Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA–peptide tetramers

Stem cell transplantation is used widely in the management of a range of diseases of the hemopoietic system. Patients are immunosuppressed profoundly in the early posttransplant period, and reactivation of cytomegalovirus (CMV) remains a significant cause of morbidity and mortality. Adoptive transfer of donor-derived CMV-specific CD8(+) T cell clones has been shown to reduce the rate of viral reactivation; however, the complexity of this approach severely limits its clinical application. We have purified CMV-specific CD8(+) T cells from the blood of stem cell transplant donors using staining with HLA-peptide tetramers followed by selection with magnetic beads. CMV-specific CD8(+) cells were infused directly into nine patients within 4 h of selection. Median cell dosage was 8.6 x 10(3)/kg with a purity of 98% of all T cells. CMV-specific CD8(+) T cells became detectable in all patients within 10 d of infusion, and TCR clonotype analysis showed persistence of infused cells in two patients studied. CMV viremia was reduced in every case and eight patients cleared the infection, including one patient who had a prolonged history of CMV infection that was refractory to antiviral therapy. This novel approach to adoptive transfer has considerable potential for antigen-specific T cell therapy

Unilateral, trifocal, diaphyseal fracture of the radius with ipsilateral mid-shaft ulna fracture in an adult: a case report

<p>Abstract</p> <p>Introduction</p> <p>To the best of our knowledge, a trifocal, diaphyseal fracture of the radius associated with ipsilateral mid-shaft fracture of the ulna in an adult has not been reported in the literature to date. The AO classification system does not include such a fracture configuration.</p> <p>Case presentation</p> <p>We report a case of trifocal, diaphyseal fracture of the radius with a mid-diaphyseal fracture of the ulna in a 53-year-old Caucasian, British, right-hand dominant woman involved in a head-on collision with another vehicle. The management of this rare fracture configuration is described and alternative treatment options discussed.</p> <p>Conclusions</p> <p>We describe an unusual, complex fracture, which with prompt surgical treatment resulted in a rapid, full and satisfactory functional recovery for our patient.</p

Comparative trends in ischemic heart disease admissions, presentation and outcomes due to the COVID-19 pandemic: First insights from a tertiary medical center in Pakistan

Introduction: COVID-19 has manifested a striking disarray in healthcare access and provision, particularly amongst patients presenting with life-threatening ischemic heart disease (IHD). The paucity of data from low-middle income countries has limited our understanding of the consequential burden in the developing world. We aim to compare volumes, presentations, management strategies, and outcomes of IHD amongst patients presenting in the same calendar months before and during the COVID-19 pandemic.Methods: We conducted a retrospective cross-sectional analysis at the Aga Khan University Hospital, one of the premier tertiary care centres in Pakistan. Data were collected on all adult patients (\u3e18 years) who were admitted with IHD (acute coronary syndrome (ACS) and stable angina) from March 1 to June 30, 2019 (pre-COVID) and March 1 to June 30, 2020 (during-COVID), respectively. Group differences for continuous variables were evaluated using student t-test or Mann-Whitney U test. The chi-squared test or Fisher test was used for categorical variables. Values of p less than 0.05 were considered statistically significant. P-value trend calculation and graphical visualization were done using STATA (StataCorp, College Station, TX).Results: Data were assimilated on 1019 patients, with 706 (69.3%) and 313 (30.7%) patients presenting in each respective group (pre-COVID and during-COVID). Current smoking status (p=0.019), admission source (p\u3c0.001), month of admission (p\u3c0.001), proportions ACS (p\u3c0.001), non-ST-elevation-myocardial-infarction (NSTEMI; p\u3c0.001), unstable angina (p=0.025) and medical management (p=0.002) showed significant differences between the two groups, with a sharp decline in the during-COVID group. Monthly trend analysis of ACS patients showed the most significant differences in admissions (p=0.001), geographic region (intra-district vs intracity vs outside city) (p\u3c0.001), time of admission (p=0.038), NSTEMI (p=0.002) and medical management (p=0.001).Conclusion: These data showcase stark declines in ACS admissions, diagnostic procedures (angiography) and revascularization interventions (angioplasty and coronary artery bypass graft surgery, CABG) in a developing country where resources and research are already inadequate. This study paves the way for further investigations downstream on the short- and long-term consequences of untreated IHD and reluctance in health-seeking behaviour

Psychological interventions in asthma

Asthma is a multifactorial chronic respiratory disease characterised by recurrent episodes of airway obstruction. The current management of asthma focuses principally on pharmacological treatments, which have a strong evidence base underlying their use. However, in clinical practice, poor symptom control remains a common problem for patients with asthma. Living with asthma has been linked with psychological co-morbidity including anxiety, depression, panic attacks and behavioural factors such as poor adherence and suboptimal self-management. Psychological disorders have a higher-than-expected prevalence in patients with difficult-to-control asthma. As psychological considerations play an important role in the management of people with asthma, it is not surprising that many psychological therapies have been applied in the management of asthma. There are case reports which support their use as an adjunct to pharmacological therapy in selected individuals, and in some clinical trials, benefit is demonstrated, but the evidence is not consistent. When findings are quantitatively synthesised in meta-analyses, no firm conclusions are able to be drawn and no guidelines recommend psychological interventions. These inconsistencies in findings may in part be due to poor study design, the combining of results of studies using different interventions and the diversity of ways patient benefit is assessed. Despite this weak evidence base, the rationale for psychological therapies is plausible, and this therapeutic modality is appealing to both patients and their clinicians as an adjunct to conventional pharmacological treatments. What are urgently required are rigorous evaluations of psychological therapies in asthma, on a par to the quality of pharmaceutical trials. From this evidence base, we can then determine which interventions are beneficial for our patients with asthma management and more specifically which psychological therapy is best suited for each patient

Patterned membrane in an energy-efficient tilted panel filtration system for fouling control in activated sludge filtration

A membrane bioreactor enhances the overall biological performance of a conventional activated sludge system for wastewater treatment by producing high-quality effluent suitable for reuse. However, membrane fouling hinders the widespread application of membrane bioreactors by reducing the hydraulic performance, shortening membrane lifespan, and increasing the operational costs for membrane fouling management. This study assesses the combined effect of membrane surface corrugation and a tilted panel in enhancing the impact of air bubbling for membrane fouling control in activated sludge filtration, applicable for membrane bioreactors. The filterability performance of such a system was further tested under variable parameters: Filtration cycle, aeration rate, and intermittent aeration. Results show that a combination of surface corrugation and panel tilting enhances the impact of aeration and leads to 87% permeance increment. The results of the parametric study shows that the highest permeance was achieved under short filtration-relaxation cycle of 5 min, high aeration rate of 1.5 L/min, and short switching period of 2.5 min, to yield the permeances of 465 ± 18, 447 ± 2, and 369 ± 9 L/(m2h bar), respectively. The high permeances lead to higher operational flux that helps to lower the membrane area as well as energy consumption. Initial estimation of the fully aerated system yields the energy input of 0.152 kWh/m3, much lower than data from the full-scale references of <0.4 kWh/m3. Further energy savings and a lower system footprint can still be achieved by applying the two-sided panel with a switching system, which will be addressed in the future

Whole genome mapping and identification of single nucleotide polymorphisms of four Bangladeshi individuals and their functional significance

Objective: The major objective of the study was to sequence the whole genome of four Bangladeshi individuals and identify variants that are known to be associated with functional changes or disease states. We also carried out an ontology analysis to identify the functions and pathways most likely to be afected by these variants. Results: We identifed around 900,000 common variants and close to 5 million unique ones in all four of the indi‑ viduals. This included over 11,500 variants that caused nonsynonymous changes in proteins. Heart function associ‑ ated pathways were heavily implicated by the ontology analysis; corroborating previous studies that claimed the Bangladeshi population as highly susceptible to heart disorders. Two variants were found that have been previously identifed as pathogenic factors in familial hypercholesteremia and structural disorders of the heart. Other pathogenic variants we found were associated with pseudoxanthoma elasticum, cancer progression, polyagglutinable erythro‑ cyte syndrome, preeclampsia, and other

PAX3-FOXO1 uses its activation domain to recruit CBP/P300 and shape RNA Pol2 cluster distribution

Activation of oncogenic gene expression from long-range enhancers is initiated by the assembly of DNA-binding transcription factors (TF), leading to recruitment of co-activators such as CBP/p300 to modify the local genomic context and facilitate RNA-Polymerase 2 (Pol2) binding. Yet, most TF-to-coactivator recruitment relationships remain unmapped. Here, studying the oncogenic fusion TF PAX3-FOXO1 (P3F) from alveolar rhabdomyosarcoma (aRMS), we show that a single cysteine in the activation domain (AD) of P3F is important for a small alpha helical coil that recruits CBP/p300 to chromatin. P3F driven transcription requires both this single cysteine and CBP/p300. Mutants of the cysteine reduce aRMS cell proliferation and induce cellular differentiation. Furthermore, we discover a profound dependence on CBP/p300 for clustering of Pol2 loops that connect P3F to its target genes. In the absence of CBP/p300, Pol2 long range enhancer loops collapse, Pol2 accumulates in CpG islands and fails to exit the gene body. These results reveal a potential novel axis for therapeutic interference with P3F in aRMS and clarify the molecular relationship of P3F and CBP/p300 in sustaining active Pol2 clusters essential for oncogenic transcription

28.2%-efficient, outdoor-stable perovskite/silicon tandem solar cell

Stacking perovskite solar cells onto crystalline silicon bottom cells in a monolithic tandem configuration enables power-conversion efficiencies (PCEs) well above those of their single-junction counterparts. However, state-of-the-art wide-band-gap perovskite films suffer from phase stability issues. Here, we show how carbazole as an additive to the perovskite precursor solution can not only reduce nonradiative recombination losses but, perhaps more importantly, also can suppress phase segregation under exposure to moisture and light illumination. This enables a stabilized PCE of 28.6% (independently certified at 28.2%) for a monolithic perovskite/silicon tandem solar cell over ∼1 cm2 and 27.1% over 3.8 cm2, built from a textured silicon heterojunction solar cell. The modified tandem devices retain ∼93% of their performance over 43 days in a hot and humid outdoor environment of almost 100% relative humidity over 250 h under continuous 1-sun illumination and about 87% during a 85/85 damp-heat test for 500 h, demonstrating the improved phase stability