Potentially Inappropriate Medication in Older Persons With Dementia: Does a Migration Background Matter?

OBJECTIVES: Previous research in the general population shows more potentially inappropriate medications (PIMs) among persons with a migration background compared with persons without a migration background. This study investigated the association between non-Western (nw) migration background (MB) and dementia-specific PIMs in older adults with dementia in the Netherlands. DESIGN: Cohort study using routinely recorded electronic health records and administrative data. SETTING AND PARTICIPANTS: Electronic health record data of general practitioners from the NIVEL-Primary Care Database, were linked to registries managed by Statistics Netherlands (2013-2014). A total of 9055 community-dwelling older adults with dementia were included, among whom 294 persons had an nw-MB from Africa, South America, or Asia, based on their country of birth. METHODS: We determined the presence of dementia-specific PIM prescriptions and compared this between persons with an nw-MB and without an MB, using logistic regression analysis adjusted for follow-up time, age, registered sex, and total number of prescriptions. Interaction effects of potentially relevant covariates were tested. The 3 largest nw-MB groups in the Netherlands were analyzed separately. RESULTS: Dementia-specific PIMs were less frequently prescribed to persons with an nw-MB compared to persons without an MB with a dementia diagnosis [30.6% vs 34.4%, odds ratio (OR) 0.71, 95% CI 0.54-0.92], with especially less often a benzodiazepine prescription in the group with an nw-MB, compared to persons without an MB (15.0% vs 19.3%, OR 0.61, 95% CI 0.43-0.84). Dementia duration, living alone, household income, and degree of urbanization did not influence the associations. CONCLUSIONS AND IMPLICATIONS: Among older adults with dementia in the Netherlands, persons with an nw-MB had less often a dementia-specific PIM prescription compared to persons without an MB. Whether this difference is a reflection of better quality of care, higher professional uncertainty, or less recognition of (mental) health problems in persons with an nw-MB and dementia, needs further investigation.

The molecular basis of phenotypic evolution: beyond the usual suspects.

It has been well documented that mutations in coding DNA or cis-regulatory elements underlie natural phenotypic variation in many organisms. However, the development of sophisticated functional tools in recent years in a wide range of traditionally non-model systems have revealed many 'unusual suspects' in the molecular bases of phenotypic evolution, including upstream open reading frames (uORFs), cryptic splice sites, and small RNAs. Furthermore, large-scale genome sequencing, especially long-read sequencing, has identified a cornucopia of structural variation underlying phenotypic divergence and elucidated the composition of supergenes that control complex multi-trait polymorphisms. In this review article we highlight recent studies that demonstrate this great diversity of molecular mechanisms producing adaptive genetic variation and the panoply of evolutionary paths leading to the 'grandeur of life'.

Enantioselective Intermolecular C-H Functionalization of Primary Benzylic C-H Bonds Using ((Aryl)(diazo)methyl)phosphonates.

Catalyst-controlled C-H functionalization using donor/acceptor carbenes has been shown to be an efficient process capable of high levels of site control and stereocontrol. This study demonstrated that the scope of the donor/acceptor carbene C-H functionalization can be extended to systems where the acceptor group is a phosphonate. When using the optimized dirhodium catalyst, Rh2(S-di-(4-Br)TPPTTL)4, ((aryl)(diazo)methyl)phosphonates undergo highly enantioselective (84-99% ee) and site-selective (>30:1 r.r.) benzylic C-H functionalization. The phosphonate group is much more sterically demanding than the previously studied carboxylate ester group, leading to much higher selectivity for a primary site versus more sterically crowded positions. The effectiveness of this methodology has been demonstrated by the late-stage primary C-H functionalization of estrone, adapalene, (S)-naproxen, clofibrate, and gemfibrozil derivatives.

How did Latinxs near the U.S.-Mexico border fare during the COVID-19 pandemic? A snapshot of anxiety, depression, and posttraumatic stress symptoms.

Introduction: The current study documented levels of anxiety, depression, posttraumatic stress, and COVID-19 fears and impacts among Latinxs living near the U.S.-Mexico border during the COVID-19 pandemic. Methods: Participants of this cross-sectional study were 305 Latinx adults living in the Rio Grande Valley (RGV) who completed an online survey between June and November 2020. Results: About half of participants scored above the cut-off for anxiety (50.2%; GAD-7 scores ≥10) and depression (48.8%; PHQ-9 scores ≥10), and more than a quarter of participants showed clinical levels of posttraumatic stress (27.3%; PCL-5 scores ≥31). Latinxs reported on average 22 types of negative pandemic life impacts on the Epidemic-Pandemic Impacts Inventory. Endorsement of mental health symptoms, severity of COVID-19 fears, and COVID-related life impacts varied based on several demographic characteristics including gender, marital status, educational attainment, employment, income, insurance coverage, vulnerability to COVID-19, and essential worker status. Discussion: Overall, the cross-sectional results of this study revealed that RGV Latinx residents experienced high levels of psychological distress during the pandemic. Results suggest that Latinx women were most affected by the psychological consequences of the pandemic. More research is needed with communities living near the U.S.-Mexico border as they may be particularly vulnerable to mental health problems during the pandemic.

Capybara Oil Improves Renal Pathophysiology and Inflammation in Obese Mice.

Obesity is an inflammatory disease associated with secondary diseases such as kidney disease, which can cause lipotoxicity, inflammation and loss of organ function. Polyunsaturated fatty acids act in the production of lipid mediators and have anti-inflammatory characteristics. In this work, the objective was to evaluate renal histopathology in obese mice and the effects of treatment with capybara oil (CO) (5000 mg/kg/day for 4 weeks). Parameters such as body mass, lipid profile, systolic blood pressure, urinary creatinine and protein excretion, structure and ultrastructure of the renal cortex, fibrosis, tissue inflammation and oxidative stress were analyzed. CO treatment in obese mice showed improvement in the lipid profile and reduction in systolic blood pressure levels, in addition to beneficial remodeling of the renal cortex. Our data demonstrated that CO decreased inflammation, oxidative stress and renal fibrosis, as evidenced by quantifying the expression of TNF-α, IL-10, CAT, SOD, α-SMA and TGF-ß. Although treatment with CO did not show improvement in renal function, ultrastructural analysis showed that the treatment was effective in restoring podocytes and pedicels, with restructuring of the glomerular filtration barrier. These results demonstrate, for the first time, that treatment with CO is effective in reducing kidney damage, being considered a promising treatment for obesity.

Do cognition and emotion matter? A study of COVID-19 vaccination decision-making in college students.

The unparalleled speed of COVID-19 vaccine development has necessitated an expansion of existing knowledge on vaccination decision-making. The current study explored (1) how cognitions and emotions shaped college students' COVID-19 vaccination decisions, and (2) where vaccination-inclined and vaccination-hesitant students converged and diverged in their decision-making process. Seventy-seven students participated in 26 focus groups to discuss their complex thoughts and feelings regarding COVID-19 vaccination, offering a more nuanced understanding of COVID-19 vaccination decision-making that has not been fully captured by quantitative studies. Thematic analysis found that vaccination-inclined participants and their hesitant counterparts reported differential patterns of positive and negative emotions, systematic appraisals, and heuristics in decision-making. Future research should investigate the roles of hope and relief, non-health-related benefits of vaccination, social trust, and interpersonal influence in vaccination decision-making.

Extracellular Vesicles from Candida haemulonii var. vulnera Modulate Macrophage Oxidative Burst.

Members of the Candida haemulonii species complex are multidrug-resistant emergent yeast pathogens able to cause superficial and invasive infections in risk populations. Fungal extracellular vesicles (EVs) play a critical role in the pathogenicity and virulence of several species and may perform essential functions during infections, such as carrying virulence factors that behave in two-way communications with the host, affecting survival and fungal resistance. Our study aimed to describe EV production from Candida haemulonii var. vulnera and evaluate whether murine macrophage RAW 264.7 cells respond to their stimuli by generating an oxidative response after 24 h. For this purpose, reactive oxygen species detection assays demonstrated that high concentrations of yeast and EVs (1010 particles/mL) of Candida haemulonii did not change macrophage viability. However, the macrophages recognized these EVs and triggered an oxidative response through the classical NOX-2 pathway, increasing O2•- and H2O2 levels. However, this stress did not cause lipid peroxidation in the RAW 264.7 cells and neither lead to the activation of the COX-2-PGE2 pathway. Thus, our data suggest that low concentrations of C. haemulonii EVs are not recognized by the classical pathway of the oxidative burst generated by macrophages, which might be an advantage allowing the transport of virulence factors via EVs, not identified by the host immune system that could work as fine tube regulators during infections caused by C. haemulonii. In contrast, C. haemulonii var. vulnera and high EV concentrations activated microbicidal actions in macrophages. Therefore, we propose that EVs could participate in the virulence of the species and that these particles could be a source of antigens to be exploited as new therapeutic targets.

Genetic Profiling of Sodium Channels in Diabetic Painful and Painless and Idiopathic Painful and Painless Neuropathies.

Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes (SCG) expressed in a nociceptive pathway in painful and painless DPN and painful and painless SFN patients, and to provide a perspective for clinicians who assess patients with painful peripheral neuropathy. Between June 2014 and September 2016, 1125 patients with painful-DPN (n = 237), painless-DPN (n = 309), painful-SFN (n = 547) and painless-SFN (n = 32), recruited in four different centers, were analyzed for SCN3A, SCN7A-SCN11A and SCN1B-SCN4B variants by single molecule Molecular inversion probes-Next Generation Sequence. Patients were grouped based on phenotype and the presence of SCG variants. Screening of SCN3A, SCN7A-SCN11A, and SCN1B-SCN4B revealed 125 different (potential) pathogenic variants in 194 patients (17.2%, n = 194/1125). A potential pathogenic variant was present in 18.1% (n = 142/784) of painful neuropathy patients vs. 15.2% (n = 52/341) of painless neuropathy patients (17.3% (n = 41/237) for painful-DPN patients, 14.9% (n = 46/309) for painless-DPN patients, 18.5% (n = 101/547) for painful-SFN patients, and 18.8% (n = 6/32) for painless-SFN patients). Of the variants detected, 70% were in SCN7A, SCN9A, SCN10A and SCN11A. The frequency of SCN9A and SCN11A variants was the highest in painful-SFN patients, SCN7A variants in painful-DPN patients, and SCN10A variants in painless-DPN patients. Our findings suggest that rare SCG genetic variants may contribute to the development of painful neuropathy. Genetic profiling and SCG variant identification should aid in a better understanding of the genetic variability in patients with painful and painless neuropathy, and may lead to better risk stratification and the development of more targeted and personalized pain treatments.

Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred.

INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10-7 or p<1×10-5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.

Patient perceptions of trauma-focused telemental health services using the Telehealth Satisfaction Questionnaire (TSQ).

Telehealth services can address many barriers to traditional office-based mental health services. Few studies have assessed youth and caregiver perceptions of and satisfaction with trauma-focused interventions delivered via telemental health. The present study reports data collected using the Telehealth Satisfaction Questionnaire (TSQ), which was developed to measure child and caregiver satisfaction with services, comfort with the telehealth equipment, and barriers to traditional office-based services. Thirteen clinicians delivered home- and school-based Trauma-Focused Cognitive Behavioral Therapy (TF-CBT) via videoconferencing on tablets and computers to 60 child patients (71.7% Latinx, 18.3% Black, and 10.0% non-Hispanic White). Patients and caregivers completed the TSQ at treatment discharge via telephone, videoconferencing, or in-person interviews. There was a high level of satisfaction among patients and caregivers receiving TF-CBT via telemental health. Furthermore, most youth and caregivers felt comfortable using the telehealth equipment from the outset of therapy, and all participants who were not initially comfortable using the equipment reported feeling more comfortable over time. The most common barriers to traditional office-based services were caregiver work schedule (57.7%), distance to mental health clinic (55.8%), and lack of transportation (44.2%). Patients and caregivers expressed a preference for telemental health services if given the option between receiving therapy via videoconferencing versus going to an office-based clinic. Findings indicated telemental health treatment addressed barriers that would have otherwise prevented families from accessing office-based services. The TSQ can be used to help clinics and providers assess patient and caregiver satisfaction with telehealth services in various settings. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Where I am from matters: factors influencing behavioral and emotional changes in autistic individuals during COVID-19 in Latin America.

Background: The COVID-19 pandemic brought an increased incidence of disease and mortality in the world at large, making it a particularly salient and stressful life event. For those individuals residing in Latin America, the pandemic was met with fragmented healthcare systems, economic downturn, and sociopolitical crisis which puts autistic individuals at risk for more detrimental outcomes. Behavioral and emotional challenges experienced by autistic individuals at the beginning of the pandemic could later develop into more severe symptomatology as the pandemic progresses. The present study aimed to explore changes in dysregulated (overt and internalizing) behaviors and preoccupation with getting sick during the COVID-19 pandemic among autistic children in 7 Latin American countries. Method: Sample consisted of 1,743 caregivers, residing in: Argentina (n = 677, 38.8%) Brazil (n = 156, 9%), Chile (n = 251, 14.4%), Dominican Republic (n = 171, 9.8%), Mexico (n = 126, 7.2%), Uruguay (n = 259, 14.9%) and Venezuela (n = 103, 5.9%). The majority of caregivers who completed the questionnaire were mothers (85.1%), and most had a male autistic child (81.6%). A series of independent sample t-tests were conducted to assess country differences in dysregulated behaviors and preoccupation with getting sick. Linear regressions were conducted to identify which demographic characteristics and micro-level contextual factors predicted dysregulated overt behaviors and psychological changes. Results: Contextual factors, such as country of residence, were related to preoccupation with getting sick and dysregulated behavior. Particularly, residing in Mexico and Brazil were related to changes in preoccupation with getting sick and mental health concerns. Coexistence predicted dysregulated internalizing behaviors, while being older significantly predicted preoccupation with getting sick. Increased screen time only predicted anxiety. Conclusion: Our findings highlight differences and predictions of behavioral challenges and psychological changes based on certain contextual factors and individual characteristics while experiencing severe life stressors such as a worldwide pandemic. This knowledge could help inform policies and decrees aimed at protecting those most vulnerable due to their increased difficulty adapting to change.

Peripheral Ion Channel Genes Screening in Painful Small Fiber Neuropathy.

Neuropathic pain is a characteristic feature of small fiber neuropathy (SFN), which in 18% of the cases is caused by genetic variants in voltage-gated sodium ion channels. In this study, we assessed the role of fifteen other ion channels in neuropathic pain. Patients with SFN (n = 414) were analyzed for ANO1, ANO3, HCN1, KCNA2, KCNA4, KCNK18, KCNN1, KCNQ3, KCNQ5, KCNS1, TRPA1, TRPM8, TRPV1, TRPV3 and TRPV4 variants by single-molecule molecular inversion probes-next-generation sequencing. These patients did not have genetic variants in SCN3A, SCN7A-SCN11A and SCN1B-SCN4B. In twenty patients (20/414, 4.8%), a potentially pathogenic heterozygous variant was identified in an ion-channel gene (ICG). Variants were present in seven genes, for two patients (0.5%) in ANO3, one (0.2%) in KCNK18, two (0.5%) in KCNQ3, seven (1.7%) in TRPA1, three (0.7%) in TRPM8, three (0.7%) in TRPV1 and two (0.5%) in TRPV3. Variants in the TRP genes were the most frequent (n = 15, 3.6%), partly in patients with high mean maximal pain scores VAS = 9.65 ± 0.7 (n = 4). Patients with ICG variants reported more severe pain compared to patients without such variants (VAS = 9.36 ± 0.72 vs. VAS = 7.47 ± 2.37). This cohort study identified ICG variants in neuropathic pain in SFN, complementing previous findings of ICG variants in diabetic neuropathy. These data show that ICG variants are central in neuropathic pain of different etiologies and provides promising gene candidates for future research.

Psychotropic medication use in Huntington's disease: A retrospective cohort study.

BACKGROUND: Whereas the treatment of motor symptoms in Huntington's disease (HD) receives much attention, less is known about the treatment of neuropsychiatric symptoms. OBJECTIVE: We aim to give an overview of psychotropic drug use in the treatment of neuropsychiatric symptoms across disease stages in HD. METHODS: We conducted a descriptive cross-sectional study of psychotropic drug prescriptions in a large longitudinal database of HD patients, Enroll HD. Across disease stages, the number of prescriptions per medication class, as well as the registered indications for these prescriptions were listed, and compared with that in gene negative participants. RESULTS: Of the 8967 included HD patients, 80% were using at least one psychotropic drug, compared to 27% of gene negative participants. In HD patients, 51% of all drug prescriptions was for psychotropic drugs. The average number of psychotropic drugs used per patient increased from 1.3 in the premanifest stage to 2.5 in stage 5. With progressing disease stages, the proportion of antidepressant drug prescriptions gradually decreased from 74.1% of all prescriptions to 27.3%, and antipsychotic drug prescriptions increased from 7.0% to 38.7%. In line with this, depression and anxiety as listed indications for prescription decreased with advancing disease stages (from 63.0% to 31.5% and from 30.0% to 15.4% respectively), whereas irritability and psychosis increased (from 3.1% to 28.6% and from 0.9% to 16.0% respectively). CONCLUSIONS: Psychotropic medication is widely prescribed in HD, for various indications. Antidepressant use decreases proportionally and antipsychotic use increases with advancing disease stages, suggesting a relative decrease in prevalence of anxiety and depression over disease stages on one hand, and a relative increase in prevalence of irritability and delusions on the other.

Bidding on the go: Links between walking, social actions, and caregiver responses in infant siblings of children with autism spectrum disorder.

The development of walking is associated with a shift in how neurotypical infants initiate social interactions. Walking infants are more likely to locate objects in distant places, carry them, and then share those objects by approaching caregivers and using gestures to show or offer their discoveries (i.e., moving bids). The simultaneous organization of the behaviors necessary to generate moving bids requires the coordination of multiple skills-walking, fine motor skills, and gesturing. Infants with an elevated likelihood (EL) for autism spectrum disorder (ASD) exhibit differences and delays in each of these behaviors. This study investigated interconnections between infant walking, social actions, and caregiver responses in 18-month-old EL infants with diverse developmental outcomes (ASD, non-ASD language delay, no diagnosis). We observed 85 infant-caregiver dyads at home during everyday activities for 45 minutes and identified all times when infants walked, instances of walking paired with social action (i.e., approaching the caregiver, approaching while carrying an object, producing a moving bid), and whether caregivers responded to their infants' social actions. There were no group differences in infants' production of social actions. Caregiver responses, however, were more clearly modulated by outcome group. While all caregivers were similarly and highly likely to respond to moving bids, caregivers of EL-ASD infants were substantially more likely to respond when their infants simply approached them (with or without an object in hand). Taken together, this research underscores the complexity of EL infant-caregiver interactions and highlights the role that each partner plays in shaping how they unfold.

Clinician's commentary to accompany "group well-child care model for Latino children in immigrant families: Adapting to and learning from the COVID-19 context".

Comments on an article by Nomi S. Weiss-Laxer et al. (see record 2022-71815-001). Providing virtual services takes time for many providers and families to get familiar with and many prefer in-person contact over telehealth; however, many of the challenges of doing telehealth can be overcome with creativity and flexibility. As clinicians, they agree with the authors that using the features of the technology to our advantage was helpful and that confirming with each person that they had privacy was vital to effective communication. Problem-solving was often needed, and most times parents had the best ideas for working around the limitations of their home environment. The article highlighted the possibility of hybrid models of care considering the needs and wants of both patients and providers. Such a hybrid approach can increase connection to clinics through in-person visits which can jump-start the establishment of therapeutic relationships and build trust (confianza) with clinicians and clinic staff. As the pandemic becomes more controlled, giving parents a choice and flexibility to change modalities can help them stay engaged and reduce drop out. Clinics will need to assess the language preferences of the families they serve to ensure they have enough staff and providers who are bilingual or multilingual to deliver such programs or use trained interpreters. These concerns would need to be addressed if implementation were increased on a large scale. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Muscle fiber type-specific autophagy responses following an overnight fast and mixed meal ingestion in human skeletal muscle.

The aim of the present study was to investigate the fiber type-specific abundance of autophagy-related proteins after an overnight fast and following ingestion of a mixed meal in human skeletal muscle. Twelve overweight, healthy young male volunteers underwent a 3-h mixed meal tolerance test following an overnight fast. Blood samples were collected in the overnight-fasted state and throughout the 180-min postmeal period. Skeletal muscle biopsies were collected in the fasted state, and at 30 and 90 min after meal ingestion. Protein content of key autophagy markers and upstream signaling responses were measured in whole muscle and pooled single fibers using immunoblotting. In the fasted state, type I fibers displayed lower LC3B-I but higher LC3B-II abundance and higher LC3B-II/LC3B-I ratio compared with type II fibers (P < 0.05). However, there were no fiber type differences in p62/SQSTM1, unc-51 like autophagy activating kinase (ULK1), ATG5, or ATG12 (P > 0.05). Compared with the fasted state, there was a reduction in LC3B-II abundance, indicative of lower autophagosome content, in whole muscle and in both type I and type II fibers following meal ingestion (P < 0.05). This reduction in autophagosome content occurred alongside similar increases in p-AktS473 and p-mTORS2448 in both type I and type II muscle fibers (P < 0.05). In human skeletal muscle, type I fibers have a greater autophagosome content than type II fibers in the overnight-fasted state despite comparable abundance of other key upstream autophagy proteins. Autophagy is rapidly inhibited in both fiber types following the ingestion of a mixed meal.NEW & NOTEWORTHY This study examined the fiber type-specific content of key autophagy proteins in human muscle. We showed that markers of autophagosome content are higher in type I fibers in the overnight-fasted state, whereas autophagy is rapidly inhibited in both type I and type II fibers after the ingestion of a mixed meal.

The RNA Content of Fungal Extracellular Vesicles: At the "Cutting-Edge" of Pathophysiology Regulation.

The role of extracellular vesicles (EVs) in interkingdom communication is widely accepted, and their role in intraspecies communication has been strengthened by recent research. Based on the regulation promoted by EV-associated molecules, the interactions between host and pathogens can reveal different pathways that ultimately affect infection outcomes. As a great part of the regulation is ascribable to RNA contained in EVs, many studies have focused on profiling RNAs in fungal and host EVs, tracking their accumulation during infection, and identifying potential target genes. Herein, we overview the main classes of RNA contained in fungal EVs and the biological processes regulated by these molecules, portraying a state-of-the-art picture of RNAs loaded in fungal EVs, while also raising several questions to drive future investigations. Our compiled data show unambiguously that EVs act as key elements in signaling pathways, and play a crucial role in pathosystems. A complete understanding of the processes that govern RNA content loading and trafficking, and its effect on recipient cells, will lead to improved technologies to ward off infectious agents that threaten human health.

Photoinduced carbamoylation reactions: unlocking new reactivities towards amide synthesis.

The preparation of amide-containing compounds is among the most interesting and challenging topics for the synthetic community. Such relevance is given by their reactive aspects explored in the context of organic synthesis and by the direct application of these compounds as pharmaceuticals and useful materials, and their key roles in biological structures. A simple and straightforward strategy for the amide moiety installation is the use of carbamoyl radicals - this nucleophilic one-electron intermediate is prone to undergo a series of transformations, providing a range of structurally relevant derivatives. In this review, we summarize the latest advances in the field from the perspective of photoinduced protocols. To this end, their synthetic applications are organized accordingly to the nature of the radical precursor (formamides through HAT, 4-substituted-1,4-dihydropyridines, oxamic acids, and N-hydroxyphthalimido esters), the mechanistic aspects also being highlighted. The discussion also includes a recent approach proceeding via photolytic C-S cleavage of dithiocarbamate-carbamoyl intermediates. By exploring fundamental concepts, this material aims to offer an understanding of the topic, which will encourage and facilitate the design of new synthetic strategies applying the carbamoyl radical.

Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy.

Neuropathic pain is common in diabetic peripheral neuropathy (DN), probably caused by pathogenic ion channel gene variants. Therefore, we performed molecular inversion probes-next generation sequencing of 5 transient receptor potential cation channels, 8 potassium channels and 2 calcium-activated chloride channel genes in 222 painful- and 304 painless-DN patients. Twelve painful-DN (5.4%) patients showed potentially pathogenic variants (five nonsense/frameshift, seven missense, one out-of-frame deletion) in ANO3 (n = 3), HCN1 (n = 1), KCNK18 (n = 2), TRPA1 (n = 3), TRPM8 (n = 3) and TRPV4 (n = 1) and fourteen painless-DN patients (4.6%-three nonsense/frameshift, nine missense, one out-of-frame deletion) in ANO1 (n = 1), KCNK18 (n = 3), KCNQ3 (n = 1), TRPA1 (n = 2), TRPM8 (n = 1), TRPV1 (n = 3) and TRPV4 (n = 3). Missense variants were present in both conditions, presumably with loss- or gain-of-functions. KCNK18 nonsense/frameshift variants were found in painless/painful-DN, making a causal role in pain less likely. Surprisingly, premature stop-codons with likely nonsense-mediated RNA-decay were more frequent in painful-DN. Although limited in number, painful-DN patients with ion channel gene variants reported higher maximal pain during the night and day. Moreover, painful-DN patients with TRP variants had abnormal thermal thresholds and more severe pain during the night and day. Our results suggest a role of ion channel gene variants in neuropathic pain, but functional validation is required.

The applicability of the digit wrinkle scan to quantify sympathetic nerve function.

Objective: Stimulated skin wrinkling test (SSW) has been launched as a non-invasive diagnostic procedure. However, no normative age dependent values have been reported that can be applied in clinical practice. The objectives of the study were to (1) collect age-dependent normative values according to the 5-point scale assessment for the SSW, to (2) determine reliability scores for the obtained norm values, and to (3) introduce a new digital method for SSW assessment, the Digit Wrinkle Scan© (DWS©) for detection of wrinkles in a more quantitative manner. Methods: Firstly, 82 healthy participants were included, divided in 5 age groups. The participants underwent SSW using lidocaine and prilocaine topical cream. Secondly, 35 healthy participants were included to test whether the DWS© could be a novel manner to assess the grade of wrinkling quantitatively. We determined the inter-observer reliability of both methods. Also, the intra-observer reliability was calculated for the DWS©. Results: We found a decrease in normative values over age. The inter-observer reliability of assessment by the 5-point scale method was moderate after SSW (Cohen's k: 0.53). Results of the DWS© indicate that total wrinkle length per mm2 showed moderate to good agreement for the 4th and 5th digits after SSW, and a low agreement for the other digits. Conclusions: Age-dependent normative values were obtained according to the 5-point scale, but its clinical application is doubtful since we found a moderate inter-observer reliability. We introduced the DWS© as a possible new method in order to quantify the grade of wrinkling. Significance: We found unsatisfactory reliability scores, which hampers its usefulness for clinical practice.