Lower Healthcare Access and Its Association With Individual Factors and Health-Related Quality of Life in Adults With Rare Diseases in Switzerland.

Objectives: This study aims to determine clusters of access to healthcare among adults with rare diseases in Switzerland, identify associated individual characteristics of access, and impact on health-related quality of life (HRQoL). Methods: Swiss adults (N = 341) diagnosed with a rare disease completed an online survey including the Perception of Access to Healthcare Questionnaire (PAHQ) and Short Form Health Survey (SF-12). We employed partition around medoids algorithm to identify patient clusters based on the PAHQ. Various sociodemographic/disease-related factors and HRQoL were assessed. Results: We identified two patient clusters: higher (n = 227) and lower access (n = 114). Significantly associated with lower access were an unstable disease course (p < 0.05), increased number of misdiagnoses (p < 0.05), and diseases affecting the nervous system (p < 0.01). Membership in the lower access cluster was significantly associated with worse HRQoL (p < 0.05). Conclusion: Findings highlight the need for comprehensive assessment of healthcare access in adults with rare diseases and identifies potential targets for tailored interventions.

Inlay total shoulder arthroplasty in the weight-bearing shoulder of wheelchair-bound patients with paraplegia. A case report.

INTRODUCTION AND IMPORTANCE: Paraplegic patients' activities of daily living (ADLs) involve the use of manual wheelchairs that increase the stress on the shoulder joint. Patients with advanced glenohumeral changes are often resistant to conservative measures and may require surgical interventions. The longevity of a Total Shoulder Arthroplasty is largely unknown in paraplegics due to a lack of studies investigating outcomes in these patients. CASE PRESENTATION: We examined the outcome of two paraplegic patients following inlay total shoulder arthroplasty (iTSA) with a non-spherical humeral head and glenoid inlay replacement. CLINICAL DISCUSSION: Two patients with paraplegia and advanced degenerative joint disease who underwent iTSA were seen at regular follow-up intervals to assess range of motion, strength, and patient-reported outcome measures. Radiographic imaging was utilized to monitor slipping, lateralization, and degradation of the joint space. CONCLUSION: Both patients have shown significant increases in strength, ROM, and PROMs. iTSA proved efficacious in paraplegic patients utilizing a manual wheelchair.

Latent profiles and predictors of barriers to care in Swiss children and adolescents with rare diseases.

OBJECTIVE: Children and adolescents with rare diseases face significant barriers when accessing healthcare. We aimed to assess and predict these barriers and investigate associations with health-related quality of life (HRQoL). METHOD: We conducted a cross-sectional survey of Swiss parents (N = 189) of children with rare diseases including the Barriers to Care Questionnaire (BCQ), containing six barriers and the Pediatric Quality of Life Inventory (PedsQL). Latent profile analysis (LPA) was used to uncover distinct classes, which were compared using chi-square tests and Mann-Whitney U tests. Relevant medical and sociodemographic class predictors were identified using Elastic Net regression, followed by regression analysis to investigate their role in predicting barriers to care and examine the effects of these classes on HRQoL. RESULTS: Two distinct groups were identified, a higher barriers class (59%) and a lower barriers class (41%). In the higher barriers class, participants showed elevated scores across all subscales and specifically on pragmatics and expectations. More barriers to care were linked to a nonstable disease course (OR = 2.27, p = .002) and a diagnosis after the age of 3 months (OR = 2.17, p = .006). Individuals in the higher barriers class exhibited more psychological comorbidities (p = .044), congenital malformations/deformations/chromosomal abnormalities (p=.042), and medical misdiagnoses (p = .006). Children in the higher barriers class had significantly lower PedsQL scores compared to the lower barriers class (p <.05). CONCLUSION: This study highlights the need for comprehensive assessment of barriers to pediatric care in rare diseases, offering potential entry points for targeted interventions.

Discovery and In Vivo Exploration of 1,3,4-Oxadiazole and α-Fluoroacrylate Containing IL-17 Inhibitors.

IL-17, a pro-inflammatory cytokine produced mainly by Th17 cells, is involved in the immune response to fungal and bacterial infections, whereas its aberrant production is associated with autoimmune and inflammatory diseases. IL-17 blocking antibodies like secukinumab (Cosentyx) have been developed and are used to treat conditions like psoriasis, psoriatic arthritis, and ankylosing spondylitis. Recently, the low molecular weight IL-17 inhibitor LY3509754 entered the clinic but was discontinued in Phase 1 due to adverse effects. In this study, we explored the replacements of furazan moiety posing a potential toxicology risk in LY3509754. By exploring replacements such as heterocycles as amide-isosteres as well as α-F-acrylamides, two compounds (18 and 26) were identified. Both compounds effectively reduced knee swelling in a rat arthritis model. However, early rat and dog toxicity studies revealed adverse findings, preventing their further development and indicating that furazan might not be responsible for the adverse effects of LY3509754.

Predicting psychosocial intervention response from baseline gene expression.

To address the challenge of predicting psychological response to a psychosocial intervention we tested the possibility that baseline gene expression profiles might provide information above and beyond baseline psychometric measures. The genomics strategy utilized individual level inferences of transcription factor activity to predict changes in loneliness and affect in response to two well-established meditation interventions. Initial algorithm development analyses focused on three a-priori defined stress-related gene regulation pathways (CREB, GR, and NF-ĸB) as inferred from TELiS promoter-based bioinformatic analysis of basal (pre-intervention) blood samples from a randomized-controlled trial comparing a compassion-based meditation (CM, n = 45) with mindfulness meditation (MM, n = 44). Greater baseline CREB activity (but not GR or NF-ĸB) predicted greater reductions from pre- to post-intervention in loneliness (b = -0.24, p = 0.016) and negative emotions (b = -0.23, p = 0.017) for CM, but not for MM. A second algorithm validation analysis applied the same approach to another randomized controlled trial comparing CM (n = 42) with MM (n = 38) and a health education control condition (n = 41). Similarly, greater baseline CREB activity predicted greater pre- to post-intervention decreases in loneliness (b = -0.24, p = 0.029) and greater increases in satisfaction with life (b = 0.21, p = 0.046) for the CM condition only. Baseline CREB activity was not associated with baseline psychometric measures in either study. Results raise the possibility that pre-intervention gene expression profiles may reflect non-conscious psychobiological states that affect psychological responses to distinct psychosocial interventions, and thereby help personalize intervention selection.

Protocol for a randomized controlled trial comparing phone-based prenatal mindfulness training to usual care for pregnant people at risk for hypertensive disorders of pregnancy.

Hypertensive disorders of pregnancy (HDP) are the most common medical conditions in pregnancy and a leading cause of maternal morbidity and mortality in the United States. There are few interventions available to prevent HDP, and those currently available do not target underlying mechanisms of disease. Mindfulness training (MT) is effective at reducing blood pressure in non-pregnant patients with pre-hypertension and hypertension and has proven more effective at blood pressure reduction than other stress management interventions. MT thus holds great promise as a mind-body intervention to prevent HDP. This randomized trial will harness subjective and objective ecological momentary assessment methodology combined with wearable biosensor technology to capture psychological, physiological, and interpersonal processes through which MT may lead to improved maternal cardiovascular parameters. Pregnant women at risk for HDP will be randomized to an 8-week phone-delivered MT intervention or usual care. Through these methods, we will evaluate psychological, physiological, and interpersonal responses to daily experiences linking MT to cardiovascular parameters among women at risk for HDP.

[Diagnosis and treatment of venous thrombosis]. / Management der Venenthrombose.

INTRODUCTION: The subject of this guideline from the Institute of Family Medicine at the University of Zurich (IHAMZ) is the management of venous thrombosis. The review summarizes the current evidence and recommendations from international guidelines (1-6). The IHAMZ-guidelines focus on primary care, they also provide guidance on the coordination of general and specialist medical care as well as on the transition between outpatient and hospital care taking into account the special features of the Swiss healthcare system. The guideline is devided in two parts. Part 1 discusses the diagnosis and treatment of deep vein thrombosis (DVT). A validated algorithm is recommended for the diagnostic process, which begins with the assessment of the clinical probability. With the inclusion of the D-dimer test, the need for subsequent imaging diagnostics can be reduced. The differences between the evaluation of an initial and recurrent DVT are shown and the indications and scope of evidence-based environmental diagnostics (thrombophilia and tumor search) are presented. All patients with DVT should receive anticoagulation (AC) for 3-6 months, as there is a high risk of recurrence with AC 3 months. The duration of the subsequent secondary prophylaxis depends on the presumed risk of recurrence on the one hand and the risk of bleeding on the other. Part 2 is dedicated to special thrombosis situations such as shoulder-arm vein thrombosis (SAVT), cancer-associated thrombosis (CAT) and superficial vein thrombosis (SVT). The article on hormone- and pregnancy-associated DVT, developed together with the Department of Gynecology at the University Hospital of Zurich, discusses the importance of hormonal contraception and menopausal hormone replacement therapy (HRT) as a thrombogenic risk factor as well as special features in the diagnosis and treatment of thrombosis in pregnancy.

Real-time detection of enzymatically formed hydrogen sulfide by pathogenic variants of cystathionine beta-synthase using hemoglobin I of Lucina pectinata as a biosensor.

Classical homocystinuria is a rare disease caused by mutations in cystathionine ß-synthase (CBS) gene (OMIM 613381). CBS catalyzes the first step of the transsulfuration pathway that converts homocysteine (Hcy) into cystathionine (Cysta) via a number of co-substrates and mechanisms. Formation of Cysta by condensation of Hcy and cysteine (Cys) produces a molar equivalent of hydrogen sulfide (H2S). H2S plays important roles in cognitive and vascular functions. Clinically, patients with CBS deficiency present with vascular, ocular, neurological and skeletal impairments. Biochemically, CBS deficiency manifests with elevated Hcy and reduced concentration of Cysta in plasma and urine. A number of pathogenic variants of human CBS have been characterized by their residual enzymatic activity, but very few studies have examined H2S production by pathogenic CBS variants, possibly due to technical hurdles in H2S detection and quantification. We describe a method for the real-time, continuous quantification of H2S formed by wild-type and pathogenic variants of human recombinant CBS, as well as by fibroblast extracts from healthy controls and patients diagnosed with CBS deficiency. The method takes advantage of the specificity and high affinity of hemoglobin I of the clam Lucina pectinata toward H2S and is based on UV-visible spectrophotometry. Comparison with the gold-standard, end-point H2S quantification method employing monobromobimane, as well as correlations with CBS enzymatic activity determined by LC-MS/MS showed agreement and correlation, and permitted the direct, time-resolved determination of H2S production rates by purified human recombinant CBS and by CBS present in fibroblast extracts. Rates of H2S production were highest for wild-type CBS, and lower for pathogenic variants. This method enables the examination of structural determinants of CBS that are important for H2S production and its possible relevance to the clinical outcome of patients.

Severe multifocal coronary artery spasms after cessation of vasodilators in a patient with a spontaneous coronary artery dissection: a case report.

Background: Vasospastic angina (VSA) and spontaneous coronary artery dissection (SCAD) are challenging causes of non-atherosclerotic acute coronary syndromes (ACS). Here, we report a unique ACS case with coexisting VSA and SCAD, highlighting specific strategies in diagnosis and management of these poorly studied conditions. Case summary: A woman in her mid-60s with a history of suspected microvascular angina and no atherosclerosis in a previously performed coronary computed tomography angiography presented with worsening chest pain. Invasive coronary angiography revealed a focal SCAD with a resulting high-degree stenosis of the right coronary artery. Shortly after successful percutaneous coronary intervention with stent implantation and stopping her previous vasodilator therapy with nitroglycerine and molsidomine, the patient developed recurrent anterior non-ST-segment elevation myocardial infarction. Surprisingly, repeat coronary angiography revealed severe multifocal coronary artery spasms that were successfully treated with intracoronary nitroglycerine. Vasospastic angina was subsequently managed with diltiazem, molsidomine, and nitrates. Discussion: Our report underscores the challenges in diagnosing and managing SCAD and VSA in ACS. The possible interplay between SCAD and VSA highlights the need for careful vasodilator therapy management, as seen in our patient, where therapy discontinuation led to severe multifocal VSA. This emphasizes the need for a comprehensive approach for optimal outcomes in complex ACS cases.

Recent Trends in Plastic Surgery: A Network Analysis of the Abstract Titles of the Largest German Plastic Surgery Congress 2023.

BACKGROUND: Every year, German-speaking experts in plastic, reconstructive, and aesthetic surgery gather to discuss the latest developments at Germany's largest conference for plastic surgery, the joint annual meeting of the German Society of Plastic, Reconstructive and Aesthetic Surgery (DGPRÄC) and the Association of German Aesthetic Plastic Surgeons (VDÄPC). Since the topics of the conference have a lasting impact on the practice and research of plastic surgery, an examination of the presented content provides insight into the driving developments in plastic surgery in Germany. MATERIALS AND METHODS: We conducted a retrospective network analysis of all abstract titles from the DGPRÄC and VDÄPC annual meeting in 2023. Data were extracted regarding titles, language, author, and place of origin, and the titles were categorized into the four pillars of the specialty. The titles were standardized and subjected to network analysis. RESULTS: A total of 299 titles from 281 lectures and 18 instructional courses were analyzed. After preprocessing the data, 2463 words with 9384 connections qualified for network analysis. The most frequently mentioned keywords throughout the congress were 'Surgery', 'Breast', 'Reconstruction', 'Flap', 'Patient', 'Tissue', and 'Therapy'. Locations contributing the highest number of abstracts were Ludwigshafen, Hanover, Leipzig, and Munich. CONCLUSION: In the era of big data, network analysis provides the ability to identify underlying structures and nodes in multidimensional, complex datasets. This study demonstrates the useful application of network analysis to identify thematic focuses and connections at the current DGPRÄC and VDÄPC annual meeting. Sites of intensified research could thus be identified.

The Benefit of Detecting Reduced Intracellular B12 Activity through Newborn Screening Remains Unclear.

Vitamin B12 (B12) deficiency (B12D) can have detrimental effects on early growth and development. The Austrian newborn screening (NBS) program targets inborn errors of cobalamin metabolism and also detects B12D. Of 59 included neonates with B12D suspected by NBS, B12D was not further investigated in 16 (27%) retrospectively identified cases, not confirmed in 28 (48%), and confirmed in 15 (25%) cases. NBS and recall biomarkers were recorded. Age at sampling of the dried blood spots for NBS and the 1st-tier methionine/phenylalanine ratio were the strongest parameters to predict B12D (67.4% correct allocations). No differences between cases with confirmed, unconfirmed, or unknown B12D or differences to norms were observed for growth and psychomotor development (Vineland III scales, phone interviews with parents of children between months 10 and 14 of life). B12 intake was below recommendations in most mothers. NBS can detect reduced intracellular B12 activity. No advantage of NBS detection and treatment regarding infant cognitive development or growth could be proven. Since conspicuous NBS findings cannot be ignored, and to prevent exposing newborns to invasive diagnostics, assessment of maternal B12 status during pregnancy seems advisable.

How ready is speech-to-text for psychological language research? Evaluating the validity of AI-generated English transcripts for analyzing free-spoken responses in younger and older adults.

For the longest time, the gold standard in preparing spoken language corpora for text analysis in psychology was using human transcription. However, such standard comes at extensive cost, and creates barriers to quantitative spoken language analysis that recent advances in speech-to-text technology could address. The current study quantifies the accuracy of AI-generated transcripts compared to human-corrected transcripts across younger (n = 100) and older (n = 92) adults and two spoken language tasks. Further, it evaluates the validity of Linguistic Inquiry and Word Count (LIWC)-features extracted from these two kinds of transcripts, as well as transcripts specifically prepared for LIWC analyses via tagging. We find that overall, AI-generated transcripts are highly accurate with a word error rate of 2.50% to 3.36%, albeit being slightly less accurate for younger compared to older adults. LIWC features extracted from either transcripts are highly correlated, while the tagging procedure significantly alters filler word categories. Based on these results, automatic speech-to-text appears to be ready for psychological language research when using spoken language tasks in relatively quiet environments, unless filler words are of interest to researchers.

RECIP 1.0 Predicts Progression-Free Survival After [177Lu]Lu-PSMA Radiopharmaceutical Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer.

Response Evaluation Criteria in Prostate-Specific Membrane Antigen Imaging (RECIP) 1.0 is an evidence-based framework to evaluate therapeutic efficacy in metastatic prostate cancer using prostate-specific membrane antigen (PSMA) PET/CT. This study aimed to evaluate the associations of interim PSMA PET/CT by RECIP 1.0 with short-term outcome after radiopharmaceutical treatment. Methods: This multicenter retrospective study included patients with metastatic castration-resistant prostate cancer who underwent [177Lu]Lu-PSMA radiopharmaceutical therapy at 3 academic centers and received PSMA PET/CT at baseline and at 12 wk. Pairs of PSMA PET/CT images were assessed by 5 readers for visual RECIP 1.0. The primary outcome was the association of RECIP with prostate-specific antigen progression-free survival (PSA-PFS) by Kaplan-Meier analysis. Results: In total, 124 of 287 screened patients met the inclusion criteria, with 0 (0%), 29 (23%), 54 (44%), and 41 (33%) of those 124 patients having complete response, partial response, stable disease, or progressive disease (PD) by visual RECIP 1.0, respectively. Patients with visual RECIP PD had a significantly shorter PSA-PFS than those with RECIP stable disease or with RECIP partial response (2.6 vs. 6.4 vs. 8.4 mo; P < 0.001). The median PSA-PFS among patients with RECIP PD versus those with non-RECIP PD was 2.6 versus 7.2 mo (hazard ratio, 13.0; 95% CI, 7.0-24.1; P < 0.001). Conclusion: PSMA PET/CT by RECIP 1.0 after 2 cycles of [177Lu]Lu-PSMA is prognostic for PSA-PFS. PSMA PET/CT by RECIP 1.0 may be used in earlier stages of prostate cancer to evaluate drug efficacy and to predict progression-free survival.

mRNA Display Identifies Potent, Paralog-Selective Peptidic Ligands for ARID1B.

The ARID1A and ARID1B subunits are mutually exclusive components of the BAF variant of SWI/SNF chromatin remodeling complexes. Loss of function mutations in ARID1A are frequently observed in various cancers, resulting in a dependency on the paralog ARID1B for cancer cell proliferation. However, ARID1B has never been targeted directly, and the high degree of sequence similarity to ARID1A poses a challenge for the development of selective binders. In this study, we used mRNA display to identify peptidic ligands that bind with nanomolar affinities to ARID1B and showed high selectivity over ARID1A. Using orthogonal biochemical, biophysical, and chemical biology tools, we demonstrate that the peptides engage two different binding pockets, one of which directly involves an ARID1B-exclusive cysteine that could allow covalent targeting by small molecules. Our findings impart the first evidence of the ligandability of ARID1B, provide valuable tools for drug discovery, and suggest opportunities for the development of selective molecules to exploit the synthetic lethal relationship between ARID1A and ARID1B in cancer.

When I am sixty-four evaluating language markers of well-being in healthy aging narratives.

Natural language use is a promising candidate for the development of innovative measures of well-being to complement self-report measures. The type of words individuals use can reveal important psychological processes that underlie well-being across the lifespan. In this preregistered, cross-sectional study, we propose a conceptual model of language markers of well-being and use written narratives about healthy aging (N = 701) and computerized text analysis (LIWC) to empirically validate the model. As hypothesized, we identified a model with three groups of language markers (reflecting affective, evaluative, and social processes). Initial validation with established self-report scales (N = 30 subscales) showed that these language markers reliably predict core components of well-being and underlying processes. Our results support the concurrent validity of the conceptual language model and allude to the added benefits of language-based measures, which are thought to reflect less conscious processes of well-being. Future research is needed to continue validating language markers of well-being across the lifespan in a theoretically informed and contextualized way, which will lay the foundation for inferring people's well-being from their natural language use.

Post-surgical inflammatory neuropathy after anterior cruciate ligament repair: a case report.

BACKGROUND: Unanticipated symptoms of peripheral nerve damage following surgery are distressing to both the patient and their clinical team, including surgeons, anesthesiologists, and neurologists. The causes that are commonly considered for perioperative neuropathy can include surgical trauma, positioning-related injury, or injury related to a regional anesthetic technique. However, these cases often do not have a clear etiology and can occur without any apparent periprocedural anomalies. Postoperative inflammatory neuropathy is a more recently described, and potentially underrecognized cause of perioperative neuropathy which may improve with corticosteroid therapy. Therefore, it is an important etiology to consider early in the evaluation of perioperative neuropathy. CASE PRESENTATION: An otherwise healthy patient presented for left anterior cruciate ligament reconstruction. He underwent femoral and sciatic ultrasound-guided single-injection peripheral nerve blocks preoperatively, followed by a general anesthetic for the surgical procedure. He developed postoperative neuropathy in the sciatic distribution with both sensory and motor deficits. The patient received multi-disciplinary consultations, including neurology and pain management, and a broad differential diagnosis was considered. Based on neurological evaluation and imaging studies, a final diagnosis of post-surgical inflammatory neuropathy was made. The patient's course improved with conservative management, but immunosuppressive treatment may have been considered for a more severe or worsening clinical course. CONCLUSIONS: There are limited publications describing postoperative inflammatory neuropathy, and this case serves to illustrate a potentially under-recognized and multifactorial cause of postoperative neuropathy. Perioperative neuropathies are a complication that surgeons and anesthesiologists strive to avoid; however, prevention and treatment of this condition have been elusive. Increased reporting and investigation of postoperative inflammatory neuropathy as one cause for this complication will help to further our understanding of this potentially devastating complication.

Optimization of Potent Ligands for the E3 Ligase DCAF15 and Evaluation of Their Use in Heterobifunctional Degraders.

Unlocking novel E3 ligases for use in heterobifunctional PROTAC degraders is of high importance to the pharmaceutical industry. Over-reliance on the current suite of ligands used to recruit E3 ligases could limit the potential of their application. To address this, potent ligands for DCAF15 were optimized using cryo-EM supported, structure-based design to improve on micromolar starting points. A potent binder, compound 24, was identified and subsequently conjugated into PROTACs against multiple targets. Following attempts on degrading a number of proteins using DCAF15 recruiting PROTACs, only degradation of BRD4 was observed. Deconvolution of the mechanism of action showed that this degradation was not mediated by DCAF15, thereby highlighting both the challenges faced when trying to expand the toolbox of validated E3 ligase ligands for use in PROTAC degraders and the pitfalls of using BRD4 as a model substrate.

Non-Hodgkin lymphoma in a kidney transplanted patient with methylmalonic acidemia: Metabolic susceptibility and the role of immunosuppression.

Methylmalonic acidemia cblB type (MMA cblB) is an autosomal recessive inborn error of amino acid metabolism that results in impaired synthesis of adenosylcobalamin, a cofactor of methylmalonyl-CoA mutase. It presents with episodes of coma, vomiting, hypotonia, metabolic acidosis, and hyperammonemia. End-stage kidney disease is a long-term complication. Treatments include vitamin B12 supplementation, L-carnitine, and a low-protein diet. Liver, kidney, or combined liver-kidney transplantations are promising options, but they are not without complications. We report a patient suffering from MMA cblB who developed end-stage kidney disease at 18 years of age. Kidney transplantation allowed him to recover normal kidney function and good metabolic control. Unfortunately, after two decades, he developed non-Hodgkin lymphoma and severe chemotherapy toxicity which led to his death. The risk of lymphoproliferative diseases is known to increase after solid organ transplantation. However, in MMA, factors including mitochondrial dysfunction and oncometabolites, may further increase the risk of malignancy and drug toxicity. Our report highlights the importance of considering the increased risk of cancer in long-term follow-up of MMA cblB patients, especially after solid organ transplantation. Moreover, when chemotherapy is needed, the increased risk of toxicity and metabolic decompensation should be considered and monitored.

Using the phospha-Michael reaction for making phosphonium phenolate zwitterions.

The reactions of 2,4-di-tert-butyl-6-(diphenylphosphino)phenol and various Michael acceptors (acrylonitrile, acrylamide, methyl vinyl ketone, several acrylates, methyl vinyl sulfone) yield the respective phosphonium phenolate zwitterions at room temperature. Nine different zwitterions were synthesized and fully characterized. Zwitterions with the poor Michael acceptors methyl methacrylate and methyl crotonate formed, but could not be isolated in pure form. The solid-state structures of two phosphonium phenolate molecules were determined by single-crystal X-ray crystallography. The bonding situation in the solid state together with NMR data suggests an important contribution of an ylidic resonance structure in these molecules. The phosphonium phenolates are characterized by UV-vis absorptions peaking around 360 nm and exhibit a negative solvatochromism. An analysis of the kinetics of the zwitterion formation was performed for three Michael acceptors (acrylonitrile, methyl acrylate, and acrylamide) in two different solvents (chloroform and methanol). The results revealed the proton transfer step necessary to stabilize the initially formed carbanion as the rate-determining step. A preorganization of the carbonyl bearing Michael acceptors allowed for reasonable fast direct proton transfer from the phenol in aprotic solvents. In contrast, acrylonitrile, not capable of forming a similar preorganization, is hardly reactive in chloroform solution, while in methanol the corresponding phosphonium phenolate is formed.

Differences and Common Ground in 177Lu-PSMA Radioligand Therapy Practice Patterns: International Survey of 95 Theranostic Centers.

177Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy effectively treats metastatic castration-resistant prostate cancer. Patients requiring treatment, and consequently the number of theranostic centers, are expected to increase significantly after Food and Drug Administration and European Medicines Agency approval. This requires standardization or harmonization among theranostic centers. The aim of this study was to assess operational differences and similarities among 177Lu-PSMA treatment centers. Methods: A questionnaire comprising 62 items, designed by a core team of 5 physicians and externally reviewed by international experts, was developed. Study participants were asked to provide answers about their center, patient selection, radiopharmaceuticals, clinical assessment before and after 177Lu-PSMA treatments, laboratory values, treatment discontinuation, posttreatment imaging, and general information. An invitation e-mail to participate in the study was sent in June 2022. Duplicates were removed to allow for only one valid response per center. Results: Ninety-five of 211 (45%) contacted centers completed the questionnaire. Most participating centers were in Europe (51%), followed by America (22%) and Asia (22%). During the 12 mo before this study, a total of 5,906 patients received 177Lu-PSMA therapy at the 95 participating centers. Most of these patients were treated in Europe (2,840/5,906; 48%), followed by Asia (1,313/5,906; 22%) and Oceania (1,225/5,906; 21%). PSMA PET eligibility for 177Lu-PSMA was determined most frequently using 68Ga-PSMA-11 (77%). Additional pretherapy imaging included 18F-FDG PET/CT, CT, renal scintigraphy, and bone scintigraphy at 41 (49%), 27 (32%), 25 (30%), and 13 (15%), respectively, of the 84 centers for clinical standard of care, compassionate care, or local research protocols and 11 (26%), 25 (60%), 9 (21%), and 28 (67%), respectively, of the 42 centers for industry-sponsored trials. PSMA PET eligibility criteria included subjective qualitative assessment of PSMA positivity at 33% of centers, VISION criteria at 23%, and TheraP criteria at 13%. The mean standard injected activity per cycle was 7.3 GBq (range, 5.5-11.1 GBq). Sixty-two (65%) centers applied standardized response assessment criteria, and PSMA PET Progression Criteria were the most applied (37%). Conclusion: Results from this international survey revealed interinstitutional differences in several aspects of 177Lu-PSMA radionuclide therapy, including patient selection, administered activity, and the response assessment strategy. Standardization or harmonization of protocols and dedicated training are desirable in anticipation of increasing numbers of patients and theranostic centers.