Anti-CD45 PBD-based antibody-drug conjugates are effective targeted conditioning agents for gene therapy and stem cell transplant.

Stem cell gene therapy and hematopoietic stem cell transplantation (SCT) require conditioning to ablate the recipient's hematopoietic stem cells (HSCs) and create a niche for gene-corrected/donor HSCs. Conventional conditioning agents are non-specific, leading to off-target toxicities and resulting in significant morbidity and mortality. We developed tissue-specific anti-human CD45 antibody-drug conjugates (ADCs), using rat IgG2b anti-human CD45 antibody clones YTH24.5 and YTH54.12, conjugated to cytotoxic pyrrolobenzodiazepine (PBD) dimer payloads with cleavable (SG3249) or non-cleavable (SG3376) linkers. In vitro, these ADCs internalized to lysosomes for drug release, resulting in potent and specific killing of human CD45+ cells. In humanized NSG mice, the ADCs completely ablated human HSCs without toxicity to non-hematopoietic tissues, enabling successful engraftment of gene-modified autologous and allogeneic human HSCs. The ADCs also delayed leukemia onset and improved survival in CD45+ tumor models. These data provide proof of concept that conditioning with anti-human CD45-PBD ADCs allows engraftment of donor/gene-corrected HSCs with minimal toxicity to non-hematopoietic tissues. Our anti-CD45-PBDs or similar agents could potentially shift the paradigm in transplantation medicine that intensive chemo/radiotherapy is required for HSC engraftment after gene therapy and allogeneic SCT. Targeted conditioning both improve the safety and minimize late effects of these procedures, which would greatly increase their applicability.

A comprehensive molecular phylogeny of the terrestrial Parasitengona (Acariformes, Prostigmata) provides insights into the evolution of their metamorphosis, invasion into aquatic habitats and classification.

Parasitengona (velvet mites, chiggers and water mites) is a highly diverse and globally distributed mite lineage encompassing over 11,000 described species, inhabiting terrestrial, freshwater and marine habitats. Certain species, such as chiggers (Trombiculidae), have a great medical and veterinary importance as they feed on their vertebrate hosts and vector pathogens. Despite extensive previous research, the classification of Parasitengona is still contentious, particularly regarding the boundaries between superfamilies and families, exacerbated by the absence of a comprehensive phylogeny. The ontogeny of most Parasitengona is distinct by the presence of striking metamorphosis, with parasitic larvae being heteromorphic compared to the predatory free-living deutonymphs and adults. The enigmatic superfamily Allotanaupodoidea is an exception, with larvae and active post-larval stages being morphologically similar, suggesting that the absence of metamorphosis may be either an ancestral state or a secondary reversal. Furthermore, there is disagreement in the literature on whether Parasitengona had freshwater or terrestrial origin. Here, we inferred phylogenetic relationships of Parasitengona (89 species, 36 families) and 307 outgroups using five genes (7,838 nt aligned). This phylogeny suggests a terrestrial origin of Parasitengona and a secondary loss of metamorphosis in Allotanaoupodoidea. We recovered the superfamily Trombidioidea (Trombidioidea sensu lato) as a large, well-supported, higher-level clade including 10 sampled families. We propose a new classification for the terrestrial Parasitengona with three new major divisions (epifamilies) of the superfamily Trombidioidea: Trombelloidae (families Audyanidae, Trombellidae, Neotrombidiidae, Johnstonianidae, Chyzeriidae); Trombidioidae (Microtrombidiidae, Neothrombiidae, Achaemenothrombiidae, Trombidiidae, Podothrombiidae); and Trombiculoidae (=Trombiculidae sensu lato). Adding them to previously recognized superfamilies Allotanaupodoidea, Amphotrombioidea, Calyptostomatoidea, Erythraeoidea, Tanaupodoidae and Yurebilloidae.

Stroke outcomes following cardiac and aortic surgery are improved by the involvement of a stroke team.

OBJECTIVES: Post-cardiac and aortic surgery stroke is often underreported. We detail our single-centre experience the following introduction of comprehensive consultant-led daily stroke service, to demonstrate the efficacy of a stroke team in recovery from stroke following cardiac and aortic surgeries. METHODS: This retrospective, single-centre observational cohort study analysed consecutive patients undergoing cardiac and aortic surgery at our institution from August 2014 to December 2020. Main outcomes included stroke rate, predictors of stroke, and neurological deficit resolution or persistence at discharge and clinic follow-up. RESULTS: A total of 12,135 procedures were carried out in the reference period. Among these, 436 (3.6%) suffered a stroke. Overall survival to discharge and follow-up were 86.0% and 84.0% respectively. Independent risk factors for post-operative stroke included advanced age (OR 1.033, 95% CI [1.023, 1.044], p < .001), female sex (OR 1.491, 95% [1.212, 1.827], p < .001), history of previous cardiac surgeries (OR 1.670, 95% CI [1.239, 2.218], p < .001), simultaneous coronary artery bypass graft + valve procedures (OR 1.825, 95% CI [1.382, 2.382], p < .001) and CPB time longer than 240 min (OR 3.384, 95% CI [2.413, 4.705], p < .001). Stroke patients managed by the multidisciplinary team demonstrated significantly higher rates of survival at discharge (87.3% vs. 61.9%, p = .001). CONCLUSIONS: Perioperative stroke can be debilitating immediately long term. The involvement of specialist stroke teams plays a key role in reducing the long-term burden and mortality of this condition.

Late Acheulean occupations at Montagu Cave and the pattern of Middle Pleistocene behavioral change in Western Cape, southern Africa.

Patterns of so-called modern human behavior are increasingly well documented in an abundance of Middle Stone Age archaeological sites across southern Africa. Contextualized archives directly preceding the southern African Middle Stone Age, however, remain scarce. Current understanding of the terminal Acheulean in southern Africa derives from a small number of localities that are predominantly in the central and northern interior. Many of these localities are surface and deflated contexts, others were excavated prior to the availability of modern field documentation techniques, and yet other relevant assemblages contain low numbers of characteristic artifacts relative to volume of excavated deposit. The site of Montagu Cave, situated in the diverse ecosystem of the Cape Floral Region, South Africa, contains the rare combination of archaeologically rich, laminated and deeply stratified Acheulean layers followed by a younger Middle Stone Age occupation. Yet little is known about the site owing largely to a lack of contextual information associated with the early excavations. Here we present renewed excavation of Levels 21-22 at Montagu Cave, located in the basal Acheulean sequence, including new data on site formation and ecological context, geochronology, and technological variability. We document intensive occupation of the cave by Acheulean tool-producing hominins, likely at the onset of interglacial conditions in MIS 7. New excavations at Montagu Cave suggest that, while Middle Stone Age technologies were practiced by 300 ka in several other regions of Africa, the classic Acheulean persisted later in the Fynbos Biome of the southwestern Cape. We discuss the implications of this regionalized persistence for the biogeography of African later Middle Pleistocene hominin populations, for the ecological drivers of their technological systems, and for the pattern and pace of behavioral change just prior to the proliferation of the southern African later Middle Stone Age.

Infection after ureteroscopy for ureteric stones: analysis of 71 305 cases in the Hospital Episode Statistics database.

OBJECTIVES: To investigate the burden of infectious complications following ureteroscopy (URS) for ureteric stones on a national level in England using data from the Hospital Episodes Statistics (HES) data warehouse. MATERIALS AND METHODS: A retrospective cohort was identified and followed up in HES during the period April 2013 to March 2020 for all procedure codes relating to ureteroscopic stone treatment (M27.1, M27.2, M27.3). Treatment episodes relating to the first URS ('index ureteroscopy') for each patient were further analysed. All subsequent admissions within 30 days were also captured. The primary outcome was diagnosis of urinary tract infection (UTI; including all codes relating to a UTI/sepsis within the first 30 days of index URS). Secondary outcomes were critical care attendance, attendance at the accident and emergency department (A&E) within 30 days, and mortality. RESULTS: A total of 71 305 index ureteroscopies were eligible for analysis. The median age was 55 years, and 81% of procedures were elective and 45% were undertaken as day-cases. At the time of index URS, 16% of patients had diabetes, 0.5% had coexisting neurological disease and 40% had an existing stent/nephrostomy. Overall, 6.8% of the cohort (n = 4822) had a diagnosis of UTI within 30 days of index URS (3.9% immediately after surgery). A total of 339 patients (0.5%) required an unplanned stay in critical care during their index URS admission; 8833 patients (12%) attended A&E within 30 days. Overall mortality was 0.18% (60 in-hospital, 65 within 30 days); 40 deaths (0.056%) included infection as a contributing cause of death. CONCLUSION: We present the largest series evaluating infectious complications after ureteroscopic stone treatment. The procedure is safe, with low inpatient infective complication and critical care admission rates.

Pharmacy professionals' perceptions of educational supervision in primary care through the lens of Proctor's model.

BACKGROUND: Educational supervision plays a vital role in postgraduate medical education and more recently in pharmacy and advanced clinical practitioner training in England. Proctor's three-function model of clinical supervision (consisting of formative, restorative, and normative functions) is assumed to apply to educational supervision, but this has not been tested empirically. The aim of this study was to establish perceptions of the purpose of educational supervision from the perspective of primary care pharmacy professionals enrolled on a national training pathway in England. METHODS: Using a mixed methods design, data were collected using a validated 25-item online survey and respondents were invited to add comments explaining their responses. The survey was sent to all 902 learners enrolled on a postgraduate training pathway for pharmacy professionals working in primary care. Principal components analysis (PCA) was used to interpret patterns in the survey data, and framework analysis of qualitative free text comments was used to identify themes and aid interpretation of quantitative findings. RESULTS: One hundred eighty-seven pharmacy professionals responded (response rate 20.7%). PCA extracted three factors explaining 71.5% of the total variance. Factor 1 corresponded with survey items linked to the formative function of Proctor's model, while factor 2 corresponded with survey items linked to the restorative function. No items corresponded with the normative function. Framework analysis of qualitative free-text comments identified two themes: learning support, which corresponded with factor 1; and personal support, which corresponded with factor 2. CONCLUSIONS: This study identified that pharmacy professionals perceived educational supervision to perform two functions, formative (educational) and restorative (pastoral), but did not perceive it to perform a normative (surveillance) function. Educational supervision has the potential to support allied health professionals advancing their roles and we suggest the need for more research to develop models of effective educational supervision which can inform practice.

Large-Area Superconducting Nanowire Single-Photon Detectors for Operation at Wavelengths up to 7.4 µm.

The optimization of superconducting thin-films has pushed the sensitivity of superconducting nanowire single-photon detectors (SNSPDs) to the mid-infrared (mid-IR). Earlier demonstrations have shown that straight tungsten silicide nanowires can achieve unity internal detection efficiency (IDE) up to λ = 10 µm. For a high system detection efficiency (SDE), the active area needs to be increased, but material nonuniformity and nanofabrication-induced constrictions make mid-IR large-area meanders challenging to yield. In this work, we improve the sensitivity of superconducting materials and optimize a high-resolution nanofabrication process to demonstrate large-area SNSPDs with unity IDE at 7.4 µm. Our approach yields large-area meanders down to 50 nm width, with average line-width roughness below 10%, and with a lower impact from constrictions compared to previous demonstrations. Our methods pave the way to high-efficiency SNSPDs in the mid-IR band with potential impacts on astronomy, imaging, and physical chemistry.

Guiding Emergency Treatment With Extended Focused Assessment With Sonography in Trauma by Emergency Responders (GET eFASTER).

OBJECTIVE: Prehospital medicine has struggled to manage critical patients without the resources available to hospital-based teams. Point-of-care ultrasound could bridge this resource gap by providing critical insight into the pathology of trauma patients. This study aimed to determine if early positive extended focused assessment with sonography in trauma (eFAST) identification would lead to improved patient outcomes. METHODS: This is a prospective observational trial that took place from February 1, 2019, to August 13, 2021. Paramedics, with no prior ultrasound experience, at a single ground ambulance agency were trained in obtaining and interpretating eFAST examinations. RESULTS: Thirty-seven paramedics were trained and performed a total of 502 eFAST examinations with a total correct interpretation rate of 97.35%. There was a sensitivity of 30.0%/75.0%, specificity of 98.75%/94.05%, a positive predictive value of 33.33%/37.5%, a negative predictive value of 98.55%/98.75%, a positive likelihood ratio of 24.05/12.6, and a negative likelihood ratio of 0.71/0.27 for all exam/patient-only scans. The time spent on scene for eFAST and non-eFAST calls was not significantly different (F3, 2,512 = 2.59, P = .051, η2 = .003). CONCLUSION: Although we were able to show successful training and interpretation of eFAST with paramedics, given the low prevalence of disease, our study did not show eFAST use improving patient outcome. However, the large likelihood ratio suggests its benefit may lie with appropriate trauma resource utilization.

Effects of climbing- and resistance-training on climbing-specific performance: a systematic review and meta-analysis.

The objective of this systematic review and meta-analysis was to examine the effects of climbing and climbing-and-resistance-training on climbing performance, and strength and endurance tests. We systematically searched three databases (SPORTDiscus, SCOPUS, and PubMed) for records published until January 2021. The search was limited to randomized-controlled trials using active climbers and measuring climbing performance or performance in climbing-specific tests. Data from the meta-analysis are presented as standardized difference in mean (SDM) with 95% confidence intervals (95% CI). Eleven studies are included in the systematic review and five studies compared training to a control group and could be meta-analyzed. The overall meta-analysis displayed an improvement in climbing-related test performance following climbing-specific resistance training compared to only climbing (SDM = 0.57, 95%CI = 0.24-0.91). Further analyses revealed that finger strength (SDM = 0.41, 95%CI 0.03-0.80), rate of force development (SDM = 0.91, 95%CI = 0.21-1.61), and forearm endurance (SDM = 1.23, 95%CI = 0.69-1.77) were improved by resistance-training of the finger flexors compared to climbing training. The systematic review showed that climbing performance may be improved by specific resistance-training or interval-style bouldering. However, resistance-training of the finger flexors showed no improvements in strength or endurance in climbing-specific tests. The available evidence suggests that resistance-training may be more effective than just climbing-training for improving performance outcomes. Importantly, interventional studies including climbers is limited and more research is needed to confirm these findings.

Renal hemofiltration prevents metabolic acidosis and reduces inflammation during normothermic machine perfusion of the vascularized composite allograft: A preclinical study.

INTRODUCTION: Recent experimental evidence suggests normothermic machine perfusion of the vascularized composite allograft results in improved preservation compared to static cold storage, with less reperfusion injury in the immediate post-operative period. However, metabolic acidosis is a common feature of vascularized composite allograft perfusion, primarily due to the inability to process metabolic by-products. We evaluated the impact of combined limb-kidney perfusion on markers of metabolic acidosis and inflammation in a porcine model. METHODS: Ten paired pig forelimbs were used for this study, grouped as either limb-only (LO, n = 5) perfusion, or limb-kidney (LK, n = 5) perfusion. Infrared thermal imaging was used to determine homogeneity of perfusion. Lactate, bicarbonate, base, pH, and electrolytes, along with an inflammatory profile generated via the quantification of cytokines and cell-free DNA in the perfusate were recorded. RESULTS: The addition of a kidney to a limb perfusion circuit resulted in the rapid stabilization of lactate, bicarbonate, base, and pH. Conversely, the LO circuit became progressively acidotic, correlating in a significant increase in pro-inflammatory cytokines. Global perfusion across the limb was more homogenous with LK compared to LO. CONCLUSION: The addition of a kidney during limb perfusion results in significant improvements in perfusate biochemistry, with no evidence of metabolic acidosis.

Contemporary Training Practices of Norwegian Powerlifters.

ABSTRACT: Shaw, MP, Andersen, V, Sæterbakken, AH, Paulsen, G, Samnøy, LE, and Solstad, TEJ. Contemporary training practices of Norwegian powerlifters. J Strength Cond Res 36(9): 2544-2551, 2022-The aim of this study was to explore the contemporary training practices of Norwegian powerlifters. One hundred twenty-four Norwegian powerlifters completed an electronic questionnaire that surveyed their current training practices with a focus on 2 areas: (a) training content and (b) training design and monitoring. One hundred seventeen respondents met the inclusion criteria, and the sample included World, European, and Norwegian champions. Where data were dichotomized, chi-square tests were used. The most frequently reported (58.1%) category of training was 5-6 times per week, with no statistically significant associations between levels of competitors (international vs. noninternational) (X 2 (1) = 0.414, p = 0.52). The most frequently reported load used in training was 71-80% 1 repetition maximum. The majority of Norwegian (76.9%) powerlifters train with variable resistance, with those competing internationally more likely to use elastic bands (X 2 (1) = 4.473, p = 0.034). 32.5% of respondents reported that they included strength training exercises in their training. Norwegian powerlifters' training differs from practices previously identified in the literature, with a higher prevalence of elastic resistance, particularly for those competing internationally, and a decreased use of strength training exercises at all levels. Norwegian powerlifters train frequently (5 or more times per week) and with submaximal loads.

Contemporary results of open thoracic and thoracoabdominal aortic surgery in a single United Kingdom center.

OBJECTIVE: To report our outcomes and identify predictors of mortality after open descending thoracic aneurysm (DTA) and thoracoabdominal aortic aneurysm (TAAA) repair in a specialist aortic center. METHODS: This retrospective observational cohort study included consecutive patients who underwent surgery at our institution between October 1998 and December 2019. The main outcome measures were mortality and major morbidities. A multivariate analysis was used to identify predictors of mortality. RESULTS: There were 430 patients who underwent DTA (n = 157) and TAA (n = 273) repair; 151 underwent surgery nonelectively. Forty-eight patients (11%) died within 30 days of surgery. The 30-day mortality was lower after elective surgery (3.1% after DTA repair and 9.9% after TAAA repair), whereas nonelective surgery had a 30-day mortality of 17.9%. Fourteen additional patients died in hospital after 30 days, one after nonelective DTA repair and 13 after TAAA repair (10 elective), all but one extent II. In-hospital mortality for the whole cohort improved over time, as the activity volume increased, except for patients undergoing extent II TAAA repair. Predictors of in-hospital mortality were age ≥70 years (odds ratio [OR], 3.36; 95% confidence interval [CI], 1.79-6.32; P < .001), extent II repair (OR, 4.39; 95% CI, 2.34-8.21; P < .001), nonelective surgery (OR, 2.72; 95% CI, 1.44, 5.12; P = .002), out-of-hours surgery (OR, 8.17; 95% CI, 2.16-30.95; P = .002), a left ventricular ejection fraction of <30% (OR, 9.86; 95% CI, 1.91-50.86; P < .006), and surgery for a degenerative aneurysm (OR, 2.20; 95% CI, 1.12-4.31; P = .02). The incidence of stroke and paraplegia was 7.1% and 0% after DTA repair and 9.9% and 3.3% after TAAA repair. Hemodialysis was necessary in 5.1% of cases after DTA repair and 22.7% after TAAA repair. CONCLUSIONS: Open thoracoabdominal aortic surgery carries significant risk to life, which is related to age, extent of aortic replacement, timing of surgery, and left ventricular function. Morbidity is considerable. Understanding these risks is fundamental for patient selection and the consent process of potential candidates for surgery, particularly in the elderly.

Assessing the validity and applicability of the French 3-year prognostic score in the UK cystic fibrosis population - a national cohort study.

Models that predict outcomes, aid prognostication and inform the assessment of urgency for lung transplantation (LT) in CF are in demand. A prognostic score derived from the French adult CF registry to predict death or LT over 3-year follow-up was described in 2017 and validated using Canadian CF registry data. We assessed its performance in the UK CF population. The French prognostic score was applied to untransplanted adults with CF. The index year (2014) and outcomes (Death or LT) were evaluated to 2017. Receiver operator characteristics plots and area under curve (AUC) was computed. 4407 adults with CF met the inclusion criteria. After 3 years, 7.1% (P < 0.001) were dead or had received LT compared to the French (12.8%) and Canadian (9.4%) cohorts. The French score deemed 592 (26.2%) 'High-risk' - death/LT occurred in 189/592 (30.2%), less than previously reported in France and Canada (P < 0.0001). The discriminatory power of the French score was lower (AUC 0.830) than reported. Recalibration yielded only marginal improvement in model performance (AUC 0.833). The French prognostic score does not perform as well in the UK as reported elsewhere. Bespoke UK scores are needed to aid prognostication and inform LT decision-making.

Primary percutaneous coronary intervention in nonagenarians: is it worthwhile?

BACKGROUND: Previous studies have demonstrated the feasibility of primary percutaneous coronary intervention (PPCI) in carefully selected nonagenarians. Although current guidelines recommend immediate revascularization in patients with ST elevation myocardial infarction (STEMI) it remains unclear whether PPCI reduces mortality in nonagenarians. The objective of this study is to compare mortality in nonagenarians presenting via the PPCI pathway who undergo coronary intervention, versus those who are managed medically. METHODS AND RESULTS: A total of 111 consecutive nonagenarians who presented to our tertiary center via the PPCI pathway between July 2013 and December 2018 with myocardial infarction were included. Clinical and angiographic details were collected alongside data on all-cause mortality. The final diagnosis was STEMI in 98 (88.3%) and NSTEMI in 13 (11.7%). PPCI was performed in 42 (37.8%), while 69 (62.2%) were medically managed. A significant number of the medically managed cohort had atrial fibrillation (23.2% vs 2.4% p = 0.003) and presented with a completed infarct (43.5% vs 4.8% p = 0.001). Other baseline and clinical variables were well matched in both groups. There was a trend towards increased 30-day mortality in the medically managed group (40.6% vs 23.8% p = 0.07). Kaplan Meier survival analysis demonstrated a significant difference in survival by 3 years (48.1% vs 21.7% p = 0.01). This was the case even when those with completed infarcts were excluded (44.3% vs 14.6%, p = 0.01). CONCLUSION: In this series of selected nonagenarians presenting with acute myocardial infarction, those undergoing PPCI appeared to have a lower mortality compared to those managed medically.

Phonon counting and intensity interferometry of a nanomechanical resonator.

In optics, the ability to measure individual quanta of light (photons) enables a great many applications, ranging from dynamic imaging within living organisms to secure quantum communication. Pioneering photon counting experiments, such as the intensity interferometry performed by Hanbury Brown and Twiss to measure the angular width of visible stars, have played a critical role in our understanding of the full quantum nature of light. As with matter at the atomic scale, the laws of quantum mechanics also govern the properties of macroscopic mechanical objects, providing fundamental quantum limits to the sensitivity of mechanical sensors and transducers. Current research in cavity optomechanics seeks to use light to explore the quantum properties of mechanical systems ranging in size from kilogram-mass mirrors to nanoscale membranes, as well as to develop technologies for precision sensing and quantum information processing. Here we use an optical probe and single-photon detection to study the acoustic emission and absorption processes in a silicon nanomechanical resonator, and perform a measurement similar to that used by Hanbury Brown and Twiss to measure correlations in the emitted phonons as the resonator undergoes a parametric instability formally equivalent to that of a laser. Owing to the cavity-enhanced coupling of light with mechanical motion, this effective phonon counting technique has a noise equivalent phonon sensitivity of 0.89 ± 0.05. With straightforward improvements to this method, a variety of quantum state engineering tasks using mesoscopic mechanical resonators would be enabled, including the generation and heralding of single-phonon Fock states and the quantum entanglement of remote mechanical elements.

Antibiotic therapy for chronic infection with Burkholderia cepacia complex in people with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) a life-limiting inherited disease affecting a number of organs, but classically associated with chronic lung infection and progressive loss of lung function. Chronic infection by Burkholderia cepacia complex (BCC) is associated with increased morbidity and mortality and therefore represents a significant challenge to clinicians treating people with CF. This review examines the current evidence for long-term antibiotic therapy in people with CF and chronic BCC infection. OBJECTIVES: The objective of this review is to assess the effects of long-term oral and inhaled antibiotic therapy targeted against chronic BCC lung infections in people with CF. The primary objective is to assess the efficacy of treatments in terms of improvements in lung function and reductions in exacerbation rate. Secondary objectives include quantifying adverse events, mortality and changes in quality of life associated with treatment. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched online trial registries and the reference lists of relevant articles and reviews. Date of last search: 12 April 2021. SELECTION CRITERIA: Randomised controlled trials (RCTs) of long-term antibiotic therapy in people with CF and chronic BCC infection. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and assessed the quality of the evidence using GRADE. MAIN RESULTS: We included one RCT (100 participants) which lasted 52 weeks comparing continuous inhaled aztreonam lysine (AZLI) and placebo in a double-blind RCT for 24 weeks, followed by a 24-week open-label extension and a four-week follow-up period. The average participant age was 26.3 years, 61% were male and average lung function was 56.5% predicted. Treatment with AZLI for 24 weeks was not associated with improvement in forced expiratory volume in one second (FEV1), mean difference 0.91% (95% confidence interval (CI) -3.15 to 4.97) (moderate-quality evidence). The median time to the next exacerbation was 75 days in the AZLI group compared to 51 days in the placebo group, but the difference was not significant (P = 0.27) (moderate-quality evidence). Similarly, the number of participants hospitalised for respiratory exacerbations showed no difference between groups, risk ratio (RR) 0.88 (95% CI 0.53 to 1.45) (moderate-quality evidence). Overall adverse events were similar between groups, RR 1.08 (95% CI 0.98 to 1.19) (moderate-quality evidence). There were no significant differences between treatment groups in relation to mortality (moderate-quality evidence), quality of life or sputum density. In relation to methodological quality, the overall risk of bias in the study was assessed to be unclear to low risk. AUTHORS' CONCLUSIONS: We found insufficient evidence from the literature to determine an effective strategy for antibiotic therapy for treating chronic BCC infection.

Systematic approach to diagnosis and management of infected prosthetic grafts in the proximal aorta.

OBJECTIVES: Management of infected prosthetic aortic grafts in the ascending and or root is complex and multifaceted. We report our diagnostic pathway, management and outcomes, identifying successful strategies. METHODS: This was a retrospective, single center, observational study. Consecutive patients who underwent management of infected aortic grafts in the ascending and/or root at our institution between October 1998 and December 2019 were included. The main outcome measures were: discharge from hospital alive with at least 1 year survival, operative mortality and success of primary treatment strategy. RESULTS: Twenty-six patients presented with infection of proximal aortic grafts and were managed through a number of strategies with an overall hospital-survival of 81% and 1 year survival of 69%. Twenty of them ultimately underwent redo surgery with 25% operative mortality (within 24 h of surgery). Five patients underwent washout and irrigation of which two were successfully treated and cured with adjunctive antibiotics and two went on to have staged explant and definitive surgery. Interval between surgery and infection was 42.5 ± 35.8 months. All patients had at least one major criterion and three minor criterions with no diagnostic uncertainty. The commonest primary strategy was 3a (definitive surgery), (13/26, 50%). CONCLUSIONS: Adopting a systematic and flexible patient specific approach to the diagnosis and management of patients with proximal aortic graft infections results in reasonable overall 1 year survival. In the majority of patients surgery is ultimately required in an attempt to achieve a curative treatment; however this comes with high operative mortality risk.

Demonstration of a Thermally Coupled Row-Column SNSPD Imaging Array.

While single-pixel superconducting nanowire single photon detectors (SNSPDs) have demonstrated remarkable efficiency and timing performance from the UV to near-IR, scaling these devices to large imaging arrays remains challenging. Here, we propose a new SNSPD multiplexing system using thermal coupling and detection correlations between two photosensitive layers of an array. Using this architecture with the channels of one layer oriented in rows and the second layer in columns, we demonstrate imaging capability in 16-pixel arrays with accurate spot tracking at the few-photon level. We also explore the performance trade-offs of orienting the top layer nanowires parallel and perpendicular to the bottom layer. The thermally coupled row-column scheme is readily able to scale to the kilopixel size with existing readout systems and, when combined with other multiplexing architectures, has the potential to enable megapixel scale SNSPD imaging arrays.

Resolving Photon Numbers Using a Superconducting Nanowire with Impedance-Matching Taper.

Time- and number-resolved photon detection is crucial for quantum information processing. Existing photon-number-resolving (PNR) detectors usually suffer from limited timing and dark-count performance or require complex fabrication and operation. Here, we demonstrate a PNR detector at telecommunication wavelengths based on a single superconducting nanowire with an integrated impedance-matching taper. The taper provides a kΩ load impedance to the nanowire, making the detector's output amplitude sensitive to the number of photon-induced hotspots. The prototyping device was able to resolve up to four absorbed photons with 16.1 ps timing jitter and <2 c.p.s. device dark count rate. Its exceptional distinction between single- and two-photon responses is ideal for high-fidelity coincidence counting and allowed us to directly observe bunching of photon pairs from a single output port of a Hong-Ou-Mandel interferometer. This detector architecture may provide a practical solution to applications that require high timing resolution and few-photon discrimination.

Comparison of Muscle Activity in Three Single-Joint, Hip Extension Exercises in Resistance-Trained Women.

The aim of the study was to compare neuromuscular activation in the gluteus maximus, the biceps femoris and the erector spinae from the Romanian deadlift, the 45-degree Roman chair back extension and the seated machine back extension. Fifteen resistance-trained females performed three repetitions with 6-RM loading in all exercises in a randomized and counterbalanced order. The activation in the whole movement as well as its lower and upper parts were analyzed. The results showed that the Romanian deadlift and the Roman chair back extension activated the gluteus maximus more than the seated machine back extension (94-140%, p < 0.01). For the biceps femoris the Roman chair elicited higher activation compared to both the Romanian deadlift and the seated machine back extension (71-174%). Further, the Romanian deadlift activated the biceps femoris more compared to the seated machine back extension (61%, p < 0.01). The analyses of the different parts of the movement showed that the Roman chair produced higher levels of activation in the upper part for both the gluteus maximus and the biceps femoris, compared to the other exercises. There were no differences in activation of the erector spinae between the three exercises (p = 1.00). In conclusion, both the Roman deadlift and the Roman chair back extension would be preferable to the seated machine back extension in regards to gluteus maximus activation. The Roman chair was superior in activating the biceps femoris compared to the two other exercises. All three exercises are appropriate selections for activating the lower back muscles. For overall lower limb activation, the Roman chair was the best exercise.