Divergent Synthesis of 6- or 7-Aza-Indazoles via Intramolecular Diels-Alder Cascade of Pyrazines.

Pyrazines are reactive 4π partners in intermolecular Diels-Alder cycloaddition with exceptionally activated dienophiles or in an intermolecular version at elevated temperatures. Herein, it is shown that an intramolecular cascade could occur even at room temperature, delivering a collection of 6- or 7-aza-indazoles. An interesting substituent effect of the cycloaddition precursor on the product distribution was uncovered, and in situ NMR studies were conducted to gain insights into this unexpected selectivity.

Framing the wider determinants of health: Reflections and learning from a knowledge mobilisation exercise with an English local authority.

Background: Health inequalities remain a persistent problem in the UK. One contributing factor may be how health inequalities are framed in professional and public debate. Dominant understandings of health focus on the individual, personal choice, lifestyle and (un)healthy behaviour. This project sought to reframe health inequalities as a 'systemic' or structural problem using extant guidance. This was intended to support the work of a local authority in England working to address health inequalities. Project design: An academic-practitioner participatory knowledge mobilisation exercise with a local authority public health team using recent guidance and reflective feedback and the iterative development of actionable tools. There were four discrete stages to the exercise. Methods: Two on-line and one face-to-face participatory, deliberative workshops designed to co-create reframed public health challenges and solutions based on team portfolios. Iterative feedback provided by the researcher to support the development of actionable tools. Results: Six topic areas were developed with a systemic framing: 1. Food insecurity, 2. Obesity, 3. Prostate cancer among Black men, 4. Cost of living, 5. Mental health, suicide prevention and Gypsy, Roma, Traveller communities, 6. Healthy streets. Reflections from the process revealed some perceived advantages of engaging in a systemic framing of the wider determinants of health, some limitations and issues to consider in a local setting. Benefits included: Clarity in a complex field; structured thinking about what to communicate and how; eliminated jargon; could be made locally relevant. Challenges included: Sustaining a consistent framing; maintaining the technique; knowing if was making a difference; slipping back into dominant (individualised) framings, especially in free-flowing discussion. Conclusions: The process of reframing the wider determinants of health using recent guidance in a local authority setting was broadly helpful in developing coherence and consistency across the public health team. There were challenges to adopting the approach and evaluation of its impact locally would be beneficial.

Bone involvement in primary cutaneous diffuse large B-cell lymphoma, leg-type.

Primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT) is an aggressive cutaneous lymphoma. Bone involvement is rare and poorly described. We present five cases of PCDLBCL-LT with bone localization. In four cases, the bone involvement was diagnosed during the initial staging with positron emission tomography (PET) or computed tomography (CT) scan, and in the fifth case after tibial fracture during treatment with rituximab (RTX) and polychemotherapy (PCT). PCDLBCL-LT can be asymptomatic and involve bone sites distant from cutaneous lesions. None had other extracutaneous involvement. In our series, all patients received RTX-PCT as first-line chemotherapy and all had early relapses or progression. Second-line treatments had poor efficacy. Our series shows that bone involvement seems to be associated with poor prognosis in PCDLBCL-LT. Bone localization is not diagnosed with initial thoracic-abdominal-pelvic CT when asymptomatic and affecting the limbs only. If there is a suspicion of PCDLBCL-LT, patients should undergo systematic investigation with alternative imaging techniques, including PET, both at baseline and if there is any concern during follow-up.

Efficacy and Safety of Osilodrostat in Paraneoplastic Cushing Syndrome: A Real-World Multicenter Study in France.

CONTEXT: Prospective studies have demonstrated the efficacy of osilodrostat in Cushing disease. No study has evaluated osilodrostat in a series of patients with paraneoplastic Cushing syndrome/ectopic adrenocorticotropin syndrome (PNCS/EAS). OBJECTIVE: This work aimed to evaluate in France the real-world efficacy and safety of osilodrostat in patients with PNCS/EAS. METHODS: A total of 33 patients with PNCS/EAS with intense/severe hypercortisolism were involved in this retrospective, multicenter, real-world study. Patients received osilodrostat between May 2019 and March 2022 at a median initial dose (range) of 4 mg/day (1-60) and maximum dose, 20 mg/day (4-100), first under patient then cohort temporary authorizations and after marketing authorization. Regimens used titration (n = 6), block and replace (n = 16), or titration followed by block and replace (n = 11). RESULTS: In 11 patients receiving osilodrostat as first-line monotherapy, median 24-hour urinary free cortisol (24h-UFC) decreased dramatically (from 26 × upper limit of normal [ULN; 2.9-659] to 0.11 × ULN [0.08-14.9]; P < .001). In 9 of them, 24h-UFC normalization was achieved in 2 weeks (median). Thirteen additional patients were previously treated with classic steroidogenesis inhibitors but 10 of these 13 were not controlled. In these patients, osilodrostat monotherapy, used as second line, induced a significantly decreased of 24h-UFC (from 2.6 × ULN [1.1-144] to 0.22 × ULN [0.12-0.66]; P < .01). Nine additional patients received osilodrostat in combination with another anticortisolic drug, decreasing 24h-UFC from 11.8 × ULN (0.3-247) to 0.43 × ULN (0.33-2.4) (P < .01). In parallel, major clinical symptoms/comorbidities improved dramatically with improvement in blood pressure, hyperglycemia, and hypokalemia, allowing the discontinuation or dose reduction of patient treatments. Adrenal insufficiency (grade 3-4) was reported in 8 of 33 patients. CONCLUSION: Osilodrostat is a rapidly efficient therapy for PNCS/EAS with severe/intense hypercortisolism. Osilodrostat was generally well tolerated; adrenal insufficiency was the main side effect.

Impact of SARS-CoV-2 pandemic on dermatology residents: A nationwide French study.

Background Coronavirus disease 2019 (COVID-19) has changed the practice of all health-care professionals. Determining the impact could prevent repercussions in future crisis. Objectives The objectives of the study were to assess the impact of the COVID-19 pandemic on dermatology residents' professional practice, working conditions, academic training and mental health. Methods An online questionnaire was sent to all French dermatology residents. We compared the activity of residents working in areas heavily impacted by COVID-19 to others. Logistic multivariate regressions were done, using as outcome variables the negative impact of the COVID crisis on residents' possibility to practice dermatology during the crisis, supervision, academic training and working more than 50 h/week. The last part of the questionnaire was the burnout questionnaire of Maslach. Results A total of 246 residents filled the questionnaire. Residents working in highly impacted COVID areas (odds ratio, OR 0.34 confidence interval, CI [0.18, 0.61], P ≤ 0.001), first-year postgraduate (PGY-1) residents (OR 0.46 CI [0.23, 0.91], P = 0.023) and those in private practice (OR 0.10 CI [0.01, 0.57], P = 0.032) were significantly less able to maintain dermatology activities. Worse supervision was significantly more frequent with non-PGY-1 residents (OR 3.24 CI [1.65, 6.65], P < 0.001). One hundred and eighty one residents claimed the pandemic to have a negative effect on their dermatology curriculum with no difference according to their regions' affection by COVID-19. This was mostly attributed to the cancelation of courses and congresses. PGY-1 residents (OR 2.09 CI [1.09, 4.04], P = 0.029) and residents in highly affected areas (OR 1.79 CI [1.01, 3.18], P = 0.049) were more at risk of working above the maximal legal working time. None of the residents was free of burnout symptoms. Conclusion Dermatology residents have been highly affected by COVID-19. It might be important to have a more integrated healthcare system to fight times of crisis with the least repercussions on residents.

Chilblains during lockdown are associated with household exposure to SARS-CoV-2: a multicentre case-control study.

OBJECTIVES: During the COVID-19 pandemic, numerous cases of chilblains have been reported. However, in most cases, RT-PCR or serology did not confirm SARS-CoV-2 infection. Hypotheses have been raised about an interferon-mediated immunological response to SARS-CoV-2, leading to effective clearance of the SARS-CoV-2 without the involvement of humoral immunity. Our objective was to explore the association between chilblains and exposure to SARS-CoV-2. METHODS: In this multicentre case-control study, cases were the 102 individuals referred to five referral hospitals for chilblains occurring during the first lockdown (March to May 2020). Controls were recruited from healthy volunteers' files held by the same hospitals. All members of their households were included, resulting in 77 case households (262 individuals) and 74 control households (230 individuals). Household exposure to SARS-CoV-2 during the first lockdown was categorized as high, intermediate or low, using a pre-established algorithm based on individual data on symptoms, high-risk contacts, activities outside the home and RT-PCR testing. Participants were offered a SARS-CoV-2 serological test. RESULTS: After adjustment for age, the association between chilblains and viral exposure was estimated at OR 3.3, 95% CI (1.4-7.3) for an intermediate household exposure, and 6.9 (2.5-19.5) for a high household exposure to SARS-CoV-2. Out of 57 case households tested, six (11%) had positive serology for SARS-CoV-2, whereas all control households tested (n = 50) were seronegative (p = 0.03). The effect of potential misclassification on exposure has been assessed in a bias analysis. DISCUSSION: This case-control study demonstrates the association between chilblains occurring during the lockdown and household exposure to SARS-CoV-2.

Clinical spectrum of primary adrenal lymphoma: results of a multicenter cohort study.

Purpose: We sought to refine the clinical picture of primary adrenal lymphoma (PAL), a rare lymphoid malignancy with predominant adrenal manifestation and risk of adrenal insufficiency. Methods: Ninety-seven patients from 14 centers in Europe, Canada and the United States were included in this retrospective analysis between 1994 and 2017. Results: Of the 81 patients with imaging data, 19 (23%) had isolated adrenal involvement (iPAL), while 62 (77%) had additional extra-adrenal involvement (PAL+). Among patients who had both CT and PET scans, 18FDG-PET revealed extra-adrenal involvement not detected by CT scan in 9/18 cases (50%). The most common clinical manifestations were B symptoms (55%), fatigue (45%), and abdominal pain (35%). Endocrinological assessment was often inadequate. With a median follow-up of 41.6 months, 3-year progression-free (PFS) and overall (OS) survival rates in the entire cohort were 35.5% and 39.4%, respectively. The hazard ratios of iPAL for PFS and OS were 40.1 (95% CI: 2.63-613.7, P = 0.008) and 2.69 (95% CI: 0.61-11.89, P = 0.191), respectively. PFS was much shorter in iPAL vs PAL+ (median 4 months vs not reached, P = 0.006), and OS also appeared to be shorter (median 16 months vs not reached), but the difference did not reach statistical significance (P = 0.16). Isolated PAL was more frequent in females (OR = 3.81; P = 0.01) and less frequently associated with B symptoms (OR = 0.159; P = 0.004). Conclusion: We found unexpected heterogeneity in the clinical spectrum of PAL. Further studies are needed to clarify whether clinical distinction between iPAL and PAL+ is corroborated by differences in molecular biology.

Making time to care.

As its name suggests, the Releasing Time to Care project in Scotland aims to eliminate inefficiency and to redirect time and resources to areas where they are most needed. The new way of working is yielding other benefits too, including improved staff morale and lower absence rates.

Those were the days.

Many nursing practices and treatments that were once standard have fallen out of favour or been discredited. For example, in the 1980s egg white was still being used to treat pressure ulcers, with 'fairly catastrophic' effects. A look back at nursing's recent past is a good remedy for misplaced nostalgia.

'How do you rate us'?

A trust that used to perform poorly in patient surveys has turned itself around by taking a strategic approach to implementing change based on patient feedback and ideas from staff. Carefully placed additional staff have made a big difference to patient care and staff stress levels.

International overview of hospital procurement.

This article was written by four French hospital director students at the Ecole des Hautes Etudes en Santé Publique (EHESP-School of Public Health) from a study conducted jointly with students at the Grenoble School of Management to present an international overview of hospital procurement methods in ten countries. An analysis of these methods showed that there was a general trend towards group purchasing, with some common aims in terms of costs and performance and some differences in legislation (competition), size of the public sector and centralization or decentralization.

Smells like teen spirit.

A third of the world's population is under 18. Adolescents are less likely than any other age group to visit their GP. Puberty can have an effect on long-term conditions.