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.

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.

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.

A Case for Below-Ground Dispersal? Insights into the Biology, Ecology and Conservation of Blind Cave Spiders in the Genus Troglodiplura (Mygalomorphae: Anamidae).

Previously described from only fragments of exoskeleton and juvenile specimens, the cave spider genus Troglodiplura (Araneae: Anamidae), endemic to the Nullarbor Plain, is the only troglomorphic member of the infraorder Mygalomorphae recorded from Australia. We investigated the distribution of Troglodiplura in South Australia, collecting and observing the first (intact) mature specimens, widening the number of caves it has been recorded in, and documenting threats to conservation. Phylogenetic analyses support the placement of Troglodiplura as an independent lineage within the subfamily Anaminae (the 'Troglodiplura group') and provide unequivocal evidence that populations from apparently isolated cave systems are conspecifics of T. beirutpakbarai Harvey & Rix, 2020, with extremely low or negligible inter-population mitochondrial divergences. This is intriguing evidence for recent or contemporary subterranean dispersal of these large, troglomorphic spiders. Observations of adults and juvenile spiders taken in the natural cave environment, and supported by observations in captivity, revealed the use of crevices within caves as shelters, but no evidence of silk use for burrow construction, contrasting with the typical burrowing behaviours seen in other Anamidae. We identify a range of threats posed to the species and to the fragile cave ecosystem, and provide recommendations for further research to better define the distribution of vulnerable taxa within caves and identify actions needed to protect them.

Feasibility of dynamic chest radiography to calculate lung volumes in adult people with cystic fibrosis: a pilot study.

INTRODUCTION: Dynamic chest radiography (DCR) is a novel, low-dose, real-time digital imaging system where software identifies moving thoracic structures and can automatically calculate lung areas. In an observational, prospective, non-controlled, single-centre pilot study, we compared it with whole-body plethysmography (WBP) in the measurement of lung volume subdivisions in people with cystic fibrosis (pwCF). METHODS: Lung volume subdivisions were estimated by DCR using projected lung area (PLA) during deep inspiration, tidal breathing and full expiration, and compared with same-day WBP in 20 adult pwCF attending routine review. Linear regression models to predict lung volumes from PLA were developed. RESULTS: Total lung area (PLA at maximum inspiration) correlated with total lung capacity (TLC) (r=0.78, p<0.001), functional residual lung area with functional residual capacity (FRC) (r=0.91, p<0.001), residual lung area with residual volume (RV) (r=0.82, p=0.001) and inspiratory lung area with inspiratory capacity (r=0.72, p=0.001). Despite the small sample size, accurate models were developed for predicting TLC, RV and FRC. CONCLUSION: DCR is a promising new technology that can be used to estimate lung volume subdivisions. Plausible correlations between plethysmographic lung volumes and DCR lung areas were identified. Further studies are needed to build on this exploratory work in both pwCF and individuals without CF. TRIAL REGISTRATION NUMBER: ISRCTN64994816.

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.

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.

Incidence of vascular complications for electrophysiology procedures in the ultrasound era: a single-centre experience over 10,000 procedures in the long term.

BACKGROUND: Ultrasound (US) is being increasingly used to guide vascular access for electrophysiology (EP) procedures in many centres. Nonetheless, the incidence and predictors of vascular complications in the US era are limited. In this study, we describe our experience of vascular access-related complications associated with EP procedures which were performed with the routine use of US-guided vascular access. METHODS: A total of 10,158 consecutive EP procedures in 8361 patients performed from April 2014 (when our centre moved to a policy of routine US-guided vascular access for EP procedures) to March 2022 were included. The outcome of interest was any vascular access-related complication that occurred within 7 days of the procedure; these were classified as severe if surgical intervention and/or blood transfusion was required, major if non-surgical intervention or delayed hospital discharge was required, or minor if it did not fulfil the criteria for severe or major. RESULTS: During the study period, 2 (0.02%) severe vascular complications occurred, including 1 pseudo-aneurysm requiring surgery and 1 retroperitoneal haemorrhage requiring blood transfusion. Nine (0.09%) major complications occurred, including 6 hematomas managed by compression devices, 1 type B aortic dissection, 1 AV fistula managed conservatively and 1 haematoma managed conservatively but delayed hospital discharge. Eighteen (0.18%) minor haematomas were seen that did not require any intervention or delayed hospital discharge. On multivariable analysis, female sex [OR (95% CI): 2.5 (1.2, 5.4)] and use of an arterial access [OR (95% CI): 19.3 (7.1, 52.3)] were seen to be independent predictors of the 29 vascular complications. CONCLUSION: With the use of US-guided vascular access in EP procedures, major vascular complications are exceedingly rare, particularly those needing surgical intervention. Our results provide additional evidence for scientific guidelines to support US use.

Preparing pharmacists for the Community Pharmacist Consultation Service: a questionnaire survey.

OBJECTIVES: The Community Pharmacist Consultation Service launched in England in 2019. Patients requiring urgent care were referred from National Health Service-based telephone/digital triage or general practice to a community pharmacist, who provided a consultation, which could include a physical examination. The aim of the study was to evaluate the effectiveness of a learning programme to prepare community pharmacists for the service. METHODS: Learning programme participants were invited to complete an online survey shortly after the workshop and another survey 3 months later. The survey collected opinions on aspects of the programme, including Likert-type statements and free text questions. The 3-month follow-up survey explored how the programme had helped pharmacists change their practice. Data were analysed in SPSS (v.25; IBM) with inferential statistics used to compare subgroups. Open comments were analysed qualitatively. KEY FINDINGS: The learning programme addressed participants' learning needs including history-taking, clinically observing the patient, performing physical examinations, structuring a consultation, safety-netting, and documenting consultations. Barriers to using skills acquired included low service uptake and a lack of equipment to perform physical examinations. While many participants recognised the importance of skills to provide person-centred care, some participants did not appear to recognise the shift in policy to a more clinical role. CONCLUSIONS: The learning programme resulted in increased confidence and a recognition of a shift in the policy vision for community pharmacist roles. Although some pharmacists appeared to embrace this, others have yet to fully appreciate the need to adapt to be ready for the opportunities that this service can provide.

Reliability and validity testing of the medicines related - consultation assessment tool for assessing pharmacists' consultations.

BACKGROUND: Demonstrating a person-centred approach in a consultation is a key component of delivering high-quality healthcare. To support development of such an approach requires training underpinned by valid assessment tools. Given the lack of a suitable pharmacy-specific tool, a new global consultation skills assessment tool: the medicines related-consultation assessment tool (MR-CAT) was designed and tested. AIM: This study aimed to test the validity and reliability of the MR-CAT using psychometric methods. METHOD: Psychometric testing involved analysis of participants' (n = 13) assessment of fifteen pre-recorded simulated consultations using the MR-CAT. Analysis included discriminant validity testing, intrarater and interrater reliability testing for each of the five sections of the MR-CAT and for the overall global assessment of the consultation. Analysis also included internal consistency testing for the whole tool. RESULTS: Internal consistency for the overall global assessment of the consultation was good (Cronbach's alpha = 0.97). The MR-CAT discriminated well for the overall global assessment of the consultation (p < 0.001). Moderate to high intrarater reliability was observed for the overall global assessment of the consultation and for all five sections of the MR-CAT (rho = 0.64-0.84) in the test-retest analysis. Moderate to good interrater reliability (Kendall's W = 0.68-0.90) was observed for the overall global assessment of the consultation and for all five sections of the MR-CAT. CONCLUSION: The MR-CAT is a valid and reliable tool for assessing person-centred pharmacist's consultations. Moreover, its unique design means that the MR-CAT can be used in both formative and summative assessment.

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.

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.

Interprofessional learning for dental and pharmacy professionals: learning together changes how you work together.

Can an interprofessionally designed and facilitated learning event change the way professionals understand each other's roles, enable them to better work with each other and improve patient care? Pharmacy and dental professionals are contractors to the NHS, providing services to the public. The way both professions are funded encourages them to generally work in isolation from the wider NHS, in contrast to other areas of healthcare and NHS systems. This study explores how working collaboratively at all stages of design, development, facilitation and engagement of a learning event impacts on the professionals taking part. It also explores how learning interprofessionally can change the way dental and pharmacy professionals work together, suggesting this way of learning is beneficial to improving working relationships between the sectors.The study explored the ways that shared learning between professions could be approached and encouraged. Pharmacy professionals expressed that they felt more informed and confident giving dental advice to patients. Dental professionals recognised that pharmacy professionals could help support and manage patients. All professionals could see the importance of multidisciplinary working to improve understanding of the other professionals' role. The workshops showed that shared learning is an important aspect to help engage and integrate healthcare systems.

Educational supervision to support pharmacy professionals' learning and practice of advanced roles.

Pharmacy professionals are increasingly moving into advanced roles, including in primary care. In England, the publicly funded Pharmacy Integration Fund (PhIF) enabled employment and training of pharmacy professionals in new patient-facing roles, including general practice and care homes. In recognition of the need for support and supervision during work-based learning and building on established support structures in medicine and nursing, one of the providers of PhIF funded learning developed a supervision structure which mirrors arrangements for postgraduate medical specialty training. This paper describes what informed this supervision model, with a particular focus on educational supervision, its delivery, and the training which was developed to support supervisors. This supervision enabled pharmacy professionals moving into primary care to practise safely, manage workplace challenges, extend their roles and make progress with their education. This model illustrates the benefits of supervision in supporting post-registration learning to facilitate the development of advanced patient-facing clinical roles.

Institutional practice in sizing of the hybrid prosthesis in frozen elephant trunk surgery.

BACKGROUND: The frozen elephant trunk (FET) technique for total arch replacement (TAR) is widely used for repair of aortic arch dissections and aneurysms. Despite its widespread adoption, there are no international or regional guidelines for the sizing of FET prostheses in TAR. We seek to highlight the heterogeneity thereof and pave the way for evidence-based guidelines to advise FET prosthesis sizing in TAR. METHODS: An online questionnaire was sent to 22 specialist aortic surgeons from 13 different countries across North America, Europe, Asia, and Australia, inquiring about each surgeon's approach to FET prosthesis sizing. The results were then pooled for frequency analysis. RESULTS: All 22 surgeons responded to the questionnaire. Zone 2 is preferred implantation zone for AAD, CAD, and TAA (selected by 72.7%, 72.7%, and 68.2% respectively). The maximal diameter of the true lumen in the DTA is the most common index measurement for AAD and CAD (40.9% and 59.1%, respectively). Stent-graft diameters equal to the index measurement is the most common approach for AAD and CAD (77.3% and 45.5%, respectively) while 59.1% of surgeons oversize the index diameter by 10% for TAA; 100 mm is the preferred length for 50.0%, 27.3%, and 40.9% of surgeons in AAD, CAD, and TAA respectively. CONCLUSIONS: There is considerable heterogeneity in sizing practices for FET prostheses internationally, with variable evidence for its impact on clinical outcomes. This issue would be aided by the development of evidence-based guidelines to inform clinical decision making.

Mobile applications for the sport and exercise nutritionist: a narrative review.

Mobile technology is widespread in modern society, and the applications (apps) that they run can serve various purposes. Features such as portability, ease of communication, storage, and relative low cost may make such technology attractive to practitioners in several fields. This review provides a critical narrative on the existing literature for apps relevant to the field of sport and exercise nutrition. Three main areas are discussed: (1) dietary analysis of athletes, (2) nutrition education for athletes, (3) estimating body composition. The key purpose of the review was to identify what literature is available, in what areas apps may have a benefit over traditional methods, and considerations that practitioners should make before they implement apps into their practice or recommend their use to coaches and athletes.