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Background: Much policy attention focuses on increasing the supply of workers in the English NHS but there has been less attention paid to the rise in leavers. This paper seeks to explore how existing data sets can illuminate the decision-making of leavers and inform actions that could mitigate this. Method: Secondary analysis of routinely collected data from 79 workforce projects in the UK (n = 46 339 participants) over a 4-year (2019–2023) period was undertaken. Free text data we extracted and analysed using content analysis, sentiment analysis and text mining. Inclusion criteria were those who stated they had resigned, had confirmed retirement date, and had secured employment elsewhere either within or without the sector but had not yet resigned. Exclusion criteria were those who had not indicated they were leaving or indicated intention to leave. These findings were then compared with themes from Herzberg's work hygiene theory and Hoffat and Woods's professional practice environment theory. Results: Multiple reasons were given for leaving. Findings were congruent with Herzberg's two factor work hygiene theory and demonstrate that leavers are driven by the inability to meet their intrinsic motivation to practice according to their professional standards as much as by terms and conditions. Leavers describe suboptimal professional practice environments which produce obstacles to achieving their work objectives and leaving their intrinsic motivation frustrated. Conclusion: Whilst reasons for leaving differ between people, there is a relationship between intrinsic motivation (why they want to do the job) and the conditions in which they try to do the job. This study suggests that looking beyond the primary reason for leaving given in the national dataset could identify how the practice environment influences the decision. [ABSTRACT FROM AUTHOR]

Neural crest (NC) is a unique vertebrate cell type arising from the border of the neural plate and epidermis that gives rise to diverse tissues along the entire body axis. Roberto Mayor and colleagues have made major contributions to our understanding of NC induction, delamination, and migration. We report that a truncating mutation of the classical tumor suppressor Adenomatous Polyposis Coli (apc) disrupts craniofacial development in zebrafish larvae, with a marked reduction in the cranial neural crest (CNC) cells that contribute to mandibular and hyoid pharyngeal arches. While the mechanism is not yet clear, the altered expression of signaling molecules that guide CNC migration could underlie this phenotype. For example, apcmcr/mcr larvae express substantially higher levels of complement c3, which Mayor and colleagues showed impairs CNC cell migration when overexpressed. However, we also observe reduction in stroma-derived factor 1 (sdf1/cxcl12), which is required for CNC migration into the head. Consistent with our previous work showing that APC directly enhances the activity of glycogen synthase kinase 3 (GSK-3) and, independently, that GSK-3 phosphorylates multiple core mRNA splicing factors, we identify 340 mRNA splicing variations in apc mutant zebrafish, including a splice variant that deletes a conserved domain in semaphorin 3f (sema3f), an axonal guidance molecule and a known regulator of CNC migration. Here, we discuss potential roles for apc in CNC development in the context of some of the seminal findings of Mayor and colleagues. [ABSTRACT FROM AUTHOR]

Introduction: Chronic lymphocytic leukemia (CLL) is commonly treated with the B-cell lymphoma 2 inhibitor (BCL-2) venetoclax. Venetoclax is associated with an increased risk of tumor lysis syndrome in this patient population. Because venetoclax undergoes CYP3A4 metabolism, strong CYP3A4 inhibitors are contraindicated during the ramp-up phase of venetoclax in patients with CLL. Case report: Our case report describes a 58 year old male initially diagnosed with CLL in 2013, whose first-line treatment consisted of ibrutinib. The patient developed a central nervous system (CNS) aspergillosis infection in 2018, and was initiated on voriconazole. He was subsequently under active surveillance until his disease progressed. The patient was started on venetoclax therapy, while on concomitant voriconazole, for management of his CLL. Management and outcome: The patient's initial venetoclax dose was 10 mg daily, and he received rasburicase on day 1 of therapy. He tolerated a modified ramp-up phase without complication. After receiving 9 days of inpatient therapy, the patient was discharged on 50 mg of venetoclax to continue outpatient dose escalation. His dose was ultimately escalated to 100 mg daily. Discussion: Although this report describes the safe administration of venetoclax with voriconazole, extreme caution should be exercised when administering venetoclax with any strong CYP3A4 inhibitor during the ramp-up phase in patients with CLL. [ABSTRACT FROM AUTHOR]

The article presents a case report of a 57-year-old woman who had resumed ovulation of her menstrual cycle at 3 years postmenopause.

We present a 74-year-old gentleman, who presented with foot ischaemia requiring bilateral amputation in the absence of radiological signs of occlusive peripheral arterial disease. He was found to have COVID-19 pneumonitis and concurrent arterial and venous thromboemboli despite no initial respiratory symptoms or signs, nor pre-existing risk factors for cardiovascular disease. Patients who present with foot ischaemia with or without respiratory symptoms or signs warrant a high index of suspicion for COVID-19 infection, particularly in those with no predisposing risk factors. [ABSTRACT FROM AUTHOR]

The coronaviruses responsible for severe acute respiratory syndrome (SARS-CoV), COVID-19 (SARS-CoV-2), Middle East respiratory syndrome-CoV, and other coronavirus infections express a nucleocapsid protein (N) that is essential for viral replication, transcription, and virion assembly. Phosphorylation of N from SARSCoV by glycogen synthase kinase 3 (GSK-3) is required for its function and inhibition of GSK-3 with lithium impairs N phosphorylation, viral transcription, and replication. Here we report that the SARS-CoV-2 N protein contains GSK-3 consensus sequences and that this motif is conserved in diverse coronaviruses, raising the possibility that SARS-CoV-2 may be sensitive to GSK-3 inhibitors, including lithium. We conducted a retrospective analysis of lithium use in patients from three major health systems who were PCRtested for SARS-CoV-2. We found that patients taking lithium have a significantly reduced risk of COVID-19 (odds ratio = 0.51 [0.35--0.74], P = 0.005). We also show that the SARS-CoV-2 N protein is phosphorylated by GSK-3. Knockout of GSK3A and GSK3B demonstrates that GSK-3 is essential for N phosphorylation. Alternative GSK-3 inhibitors block N phosphorylation and impair replication in SARS-CoV-2 infected lung epithelial cells in a cell-type--dependent manner. Targeting GSK-3 may therefore provide an approach to treat COVID-19 and future coronavirus outbreaks. [ABSTRACT FROM AUTHOR]

Introduction: Acute graft-versus-host disease (aGVHD) is a significant immune-mediated complication of allogeneic hematopoietic stem cell transplant (HSCT). Despite prophylactic immunosuppression, the incidence of grades II–IV aGVHD post-HSCT varies from 20 to 80%. Tumor necrosis factor (TNF) is an important cytokine involved in the pathogenesis of GVHD, and medications such as infliximab (Remicade®) have been utilized as second-line treatment options in patients with steroid-refractory GHVD. Infliximab-dyyb (Inflectra®) and infliximab-qbtx (Ixifi®) are biosimilars approved by the FDA for a variety of autoimmune disorders. This is the first case report documenting the utility of infliximab-dyyb and -qbtx for the management of steroid-refractory aGVHD. Case report: We report the post-transplant course of three patients treated with infliximab biosimilars as a part of therapy for management of steroid-refractory aGVHD. Management and outcome: Steroid-refractory aGVHD is associated with poor prognosis and its management, as highlighted in our three patient cases, and can be very diverse often requiring different therapeutic modalities which overlap in administration. Discussion: In these patients with steroid-refractory aGVHD, we were able to show that infliximab biosimilars could be used in lieu of the reference infliximab product. Although we had important limitations, this case report supports the use of anti-TNF agents in highly mortal steroid-refractory acute GI GVHD and that replacement of infliximab with its biosimilars is feasible. [ABSTRACT FROM AUTHOR]

Introduction: Citrobacter bacteria are gram-negative anaerobic bacilli commonly found in water, soil, food, and the intestinal tracts of animals and humans. Patients at highest risk of these nosocomial infections include neonates and adults who are ≥65 years of age, debilitated, or immunocompromised. Citrobacter braakii (C. braakii), specifically, has been reported to cause sepsis in immunocompromised patients. Herein, we describe a case of an allogeneic stem cell transplant (SCT) adult patient with C. braakii bloodstream infection. Case Report: We report our experience managing a central line-associated bloodstream infection (CLABSI) due to C. braakii in an allogeneic SCT patient. Management and Outcomes: Our patient was initially managed with cefepime. The central venous catheter (CVC) was removed. Blood cultures cleared 24 hours after antibiotic initiation. Therapy was transitioned to oral levofloxacin once susceptibilities resulted. Discussion: The course of this patient highlights the important relationship between an unusual pathogen, C. braakii, in an immunocompromised allogeneic SCT patient. In our case, the source of the bacteremia was most likely a CLABSI given the positive catheter tip cultures. Although this report describes the successful utilization of cefepime and levofloxacin in the treatment of C. braakii infection, caution should be exercised when choosing empiric antimicrobial therapy as AmpC resistance. This clinical scenario can aid health care providers in making informed treatment decisions when faced with patients diagnosed with this relatively uncommon pathogen. Further reports should be published to determine C. braakii bacteremia management in hematopoietic stem cell transplant patients. [ABSTRACT FROM AUTHOR]

Introduction: Gilteritinib is a multitargeted tyrosine kinase inhibitor (TKI) approved by the Food and Drug Administration (FDA) for acute myeloid leukemia (AML) with a FMS-related tyrosine kinase 3 (FLT3) mutation. The pharmacokinetics of gilteritinib in the setting of severe renal impairment (creatinine clearance [CrCl] 15-29 mL/min utilizing Cockcroft-Gault method) and end-stage renal disease are unknown. Gilteritinib is primarily metabolized by the liver through the CYP3A4 enzyme and is eliminated in both the feces and urine. Its excretion is primarily through the fecal route, accounting for 64.5% of the recovered dose. Only about 16.4% of the recovered dose has been detected in the urine of human subjects. Case Report: We describe our patient case documenting the administration of gilteritinib in the setting of end-stage renal disease (ESRD) and hemodialysis (HD). Management and Outcomes: Our patient was initiated on single agent gilteritinib 120 mg by mouth once daily for relapse FLT3-TDK positive AML. Treatment course was complicated by pancytopenia, neutropenic fever, and staphylococcus lugdunensis bacteremia requiring temporary interruption of therapy. Discussion: Given that gilteritinib is metabolized by the liver and eliminated primarily in the feces, one does not expect an increase in toxicity related to impaired renal function. Although this report describes the successful utilization of gilteritinib, caution should be exercised when administering in patient populations with end organ disease, and patient comorbidities should be taken into account. [ABSTRACT FROM AUTHOR]

The American Medical Society for Sports Medicine (AMSSM) convened a group of experts to develop a Position Statement addressing the problem of sexual violence in sport. The AMSSM Sexual Violence in Sport Task Force held a series of meetings over 7 months, beginning in July 2019. Following a literature review, the Task Force used an iterative process and expert consensus to finalise the Position Statement. The objective of this Position Statement is to raise awareness of this critical issue among sports medicine physicians and to declare a commitment to engage in collaborative, multidisciplinary solutions to reduce sexual violence in sport. [ABSTRACT FROM AUTHOR]

The American Medical Society for Sports Medicine (AMSSM) convened a group of experts to develop a position statement addressing the problem of sexual violence in sport. The AMSSM Sexual Violence in Sport Task Force held a series of meetings over 7 months, beginning in July 2019. Following a literature review, the task force used an iterative process and expert consensus to finalize the position statement. The objective of this position statement is to raise awareness of this critical issue among sports medicine physicians and to declare a commitment to engage in collaborative, multidisciplinary solutions to reduce sexual violence in sport. [ABSTRACT FROM AUTHOR]

Smith-Lemli-Opitz syndrome (SLOS) is a cholesterol synthesis disorder characterized by physical, mental, and behavioral symptoms. It is caused bymutations in 7-dehydroxycholesterolreductase gene (DHCR7) encoding DHCR7 protein, which is the rate-limiting enzyme in the cholesterol synthesis pathway. Here we demonstrate that pathogenic mutations in DHCR7 protein are located either within the transmembrane region or are near the ligand-binding site, and are highly conserved among species. In contrast, non-pathogenic mutations observed in the general population are located outside the transmembrane region and have different effects on the conformational dynamics of DHCR7. All together, these observations suggest that the non-classified mutation R228Q is pathogenic. Our analyses indicate that pathogenic effects may affect protein stability and dynamics and alter the binding affinity and flexibility of the binding site. [ABSTRACT FROM AUTHOR]

Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In this Review we describe how the advent of machines is impacting on organic synthesis programs, with particular emphasis on the practical issues associated with the design of chemical reactors. In the rapidly changing, multivariant environment of the research laboratory, equipment needs to be modular to accommodate high and low temperatures and pressures, enzymes, multiphase systems, slurries, gases, and organometallic compounds. Additional technologies have been developed to facilitate more specialized reaction techniques such as electrochemical and photochemical methods. All of these areas create both opportunities and challenges during adoption as enabling technologies. [ABSTRACT FROM AUTHOR]

Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Organic synthesis is changing; in a world where budgets are constrained and the environmental impacts of practice are scrutinized, it is increasingly recognized that the efficient use of human resource is just as important as material use. New technologies and machines have found use as methods for transforming the way we work, addressing these issues encountered in research laboratories by enabling chemists to adopt a more holistic systems approach in their work. Modern developments in this area promote a multi-disciplinary approach and work is more efficient as a result. This Review focuses on the concepts, procedures and methods that have far-reaching implications in the chemistry world. Technologies have been grouped as topics of opportunity and their recent applications in innovative research laboratories are described. [ABSTRACT FROM AUTHOR]

Flow chemistry and continuous processing techniques are beginning to have a profound impact on the production of functional materials ranging from quantum dots, nanoparticles and metal organic frameworks to polymers and dyes. These techniques provide robust procedures which not only enable accurate control of the product material's properties but they are also ideally suited to conducting experiments on scale. The modular nature of flow and continuous processing equipment rapidly facilitates reaction optimisation and variation in function of the products. [ABSTRACT FROM AUTHOR]

Emergent resistance can be progressive and driven by global signaling aberrations. All-trans retinoic acid (RA) is the standard therapeutic agent for acute promyelocytic leukemia, but 10–20% of patients are not responsive, and initially responsive patients relapse and develop retinoic acid resistance. The patient-derived, lineage-bipotent acute myeloblastic leukemia (FAB M2) HL-60 cell line is a potent tool for characterizing differentiation-induction therapy responsiveness and resistance in t(15;17)-negative cells. Wild-type (WT) HL-60 cells undergo RA-induced granulocytic differentiation, or monocytic differentiation in response to 1,25-dihydroxyvitamin D3 (D3). Two sequentially emergent RA-resistant HL-60 cell lines, R38+ and R38-, distinguishable by RA-inducible CD38 expression, do not arrest in G1/G0 and fail to upregulate CD11b and the myeloid-associated signaling factors Vav1, c-Cbl, Lyn, Fgr, and c-Raf after RA treatment. Here, we show that the R38+ and R38- HL-60 cell lines display a progressive reduced response to D3-induced differentiation therapy. Exploiting the biphasic dynamic of induced HL-60 differentiation, we examined if resistance-related defects occurred during the first 24 h (the early or “precommitment” phase) or subsequently (the late or “lineage-commitment” phase). HL-60 were treated with RA or D3 for 24 h, washed and retreated with either the same, different, or no differentiation agent. Using flow cytometry, D3 was able to induce CD38, CD11b and CD14 expression, and G1/G0 arrest when present during the lineage-commitment stage in R38+ cells, and to a lesser degree in R38- cells. Clustering analysis of cytometry and quantified Western blot data indicated that WT, R38+ and R38- HL-60 cells exhibited decreasing correlation between phenotypic markers and signaling factor expression. Thus differentiation induction therapy resistance can develop in stages, with initial partial RA resistance and moderate vitamin D3 responsiveness (unilineage maturation block), followed by bilineage maturation block and progressive signaling defects, notably the reduced expression of Vav1, Fgr, and c-Raf. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to test the potential therapeutic effects of the substituted pyrimidine, KP544, which has been shown to amplify the effects of nerve growth factor in vitro, on motor deficits in the R6/2 transgenic mouse model of Huntington's disease (HD). Methods: Young, female R6/2 mice were given daily oral intubation of either 10 mg/kg KP544 or vehicle (0.5% methylcellulose) at 6 weeks of age and tested from postnatal weeks 8 through 12 on a battery of motor tasks, including assessments of clasping (drawing of the limbs to the torso when suspended by the tail), motor coordination on the rotarod, and spontaneous motor activity in the open-field. Following testing, the mice were sacrificed and the brains were sectioned and stained with cresyl violet for histological examination. Results: KP544 treatment decreased balance deficits on the rotarod task, reduced clasping, delayed the onset of hypoactivity, and reduced enlargement of the lateral ventricles in R6/2 mice. Conclusion: These results suggest that KP544 can reduce motor deficits and anatomical alterations in R6/2 mice. Further research into the use of KP544 as a potential pharmacotherapy HD is warranted. [ABSTRACT FROM AUTHOR]

Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement, increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively. Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement. Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury. [ABSTRACT FROM AUTHOR]

The thapsigargins are a family of complex guaianolides with potent and selective Ca2+-modulating properties. This article documents the evolution of a synthetic route through several iterations to a final practical and scaleable synthetic route capable of generating both unnatural and natural products based around the guaianolide skeleton. [ABSTRACT FROM AUTHOR]

The physical environment can promote the functional ability of persons with dementia. Many care facilities use environmental signage (e.g., names on doors) to facilitate adaptive behavior (e.g., room finding). However, the effects of such signage on residents' functioning are not well understood. In three experiments, we investigated if persons with moderate to severe dementia had the required skills necessary to benefit from signage. Compared to a control condition (recognition of fellow residents' photographs), a high percentage of participants could identify written names and photographs of themselves (Experiment 1). Moreover, name and photographic labels helped participants identify belongings (Experiment 2). Training improved some participants' recognition of their own photographs but not of their fellow residents' photographs (Experiment 3). These findings are consistent with research on self-reference and age-related changes in face recognition and reading, and they suggest that many persons with dementia may have the requisite abilities to benefit from prosthetic signage. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the accuracy of self-reported 24-h dietary recalls of overweight and normal-weight adults. Forty female college students (21 overweight, 19 normal weight) consumed a lunch meal at the university cafeteria while being unobtrusively observed. The following day subjects returned to the lab and completed a 24-h recall of their food intake. Accuracy of recalls was assessed by comparing directly observed intake with self-reported intake. Correlated t tests comparing observed and reported intake found a significant amount of overreporting of consumption for the entire sample. When analyses were conducted on individual groups (normal weight vs overweight), no between-group differences were found. A series of one-way analyses of variance (ANOVA) (normal weight vs overweight) and a mubtivariate ANOVA were performed for total calories, nutrients, and the amount of over- and underreporting. No significant differences between groups were observed. [ABSTRACT FROM AUTHOR]

To enhance the timeliness of medical evaluation for cholera-like illness during the 2011 cholera outbreak in Hispaniola, printed Travel Health Alert Notices (T-HANs) were distributed to travelers from Haiti to the United States. Evaluation of the T-HANs' influence on travelers' health care-seeking behavior suggested T-HANs might positively influence health care-seeking behavior. [ABSTRACT FROM AUTHOR]