Monitoring for Breast Cancer Recurrence Following Goldilocks Breast Reconstruction.

BACKGROUND: The Goldilocks breast reconstruction utilizes redundant mastectomy skin flaps to fashion a breast mound; however, there is concern that imbrication of these skin flaps may predispose to fat necrosis and make detection of local breast cancer recurrence more difficult. Goldilocks patients follow a traditional postmastectomy screening pathway that includes clinical examination for locoregional recurrence, but it is unclear if this is sufficient. We evaluate our Goldilocks reconstruction case series to determine rates of diagnostic imaging, biopsy, and locoregional and distant recurrence. METHODS: Sixty-six patients (94 breasts) undergoing Goldilocks breast reconstruction were retrospectively reviewed. Any diagnostic postoperative imaging/biopsies performed and that confirmed local or distant breast cancer recurrence were noted. RESULTS: Average time of follow-up was 45 months. Most patients in this cohort had stage 0 (27.3%) or stage I (40.9%) breast cancer. There were a total of 11 (11.7%) concerning breast masses identified. Seven (7.4%) masses were biopsied, of which 5 were benign and 2 were invasive cancer recurrence. Four masses (4.3%) underwent diagnostic imaging only, all with benign findings. Five patients in this series were found to have either distant disease or a second primary cancer in the nonoperative contralateral breast. CONCLUSIONS: Rates of local recurrence following Goldilocks are not higher than expected after other types of postmastectomy reconstruction. Clinical monitoring successfully detected local recurrence in all affected patients in this series. More definite guidelines around the routine screening of Goldilocks mastectomy patients may aid in early detection of local breast cancer recurrence.

Trichinella: Becoming a parasite.

Phylogenetic evidence indicates that free-living nematodes gave rise to parasitic nematodes where parasitism evolved independently at least 15 times. The high level of genetic and biological diversity among parasites dictates an equally high level of diversity in the transition to parasitism. We previously hypothesized that horizontal gene transfer (HGT) played an important role in the evolution of parasitism among early ancestors of Trichinella, mediated by an interplay of ecological and evolutionary pathways that contributed to persistence and diversification. We propose that host selection may have been associated with the metabolism of ammonia and engender a new paradigm whereby the reprogrammed nurse cell is capable of generating cyanate thereby enabling the importance of the Trichinella cyanase in the longevity of the cell. Parasites and parasitism have revealed considerable resilience against a backdrop of climate change and environmental perturbation. Here we provide a putative link between key periods in the evolution of Trichinella and major geological and climatological events dating back 500 million years. A useful lens for exploring such ideas, the Stockholm Paradigm, integrates Ecological Fitting (a foundation for host colonization and diversification), the Oscillation Hypothesis (recurring shifts between trends in generalization and specialization relative to host range), the Geographic Mosaic Theory of Coevolution (microevolutionary co-adaptive processes), and the Taxon Pulse Hypothesis (alternating events of biotic expansion i.e., exploitation in evolutionary and ecological time). Here we examine how one or more of these interactive theories, in a phylogenetic-historical context and in conjunction with HGT, may help explain the scope and depth of diversity among Trichinella genotypes.

Scalp Reconstruction With Free Tissue Transfer as a Palliative Surgical Intervention in a High-Risk Population.

Microvascular reconstruction of the scalp is frequently indicated in patients with locally advanced tumors, among other etiologies, in a relatively high-risk, older patient population that often has multiple medical comorbidities. A retrospective analysis was performed on patients undergoing microvascular scalp reconstruction at Emory University Hospital and Grady Memorial Hospital between 2011 and 2021. Patient demographics, wound characteristics, operative details, and complications were recorded. Statistical analysis using univariate and multivariate models was performed. Forty-two patients underwent 45 microvascular scalp reconstructive procedures during the study period. The median age was 63 years. Wounds were predominantly oncologic (n=38, 84.4%) and frequently involved deeper structures [calvarium (n=38, 84.4%), dura (n=17, 37.8%)]. At a median follow-up of 350 days, 33 patients (73.3%) had healed flaps, 9 (20.0%) had wound healing issues but ultimately successful reconstruction, and 3 (6.7%) experienced flap failure. Most patients (n=33, 80.9%) were discharged home or to a rehabilitation facility, while the remaining 8 patients (19.1%) were discharged to hospice or died. The 30-day mortality was 4 patients (8.9%) and the 6-month mortality was 8 patients (20.5%). There was a statistically significant difference in 30-day mortality (P=0.0001) on univariate analysis and 6-month mortality (P=0.003) on both univariate and multivariate analysis for patients >70 years. While age >70 years is a risk factor for mortality in patients undergoing microvascular scalp reconstruction, mortality was commonly related to underlying disease processes rather than complication of surgery. Microvascular reconstruction for scalp defects has a high success rate and can be offered as a palliative procedure for patients with locally advanced cancers, advanced age, and multiple comorbidities.

Evaluation of the ultrasound findings of thyroid gland enlargement in Cape Coast Teaching Hospital, Ghana: A retrospective cross-sectional study.

Background and Aim: Goiter is a major source of morbidity in the world, especially in the developing world, where dietary iodine deficiency, a known cause of this condition, is endemic. The diagnosis is mostly by ultrasonography (USG) scan, which can give anatomical, pathological, and functional information for the management of goiter. This study aimed to determine the commonest ultrasound findings of goiter in Ghana. Method: The records of all 213 patients with goiter diagnosed by USG scan over a 5-year period were retrieved. Data collected were sociodemographics, ultrasound features, thyroid nodules diameter, and Thyroid Imaging Reporting and Data System (TI-RADS) scores, which were analyzed using GNU PSPP, version 1.2.0-3. χ 2 and two-tailed independent samples t-test were also employed, with p ≤ 0.05. Results: A total of 213 patients with goiter diagnosed by USG scan were obtained over the study period. The mean age of the participants was 50.01 ± 17.27 years, with an age range of 16-92 years and females constituting the majority (82.16%). The commonest ultrasound features were well-defined solid nodules. The lesion sites for most patients were the whole thyroid (28.17%), both lobes (24.41%), and the right lobe (20.19%). The mean difference in sizes of cysts and solid nodules among genders was 0.26 (CI: -0.14 to 0.67, p = 0.20) and 0.12 (CI: -0.43 to 0.66, p = 0.67), respectively. The TI-RADS score featured TI-RADS 4 (36.62%), TI-RADS 1 (28.17%), TI-RADS 3 (25.82%), TI-RADS 5 (5.16%), and TI-RADS 2 (4.23%). Solid nodules (49.32%, p = 0.001) and cysts (35.71%, p = 0.003) were more common within 41-60 years and less frequent in those <21 years. A p ≤ 0.05 was considered significant in this study. Conclusion: The predominant ultrasound features were well-defined solid nodules, simple cysts, and solid nodules with cystic changes, mostly located in the entire thyroid gland and least located in the isthmus only. Cysts and solid nodules were mostly seen in the 41-60 years age group.

Comparison of the Backbone Dynamics of Dehaloperoxidase-Hemoglobin Isoenzymes.

Dehaloperoxidase (DHP) is a multifunctional hemeprotein with a functional switch generally regulated by the chemical class of the substrate. Its two isoforms, DHP-A and DHP-B, differ by only five amino acids and have an almost identical protein fold. However, the catalytic efficiency of DHP-B for oxidation by a peroxidase mechanism ranges from 2- to 6-fold greater than that of DHP-A depending on the conditions. X-ray crystallography has shown that many substrates and ligands have nearly identical binding in the two isoenzymes, suggesting that the difference in catalytic efficiency could be due to differences in the conformational dynamics. We compared the backbone dynamics of the DHP isoenzymes at pH 7 through heteronuclear relaxation dynamics at 11.75, 16.45, and 19.97 T in combination with four 300 ns MD simulations. While the overall dynamics of the isoenzymes are similar, there are specific local differences in functional regions of each protein. In DHP-A, Phe35 undergoes a slow chemical exchange between two conformational states likely coupled to a swinging motion of Tyr34. Moreover, Asn37 undergoes fast chemical exchange in DHP-A. Given that Phe35 and Asn37 are adjacent to Tyr34 and Tyr38, it is possible that their dynamics modulate the formation and migration of the active tyrosyl radicals in DHP-A at pH 7. Another significant difference is that both distal and proximal histidines have a 15-18% smaller S2 value in DHP-B, thus their greater flexibility could account for the higher catalytic activity. The distal histidine grants substrate access to the distal pocket. The greater flexibility of the proximal histidine could also accelerate H2O2 activation at the heme Fe by increased coupling of an amino acid charge relay to stabilize the ferryl Fe(IV) oxidation state in a Poulos-Kraut "push-pull"-type peroxidase mechanism.

Exploring Transcriptional Regulation of Beta Cell SASP by Brd4-Associated Proteins and Cell Cycle Control Protein p21.

Type 1 diabetes (T1D) is a metabolic disease resulting from progressive autoimmune destruction of insulin-producing pancreatic beta cells. Although the majority of beta cells are lost in T1D, a small subset undergoes senescence, a stress response involving growth arrest, DNA damage response, and activation of a senescence-associated secretory phenotype (SASP). SASP in beta cells of the nonobese diabetic (NOD) mouse model of T1D and primary human islets is regulated at the level of transcription by bromodomain extra-terminal (BET) proteins, but the mechanisms remain unclear. To explore how SASP is transcriptionally regulated in beta cells, we used the NOD beta cell line NIT-1 to model beta cell SASP and identified binding partners of BET protein Brd4 and explored the role of the cyclin-dependent kinase inhibitor p21. Brd4 interacted with a variety of proteins in senescent NIT-1 cells including subunits of the Ino80 chromatin remodeling complex, which was expressed in beta cells during T1D progression in NOD mice and in human beta cells of control, autoantibody-positive, and T1D donors as determined from single-cell RNA-seq data. RNAi knockdown of p21 during senescence in NIT-1 cells did not significantly impact viability or SASP. Taken together, these results suggest that Brd4 interacts with several protein partners during senescence in NIT-1 cells, some of which may play roles in SASP gene activation and that p21 is dispensable for the SASP in this beta cell model.

Techniques in Nipple Areolar Reconstruction: A Retrospective Analysis of Surgical Interventions and Patient-reported Satisfaction Scores.

Background: Nipple areolar complex (NAC) reconstruction often signifies completion of the breast reconstruction process for some patients and has been shown to improve both psychosocial and sexual well-being. Several techniques have been described; however, there currently exists little evidence in the literature describing outcomes or patient satisfaction. Methods: A retrospective analysis of NAC reconstructions over the last decade was queried for patient demographics, operative technique, and postoperative outcomes. A standardized, validated survey was also utilized to evaluate overall satisfaction, with a focus on aesthetic outcome, shape, color, and projection. Results: Eighty-three patients were identified, with 49 (59.0%) completing the survey. The modalities used for reconstruction include the C-V flap (45.7%), the modified skate flap technique (42.2%), and free nipple grafting (FNG, 12.0%). No significant differences in age, BMI, or comorbidities were found among the three types. The most utilized donor site for skate flap reconstruction was the suprapubic area (37.1%). There were also no significant differences in complication rate (C-V 10.5%, FNG 10%, skate 5.7%, P = 0.630) or revision surgery (C-V 2.6%, FNG 0%, skate 5.7%, P = 0.732). The most common complication was nipple necrosis. Adjusting for time to follow-up using multivariate analysis, there was a significant difference in overall patient satisfaction when compared across all three techniques, with the modified skate flap having the highest mean overall satisfaction scores. Conclusions: NAC reconstruction can be completed safely and effectively with a variety of techniques. The modified skate flap technique was associated with high levels of patient satisfaction and a low complication rate.

Cost-effectiveness of low-dose colchicine in patients with chronic coronary disease in the netherlands.

AIMS: Recent trials have shown that low-dose colchicine (0.5 mg once daily) reduces major cardiovascular events in patients with acute and chronic coronary syndromes. We aimed to estimate the cost-effectiveness of low-dose colchicine therapy in patients with chronic coronary disease when added to standard background therapy. METHODS AND RESULTS: This Markov cohort cost-effectiveness model used estimates of therapy effectiveness, transition probabilities, costs and quality of life obtained from the Low-dose Colchicine 2 (LoDoCo2) trial, as well as meta-analyses and public sources. In this trial, Low-dose colchicine was added to standard of care and compared to placebo. The main outcomes were cardiovascular events including myocardial infarction, stroke and coronary revascularisation, quality-adjusted life-year (QALY), the cost per QALY gained (incremental cost-effectiveness ratio), and net monetary benefit. In the model, low-dose colchicine therapy yielded 0.04 additional QALYs compared with standard of care at an incremental cost of €455 from a societal perspective and €729 from a healthcare perspective, resulting in a cost per QALY gained of €12,176/QALY from a societal perspective and €19,499/QALY from a healthcare perspective. Net monetary benefit was €1,414 from a societal perspective and €1,140 from a healthcare perspective. Low-dose colchicine has a 96% and 94% chance of being cost effective, from respectively a societal and healthcare perspective when using a willingness to pay of €50,000/QALY. Net monetary benefit would decrease below zero when annual low-dose colchicine costs would exceed an annual cost of €221 per patient. CONCLUSION: Adding low-dose colchicine to standard of care in patients with chronic coronary disease is cost-effective according to commonly accepted thresholds in Europe and Australia and compares favourably in cost-effectiveness to other drugs used in chronic coronary disease.

Protocol for quantifying SA-ß-gal activity as a measure of senescence in islets of a mouse model of type 1 diabetes.

A subpopulation of pancreatic beta cells becomes senescent during type 1 diabetes (T1D) progression, and removal of these populations protects against T1D in mice. Here, we present a protocol to measure senescence in murine pancreatic islet cells through analysis of senescence-associated ß-galactosidase activity. We describe steps for staining with the fluorogenic substrate C12FDG and analysis by flow cytometry. Increased cell size is another marker of senescence and can also be concurrently measured in the same experiment. For complete details on the use and execution of this protocol, please refer to Lee et al.1 and Helman et al.2.

Establishing evidence for immune surveillance of ß-cell senescence.

Cellular senescence is a programmed state of cell cycle arrest that involves a complex immunogenic secretome, eliciting immune surveillance and senescent cell clearance. Recent work has shown that a subpopulation of pancreatic ß-cells becomes senescent in the context of diabetes; however, it is not known whether these cells are normally subject to immune surveillance. In this opinion article, we advance the hypothesis that immune surveillance of ß-cells undergoing a senescence stress response normally limits their accumulation during aging and that the breakdown of these mechanisms is a driver of senescent ß-cell accumulation in diabetes. Elucidation and therapeutic activation of immune surveillance mechanisms in the pancreas holds promise for the improvement of approaches to target stressed senescent ß-cells in the treatment of diabetes.

Fructose regulates the pentose phosphate pathway and induces an inflammatory and resolution phenotype in Kupffer cells.

Over-consumption of fructose in adults and children has been linked to increased risk of non-alcoholic fatty liver disease (NAFLD). Recent studies have highlighted the effect of fructose on liver inflammation, fibrosis, and immune cell activation. However, little work summarizes the direct impact of fructose on macrophage infiltration, phenotype, and function within the liver. We demonstrate that chronic fructose diet decreased Kupffer cell populations while increasing transitioning monocytes. In addition, fructose increased fibrotic gene expression of collagen 1 alpha 1 (Col1a1) and tissue metallopeptidase inhibitor 1 (Timp1) as well as inflammatory gene expression of tumor necrosis factor alpha (Tnfa) and expression of transmembrane glycoprotein NMB (Gpnmb) in liver tissue compared to glucose and control diets. Single cell RNA sequencing (scRNAseq) revealed fructose elevated expression of matrix metallopeptidase 12 (Mmp12), interleukin 1 receptor antagonist (Il1rn), and radical S-adenosyl methionine domain (Rsad2) in liver and hepatic macrophages. In vitro studies using IMKC and J774.1 cells demonstrated decreased viability when exposed to fructose. Additionally, fructose increased Gpnmb, Tnfa, Mmp12, Il1rn, and Rsad2 in unpolarized IMKC. By mass spectrometry, C13 fructose tracing detected fructose metabolites in glycolysis and the pentose phosphate pathway (PPP). Inhibition of the PPP further increased fructose induced Il6, Gpnmb, Mmp12, Il1rn, and Rsad2 in nonpolarized IMKC. Taken together, fructose decreases cell viability while upregulating resolution and anti-inflammatory associated genes in Kupffer cells.

Rift Valley Fever virus M and L genome segment detection: a comparison of field-deployable reverse transcription insulated isothermal PCR (RT-iiPCR) and laboratory-based multiplex reverse transcription real-time PCR.

Rift Valley Fever phlebovirus (RVFV) is a mosquito-borne zoonotic pathogen that causes major agricultural and public health problems in Africa and the Arabian Peninsula. It is considered a potential agro-bioterrorism agent for which limited countermeasures are available. To address diagnostic needs, here we describe a rapid and sensitive molecular method immediately employable at sites of suspected outbreaks in animals that commonly precede outbreaks in humans. The strategy involves the concurrent detection of two of the three RVFV genome segments (large and medium) using reverse transcription insulated isothermal PCR (RT-iiPCR) performed on a portable, touch screen nucleic acid analyzer, POCKIT. The analytical sensitivity for both the RT-iiPCR and a laboratory-based L and M multiplex reverse transcription real-time PCR assay was estimated at approximately 0.1-3 copies/reaction using synthetic RNA or viral RNA. The diagnostic sensitivity and specificity of detection of RVFV on the POCKIT, determined using sera from sheep and cattle (n = 181) experimentally infected with two strains of RVFV (SA01 and Ken06), were 93.8% and 100% (kappa = 0.93), respectively. Testing of ruminant field sera (n = 193) in two locations in Africa demonstrated 100% diagnostic sensitivity and specificity. We conclude that the POCKIT dual-gene RVFV detection strategy can provide reliable, sensitive, and specific point-of-need viral RNA detection. Moreover, the field detection of RVFV in vectors or susceptible animal species can aid in the surveillance and epidemiological studies to better understand and control RVFV outbreaks. IMPORTANCE: The content of this manuscript is of interest to the diverse readership of the Journal of Clinical Microbiology, including research scientists, diagnosticians, healthcare professionals, and policymakers. Rift Valley Fever virus (RVFV) is a zoonotic mosquito-borne pathogen that causes major agricultural and public health problems. Current and most sensitive diagnostic approaches that are molecular-based are performed in highly specialized molecular diagnostic laboratories. To address diagnostic needs, we developed a novel, rapid, and sensitive molecular method using a portable PCR machine, POCKIT, capable of immediate deployment at sites of suspected outbreaks. Here, we demonstrate that field-deployable RVFV detection can provide reliable, sensitive, and specific point-of-need viral RNA detection that could be used for diagnostic investigations and epidemiological studies, and can be performed in the field.

Simultaneous estimation of the temporal and spatial extent of animal migration using step lengths and turning angles.

BACKGROUND: Animals of many different species, trophic levels, and life history strategies migrate, and the improvement of animal tracking technology allows ecologists to collect increasing amounts of detailed data on these movements. Understanding when animals migrate is important for managing their populations, but is still difficult despite modelling advancements. METHODS: We designed a model that parametrically estimates the timing of migration from animal tracking data. Our model identifies the beginning and end of migratory movements as signaled by change-points in step length and turning angle distributions. To this end, we can also use the model to estimate how an animal's movement changes when it begins migrating. In addition to a thorough simulation analysis, we tested our model on three datasets: migratory ferruginous hawks (Buteo regalis) in the Great Plains, barren-ground caribou (Rangifer tarandus groenlandicus) in northern Canada, and non-migratory brown bears (Ursus arctos) from the Canadian Arctic. RESULTS: Our simulation analysis suggests that our model is most useful for datasets where an increase in movement speed or directional autocorrelation is clearly detectable. We estimated the beginning and end of migration in caribou and hawks to the nearest day, while confirming a lack of migratory behaviour in the brown bears. In addition to estimating when caribou and ferruginous hawks migrated, our model also identified differences in how they migrated; ferruginous hawks achieved efficient migrations by drastically increasing their movement rates while caribou migration was achieved through significant increases in directional persistence. CONCLUSIONS: Our approach is applicable to many animal movement studies and includes parameters that can facilitate comparison between different species or datasets. We hope that rigorous assessment of migration metrics will aid understanding of both how and why animals move.

Characterization of an Injectable Chitosan Hydrogel for the Tunable, Localized Delivery of Immunotherapeutics.

Localized delivery of immunotherapeutics within a tumor has the potential to reduce systemic toxicities and improve treatment outcomes in cancer patients. Unfortunately, local retention of therapeutics following intratumoral injection is problematic and is insufficiently considered. Dense tumor architectures and high interstitial pressures rapidly exclude injections of saline and other low-viscosity solutions. Hydrogel-based delivery systems, on the other hand, can resist shear forces that cause tumor leakage and thus stand to improve the local retention of coformulated therapeutics. The goal of the present work was to construct a novel, injectable hydrogel that could be tuned for localized immunotherapy delivery. A chitosan-based hydrogel, called XCSgel, was developed and subsequently characterized. Nuclear magnetic resonance studies were performed to describe the chemical properties of the new entity, while cryo-scanning electron microscopy allowed for visualization of the hydrogel's cross-linked network. Rheology experiments demonstrated that XCSgel was shear-thinning and self-healing. Biocompatibility studies, both in vitro and in vivo, showed that XCSgel was nontoxic and induced transient mild-to-moderate inflammation. Release studies revealed that coformulated immunotherapeutics were released over days to weeks in a charge-dependent manner. Overall, XCSgel displayed several clinically important features, including injectability, biocompatibility, and imageability. Furthermore, the properties of XCSgel could also be controlled to tune the release of coformulated immunotherapeutics.

Chromosomal scale assembly reveals localized structural variants in avian caecal coccidian parasite Eimeria tenella.

Eimeria tenella is a major cause of caecal coccidiosis in commercial poultry chickens worldwide. Here, we report chromosomal scale assembly of Eimeria tenella strain APU2, a strain isolated from commercial broiler chickens in the U.S. We obtained 100× sequencing Oxford Nanopore Technology (ONT) and more than 800× Coverage of Illumina Next-Seq. We created the assembly using the hybrid approach implemented in MaSuRCA, achieving a contiguous 51.34 Mb chromosomal-scale scaffolding enabling identification of structural variations. The AUGUSTUS pipeline predicted 8060 genes, and BUSCO deemed the genomes 99% complete; 6278 (78%) genes were annotated with Pfam domains, and 1395 genes were assigned GO-terms. Comparing E. tenella strains (APU2, US isolate and Houghton, UK isolate) derived Houghton strain of E. tenella revealed 62,905 high stringency differences, of which 45,322 are single nucleotide polymorphisms (SNPs) (0.088%). The rate of transitions/transversions among the SNPs are 1.63 ts/tv. The strains possess conserved gene order but have profound sequence heterogeneity in a several chromosomal segments (chr 2, 11 and 15). Genic and intergenic variation in defined gene families was evaluated between the two strains to possibly identify sequences under selection. The average genic nucleotide diversity of 2.8 with average 2 kb gene length (0.145%) at genic level. We examined population structure using available E. tenella sequences in NCBI, revealing that the two E. tenella isolates from the U.S. (E. tenella APU2 and Wisconsin, "ERR296879") share a common maternal inheritance with the E. tenella Houghton. Our chromosomal level assembly promotes insight into Eimeria biology and evolution, hastening drug discovery and vaccine development.

Posttraumatic stress moderates return intentions: a factorial survey experiment with internally displaced persons in Nigeria.

Background: Persons displaced by conflict often consider returning to their area of origin. Lack of reliable information about conditions in the area of origin makes this decision more difficult. Displaced persons address this by seeking information from other sources, but must then assess the credibility of these sources.Objective: This study examines the role of symptoms of posttraumatic stress as a moderator of how information from a trustworthy source influences return intentions among displaced persons.Method: We test our hypotheses with a factorial survey experiment, drawing participants (N = 822) from residents of internally displaced person (IDP) camps in northeastern Nigeria.Results: Information from a more trustworthy source led to increased return intentions. However, the more participants reported symptoms of posttraumatic stress, the smaller the effect source trustworthiness had on their return intentions.Conclusions: Findings highlight how traumatic experiences during wartime can undermine the effectiveness of the provision of information from a trustworthy source about good conditions in displaced persons' areas of origin, and suggest that interventions addressing posttraumatic stress could have downstream effects on safe, durable, and dignified return.

Examines the impact of posttraumatic stress on the decision-making process of internally displaced persons in Nigeria.Credible information from trustworthy sources can positively influence return intentions, but this effect is diminished by symptoms of posttraumatic stress.Highlights the importance of addressing both information needs and mental health concerns to support displaced persons in making informed decisions about their future.

Experience of an NIHR Clinical Lectureship (medical/dental) and the determining factors for a clinical academic career post lectureship: a mixed-method evaluation.

OBJECTIVES: The objective of this study is to investigate early-to-late postdoctoral clinical academic progression and the experiences of NIHR Clinical Lectureship (CL) fellows, considering enablers and barriers to success, and identifying the factors associated with immediate progression to a clinical academic role following completion of the award. SETTING: Datasets of CL awardees across the UK. PARTICIPANTS: For semistructured interviews, n=40 CL awardees that had finished their award within the previous 5 years. For quantitative analysis, n=1226 completed or currently active CL awardees. OUTCOME MEASURES: The responses from the semistructured interviews to the defined questions on experiences during the award, postaward progression, and enablers and barriers to academic progression. Other primary outcome measures were quantitative data on first destinations postaward, demographic data, and whether an awardee had previously held an NIHR Academic Clinical Fellowship (ACF) or was a recipient of the Academy of Medical Sciences (AMS) Starter Grant. RESULTS: CL awardees identified numerous benefits to the award, with the majority achieving their aims. Most awardees progressed to a clinical academic role; however, some returned to a clinical only position, citing concerns around the time pressure associated with balancing clinical and academic responsibilities, and the competition to attain further postdoctoral awards. The region of the award partnership, year of award end and success in applying for an AMS Starter Grant were associated with progression to a clinical academic role. Gender, holding an ACF and having a craft or non-craft specialty had no independent statistical association with clinical academic progression. CONCLUSIONS: The CL is a valued element of the Integrated Academic Pathway. By addressing issues around later postdoctoral progression opportunities, responding to challenges experienced by CLs, and by understanding the factors identified in this study associated with clinical academic progression, it should be possible to increase the proportion of CLs that become fully independent clinical academic research leaders. PARTICIPANTS: 1226 NIHR CLs active or completed on the award between 2006 and 2020.

Excision of a Protein-Derived Amine for p-Aminobenzoate Assembly by the Self-Sacrificial Heterobimetallic Protein CADD.

Chlamydia protein associating with death domains (CADD), the founding member of a recently discovered class of nonheme dimetal enzymes termed hemeoxygenase-like dimetaloxidases (HDOs), plays an indispensable role in pathogen survival. CADD orchestrates the biosynthesis of p-aminobenzoic acid (pABA) for integration into folate via the self-sacrificial excision of a protein-derived tyrosine (Tyr27) and several additional processing steps, the nature and timing of which have yet to be fully clarified. Nuclear magnetic resonance (NMR) and proteomics approaches reveal the source and probable timing of amine installation by a neighboring lysine (Lys152). Turnover studies using limiting O2 have identified a para-aminobenzaldehyde (pABCHO) metabolic intermediate that is formed on the path to pABA formation. The use of pABCHO and other probe substrates shows that the heterobimetallic Fe/Mn form of the enzyme is capable of oxygen insertion to generate the pABA-carboxylate.

Stress-induced ß cell early senescence confers protection against type 1 diabetes.

During the progression of type 1 diabetes (T1D), ß cells are exposed to significant stress and, therefore, require adaptive responses to survive. The adaptive mechanisms that can preserve ß cell function and survival in the face of autoimmunity remain unclear. Here, we show that the deletion of the unfolded protein response (UPR) genes Atf6α or Ire1α in ß cells of non-obese diabetic (NOD) mice prior to insulitis generates a p21-driven early senescence phenotype and alters the ß cell secretome that significantly enhances the leukemia inhibitory factor-mediated recruitment of M2 macrophages to islets. Consequently, M2 macrophages promote anti-inflammatory responses and immune surveillance that cause the resolution of islet inflammation, the removal of terminally senesced ß cells, the reduction of ß cell apoptosis, and protection against T1D. We further demonstrate that the p21-mediated early senescence signature is conserved in the residual ß cells of T1D patients. Our findings reveal a previously unrecognized link between ß cell UPR and senescence that, if leveraged, may represent a novel preventive strategy for T1D.