Inflammatory Caspases: Toward a Unified Model for Caspase Activation by Inflammasomes.

Inflammasomes are inflammatory signaling complexes that provide molecular platforms to activate the protease function of inflammatory caspases. Caspases-1, -4, -5, and -11 are inflammatory caspases activated by inflammasomes to drive lytic cell death and inflammatory mediator production, thereby activating host-protective and pathological immune responses. Here, we comprehensively review the mechanisms that govern the activity of inflammatory caspases. We discuss inflammatory caspase activation and deactivation mechanisms, alongside the physiological importance of caspase activity kinetics. We also examine mechanisms of caspase substrate selection and how inflammasome and cell identities influence caspase activity and resultant inflammatory and pyroptotic cellular programs. Understanding how inflammatory caspases are regulated may offer new strategies for treating infection and inflammasome-driven disease.

Engaging Alkenes in Metallaphotoredox: A Triple Catalytic, Radical Sorting Approach to Olefin-Alcohol Cross-Coupling.

Metallaphotoredox cross-coupling is a well-established strategy for generating clinically privileged aliphatic scaffolds via single-electron reactivity. Correspondingly, expanding metallaphotoredox to encompass new C(sp3)-coupling partners could provide entry to a novel, medicinally relevant chemical space. In particular, alkenes are abundant, bench-stable, and capable of versatile C(sp3)-radical reactivity via metal-hydride hydrogen atom transfer (MHAT), although metallaphotoredox methodologies invoking this strategy remain underdeveloped. Importantly, merging MHAT activation with metallaphotoredox could enable the cross-coupling of olefins with feedstock partners such as alcohols, which undergo facile open-shell activation via photocatalysis. Herein, we report the first C(sp3)-C(sp3) coupling of MHAT-activated alkenes with alcohols by performing deoxygenative hydroalkylation via triple cocatalysis. Through synergistic Ir photoredox, Mn MHAT, and Ni radical sorting pathways, this branch-selective protocol pairs diverse olefins and methanol or primary alcohols with remarkable functional group tolerance to enable the rapid construction of complex aliphatic frameworks.

The prokaryotic and eukaryotic microbiome of Pacific oyster spat is shaped by ocean warming but not acidification.

Pacific oysters (Magallana gigas, a.k.a. Crassostrea gigas), the most widely farmed oysters, are under threat from climate change and emerging pathogens. In part, their resilience may be affected by their microbiome, which, in turn, may be influenced by ocean warming and acidification. To understand these impacts, we exposed early-development Pacific oyster spat to different temperatures (18°C and 24°C) and pCO2 levels (800, 1,600, and 2,800 µatm) in a fully crossed design for 3 weeks. Under all conditions, the microbiome changed over time, with a large decrease in the relative abundance of potentially pathogenic ciliates (Uronema marinum) in all treatments with time. The microbiome composition differed significantly with temperature, but not acidification, indicating that Pacific oyster spat microbiomes can be altered by ocean warming but is resilient to ocean acidification in our experiments. Microbial taxa differed in relative abundance with temperature, implying different adaptive strategies and ecological specializations among microorganisms. Additionally, a small proportion (~0.2% of the total taxa) of the relatively abundant microbial taxa were core constituents (>50% occurrence among samples) across different temperatures, pCO2 levels, or time. Some taxa, including A4b bacteria and members of the family Saprospiraceae in the phyla Chloroflexi (syn. Chloroflexota) and Bacteroidetes (syn. Bacteroidota), respectively, as well as protists in the genera Labyrinthula and Aplanochytrium in the class Labyrinthulomycetes, and Pseudoperkinsus tapetis in the class Ichthyosporea were core constituents across temperatures, pCO2 levels, and time, suggesting that they play an important, albeit unknown, role in maintaining the structural and functional stability of the Pacific oyster spat microbiome in response to ocean warming and acidification. These findings highlight the flexibility of the spat microbiome to environmental changes.IMPORTANCEPacific oysters are the most economically important and widely farmed species of oyster, and their production depends on healthy oyster spat. In turn, spat health and productivity are affected by the associated microbiota; yet, studies have not scrutinized the effects of temperature and pCO2 on the prokaryotic and eukaryotic microbiomes of spat. Here, we show that both the prokaryotic and, for the first time, eukaryotic microbiome of Pacific oyster spat are surprisingly resilient to changes in acidification, but sensitive to ocean warming. The findings have potential implications for oyster survival amid climate change and underscore the need to understand temperature and pCO2 effects on the microbiome and the cascading effects on oyster health and productivity.

Long-term outcomes and cost savings of office fulguration of papillary Ta low-grade bladder cancer.

OBJECTIVES: To assess whether office-based fulguration (OF) under local anaesthesia for small, recurrent, pathological Ta low-grade (LG) non-muscle-invasive bladder cancer (NMIBC) is an effective alternative to transurethral resection of bladder tumour (TURBT), avoiding the costs and risks of procedure, and anesthesia. PATIENTS AND METHODS: Of 521 patients with primary TaLG NMIBC, this retrospective study included 270 patients who underwent OF during follow-up for recurrent, small, papillary LG-appearing tumours at a university centre (University Health Network, University of Toronto, Canada). We assessed the cumulative incidence of cancer-specific mortality (CSM) and disease progression (to MIBC or metastases), as well as possible direct cost savings. RESULTS: In the 270 patients with recurrent TaLG NMIBC treated with OF, the mean (sd) age was 64.9 (13.3) years, 70.8% were men, and 60.3% had single tumours. The mean (sd, range) number of OF procedures per patient was 3.1 (3.2, 1-22). The median (interquartile range) follow-up was 10.1 (5.8-16.2) years. Patients also underwent a mean (sd) of 3.6 (3.0) TURBTs during follow-up in case of numerous or bulkier recurrence. In all, 44.4% of patients never received intravesical therapy. The 10-year incidence of CSM and progression were 0% and 3.1% (95% confidence interval 0.8-5.4%), respectively. Direct cost savings in Ontario were estimated at $6994.14 (Canadian dollars) per patient over the study follow-up. CONCLUSIONS: This study supports that properly selected patients with recurrent, apparent TaLG NMIBC can be safely managed with OF under local anaesthesia with occasional TURBT for larger or numerous recurrent tumours, without compromising long-term oncological outcomes. This approach could generate substantial cost-saving to healthcare systems, is patient-friendly, and could be adopted more widely.

Uncovering the magnitude of African pangolin poaching with extensive nanopore DNA genotyping of seized scales.

Trade in pangolins is illegal, and yet tons of their scales and products are seized at various ports. These large seizures are challenging to process and comprehensively genotype for upstream provenance tracing and species identification for prosecution. We implemented a scalable DNA barcoding pipeline in which rapid DNA extraction and MinION sequencing were used to genotype a substantial proportion of pangolin scales subsampled from 2 record shipments seized in Singapore in 2019 (37.5 t). We used reference sequences to match the scales to phylogeographical regions of origin. In total, we identified 2346 cytochrome b (cytb) barcodes of white-bellied (Phataginus tricuspis) (from 1091 scales), black-bellied (Phataginus tetradactyla) (227 scales), and giant (Smutsia gigantea) (1028 scales) pangolins. Haplotype diversity was higher for P. tricuspis scales (121 haplotypes, 66 novel) than that for P. tetradactyla (22 haplotypes, 15 novel) and S. gigantea (25 haplotypes, 21 novel) scales. Of the novel haplotypes, 74.2% were likely from western and west-central Africa, suggesting potential resurgence of poaching and newly exploited populations in these regions. Our results illustrate the utility of extensively subsampling large seizures and outline an efficient molecular approach for rapid genetic screening that should be accessible to most forensic laboratories and enforcement agencies.

Revelación de la magnitud de la caza furtiva del pangolín africano mediante el genotipo extenso de nanoporos de ADN de escamas incautadas Resumen Aunque el mercado de pangolines es ilegal, se incautan toneladas de sus escamas y productos derivados en varios puertos comerciales. Es un reto procesar estas magnas incautaciones y obtener el genotipo completo para usarlo en la trazabilidad logística ascendente e identificación de la especie y así imponer sanciones. Implementamos una canalización escalable del código de barras de ADN en el cual usamos la extracción rápida de ADN y la secuenciación MinION para obtener el genotipo de una proporción sustancial de las escamas de pangolín submuestreadas en dos cargamentos incautados en 2019 en Singapur (37.5 t). Usamos secuencias referenciales para emparejar las escamas con las regiones filogeográficas de origen. Identificamos en total 2,346 códigos de citocromo b (cytb) del pangolín de vientre blanco (Phataginus tricuspis) (de 1,091 escamas), de vientre negro (P. tetradactyla) (227 escamas) y del pangolín gigante (Smutsia gigantea) (1,028 escamas). La diversidad de haplotipos fue mayor en las escamas de P. tricuspis (121 haplotipos, 66 nuevos) que en las de P. tetradactyla (22 haplotipos, 15 nuevos) y S. gigantea (25 haplotipos, 21 nuevos). De los haplotipos nuevos, el 74.2% probablemente provenía del occidente y centro­occidente de África, lo que sugiere un resurgimiento potencial de la caza furtiva y poblaciones recién explotadas en estas regiones. Nuestros resultados demuestran la utilidad de submuestrear extensivamente las grandes incautaciones y esboza una estrategia molecular eficiente para un análisis genético rápido que debería ser accesible para la mayoría de los laboratorios forenses y las autoridades de aplicación.

Metallaphotoredox: The Merger of Photoredox and Transition Metal Catalysis.

The merger of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, has become a mainstay in synthetic methodology over the past decade. Metallaphotoredox catalysis has combined the unparalleled capacity of transition metal catalysis for bond formation with the broad utility of photoinduced electron- and energy-transfer processes. Photocatalytic substrate activation has allowed the engagement of simple starting materials in metal-mediated bond-forming processes. Moreover, electron or energy transfer directly with key organometallic intermediates has provided novel activation modes entirely complementary to traditional catalytic platforms. This Review details and contextualizes the advancements in molecule construction brought forth by metallaphotocatalysis.

Persistent Opioid Use After Hospital Admission From Surgery in New Zealand: A Population-Based Study.

BACKGROUND: Persistent opioid use (POU) is common after surgery and is associated with an increased risk of mortality and morbidity. There have been no population-based studies exploring POU in opioid-naïve surgical patients in New Zealand (NZ). This study aimed to determine the incidence and risk factors for POU in opioid-naïve patients undergoing surgery in all NZ hospitals. METHOD: We included all opioid-naïve patients who underwent surgery without a concomitant trauma diagnosis and received opioids after discharge from any NZ hospital between January 2007 and December 2019. Patients were considered opioid naïve if no opioids had been dispensed to them or if they did not have a prior diagnosis of an opioid-use disorder up to 365 days preceding the index date. The primary outcome was the incidence of POU, defined a priori as opioid use after discharge between 91 and 365 days. We used a multivariable logistic regression to identify risk factors for POU. RESULTS: We identified 1789,407 patients undergoing surgery with no concomitant diagnosis of trauma; 377,144 (21.1%) were dispensed opioids and 260,726 patients were eligible and included in the analysis. Of those included in the final sample, 23,656 (9.1%; 95% confidence interval [CI], 9.0%-9.2%) developed POU. Risk factors related to how opioids were prescribed included: changing to different opioid(s) after discharge (adjusted odds ratio [aOR], 3.21; 95% CI, 3.04-3.38), receiving multiple opioids on discharge (aOR, 1.37; 95% CI, 1.29-1.45), and higher total oral morphine equivalents (>400 mg) (aOR, 1.23; 95% CI, 1.23-1.45). Conversely, patients who were coprescribed nonopioid analgesics on discharge had lower odds of POU (aOR, 0.91; 95% CI, 0.87-0.95). Only small differences were observed between different ethnicities. Other risk factors associated with increased risk of POU included undergoing neurosurgery (aOR, 2.02; 95% CI, 1.83-2.24), higher comorbidity burden (aOR, 1.90; 95% CI, 1.75-2.07), preoperative nonopioid analgesic use (aOR, 1.65; 95% CI, 1.60-1.71), smoking (aOR, 1.44; 95% CI, 1.35-1.54), and preoperative hypnotics use (aOR, 1.35; 95% CI, 1.28-1.42). CONCLUSIONS: Approximately 1 in 11 opioid-naïve patients who were dispensed opioids on surgical discharge, developed POU. Potentially modifiable risk factors for POU, related to how opioids were prescribed included changing opioids after discharge, receiving multiple opioids, and higher total dose of opioids given on discharge. Clinicians should discuss the possibility of developing POU with patients before and after surgery and consider potentially modifiable risk factors for POU when prescribing analgesia on discharge after surgery.

Poor sleep quality and its associated neurocognitive function in children with obesity with or without obstructive sleep apnea.

OBJECTIVE: To evaluate the associations of OSA severity, snoring symptoms, subjective sleep quality, and daytime sleepiness with executive functioning and behaviors in children with obesity. METHODS: This was a cross-sectional study of children aged 8-18 years with obesity and symptoms suggestive of OSA. All participants underwent an overnight polysomnography and completed a set of questionnaires to assess their sleep-related breathing disordered (SRBD) symptoms [Pediatric Sleep Questionnaire (SRBD-PSQ)], sleep quality [Pittsburgh Sleep Quality Index (PSQI)], executive function [Behavior Rating Inventory of Executive Function (BRIEF)], and inattention and hyperactivity symptoms (Conners-3 Parent Short Form). RESULTS: A total of 85 children (62% male, mean age: 13.9 ± 3.0 years) were included in this analysis, of whom 36, 16, and 33 were categorized into the non-OSA (obstructive apnea hypopnea index, OAHI < 1.5/h), mild OSA (OAHI 1.5-5/h), and moderate-severe OSA (OAHI ≥ 5/h) groups, respectively. Of 85 participants, 27 (32%) were classified with poor sleep quality (PSQI composite score ≥ 8). From multiple linear regression analyses, poor sleep quality and sleepiness were both independently associated with higher BRIEF behavioral regulation T-score, metacognition T-score, and global executive composite T-score in the fully adjusted model. In addition, poor sleep quality was also independently associated with higher Conners-3 inattention and executive functioning T-scores, while greater sleepiness was also associated with a higher learning problem T-score. The presence of OSA and snoring were not associated with any cognitive outcomes. CONCLUSIONS: Subjective sleep quality and daytime sleepiness, but not OSA severity and snoring symptoms, were independently associated with executive functioning and behavioral problems in children with obesity.

Vaccine decision making in New Zealand: a discrete choice experiment.

BACKGROUND: Vaccine hesitancy is a significant threat to global health. A key part of addressing hesitancy is to ensure that public health messaging prioritises information that is considered important to the public. This study aimed to examine how different vaccine characteristics affect public preferences for vaccines in New Zealand, what trade-offs they are willing to make between different vaccine characteristics, and how their preferences are affected by their vaccine-related conspiracy beliefs and COVID-19 vaccination status. METHODS: An online discrete choice experiment (DCE) was designed to elicit individual preferences about vaccines using the 1000minds platform. Members of the general population of New Zealand aged ≥ 18 years were invited to complete the DCE. Participants were asked to indicate their preference between two options showing different combinations of vaccine characteristics. Data on sociodemographic characteristics were collected. Beliefs were measured using the vaccine conspiracy beliefs scale (VCBS) with scores ≥ 19 indicating strong vaccine-related conspiracy beliefs. The DCE was analysed using the PAPRIKA method (Potentially All Pairwise RanKings of all possible Alternatives) and preferences compared between respondents with high versus low VCBS scores and vaccinated versus unvaccinated respondents for COVID-19. RESULTS: A total of 611 respondents from 15 regions completed the DCE. Mean (SD) age was 45.9 (14.7) years with most having had 2 or more doses of the coronavirus vaccine (86%). Mean (SD) VCBS score was 18.5 (12.4) indicating moderate vaccine-related conspiracy beliefs. Risk of severe adverse effects was the most highly valued vaccine characteristic, followed by vaccine effectiveness and duration of protection. Vaccine origin and route of administration were ranked least important. Respondents scoring high on the VCBS placed less value on the effectiveness of vaccines but greater value on development time and total number of doses (p < 0.001). COVID-19 unvaccinated respondents ranked development time and total number of doses more highly than those vaccinated respondents (p < 0.001). CONCLUSIONS: Risk of severe adverse effects, vaccine effectiveness and duration of protection were rated by the New Zealand public as the top three most important vaccine characteristics. This information is important for informing public health messaging to promote vaccine uptake and inform vaccine decision-making.

Incidence and risk factors of new persistent opioid use after surgery and trauma: A systematic review.

BACKGROUND: Persistent opioid use (POU) can occur with opioid use after surgery or trauma. Current systematic reviews include patients with previous exposure to opioids, meaning their findings may not be relevant to patients who are opioid naïve (i.e. Most recent exposure was from surgery or trauma). The aim of this review was to synthesise narratively the evidence relating to the incidence of, and risk factors for POU in opioid-naïve surgical or trauma patients. METHOD: Structured searches of Embase, Medline, CINAHL, Web of Science, and Scopus were conducted, with final search performed on the 17th of July 2023. Searches were limited to human participants to identify studies that assessed POU following hospital admission due to surgery or trauma. Search terms relating to 'opioid', 'analgesics', 'surgery', 'injury', 'trauma' and 'opioid-related disorder' were combined. The Newcastle-Ottawa Scale for cohort studies was used to assess the risk of bias for studies. RESULTS: In total, 22 studies (20 surgical and two trauma) were included in the analysis. Of these, 20 studies were conducted in the United States (US). The incidence of POU for surgical patients 18 and over ranged between 3.9% to 14.0%, and for those under 18, the incidence was 2.0%. In trauma studies, the incidence was 8.1% to 10.5% among patients 18 and over. Significant risk factors identified across surgical and trauma studies in opioid-naïve patients were: higher comorbidity burden, having pre-existing mental health or chronic pain disorders, increased length of hospital stay during the surgery/trauma event, or increased doses of opioid exposure after the surgical or trauma event. Significant heterogeneity of study design precluded meta-analysis. CONCLUSION: The quality of the studies was generally of good quality; however, most studies were of US origin and used medico-administrative data. Several risk factors for POU were consistently and independently associated with increased odds of POU, primarily for surgical patients. Awareness of these risk factors may help prescribers recognise the risk of POU after surgery or trauma, when considering continuing opioids after hospitalisation. The review found gaps in the literature on trauma patients, which represents an opportunity for future research. TRIAL REGISTRATION: PROSPERO registration: CRD42023397186.

Investigating Machine Learning Techniques for Predicting Risk of Asthma Exacerbations: A Systematic Review.

Asthma, a common chronic respiratory disease among children and adults, affects more than 200 million people worldwide and causes about 450,000 deaths each year. Machine learning is increasingly applied in healthcare to assist health practitioners in decision-making. In asthma management, machine learning excels in performing well-defined tasks, such as diagnosis, prediction, medication, and management. However, there remain uncertainties about how machine learning can be applied to predict asthma exacerbation. This study aimed to systematically review recent applications of machine learning techniques in predicting the risk of asthma attacks to assist asthma control and management. A total of 860 studies were initially identified from five databases. After the screening and full-text review, 20 studies were selected for inclusion in this review. The review considered recent studies published from January 2010 to February 2023. The 20 studies used machine learning techniques to support future asthma risk prediction by using various data sources such as clinical, medical, biological, and socio-demographic data sources, as well as environmental and meteorological data. While some studies considered prediction as a category, other studies predicted the probability of exacerbation. Only a group of studies applied prediction windows. The paper proposes a conceptual model to summarise how machine learning and available data sources can be leveraged to produce effective models for the early detection of asthma attacks. The review also generated a list of data sources that other researchers may use in similar work. Furthermore, we present opportunities for further research and the limitations of the preceding studies.

Predictors of persistent opioid use in non-cancer older adults: a retrospective cohort study.

BACKGROUND: Long-term opioid use and associated adverse outcomes have increased dramatically in recent years. Limited research is available on long-term opioid use in older adults. OBJECTIVE: We aimed to determine the incidence and predictors of long-term or persistent opioid use (POU) amongst opioid-naïve older adults without a cancer diagnosis. METHODS: This was a retrospective cohort study using five national administrative healthcare databases in New Zealand. We included all opioid-naïve older adults (≥65 years) who were initiated on opioid therapy between January 2013 and June 2018. The outcome of interest was POU, defined as having continuously filled ≥1 opioid prescription within 91-180 days after the index opioid prescription. Multivariable logistic regression was used to examine the predictors of POU. RESULTS: The final sample included 268,857 opioid-naïve older adults; of these, 5,849(2.2%) developed POU. Several predictors of POU were identified. The use of fentanyl (adjusted odds ratio (AOR) = 3.61; 95% confidence interval (CI) 2.63-4.95), slow-release opioids (AOR = 3.02; 95%CI 2.78-3.29), strong opioids (AOR = 2.03; 95%CI 1.55-2.65), Charlson Comorbidity Score ≥ 3 (AOR = 2.09; 95% CI 1.78-2.46), history of substance abuse (AOR = 1.52; 95%CI 1.35-1.72), living in most socioeconomically deprived areas (AOR = 1.40; 95%CI 1.27-1.54), and anti-epileptics (AOR = 2.07; 95%CI 1.89-2.26), non-opioid analgesics (AOR = 2.05; 95%CI 1.89-2.21), antipsychotics (AOR = 1.96; 95%CI 1.78-2.17) or antidepressants (AOR = 1.50; 95%CI 1.41-1.59) medication use were the strongest predictors of POU. CONCLUSION: A significant proportion of patients developed POU, and several factors were associated with POU. The findings will enable healthcare providers and policymakers to target early interventions to prevent POU and related adverse events.

Suspected clinical toxoplasmosis in a 12-week-old puppy in Singapore.

BACKGROUND: Toxoplasma gondii is traditionally known as a parasite of felids, with possible infection in intermediate hosts such as dogs and humans, and thus a disease of public health significance. Published data on the prevalence of toxoplasmosis in dogs and cats in Singapore is scanty, and this paper documents a suspect clinical case of toxoplasmosis in a free-roaming puppy trapped from an offshore island of Singapore. CASE PRESENTATION: A 12-week-old puppy presented with hindlimb weakness and sarcopenia, with rapidly progressing ascending paralysis and respiratory distress, one week after trapping. Toxoplasmosis was suspected after indirect fluorescence antibody testing (IFAT) revealed anti-T. gondii antibodies. The puppy responded quickly to clindamycin treatment and was discharged from hospital after 10 days. CONCLUSION: While rare and undocumented, veterinary clinicians in Singapore are advised to also include toxoplasmosis infection as a differential diagnosis in dogs presenting with similar clinical signs. This is especially so for dogs which have access to the outdoors.

Attitude towards deprescribing and its association with frailty and complexity of medication regimen: A survey of older inpatients in a district health board in New Zealand.

BACKGROUND: Older inpatients, particularly those with frailty, have increased exposure to complex medication regimens. It is not known whether frailty and complexity of medication regimens influence attitudes toward deprescribing. This study aimed to investigate (1) older inpatients' attitudes toward deprescribing; (2) if frailty and complexity of medication regimen influence attitudes and willingness to deprescribe - a relationship that has not been investigated in previous studies. METHODS: In this cross-sectional study, older adults (≥ 65 years) recruited from general medicine and geriatric services in a New Zealand hospital completed the revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire. Hospital frailty risk score (HFRS) was calculated using diagnostic codes and other relevant information present at the time of index hospital admission; higher scores indicate higher frailty risk. Medication regimen complexity was quantified using the medication regimen complexity index (MRCI); higher scores indicate greater complexity. Logistic regression analysis was used to identify predictors of attitudes and willingness to deprescribe. RESULTS: A total of 222 patients were included in the study, the median age was 83 years and 63% were female. One in two patients reported feeling they were taking too many medications, and 1 in 5 considered their medications burdensome. Almost 3 in 4 (73%) wanted to be involved in decision-making about their medications, and 4 in 5 (84%) were willing to stop one or more of their medications if their prescriber said it was possible. Patients with higher MRCI had increased self-reported medication burden (adjusted odds ratio (AOR) 2.6, 95% CI 1.29, 5.29) and were more interested in being involved in decision-making about their medications (AOR 1.8, CI 0.99, 3.42) than those with lower MRCI. Patients with moderate HFRS had lower odds of willingness to deprescribe (AOR 0.45, CI 0.22,0.92) compared to the low-risk group. Female patients had a lower desire to be involved in decision-making. The oldest old age group( > 80 years) had lower self-reported medication burden and were less likely to want to try stopping their medications. CONCLUSION: Most older inpatients wanted to be involved in decision-making about their medications and were willing to stop one or more medications if proposed by their prescriber. Medication complexity and frailty status influence patients' attitudes toward deprescribing and thus should be taken into consideration when making deprescribing decisions. Further research is needed to investigate the relationship between frailty and the complexity of medication regimens.

Anti-dementia medication use in Aotearoa New Zealand: An exploratory study using health data from the Integrated Data Infrastructure (IDI).

OBJECTIVE: Anti-dementia medications such as acetylcholinesterase inhibitors are an important part of the management pathway for dementia. However, there are limited data in New Zealand that have examined the rates and patterns of use of funded anti-dementia medication and how use differs with ethnicity, age and sex. METHODS: This was a retrospective population-based descriptive study. Using the Integrated Data Infrastructure, we identified individuals of all ages coded for a diagnosis of dementia and estimated the proportion dispensed funded anti-dementia medication - donepezil tablets and rivastigmine patches - between 1 July 2016 and 30 June 2020. Rates of medication use in five main ethnic groups (Maori, Pacific peoples, Asian, European, and Middle Eastern, Latin American and African) in the <65, 65-79 and 80 and over (80+) age groups were compared and also between males and females in all sub-groups. Log-binomial models were used to calculate relative risks to determine any differences in anti-dementia medication use in the five ethnic groups and the three age groups and between males and females in each of the four study years. RESULTS: Overall, one-third of the dementia population received a funded anti-dementia medication in the total population (all ages) between 2016 and 2020. Donepezil tablets were dispensed in 31.6-34.0% and rivastigmine patches in 1.4-2.1% across the four study years. Compared to people of European ethnicity, Maori, Pacific peoples, and Middle Eastern, Latin American and African groups were less likely to be dispensed an anti-dementia medication (Maori: relative risk = 0.79-0.81, p < 0.0001; Pacific peoples: relative risk = 0.72-0.74, p < 0.0001; Middle Eastern, Latin American and African: relative risk = 0.73-0.78, p < 0.05). Compared to the age 80+ group, the 65-79 age group was more likely (relative risk = 1.50-1.54, p < 0.0001), while the age <65 group was less likely (relative risk = 0.67-0.71, p < 0.0001) to be dispensed an anti-dementia medication. There were no statistically significant differences in anti-dementia medication use between males and females. CONCLUSION: This study provides important information about funded anti-dementia medication use in New Zealand and how this differs by ethnicity, age and sex. Despite higher dementia prevalence in Maori and Pacific peoples, these groups were less likely to receive funded anti-dementia medication.

Providing culturally responsive care in a pediatric setting: are our trainees ready?

BACKGROUND: Extensive data consistently demonstrates inequities in access and delivery of healthcare for patients from historically marginalized populations, resulting in poorer health outcomes. To address this systemic oppression in healthcare, it is necessary to embed principles of equity, diversity, and inclusion (EDI) at an early stage within medical education. This study aimed to assess pediatric trainees' perceived interest in EDI curricula as well as their confidence in applying this knowledge to provide culturally responsive care. METHODS: An anonymous online survey was distributed to pediatric trainees at the University of Toronto. Closed-ended questions used a Likert scale to assess respondents' confidence and interest in providing culturally responsive care to patients. Open-ended questions explored trainees' perceptions of effective EDI learning modalities. A mixed methods approach was utilized, where quantitative data was summarized using descriptive statistics and descriptive content analysis was used to highlight themes within qualitative data. RESULTS: 116 pediatric trainees completed the survey, of which 72/116 (62%) were subspecialty residents/fellows and 44/116 (38%) were core residents. 97% of all responses agreed or strongly agreed that it was important to learn about providing culturally responsive care to patients from historically marginalized communities; however, many trainees lacked confidence in their knowledge of providing culturally responsive care (42%) and applying their knowledge in clinical practice (47%). Respondents identified direct clinical exposure through rotations, immersive experiences, and continuity clinics as effective EDI teaching modalities. Identified barriers included time constraints in the clinical environment, burnout, and lack of exposure to diverse patient populations. CONCLUSION: Most pediatric trainees want to provide culturally responsive care to patients from historically marginalized communities, but do not feel confident in their knowledge to do so. Trainees value learning about EDI through direct clinical exposure and immersive experiences, rather than didactic lectures or modules. These study findings will be utilized to develop and implement an enhanced EDI education curriculum for pediatric trainees at the University of Toronto and other postgraduate residency programs.

Prevalence of young-onset dementia: nationwide analysis of routinely collected data.

INTRODUCTION: Young-onset dementia prevalence is understudied internationally. Previous studies have been limited by low case numbers, reliance on single sources of routinely collected health data for case identification and inclusion of a limited age range. Our objective was to determine the 1-year period prevalence of diagnosed dementia in people aged 0-64 in the entire New Zealand population using routinely collected health data. METHODS: A population-based descriptive study was carried out in New Zealand (population 4.8 million) using routinely collected deidentified health data from 2016 to 2020. Dementia cases in seven linked health datasets in the New Zealand Integrated Data Infrastructure were identified using diagnostic codes and/or use of antidementia medication. Prevalence for each of the four study years was calculated by age, sex and ethnicity. RESULTS: From a total population of 4 027 332-4 169 754 individuals aged 0-64, we identified 3396-3474 cases of 'all-cause' dementia in each of the study years (prevalence crude range: 83-84/100 000 people aged 0-64; 139-141/100 000 people aged 30-64 years; 204-207/100 000 people aged 45-64 years). Age-standardised prevalence was higher in males than females. Age-standardised and sex-standardised prevalence was higher in Maori and Pacific People than European and Asian. DISCUSSION: By using a large study population and multiple national health datasets, we have minimised selection bias and estimated the national prevalence of diagnosed young-onset dementia with precision. Young-onset dementia prevalence for the total New Zealand population was similar to reported global prevalence, validating previous estimates. Prevalence differed by ethnicity, which has important implications for service planning.

Primary Extranodal NK/T-Cell Lymphoma Presenting as Neurolymphomatosis Involving Multiple Cranial Nerves: A Case Report.

Neurolymphomatosis (NL) is a rare condition caused by the lymphomatous or leukemic infiltration of nerves and manifests as neuropathy. Most often, NL is associated with B-lineage non-Hodgkin lymphoma (NHL) and only infrequently occurs in conjunction with T- or NK-lineage NHL. Extranodal NK/T-cell lymphoma (ENKTL)-associated NL is exceedingly unusual, with only 9 cases described in the English language literature, in addition to our case. Diagnosis of NL is challenging, as the entity can mimic neuropathies of more common etiologies, and an adequate biopsy may be difficult to obtain. Timely diagnosis demands a high index of suspicion, especially for patients without a history of hematologic malignancy. We expand upon a unique case of NL exclusively involving cranial nerves and cauda equina nerve roots, as the initial manifestation of ENKTL, and contextualize our findings within the framework of previously reported NK/T-lineage NL cases.

Digital interventions to improve adherence to maintenance medication in asthma.

BACKGROUND: Asthma is the most common chronic lung condition worldwide, affecting 334 million adults and children globally. Despite the availability of effective treatment, such as inhaled corticosteroids (ICS), adherence to maintenance medication remains suboptimal. Poor ICS adherence leads to increased asthma symptoms, exacerbations, hospitalisations, and healthcare utilisation. Importantly, suboptimal use of asthma medication is a key contributor to asthma deaths. The impact of digital interventions on adherence and asthma outcomes is unknown. OBJECTIVES: To determine the effectiveness of digital interventions for improving adherence to maintenance treatments in asthma. SEARCH METHODS: We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted the most recent searches on 1 June 2020, with no restrictions on language of publication. A further search was run in October 2021, but studies were not fully incorporated. SELECTION CRITERIA: We included randomised controlled trials (RCTs) including cluster- and quasi-randomised trials of any duration in any setting, comparing a digital adherence intervention with a non-digital adherence intervention or usual care. We included adults and children with a clinical diagnosis of asthma, receiving maintenance treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures for data collection. We used GRADE to assess quantitative outcomes where data were available. MAIN RESULTS: We included 40 parallel randomised controlled trials (RCTs) involving adults and children with asthma (n = 15,207), of which eight are ongoing studies. Of the included studies, 30 contributed data to at least one meta-analysis. The total number of participants ranged from 18 to 8517 (median 339). Intervention length ranged from two to 104 weeks. Most studies (n = 29) reported adherence to maintenance medication as their primary outcome; other outcomes such as asthma control and quality of life were also commonly reported. Studies had low or unclear risk of selection bias but high risk of performance and detection biases due to inability to blind the participants, personnel, or outcome assessors. A quarter of the studies had high risk of attrition bias and selective outcome reporting. We examined the effect of digital interventions using meta-analysis for the following outcomes: adherence (16 studies); asthma control (16 studies); asthma exacerbations (six studies); unscheduled healthcare utilisation (four studies); lung function (seven studies); and quality of life (10 studies). Pooled results showed that patients receiving digital interventions may have increased adherence (mean difference of 14.66 percentage points, 95% confidence interval (CI) 7.74 to 21.57; low-certainty evidence); this is likely to be clinically significant in those with poor baseline medication adherence. Subgroup analysis by type of intervention was significant (P = 0.001), with better adherence shown with electronic monitoring devices (EMDs) (23 percentage points over control, 95% CI 10.84 to 34.16; seven studies), and with short message services (SMS) (12 percentage points over control, 95% CI 6.22 to 18.03; four studies). No significant subgroup differences were seen for interventions having an in-person component versus fully digital interventions, adherence feedback, one or multiple digital components to the intervention, or participant age. Digital interventions were likely to improve asthma control (standardised mean difference (SMD) 0.31 higher, 95% CI 0.17 to 0.44; moderate-certainty evidence) - a small but likely clinically significant effect. They may reduce asthma exacerbations (risk ratio 0.53, 95% CI 0.32 to 0.91; low-certainty evidence). Digital interventions may result in a slight change in unscheduled healthcare utilisation, although some studies reported no or a worsened effect. School or work absence data could not be included for meta-analysis due to the heterogeneity in reporting and the low number of studies. They may result in little or no difference in lung function (forced expiratory volume in one second (FEV1)): there was an improvement of 3.58% predicted FEV1, 95% CI 1.00% to 6.17%; moderate-certainty evidence); however, this is unlikely to be clinically significant as the FEV1 change is below 12%. Digital interventions likely increase quality of life (SMD 0.26 higher, 95% CI 0.07 to 0.45; moderate-certainty evidence); however, this is a small effect that may not be clinically significant. Acceptability data showed positive attitudes towards digital interventions. There were no data on cost-effectiveness or adverse events. Our confidence in the evidence was reduced by risk of bias and inconsistency. AUTHORS' CONCLUSIONS: Overall, digital interventions may result in a large increase in adherence (low-certainty evidence). There is moderate-certainty evidence that digital adherence interventions likely improve asthma control to a degree that is clinically significant, and likely increase quality of life, but there is little or no improvement in lung function. The review found low-certainty evidence that digital interventions may reduce asthma exacerbations. Subgroup analyses show that EMDs may improve adherence by 23% and SMS interventions by 12%, and interventions with an in-person element and adherence feedback may have greater benefits for asthma control and adherence, respectively. Future studies should include percentage adherence as a routine outcome measure to enable comparison between studies and meta-analysis, and use validated questionnaires to assess adherence and outcomes.

Metformin in nucleus accumbens core reduces cue-induced cocaine seeking in male and female rats.

This study investigated the potential therapeutic effects of the FDA-approved drug metformin on cue-induced reinstatement of cocaine seeking. Metformin (dimethyl-biguanide) is a first-line treatment for type II diabetes that, among other mechanisms, is involved in the activation of adenosine monophosphate activated protein kinase (AMPK). Cocaine self-administration and extinction is associated with decreased levels of phosphorylated AMPK within the nucleus accumbens core (NAcore). Previously, it was shown that increasing AMPK activity in the NAcore decreased cue-induced reinstatement of cocaine seeking. Decreasing AMPK activity produced the opposite effect. The goal of the present study was to determine if metformin in the NAcore reduces cue-induced cocaine seeking in adult male and female Sprague Dawley rats. Rats were trained to self-administer cocaine followed by extinction prior to cue-induced reinstatement trials. Metformin microinjected in the NAcore attenuated cue-induced reinstatement in male and female rats. Importantly, metformin's effects on cocaine seeking were not due to a general depression of spontaneous locomotor activity. In female rats, metformin's effects did generalize to a reduction in cue-induced reinstatement of sucrose seeking. These data support a potential role for metformin as a pharmacotherapy for cocaine use disorder but warrant caution given the potential for metformin's effects to generalize to a natural reward in female rats.