Indo-Pacific Walker circulation drove Pleistocene African aridification.

Today, the eastern African hydroclimate is tightly linked to fluctuations in the zonal atmospheric Walker circulation1,2. A growing body of evidence indicates that this circulation shaped hydroclimatic conditions in the Indian Ocean region also on much longer, glacial-interglacial timescales3-5, following the development of Pacific Walker circulation around 2.2-2.0 million years ago (Ma)6,7. However, continuous long-term records to determine the timing and mechanisms of Pacific-influenced climate transitions in the Indian Ocean have been unavailable. Here we present a seven-million-year-long record of wind-driven circulation of the tropical Indian Ocean, as recorded in Mozambique Channel Throughflow (MCT) flow-speed variations. We show that the MCT flow speed was relatively weak and steady until 2.1 ± 0.1 Ma, when it began to increase, coincident with the intensification of the Pacific Walker circulation6,7. Strong increases during glacial periods, which reached maxima after the Mid-Pleistocene Transition (0.9-0.64 Ma; ref. 8), were punctuated by weak flow speeds during interglacial periods. We provide a mechanism explaining that increasing MCT flow speeds reflect synchronous development of the Indo-Pacific Walker cells that promote aridification in Africa. Our results suggest that after about 2.1 Ma, the increasing aridification is punctuated by pronounced humid interglacial periods. This record will facilitate testing of hypotheses of climate-environmental drivers for hominin evolution and dispersal.

Responsible north-south research and innovation: A framework for transdisciplinary research leadership and management.

The number, scale and ambition of transdisciplinary research initiatives between the global north and the global south is increasing, yet there is very little theoretical or empirical scholarship on how to lead and manage implementation to promote responsible practice. Within science, technology and innovation (STI) studies and decolonising research frameworks, and utilising collaborative autoethnography, this study codifies experience with implementing the 'Revitalising Informal Settlements and their Environments' (RISE) program (2017-2020). Our specific aim is to explore the leadership and management tensions and challenges of implementing transboundary transdisciplinary research. The findings reaffirm the importance of research leaders and managers carefully operationalising north-south research by critically reflecting on power asymmetries between disciplines, partners and locations, leveraging the potential for transdisciplinary consortia to build research capabilities in the global south, and creating a culture of reflexivity on the historical and social positionality in which research is designed, funded, implemented and evaluated. The findings foreground the role of boundary-spanning 'integrators' and 'pracademics', roles that have received little attention to date but are essential for effective delivery and societal impact beyond scientific advances. A framework for implementing north-south transdisciplinary research is outlined with five domains: (1) collaborative leadership; (2) agile management; (3) flexible consortia; (4) researcher positionality; and (5) co-design and participation. The framework can support efforts for responsibly designing and implementing large, transdisciplinary, cross-country research programs in line with ambitions for decolonising north-south research.

Joint Food and Water Insecurity Had a Multiplicative Effect on Women's Depression in Urban Informal Settlements in Makassar, Indonesia during the COVID-19 Pandemic.

BACKGROUND: Women living in urban informal settlements may be particularly vulnerable to the detrimental effects of the COVID-19 pandemic because of increased economic and psychosocial stressors in resource-limited environments. OBJECTIVES: The objective of this study was to assess the associations between food and water insecurity during the pandemic and depression among women living in the urban informal settlements in Makassar, Indonesia. METHODS: We implemented surveys at 3 time points among women enrolled in the Revitalizing Informal Settlements and their Environments trial. Depression was measured using the Center for Epidemiologic Studies Depression Scale-10 (CESD-10) between November and December 2019 and again between February and March 2021. Food insecurity was measured using questions from the Innovation for Poverty Action's Research for Effective COVID-19 Reponses survey and water insecurity was measured using the Household Water Insecurity Experiences Short Form. Both were measured between August and September 2020. We built 3 multivariate quantile linear regression models to assess the effects of water insecurity, food insecurity, and joint food and water insecurity during the COVID-19 pandemic on CESD-10 score. RESULTS: In models with the full sample (n = 323), food insecurity (ß: 1.48; 95% CI: 0.79, 2.17), water insecurity (ß: 0.13; 95% CI: -0.01, 0.26), and joint food and water insecurity (ß: 2.40; 95% CI: 1.43, 3.38) were positively associated with CESD-10 score. In subgroup analyses of respondents for whom we had prepandemic CESD-10 scores (n = 221), joint food and water insecurity (ß: 1.96; 95% CI: 0.78, 3.15) maintained the strongest relationship with CESD-10 score. A limitation of this study is that inconsistency in respondents from households across the survey waves reduced the sample size used for this study. CONCLUSIONS: Our results find a larger association between depression and joint resource insecurity than with water or food insecurity alone, underlining the importance of addressing food and water insecurity together, particularly as they relate to women's mental health and well-being.

The technology in cryotechnology.

The process of freezing biological material at extremely low temperatures is known as cryopreservation. To ensure the preservation of cells and tissues over an extended period of time, low temperatures are applied since biological processes, including the biochemical ones, come to a halt under cryogenic conditions and thus it is possible to maintain their structural and functional integrity. The field of cryopreservation gained more prominence in the 20th century and emerged as an unavoidable technology for different applications such as cell therapy, tissue engineering, or assisted fertilization. In this work we provide an overview of various technologies in the field of cryotechnology with regard to the freezing, storage and thawing of living cells. The first part covers the freezing process, starting with cryoprotective agents regarding their protection mechanisms and compositions, passing by cryo-imaging, micro-fluidic systems, and the currently available freezing and biobanking equipment. The second part focusses on the thawing process as well as the hypothermic preservation for the short-term storage of biological materials and constructs. Doi.org/10.54680/fr23610110112.

Reforming the workers' compensation process for occupational lung disease among miners in South Africa: an efficiency study of claims assessment.

PURPOSE: The large burden of silicosis and tuberculosis (TB) in the South African mining industry, coupled with an under-resourcing of the compensation agencies responsible for certifying occupational lung disease, have resulted in serious backlogs. This work aimed to measure the efficiency gains from triaging occupational lung disease claims using claim type, years of mining exposure and computer aided detection (CAD) to save on scarce medical adjudicators. METHODS: During 2020, the compensation authority started to triage claims for TB and those of miners with < 10 years of service to two-person panels instead of the four-person panel plus radiologist used previously. Efficiency gain was calculated in medical person-units saved and reduction in delays. Different service thresholds predictive of silicosis were simulated, as well as the impact of pre-classification of chest X-rays with CAD using different combinations of sensitivity and specificity. RESULTS: The new triage system saved 20.3% in person-time units and reduced delays by 10-20 days. Without CAD the greatest efficiency gain (28%) was projected from dispensing with a mining service threshold and routing all non-TB claims to the small panels at the outset. Simulation of four different CAD sensitivity/specificity combinations yielded efficiency gains of 18.2-36.1%, with 31.1% judged the most realistic. Use of sensitivity of close to 100% would not be feasible because of the very low resulting specificity. CONCLUSION: Pre-adjudication triage of claims at the compensation agency is capable of saving a substantial proportion of adjudicator time and reducing certification delays. Additional efficiency gains are achievable by referring all claims to small panels to begin with and improvement of CAD performance for this ex-miner population.

Are social isolation, lack of social support or loneliness risk factors for cardiovascular disease in Australia and New Zealand? A systematic review and meta-analysis.

BACKGROUND: An international systematic review concluded that individuals with poor social health (social isolation, lack of social support or loneliness) are 30% more likely to develop coronary heart disease (CHD) and stroke. Notably, the two included Australian papers reported no association between social health and CHD or stroke. OBJECTIVE: We undertook a systematic review and meta-analysis to investigate the association between social isolation, lack of social support and loneliness and cardiovascular disease (CVD) incidence among people living in Australia and New Zealand. METHODS: Four electronic databases were systematically searched for longitudinal studies published until June 2020. Two reviewers undertook title/abstract screen and one reviewer undertook full-text screen and data extraction. Quality was assessed using the Newcastle - Ottawa Quality Assessment Scale. RESULTS: Of the 725 unique records retrieved, five papers met our inclusion criteria. These papers reported data from three Australian longitudinal datasets, with a total of 2137 CHD and 590 stroke events recorded over follow-up periods ranging from 3 to 16 years. Reports of two CHD and two stroke outcomes were suitable for meta-analysis. The included papers reported no association between social health and incidence of CVD in all fully adjusted models and most unadjusted models. CONCLUSIONS: Our systematic review is inconclusive as it identified only a few studies, which relied heavily on self-reported CVD. Further studies using medical diagnosis of CVD, and assessing the potential influence of residential remoteness, are needed to better understand the relationship between social health and CVD incidence in Australia and New Zealand.

Household Water Storage Management, Hygiene Practices, and Associated Drinking Water Quality in Rural India.

Household drinking water storage is commonly practiced in rural India. Fecal contamination may be introduced at the water source, during collection, storage, or access. Within a trial of a community-level water supply intervention, we conducted five quarterly household-level surveys to collect information about water, sanitation, and hygiene practices in rural India. In a random subsample of households, we tested stored drinking water samples for Escherichia coli, concurrently observing storage and access practices. We conducted 9961 surveys and collected 3296 stored water samples. Stored water samples were frequently contaminated with E. coli (69%), and E. coli levels were the highest during the wet season. Most households contributing two or more drinking water samples had detectable E. coli in some (47%) or all (44%) samples. Predictors of stored water contamination with E. coli included consumption of river water and open defecation; consumption of reverse osmosis-treated water and safe water access practices appeared to be protective. Until households can be reached with on-premises continuous safe water supplies, suboptimal household water storage practices are likely to continue. Improvements to source water quality alone are unlikely to prevent exposure to contaminated drinking water unless attention is also given to improving household water storage, access, and sanitation practices.

Effect of hygiene interventions on acute respiratory infections in childcare, school and domestic settings in low- and middle-income countries: a systematic review.

OBJECTIVES: Acute respiratory infections (ARIs) disproportionately affect those living in low- and middle-income countries (LMICs). We aimed to determine whether hygiene interventions delivered in childcare, school or domestic settings in LMICs effectively prevent or reduce ARIs. METHODS: We registered our systematic review with PROSPERO (CRD42017058239) and searched MEDLINE, EMBASE, CENTRAL, and Scopus from inception to 17 October 2017 for randomised controlled trials (RCTs) examining the impact of hygiene interventions on ARI morbidity in adults and children in community-based settings in LMICs. We stratified data into childcare, school and domestic settings and used the Grading of Recommendations Assessment, Development and Evaluation approach to assess evidence quality. RESULTS: We identified 14 cluster RCTs evaluating hand-hygiene interventions in LMICs with considerable heterogeneity in setting, size, intervention delivery and duration. We found reduced ARI-related absenteeism and illness in childcare settings (low- to moderate-quality evidence). In school settings, we found reduced ARI-related absenteeism and laboratory-confirmed influenza (moderate- to high-quality evidence), but no reduction in ARI illness (low-quality evidence). In domestic settings, we found reduced ARI illness and pneumonia amongst children in urban settlements (high-quality evidence) but not in rural settlements (low-quality evidence), and no effect on secondary transmission of influenza in households (moderate-quality evidence). CONCLUSIONS: Evidence suggests that hand-hygiene interventions delivered in childcare, school and domestic settings can reduce ARI morbidity, but effectiveness varies according to setting, intervention target and intervention compliance. Further studies are needed to develop, deliver and evaluate targeted and sustainable hygiene interventions in LMICs.

The comparative landscape of duplications in Heliconius melpomene and Heliconius cydno.

Gene duplications can facilitate adaptation and may lead to interpopulation divergence, causing reproductive isolation. We used whole-genome resequencing data from 34 butterflies to detect duplications in two Heliconius species, Heliconius cydno and Heliconius melpomene. Taking advantage of three distinctive signals of duplication in short-read sequencing data, we identified 744 duplicated loci in H. cydno and H. melpomene and evaluated the accuracy of our approach using single-molecule sequencing. We have found that duplications overlap genes significantly less than expected at random in H. melpomene, consistent with the action of background selection against duplicates in functional regions of the genome. Duplicate loci that are highly differentiated between H. melpomene and H. cydno map to four different chromosomes. Four duplications were identified with a strong signal of divergent selection, including an odorant binding protein and another in close proximity with a known wing colour pattern locus that differs between the two species.

Alcohol, drug and related health and wellbeing issues among young people completing an online screen.

OBJECTIVE: Despite high levels of alcohol use, drug use and risky behaviors, rates of help-seeking amongst young people are typically low. This study explored the profile of young people (under the age of 25 years) completing an online screen, assessing substance use problem severity and wellbeing in comparison with adults completing the same screen, so as to inform development of better targeted approaches for this in-need population. METHODS: Between 2012 and 2014, an online alcohol and drug screen was promoted across Australia on a national online counseling service. The screen assessed severity of substance use, mental health and wellbeing. RESULTS: A total of 2939 screens were completed between December 2012 and May 2014, with 18% completed by young people. Young people reported a high severity of substance use problems (44% reported likely drug dependence) and reported significantly poorer mental health and wellbeing than adults completing the screen. This suggests that there is a population of young people in need of support who could be initially engaged through online screening. CONCLUSIONS: Online screening should be a key component of engagement strategies for adolescent and early adult help-seeking.

A tiered model of substance use severity and life complexity: Potential for application to needs-based planning.

BACKGROUND: In order to improve long-term outcomes for individuals with substance use problems, one approach is to adopt a system planning model that considers both addiction severity and life complexities. The tiered approach has been developed and tested to describe systems-level need based on levels of risk and problem severity. METHODS: An existing tiered model was modified to accommodate Australian data, incorporating substance use severity and life complexity. The hypothesis was that tiers would reflect differences in well-being amongst help seekers such that an increase in tier would be associated with a reduction in well-being, suggesting the need for more intensive (and integrated) interventions. The model was tested using 2 data sets of screening data, collected from face-to-face alcohol and other drug (AOD) service (n = 430) and online help (n = 309) seekers, drawn from a larger sample of 2,766 screens. The screen included demographic information and substance use, mental health, and quality of life measures. RESULTS: There was a significant relationship between well-being and tier ranking, suggesting that the model adequately captured elements of severity and complexity that impact on well-being. There were notable differences between the help-seeking populations with a higher proportion of online respondents allocated to lower tiers and more face-to-face respondents allocated to higher tiers. However, there was an overlap in these populations, with more than half of online respondents classified as higher tiers and one fifth of face-to-face respondents classified as lower tiers. This suggests that the model can be used both to assess unmet need in out-of-treatment groups and demand in the absence of dependence in a subpopulation of the face-to-face treatment population. CONCLUSIONS: The tiered model provides a method to understand levels of AOD treatment need and, as part of needs-based planning, may be used to optimize treatment responses and resourcing.

Impact of the Diabetes Inpatient Care and Education (DICE) project and the DICE Care Pathway on patient outcomes and trainee doctor's knowledge and confidence.

AIM: To evaluate the impact of the Diabetes Inpatient Care and Education project and a comprehensive diabetes care pathway, the Diabetes Inpatient Care and Education Care Pathway, on patient outcomes and on the knowledge and confidence of trainee doctors. METHODS: The effect on patient outcomes was evaluated by comparing the National Diabetes Inpatient Audit data before (2012) and after (2013) implementing the Diabetes Inpatient Care and Education project. The impact on trainee doctors was evaluated using the Modified Kirkpatrick model. Just before the project began and again 3 months later, trainee doctors were surveyed to assess their knowledge and confidence in inpatient diabetes care. RESULTS: Patient harm was found to have been reduced significantly when National Diabetes Inpatient Audit data for 2012 and 2013 were compared. Severe hypoglycaemia decreased from 15.4 to 9.7%, medication errors from 56.9 to 21.1% and insulin errors from 31 to 7%. Across the 96 trainee doctors surveyed, the mean (sd) knowledge and confidence scores increased significantly (P < 0.001 for both) from 57.1 (16.8) and 61.8 (14.9) to 68.4 (13.3) and 74.3 (11.7), respectively. CONCLUSION: The Diabetes Inpatient Care and Education project and the Diabetes Inpatient Care and Education Care Pathway improved patient outcomes and the knowledge and confidence of trainee doctors in this hospital. The impact of a similar project in other hospitals needs to be evaluated.

SNPs in Entire Mitochondrial Genome Sequences (≈15.4 kb) and cox1 Sequences (≈486 bp) Resolve Body and Head Lice From Doubly Infected People From Ethiopia, China, Nepal, and Iran But Not France.

Some people host lice on the clothing as well as the head. Whether body lice and head lice are distinct species or merely variants of the same species remains contentious. We sought to ascertain the extent to which lice from these different habitats might interbreed on doubly infected people by comparing their entire mitochondrial genome sequences. Toward this end, we analyzed two sets of published genetic data from double-infections of body lice and head lice: 1) entire mitochondrial coding regions (≈15.4 kb) from body lice and head lice from seven doubly infected people from Ethiopia, China, and France; and 2) part of the cox1 gene (≈486 bp) from body lice and head lice from a further nine doubly infected people from China, Nepal, and Iran. These mitochondrial data, from 65 lice, revealed extraordinary variation in the number of single nucleotide polymorphisms between the individual body lice and individual head lice of double-infections: from 1.096 kb of 15.4 kb (7.6%) to 2 bps of 15.4 kb (0.01%). We detected coinfections of lice of Clades A and C on the scalp hair of three of the eight people from Nepal: one person of the two people from Kathmandu and two of the six people from Pokhara. Lice of Clades A and B coinfected the scalp hair of one person from Atherton, Far North Queensland, Australia. These findings argue for additional large-scale studies of the body lice and head lice of double-infected people.

Second-generation sequencing of entire mitochondrial coding-regions (∼15.4 kb) holds promise for study of the phylogeny and taxonomy of human body lice and head lice.

The Illumina Hiseq platform was used to sequence the entire mitochondrial coding-regions of 20 body lice, Pediculus humanus Linnaeus, and head lice, P. capitis De Geer (Phthiraptera: Pediculidae), from eight towns and cities in five countries: Ethiopia, France, China, Australia and the U.S.A. These data (∼310 kb) were used to see how much more informative entire mitochondrial coding-region sequences were than partial mitochondrial coding-region sequences, and thus to guide the design of future studies of the phylogeny, origin, evolution and taxonomy of body lice and head lice. Phylogenies were compared from entire coding-region sequences (∼15.4 kb), entire cox1 (∼1.5 kb), partial cox1 (∼700 bp) and partial cytb (∼600 bp) sequences. On the one hand, phylogenies from entire mitochondrial coding-region sequences (∼15.4 kb) were much more informative than phylogenies from entire cox1 sequences (∼1.5 kb) and partial gene sequences (∼600 to ∼700 bp). For example, 19 branches had > 95% bootstrap support in our maximum likelihood tree from the entire mitochondrial coding-regions (∼15.4 kb) whereas the tree from 700 bp cox1 had only two branches with bootstrap support > 95%. Yet, by contrast, partial cytb (∼600 bp) and partial cox1 (∼486 bp) sequences were sufficient to genotype lice to Clade A, B or C. The sequences of the mitochondrial genomes of the P. humanus, P. capitis and P. schaeffi Fahrenholz studied are in NCBI GenBank under the accession numbers KC660761-800, KC685631-6330, KC241882-97, EU219988-95, HM241895-8 and JX080388-407.

Risk of norovirus gastroenteritis from consumption of vegetables irrigated with highly treated municipal wastewater--evaluation of methods to estimate sewage quality.

Quantitative microbial risk assessment was used to assess the risk of norovirus gastroenteritis associated with consumption of raw vegetables irrigated with highly treated municipal wastewater, using Melbourne, Australia as an example. In the absence of local norovirus concentrations, three methods were developed: (1) published concentrations of norovirus in raw sewage, (2) an epidemiological method using Melbourne prevalence of norovirus, and (3) an adjustment of method 1 to account for prevalence of norovirus. The methods produced highly variable results with estimates of norovirus concentrations in raw sewage ranging from 10(4) per milliliter to 10(7) per milliliter and treated effluent from 1 × 10(-3) per milliliter to 3 per milliliter (95th percentiles). Annual disease burden was very low using method 1, from 4 to 5 log10 disability adjusted life years (DALYs) below the 10(-6) threshold (0.005-0.1 illnesses per year). Results of method 2 were higher, with some scenarios exceeding the threshold by up to 2 log10 DALYs (up to 95,000 illnesses per year). Method 3, thought to be most representative of Melbourne conditions, predicted annual disease burdens >2 log10 DALYs lower than the threshold (∼ 4 additional cases per year). Sensitivity analyses demonstrated that input parameters used to estimate norovirus concentration accounted for much of the model output variability. This model, while constrained by a lack of knowledge of sewage concentrations, used the best available information and sound logic. Results suggest that current wastewater reuse behaviors in Melbourne are unlikely to cause norovirus risks in excess of the annual DALY health target.

Advice to risk assessors modeling viral health risk associated with household graywater.

Quantitative microbial risk assessment (QMRA) is a valuable tool that can be used to predict the risk associated with human exposure to specific microbial contaminants in water sources. The transparency inherent in the QMRA process benefits discussions between multidisciplinary teams because members of such teams have different expertise and their confidence in the risk assessment output will depend upon whether they regard the selected input data and assumptions as being suitable and/or plausible. Selection of input data requires knowledge of the availability of appropriate data sets, the limitations of using a particular data set, and the logic of using alternative approaches. In performing QMRA modeling and in the absence of directly relevant data, compromises must be made. One such compromise made is to use available Escherichia coli data and apply a ratio of enteric viruses to indicator E. coli in wastewater obtained from prior studies to estimate the concentration of enteric viruses in other wastewater types/sources. In this article, we have provided an argument for why we do not recommend the use of a pathogen to E. coli ratio to estimate virus concentrations in single household graywater and additionally suggested circumstances in which use of such a ratio may be justified.

Alcohol problems among migrants in substance use treatment: the role of drinking patterns in countries of birth.

Migrants' beliefs about when to seek help for alcohol problems may differ from host-country norms. We undertook an audit of 393 cases of screening in specialist alcohol and other drug services in Victoria, Australia, to examine whether alcohol problem severity at the time of help-seeking was influenced by drinking norms in countries of birth. Alcohol problem severity was measured using the Alcohol Use Disorders Identification Test, and World Health Organization per capita alcohol consumption data was used to form three categories of clients relative to Australian consumption: (1) Australian born; (2) born in low alcohol consumption countries; and (3) born in high alcohol consumption countries. Clients born in high consumption countries such as those in Europe and the UK had significantly higher levels of alcohol problem severity at intake compared with Australian-born clients and clients born in low consumption countries. This suggests that clients from high consumption countries might have delayed seeking help in line with the alcohol norms in their country of origin. Screening this group for alcohol problems in primary health care might avoid significant cumulative harm.

Patient-reported outcomes with selpercatinib treatment in patients with RET-driven cancers in the phase I/II LIBRETTO-001 trial.

BACKGROUND: This post-hoc retrospective study describes long-term patient-reported outcomes (PROs) for REarranged during Transfection (RET)-altered non-small-cell lung cancer (NSCLC), medullary thyroid cancer (MTC), non-MTC thyroid cancer (TC), and tumor agnostic (TA) patients (Data cut-off: January 2023) from the LIBRETTO-001 trial. PATIENTS AND METHODS: Patients completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30). Patients with MTC also completed a modified version of the Systemic Therapy-Induced Diarrhea Assessment Tool (mSTIDAT). The proportion of patients with improved, stable, or worsened status after baseline was reported. PROs were summarized at 3 years (cycle 37) post-baseline for the NSCLC and MTC cohorts, and at 2 years (cycle 25) post-baseline for the TC and TA cohorts. Time-to-event outcomes (time to first improvement or worsening and duration of improvement) were reported. RESULTS: The baseline assessment was completed by 200 (63.3%), 209 (70.8%), 50 (76.9%), and 38 (73.1%) patients in the NSCLC, MTC, TC, and TA cohorts, respectively. The total compliance rate was 80%, 82%, 70%, and 85%, respectively. Approximately 75% (NSCLC), 81% (MTC), 75% (TC), and 40% (TA) of patients across all cohorts reported improved or stable QLQ-C30 scores at year 3 (NSCLC and MTC) or year 2 (TC and TA) with continuous selpercatinib use. Across cohorts, the median time to first improvement ranged from 2.0 to 19.4 months, the median duration of improvement ranged from 1.9 to 28.2 months, and the median time to first worsening ranged from 5.6 to 44.2 months. The total compliance rate for the mSTIDAT was 83.7% and the proportion of patients with MTC who reported diarrhea on the mSTIDAT was reduced from 80.8% at baseline to 35.6% at year 3. CONCLUSIONS: A majority of patients with RET-driven cancers improved or remained stable on most QLQ-C30 domains, demonstrating favorable health-related quality of life as measured by the QLQ-C30 during long-term treatment with selpercatinib.