused on increased education about potential delays in screening, better description of possible complications for recipients, and provision of emotional support following donation.

Contains fulltext : 225492.pdf (Publisher’s version ) (Open Access) Aberrant fetal growth remains a leading cause of perinatal morbidity and mortality and is associated with a risk of developing non-communicable diseases later in life. We performed a systematic review and meta-analysis combining human and animal studies to assess whether prenatal amino acid (AA) supplementation could be a promising approach to promote healthy fetal growth. PubMed, Embase and Cochrane libraries were searched to identify studies orally supplementing the following AA groups during gestation: (1) arginine family; (2) branched chain (BCAA); (3) methyl donors. Primary outcome was fetal/birth weight. 22 human and 89 animal studies were included in the systematic review. The arginine family, and especially arginine itself, was studied most. Our meta-analysis showed beneficial effects of arginine and (N-Carbamyl) glutamate (NCG), but not aspartic acid and citrulline on fetal/birth weight. However, no effects were reported when isonitrogenous control diet was included. BCAA and methyl donor supplementation did not affect fetal/birth weight. Arginine family supplementation, in particular arginine and NCG, improves fetal growth in complicated pregnancies. BCAA and methyl donor supplementation do not seem to be as promising to target fetal growth. Well controlled research in complicated pregnancies is needed before ruling out AA supplements or preferring arginine above other AAs.