Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.

Maintaining protein lipoylation is vital for cell metabolism. The H-protein encoded by GCSH has a dual role in protein lipoylation required for bioenergetic enzymes including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase, and in the one-carbon metabolism through its involvement in glycine cleavage enzyme system, intersecting two vital roles for cell survival. Here, we report six patients with biallelic pathogenic variants in GCSH and a broad clinical spectrum ranging from neonatal fatal glycine encephalopathy to an attenuated phenotype of developmental delay, behavioral problems, limited epilepsy and variable movement problems. The mutational spectrum includes one insertion c.293-2_293-1insT, one deletion c.122_(228 + 1_229-1) del, one duplication of exons 4 and 5, one nonsense variant p.Gln76*and four missense p.His57Arg, p.Pro115Leu and p.Thr148Pro and the previously described p.Met1?. Via functional studies in patient's fibroblasts, molecular modeling, expression analysis in GCSH knockdown COS7 cells and yeast, and in vitro protein studies, we demonstrate for the first time that most variants identified in our cohort produced a hypomorphic effect on both mitochondrial activities, protein lipoylation and glycine metabolism, causing combined deficiency, whereas some missense variants affect primarily one function only. The clinical features of the patients reflect the impact of the GCSH changes on any of the two functions analyzed. Our analysis illustrates the complex interplay of functional and clinical impact when pathogenic variants affect a multifunctional protein involved in two metabolic pathways and emphasizes the value of the functional assays to select the treatment and investigate new personalized options.

Standardising personalised diabetes care across European health settings: A person-centred outcome set agreed in a multinational Delphi study.

OBJECTIVE: Standardised person-reported outcomes (PRO) data can contextualise clinical outcomes enabling precision diabetes monitoring and care. Comprehensive outcome sets can guide this process, but their implementation in routine diabetes care has remained challenging and unsuccessful at international level. We aimed to address this by developing a person-centred outcome set for Type 1 and Type 2 diabetes, using a methodology with prospects for increased implementability and sustainability in international health settings. METHODS: We used a three-round questionnaire-based Delphi study to reach consensus on the outcome set. We invited key stakeholders from 19 countries via purposive snowball sampling, namely people with diabetes (N = 94), healthcare professionals (N = 65), industry (N = 22) and health authorities (N = 3), to vote on the relevance and measurement frequency of 64 previously identified clinical and person-reported outcomes. Subsequent consensus meetings concluded the study. RESULTS: The list of preliminary outcomes was shortlisted via the consensus process to 46 outcomes (27 clinical outcomes and 19 PROs). Two main collection times were recommended: (1) linked to a medical visit (e.g. diabetes-specific well-being, symptoms and psychological health) and (2) annually (e.g. clinical data, general well-being and diabetes self management-related outcomes). CONCLUSIONS: PROs are often considered in a non-standardised way in routine diabetes care. We propose a person-centred outcome set for diabetes, specifically considering psychosocial and behavioural aspects, which was agreed by four international key stakeholder groups. It guides standardised collection of meaningful outcomes at scale, supporting individual and population level healthcare decision making. It will be implemented and tested in Europe as part of the H2O project.

"Teaching capital"- a sociological analysis of medical educator portfolios for promotion.

Medical educator portfolios (MEP) are increasingly recognized as a tool for developing and documenting teaching performance in Health Professions Education. However, there is a need to better understand the complex interplay between institutional guidelines and how teachers decode those guidelines and assign value to teaching merits. To gain a deeper understanding of this dynamic, this study employed a sociological analysis to understand how medical educators aspiring to professorships use MEPs to display their teaching merits and how cultural capital is reflected in these artefacts. We collected 36 medical educator portfolios for promotion from a large research-intensive university and conducted a deductive content analysis using institutional guidelines that distinguished between mandatory (accounting for the total body of teaching conducted) and optional content (arguing for pedagogical choices and evidencing the quality, respectively). Our analysis showed that the portfolios primarily included quantifiable data about teaching activities, e.g., numbers of students, topics and classes taught. Notably, they often lacked evidence of quality and scholarship of teaching. Looking at these findings through a Bourdieusian lens revealed that teachers in this social field exchange objectified evidence of hours spent on teaching into teaching capital recognized by their institution. Our findings highlight how institutional guidelines for MEPs construct a pedagogical battlefield, where educators try to decode and exchange the "right" and recognized teaching capital. This indicates that MEPs reflect the norms and practices of the academic field more than individual teaching quality.

Significant reduction in diabetes distress and improvements in psychosocial outcomes: A pilot test of an intervention to reduce diabetes distress in adults with type 1 diabetes and moderate-to-severe diabetes distress (REDUCE).

AIM: To pilot-test an intervention, co-designed with people with type 1 diabetes (T1DM) and diabetes specialist nurses, to reduce diabetes distress (DD) in adults with T1DM and moderate-to-severe DD. METHODS: A group-based programme to reduce DD in people with T1DM and moderate-to-severe DD (REDUCE) was pilot-tested in four groups with five bi-weekly two and a half-hour meetings facilitated by two trained diabetes specialist nurses. Data collection included baseline and post-intervention questionnaires measuring DD and psychosocial outcomes and semi-structured interviews with participants post-intervention (n = 18). Data were analysed using descriptive statistics and systematic text condensation. RESULTS: Twenty-five adults with T1DM participated in the study. The median age and diabetes duration of participants were 50 (IQR: 32;57.5) years and 26 (IQR: 18;45) years, respectively. Seventeen (68%) were women. The pilot study showed a significant reduction in DD (measured by Type 1 Diabetes Distress Scale) between baseline and post-intervention from 2.6 ± 0.7 to 1.9 ± 0.6 (mean ± SD) (p < 0.001). The largest reductions were seen on the subscales: powerlessness 1.2 ± 1.1, eating distress 0.9 ± 1.2 and fear of hypoglycaemia 0.8 ± 1.0 (mean ± SD). Significant improvements were also seen for quality of life, diabetes empowerment and emotion regulation. Qualitative data showed that REDUCE supported participants in verbalizing emotions and seeing worries in a more constructive perspective. Acknowledgement of negative diabetes experiences eased negative self-judgments. Sharing experiences among peers increased relatedness and reduced loneliness. CONCLUSION: Participation in REDUCE was associated with significant reduction in DD and significant increase in quality of life. Larger scale studies are planned to determine sustained effectiveness of REDUCE.

Psychosocial aspects and perspectives of adult-onset type 1 diabetes: A systematic scoping review.

AIM: To map existing research on psychosocial aspects of adult-onset type 1 diabetes (T1D), including psychosocial health status, ways psychosocial aspects may affect management of T1D in everyday life, and interventions targeting management of adult-onset T1D. METHODS: We conducted a systematic search in MEDLINE, EMBASE, CINAHL and PsycInfo. Search results were screened with predefined eligibility criteria, followed by data extraction of the included studies. Charted data were summarized in narrative and tabular form. RESULTS: We included 10 reports describing nine studies from the 7302 identified in the search. All studies were conducted in Europe. Participant characteristics were missing in several studies. Five of the nine studies incorporated psychosocial aspects as the main aim of the study. Limited information on psychosocial aspects was available in the remaining studies. We identified three overarching themes related to psychosocial aspects: (1) the impact of the diagnosis on everyday life, (2) the influence of psychosocial health on metabolic levels and adaptation, and (3) provision of self-management support. CONCLUSIONS: Research focussing on psychosocial aspects of the adult-onset population is scarce. Future research should involve participants across the adult life age span and from a wider geographical area. Sociodemographic information should be collected to explore different perspectives. Further exploration of suitable outcome measures considering adults' limited experience of living with the condition is needed. This would help to better understand how psychosocial aspects may affect management of T1D in everyday life and thus enable healthcare professionals to provide appropriate support to adults with new-onset T1D.

Ticket to perform: an explorative study of trainees' engagement in and transfer of surgical training.

BACKGROUND: Research suggests that simulation-based surgical skills training translates into improved operating room performance. Previous studies have predominantly focused on training methods and design and subsequent assessable performances and outcomes in the operating room, which only covers some aspects of training engagement and transfer of training. The purpose of this qualitative study was to contribute to the existing body of literature by exploring characteristics of first-year trainees' engagement in and perceptions of transfer of surgical skills training. METHODS: We conducted an explorative study based on individual interviews with first-year trainees in General Surgery, Urology, and Gynaecology and Obstetrics who participated in a laparoscopic skills training program. Informants were interviewed during and two months after the training program. A thematic cross-case analysis was conducted using systematic text condensation. RESULTS: We interviewed 12 informants, which produced 24 transcripts for analysis. We identified four main themes: (1) sportification of training, (2) modes of orientation, (3) transferrable skills, and (4) transfer opportunities. Informants described their surgical training using sports analogies of competition, timing, and step-by-step approaches. Visual orientations, kinaesthetic experiences, and elicited dialogues characterised training processes and engagement. These characteristics were identified in both the simulated and the clinical environment. Experiences of specific skills transfer included ambidexterity, coordination, instrument handling, and visuospatial ability. General transfer experiences were salient in informants' altered training approaches. Informants considered the simulation-based training an entry ticket to perform in the operating room and mentioned supervisor-trainee relationships and opportunities in the workplace as critical conditions of transfer. CONCLUSIONS: Our findings elucidate characteristics of surgical training engagement that can be interpreted as self-regulated learning processes that transcend surgical training environments. Despite appreciating the immediate skills improvements resulting from training, trainees' narratives reflected a struggle to transfer their training to the clinical setting. Tensions existed between perceptions of transferable skills and experiences of transfer within the clinical work environments. These results resonate with research emphasising the importance of the work environment in the transfer process. Our findings provide insights that may inform the development of training programs that support self-regulated learning and transfer of training from the simulated to the clinical environment.

Person-specific evidence has the ability to mobilize relational capacity: A four-step grounded theory developed in people with long-term health conditions.

Person-specific evidence was developed as a grounded theory by analyzing 20 selected case descriptions from interventions using the guided self-determination method with people with various long-term health conditions. It explains the mechanisms of mobilizing relational capacity by including person-specific evidence in shared decision-making. Person-specific self-insight was the first step, achieved as individuals completed reflection sheets enabling them to clarify their personal values and identify actions or omissions related to self-management challenges. This step paved the way for sharing these insights and challenges in a relationship with a supportive health professional, who could then rely on person-specific evidence instead of assumptions or a narrow disease perspective for shared decision-making. Trust in the evidence encouraged the supportive health professional to transfer it to the interdisciplinary team. Person-specific evidence then enhanced the ability of team members to apply general evidence in a meaningful way. The increased openness achieved by individuals through these steps enabled them to eventually share their new self-insights in daily life with other people, decreasing loneliness they experienced in self-management. Relational capacity, the core of the theory, is mobilized in both people with long-term health conditions and healthcare professionals. Further research on person-specific evidence and relational capacity in healthcare is recommended.

Remote training in laparoscopy: a randomized trial comparing home-based self-regulated training to centralized instructor-regulated training.

BACKGROUND: Simulation-based surgical training (SBST) is key to securing future surgical expertise. Proficiency-based training (PBT) in laparoscopy has shown promising results on skills transfer. However, time constraints and limited possibilities for distributed training constitute barriers to effective PBT. Home-based training may provide a solution to these barriers and may be a feasible alternative to centralized training in times of assembly constraints. METHODS: We randomly assigned first-year trainees in abdominal surgery, gynecology, and urology to either centralized instructor-regulated training (CIRT) or home-based self-regulated training (HSRT) in laparoscopy. All participants trained on portable box trainers providing feedback on metrics and possibility for video reviewing. Training in both groups was structured as PBT with graded proficiency exercises adopted from the Fundamentals of Laparoscopic Surgery (FLS). The HSRT group trained at home guided by online learning materials, while the CIRT group attended two training sessions in the simulation center with feedback from experienced instructors. Performance tests consisted of hand-eye and bimanual coordination, suture and knot-tying, and FLS exercises. We analyzed passing rates, training time and distribution, and test performances. RESULTS: Passing rates were 87% and 96% in the CIRT and HSRT group, respectively. HSRT facilitated distributed training and resulted in greater variation in training times. Task times for hand-eye and bimanual coordination were significantly reduced between pretest and posttest in both groups. Trainees maintained their posttest performances at the 6-month retention test. Our analyses revealed no significant inter-group differences in performances at pretest, posttest, or retention test. Performance improvements in the two groups followed similar patterns. CONCLUSION: CIRT and HSRT in laparoscopy result in comparable performance improvements. HSRT in laparoscopy is a feasible and effective alternative to CIRT when offered inside a supportive instructional design. Further research is needed to clarify trainees' preferences and explore facilitators and barriers to HSRT.

'Making room for student autonomy' - an ethnographic study of student participation in clinical work.

Participation in clinical work is important for medical students' professional development. However, students often report that they experience a passive observer role, and further research on contextual factors that influence student participation is needed. The theory of practice architectures contributes a new perspective to this challenge by elucidating how cultural-discursive, material-economic, and social-political arrangements enable and constrain student participation in clinical work. The aim of this study was to explore how practice architectures in clinical learning environments enable and constrain medical students' participation. The study was designed as an ethnographic field study in three student clinics: 106 h of observation. Analysis comprised ethnographic analysis followed by application of the theory of practice architectures. The ethnographic analysis resulted in six themes: setting the scene, when to call for help, my room - my patient, getting in a routine, I know something you don't, and my work is needed. Applying the theory of practice architectures showed that material-economic arrangements, such as control of the consultation room and essential artefacts, were crucial to student participation and position in the clinical workplace. Furthermore, co-production of a student mandate to independently perform certain parts of a consultation enabled a co-productive student position in the hierarchy of care-producers. The findings offer a conceptually generalisable model for the study of material and social dimensions of clinical learning environments. Although not all clinical learning environments may wish to or have the resources to implement a student clinic, the findings offer insights into general issues about the arrangements of student participation relevant to most clinical teaching contexts.

Embodied teacher identity: a qualitative study on 'practical sense' as a basic pedagogical condition in times of Covid-19.

Worldwide, the Covid-19 pandemic has transformed teaching contexts rapidly. Studies on the effects of the Covid-19 pandemic have largely focused on students' learning and well-being. In contrast, little is known about how emergency online teaching affects teachers. The aim of this study was to examine how disrupted teaching contexts during the Covid-19 pandemic affected academic teacher identities in health science education. Interviews were conducted with 19 experienced lecturers in health science education from two universities. Interview data were analysed using systematic text condensation. The established codes were compared across interviews to identify common themes and subsequently synthesized into descriptions of the emerging phenomena. Findings indicated that a form of embodied teacher identity, i.e. internalized teaching practices turned into dispositions, constituted a basic pedagogical condition and a resource for the teachers, and that the sudden change in the teaching context caused a loss of teacher identity. This identity loss was related to an incorporated understanding and use of the teacher's sense of the classroom (subtheme 1), non-verbal feedback from students (subtheme 2) and reciprocal visual contact (subtheme 3). Data also indicated that teachers' ability to adapt their teaching to students' needs while teaching and teachers' motivation and job satisfaction may have suffered. Universities should carefully consider how to cultivate sustainable and adaptive teacher identities compatible with the increasing digitalization of learning environments. Teaching is an embodied affair, and teacher identities are sensitive to structural changes in teaching contexts.

The impact of the COVID-19 pandemic on people with diabetes and diabetes services: A pan-European survey of diabetes specialist nurses undertaken by the Foundation of European Nurses in Diabetes survey consortium.

AIM: To describe diabetes nurses' perspectives on the impact of the COVID-19 pandemic on people with diabetes and diabetes services across Europe. METHODS: An online survey developed using a rapid Delphi method. The survey was translated into 17 different languages and disseminated electronically in 27 countries via national diabetes nurse networks. RESULTS: Survey responses from 1829 diabetes nurses were included in the analysis. The responses indicated that 28% (n = 504) and 48% (n = 873) of diabetes nurses felt the COVID-19 pandemic had impacted 'a lot' on the physical and psychological risks of people with diabetes, respectively. The following clinical problems were identified as having increased 'a lot': anxiety 82% (n = 1486); diabetes distress 65% (n = 1189); depression 49% (n = 893); acute hyperglycaemia 39% (n = 710) and foot complications 18% (n = 323). Forty-seven percent (n = 771) of respondents identified that the level of care provided to people with diabetes had declined either extremely or quite severely. Self-management support, diabetes education and psychological support were rated by diabetes nurse respondents as having declined extremely or quite severely during the COVID-19 pandemic by 31% (n = 499), 63% (n = 1,027) and 34% (n = 551), respectively. CONCLUSION: The findings show that diabetes nurses across Europe have seen significant increases in both physical and psychological problems in their patient populations during COVID-19. The data also show that clinical diabetes services have been significantly disrupted. As the COVID-19 situation continues, we need to adapt care systems with some urgency to minimise the impact of the pandemic on the diabetes population.

Using a limited sampling strategy to investigate the interindividual pharmacokinetic variability in metformin: A large prospective trial.

AIMS: Recently a limited sampling strategy (LSS) for determination of metformin' pharmacokinetics was developed. The LSS utilizes the plasma concentration of metformin 3 and 10 hours after oral intake of a single dose to estimate the area under the concentration-time curve up to 24 hours (AUC0-24h ). The main purpose of this study was to support the feasibility of this strategy in a large prospective trial. METHODS: Volunteers orally ingested two 500-mg tablets of metformin hydrochloride. A blood sample was drawn three and ten hours after the ingestion. Urine was collected for 0-10 and 10-24 hours and urine volumes recorded. The AUC0-24h was calculated using the equation AUC0-24h = 4.779 * C3 + 13.174 * C10 . Additionally, all participants were genotyped for the single-nucleotide polymorphism A270S in OCT2, g.-66 T > C in MATE1, R61C, G465R, G401S and the deletion M420del in OCT1. RESULTS: In total, 212 healthy volunteers participated. The median (25th - 75th interquartile range) AUC0 - 24h , CLrenal , C3 and C10 , were 10 600 (8470-12 500) ng* hr* mL-1 , 29 (24-34) L* hour-1 , 1460 (1180-1770) and 260 (200-330) ng* mL-1 , respectively, which is in agreement with our previous results. GFRi was correlated with metformin AUC and CLrenal (P < .001). As expected, we found a great pharmacokinetic interindividual variability among the volunteers and no effect of the OCT1 genotype on the AUC0 - 24h . We were unable to reproduce our previous finding of a gene-gene interaction (OCT2 and MATE1) effect on CLrenal in this cohort. CONCLUSION: This study further supports the use of the 2-point LSS algorithm in large pharmacokinetic trials.

Citrulline as a biomarker of bacteraemia during induction treatment for childhood acute lymphoblastic leukaemia.

BACKGROUND: Systemic infections are a major cause of morbidity in children with acute lymphoblastic leukaemia (ALL). However, identification of patients at increased risk is still a challenge. Knowing that both neutropaenia and gastrointestinal toxicity are risk factors for bacteraemia, we aimed at comparing absolute neutrophil counts (ANC) and plasma citrulline levels (indicating enterocyte loss) in children with ALL with and without bacteraemia during induction treatment. PROCEDURE: We prospectively included 61 children with ALL treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 protocol. ANC and plasma C-reactive protein (CRP) were measured on treatment days 1, 8, 15, 22 and 29. Plasma citrulline was measured on days 1, 8, 15 and 29. Bacteraemia episodes during induction treatment were recorded retrospectively. RESULTS: Nineteen of sixty-one (31%) patients experienced bacteraemia occurring on median day 13 (range 5-20). Patients with bacteraemia during induction treatment had lower citrulline level on day 15 (P < .01) compared to patients without bacteraemia, indicating more severe enterocyte loss. Nevertheless, ANC was similar in the two patient groups on days 8 and 15. CRP was negatively correlated with same-day citrulline (P < .03 for all) and ANC (P < .04 for all). CONCLUSIONS: During chemotherapy-induced neutropaenia, plasma citrulline may help identify patients at increased risk of bacteraemia.

Idiopathic early ovarian aging: is there a relation with premenopausal accelerated biological aging in young women with diminished response to ART?

PURPOSE: To evaluate whether young women with idiopathic early ovarian aging, as defined by producing fewer oocytes than expected for a given age over multiple in vitro fertilization (IVF) cycles, have changes in telomere length and epigenetic age indicating accelerated biological aging (i.e., increased risk of morbidity and mortality). METHODS: A prospective cohort study was conducted at two Danish public fertility clinics. A total of 55 young women (≤ 37 years) with at least two IVF cycles with ≤ 5 harvested oocytes despite sufficient stimulation with follicle-stimulating hormone (FSH) were included in the early ovarian aging group. As controls, 52 young women (≤ 37 years) with normal ovarian function, defined by at least eight harvested oocytes, were included. Relative telomere length (rTL) and epigenetic age acceleration (AgeAccel) were measured in white blood cells as markers of premenopausal accelerated biological aging. RESULTS: rTL was comparable with a mean of 0.46 (± SD 0.12) in the early ovarian aging group and 0.47 (0.14) in the normal ovarian aging group. The AgeAccel of the early ovarian aging group was, insignificantly, 0.5 years older, but this difference disappeared when adjusting for chronological age. Sub-analysis using Anti-Müllerian hormone (AMH) as selection criterion for the two groups did not change the results. CONCLUSION: We did not find any indications of accelerated aging in whole blood from young women with idiopathic early ovarian aging. Further investigations in a similar cohort of premenopausal women or other tissues are needed to fully elucidate the potential relationship between premenopausal accelerated biological aging and early ovarian aging.

Near-Infrared Reflectance Spectroscopy for Predicting the Phospholipid Fraction and the Total Fatty Acid Composition of Freeze-Dried Beef.

Research on fatty acids (FA) is important because their intake is related to human health. NIRS can be a useful tool to estimate the FA of beef but due to the high moisture and the high absorbance of water makes it difficult to calibrate the analyses. This work evaluated near-infrared reflectance spectroscopy as a tool to assess the total fatty acid composition and the phospholipid fraction of fatty acids of beef using freeze-dried meat. An average of 22 unrelated pure breed young bulls from 15 European breeds were reared on a common concentrate-based diet. A total of 332 longissimus thoracis steaks were analysed for fatty acid composition and a freeze-dried sample was subjected to near-infrared spectral analysis. 220 samples (67%) were used as a calibration set with the remaining 110 (33%) being used for validation of the models obtained. There was a large variation in the total FA concentration across the animals giving a good data set for the analysis and whilst the coefficient of variation was nearly 68% for the monounsaturated FA it was only 27% for the polyunsaturated fatty acids (PUFA). PLS method was used to develop the prediction models. The models for the phospholipid fraction had a low R2p and high standard error, while models for neutral lipid had the best performance, in general. It was not possible to obtain a good prediction of many individual PUFA concentrations being present at low concentrations and less variable than other FA. The best models were developed for Total FA, saturated FA, 9c18:1 and 16:1 with R2p greater than 0.76. This study indicates that NIRS is a feasible and useful tool for screening purposes and it has the potential to predict most of the FA of freeze-dried beef.

Gender differences in dentistry: A qualitative study on students' intrinsic and extrinsic motivations for entering dentistry at higher education.

INTRODUCTION: Having a balanced gender distribution is thought to ensure the diversity of knowledge and know-how and take better into account the different needs in society. The aim of the study is to explore and understand possible gender differences in (a) the students' motivational spectrum to choose a dental education and (b) their prospect of a professional career in dentistry. METHODS: We conducted in-depth interviews with male and female dental students (n = 14) followed by a theoretical reading based on Self-Determination Theory to explore the students' intrinsic and extrinsic motivations for entering dentistry in Denmark. RESULTS: Regardless gender, the dental students are motivated by role models, people orientation and strong interest in health sciences, but prefer dentistry to medicine, because of the responsibilities and working conditions. They were also motivated by the dental school's combination of theory and practice in students' learning of craftsmanship. Moreover, students valued the prospect of job security and a good work-life balance. However, there were markedly gender differences in motivation in relation to financial incentives as well as working life and career as a dentist, as it seemed that dental students needed gendered relatedness in relation to specialisation and employment in public versus private sector. CONCLUSION: The motivational spectrum varies widely, regardless of gender. In line with the standpoint feminist theory, a balanced gender distribution in dental education helps to meet the different needs in society and labour market. Consequently, a gender-sensitive recruitment strategy reflecting the gender differences in identities, knowledge and interests will be needed.

Response evaluation of bone metastasis in prostate cancer: Preliminary comparison of computerized bone scan index versus standardized clinical criteria.

OBJECTIVE: The correlation between the computer-assisted bone scan index (BSI) responses versus clinical response classification if bone metastases in prostate cancer patients are not clear. We compared changes in BSI with Prostate Cancer Working Group-3 (PCWG3) and MD Anderson (MDA) criteria. MATERIALS AND METHODS: Fifty-six consecutive patients with at least two bone scans (BS) within 12 months were included, who had BS before and after treatment with the same anticancer agent. RESULTS: Progressive disease (PD) by PCWG3 criteria was seen in 28% of the cases (median BSI increased by 1.69 units) versus non-PD in 72% (BSI change -0.13). MDAnderson showed PD in 34% (BSI increase 0.49), 45% stable disease (BSI change 0.00), and 20% partial responses (BSI decrease 1.44). Absolute BSI changes differed significantly among response categories by PCWG3 and MDA criteria (both P<0.0001). Response classification using dichotomized BSI data (>0/≤0 and >0.3/≤0.3 BSI units) showed a significant correlation with PCWG3 and MDA criteria (all P<0.001). Absolute BSI changes and dichotomized BSI correlated to prostate-specific antigen responses (both P<0.001) but not to clinical responses. CONCLUSION: Absolute changes in BSI and BSI response classification correlated significantly with standardized clinical response criteria for the assessment of treatment responses of skeletal metastases in prostate cancer.

An Experimental Stereoselective Photochemical [1s,3s]-Sigmatropic Silyl Shift and the Existence of Silyl/Allyl Conical Intersections.

We report an experimental discovery and computational investigation of the first photochemical stereoselective [1,3]-sigmatropic silyl shift of an allylsilane. An organocatalytic enantioselective cascade annulation generates a trimethylsilyl-o-isotoluene reactant in >99:1 e.r., and this trimethylsilyl-o-isotoluene contains an allylic silane moiety that undergoes a stereoselective photochemical [1,3]-silyl shift to form a benzylsilane with 96:4 e.r. The mechanism of this unprecedented [1,3]-silyl shift has been elucidated by a series of experimental studies and CASSCF, DFT, and TD-DFT calculations on model systems and the experimental system. The highly stereoselective photoreaction is proposed to occur via a singlet silyl/allyl conical intersection. This is a new demonstration of the role of conical intersections in selective photochemistry.

Lack of P2X7 Receptors Protects against Renal Fibrosis after Pyelonephritis with α-Hemolysin-Producing Escherichia coli.

Severe urinary tract infections are commonly caused by sub-strains of Escherichia coli secreting the pore-forming virulence factor α-hemolysin (HlyA). Repeated or severe cases of pyelonephritis can cause renal scarring that subsequently can lead to progressive failure. We have previously demonstrated that HlyA releases cellular ATP directly through its membrane pore and that acute HlyA-induced cell damage is completely prevented by blocking ATP signaling. Local ATP signaling and P2X7 receptor activation play a key role in the development of tissue fibrosis. This study investigated the effect of P2X7 receptors on infection-induced renal scarring in a murine model of pyelonephritis. Pyelonephritis was induced by injecting 100 million HlyA-producing, uropathogenic E. coli into the urinary bladder of BALB/cJ mice. A similar degree of pyelonephritis and mortality was confirmed at day 5 after infection in P2X7+/+ and P2X7-/- mice. Fibrosis was first observed 2 weeks after infection, and the data clearly demonstrated that P2X7-/- mice and mice exposed to the P2X7 antagonist, brillian blue G, show markedly less renal fibrosis 14 days after infection compared with controls (P < 0.001). Immunohistochemistry revealed comparable early neutrophil infiltration in the renal cortex from P2X7+/+ and P2X7-/- mice. Interestingly, lack of P2X7 receptors resulted in diminished macrophage infiltration and reduced neutrophil clearance in the cortex of P2X7-/- mice. Hence, this study suggests the P2X7 receptor to be an appealing antifibrotic target after renal infections.

Enantioselective 1,3-Dipolar [6+4] Cycloaddition of Pyrylium Ions and Fulvenes towards Cyclooctanoids.

Organocatalytic enantioselective 1,3-dipolar [6+4] cycloadditions of pyrylium ion intermediates with fulvenes promoted by a chiral primary amine catalyst have been developed to proceed in moderate to good yields and high enantioselectivities. The resultant chiral bicyclo[6.3.0]undecane scaffold containing a transannular bridging ether is densely functionalised providing a rigid scaffold for further manipulations. Computational studies give important insights into the role of the primary amine catalyst. Analysis of the reaction shows that the catalytic reaction proceeds in a step-wise manner and rationalises the stereochemical outcome of the reaction. Several stereoselective complexity-generating transformations, facilitated by the diverse functional groups and transannular bridge, are presented, highlighting the versatility of the core towards a number of the cyclooctanoid natural products.