Surgical management of rare hepatobiliary sarcomas in a regional teaching hospital: a collaborative model for optimal care with case studies.

Sarcomas are challenging and conventionally referred to sarcoma specialist centres. In select cases with required surgical expertise, collaboration with a quaternary sarcoma centre rather than an upfront transfer of care may reduce logistic challenges without compromising patient care.We present a case series of three rare tumours of hepatobiliary origin-two cases of undifferentiated embryonal liver sarcoma in adults and one case of follicular dendritic sarcoma of the cystic lymph node.All three patients underwent surgery in a non-sarcoma specialist centre by hepatobiliary specialist surgeons with concurrent remote referrals to a sarcoma specialist quaternary centre. Both centres belong to the same cluster. R0 resection and no significant postoperative morbidity were achieved. All three patients currently remain disease-free.The unique and integrated healthcare systems within Singapore render cross-institution management possible. This case series suggests that an established setup for cross-centre collaboration facilitates wholistic patient care with good outcomes.

Reliability of ChatGPT in automated essay scoring for dental undergraduate examinations.

BACKGROUND: This study aimed to answer the research question: How reliable is ChatGPT in automated essay scoring (AES) for oral and maxillofacial surgery (OMS) examinations for dental undergraduate students compared to human assessors? METHODS: Sixty-nine undergraduate dental students participated in a closed-book examination comprising two essays at the National University of Singapore. Using pre-created assessment rubrics, three assessors independently performed manual essay scoring, while one separate assessor performed AES using ChatGPT (GPT-4). Data analyses were performed using the intraclass correlation coefficient and Cronbach's α to evaluate the reliability and inter-rater agreement of the test scores among all assessors. The mean scores of manual versus automated scoring were evaluated for similarity and correlations. RESULTS: A strong correlation was observed for Question 1 (r = 0.752-0.848, p < 0.001) and a moderate correlation was observed between AES and all manual scorers for Question 2 (r = 0.527-0.571, p < 0.001). Intraclass correlation coefficients of 0.794-0.858 indicated excellent inter-rater agreement, and Cronbach's α of 0.881-0.932 indicated high reliability. For Question 1, the mean AES scores were similar to those for manual scoring (p > 0.05), and there was a strong correlation between AES and manual scores (r = 0.829, p < 0.001). For Question 2, AES scores were significantly lower than manual scores (p < 0.001), and there was a moderate correlation between AES and manual scores (r = 0.599, p < 0.001). CONCLUSION: This study shows the potential of ChatGPT for essay marking. However, an appropriate rubric design is essential for optimal reliability. With further validation, the ChatGPT has the potential to aid students in self-assessment or large-scale marking automated processes.

Fear really comes from the unknowns: exploring the impact of HIV stigma and discrimination on quality of life for people living with HIV in Singapore through the minority stress model.

Background Structural stigma and institutionalised discrimination towards people living with HIV remain pervasive in many settings. However, qualitative explorations of experiences of stigma, health and social service engagement, and quality of life among people living with HIV in Singapore remain under-researched. Methods Semi-structured interviews were conducted with 73 participants in Singapore. These included 56 people living with HIV (30 men who have sex with men, 23 heterosexual men, and 3 women) and 17 stakeholders including healthcare professionals and other allied workers. Interviews focused on participant perspectives or experiences of HIV diagnosis, navigating healthcare, attitudes towards HIV, and impact of HIV on relationships. Data were analysed through inductive thematic analysis. Results Our findings were framed within a minority stress model, highlighting the distal and proximal stressors relating to living with HIV. With regard to distal stressors, participants highlighted that they had experienced or were aware of institutionalised discrimination towards people living with HIV across various aspects of their lives. These included experiences - overt and covert - of discrimination in education, workplace, and healthcare settings. With regard to proximal stressors, participants highlighted the role of anticipated stigma and the stress of concealment. This included participants' fear of potential legal and/or social repercussions resulting from the disclosure of their HIV status, actions that they may not be able to anticipate and articulate. Although employers may not overtly discriminate, the fear of such anticipated discrimination influenced decisions to conceal HIV status in job applications and workplaces. This restricted agency for the people living with HIV in our study by affecting their regular medical follow-ups, socialising behaviours, and overall quality of life. Consequently, many participants felt that concealment of their status, and forgoing potential educational, employment, and even health opportunities, were the only ways of protecting themselves from such forms of stigma and discrimination. Conclusions This study found that anticipated stigma and discrimination diminished the quality of life of people living with HIV in Singapore. Implementing an anti-discrimination framework could address the unpredictability and alleviate the manifold unknowns of anticipated stigma.

Tandem mass spectral metabolic profiling of 54 actinobacterial strains and their 459 mutants.

Natural products encompass a diverse range of compounds with high impact applications in consumer care, agriculture and most notably, therapeutics. However, despite the expansive chemical repertoire indicated in genomic information of microbes, only a small subset can be obtained under laboratory conditions. To increase accessible chemical space and realize Nature's full chemical potential, a multi-pronged genetic- and cultivation-based strategy has been employed to activate and upregulate natural product biosyntheses in native and heterologous strains. This data descriptor documents a characterized collection of 2,138 liquid chromatography-tandem mass spectrometry (LC/MS-MS) spectra of fermentation extracts from 54 native actinobacterial strains collected from soil and marine environments in Singapore, and their 459 activated mutants in 3 to 5 media. A total of 743 unique metabolites have been identified, with the activated mutants demonstrating an approximately 2-fold expansion in accessible chemical space over wild type strains. Interrogating this expanded chemical diversity with cheminformatic tools can provide direction for the discovery of novel natural products with desirable functional activity.

Sleeping behaviors are determined by lockdown and not work-from-home arrangements.

Lockdowns and work-from-home arrangements became abrupt realities for people at an unprecedented scale during the COVID-19 pandemic. Here, considering the case of Singapore, we study how peoples' sleep behaviors-which are closely linked to their mental health-varied as a result. However, different from most studies, this paper uses household electricity consumption data to estimate the sleeping behaviors of nearly 10,000 households in the city-state. With this, we study how the residents' daily sleep durations changed dynamically during the lockdown and afterwards when restrictions were progressively eased, and show their strong connection to major changes in the public health policy and current events during this period. Our results add to the evidence for the stress endured by the populace during the lockdown; we find that sleep durations for all demographics, while higher than before the lockdown, became more fluctuating across days. A major, and surprising, finding is that it was the lockdown that determined the residents' sleeping duration, rather than simply working-from-home arrangements. That is, the sleeping durations largely reverted back to their pre-pandemic levels when the lockdown was lifted-with small variations based on demographic factors-although a vast majority of people continued to work from home. This highlights the resilience of the daily routines of the Singapore populace. While providing insights into how a pandemic influences the dynamics of urban sleep patterns, our finding also has broader implications regarding the efficiency of the workforce, suggesting that concerns about asynchronous work routines and productivity may be overblown.

Consumption of different types of meat and the risk of chronic limb-threatening ischemia: the Singapore Chinese Health Study.

BACKGROUND: Although red meat consumption has been associated with risk of atherosclerotic coronary artery disease and stroke, no prospective study has examined this with the risk of chronic limb-threatening ischemia (CLTI). METHODS: In a prospective study of 63,257 Chinese in Singapore, who were aged 45-74 years old at recruitment, diet was assessed via a validated semi-quantitative food frequency questionnaire. Incident CLTI cases were ascertained via linkage with nationwide hospital records for lower extremity amputation or angioplasty for peripheral arterial disease. Multivariable Cox models were used to examine associations between quartiles of meat intake and CLTI risk. RESULTS: After a mean follow-up of 18.8 years, there were 1069 cases of CLTI. Higher intake of red meat intake was associated with increased risk of CLTI in a stepwise manner. Comparing extreme quartiles of red meat intake, the hazard ratio (HR) for the association with CLTI risk was 1.24 [95% confidence interval (CI) = 1.03-1.49; P-trend = 0.02]. In stratified analysis, red meat intake had a stronger association with CLTI risk among those without diabetes [HR (95% CI) comparing extreme quartiles = 1.41 (1.10-1.80); P-trend = 0.03] than among those with diabetes at baseline [HR (95% CI) comparing extreme quartiles = 1.04 (0.79-1.38); P-trend = 0.05] (P-interaction = 0.03). Otherwise, the associations were not different by sex, BMI, smoking status, hypertension, alcohol consumption, or history of cardiovascular diseases. Using a theoretical model in substitution analysis that substituted three servings per week of red meat with poultry or fish/shellfish, the relative risk of CLTI was reduced by 13-14%. CONCLUSIONS: Consumption of red meat was associated with higher CLTI risk in this Asian cohort. Substituting red meat with poultry or fish/shellfish may reduce this risk.

Effectiveness of Wolbachia-mediated sterility coupled with sterile insect technique to suppress adult Aedes aegypti populations in Singapore: a synthetic control study.

BACKGROUND: Incompatible insect technique (IIT) coupled with sterile insect technique (SIT) via the release of sterile male Wolbachia-infected mosquitoes is a promising tool for Aedes-borne disease control. Yet, real-world evidence on the suppressive effectiveness of IIT-SIT on mosquito abundance remains mostly limited to small semi-rural village and suburban localities over short trial durations. However, a large proportion of Aedes-borne diseases occur in dense, urban, and high-rise locations, limiting the applicability of previous studies for these settings with high disease burden. The sustainability and use of this technology over multiple years is also unknown. METHODS: In this synthetic control study, we conducted a large-scale, field trial of IIT-SIT targeting Aedes aegypti among high-rise public housing estates in Singapore, an equatorial city state. Routinely collected data from a large, nationwide surveillance system of 57 990 unique mosquito traps, combined with a high-dimensional set of anthropogenic and environmental confounders were collected to ascertain mosquito abundance and its key drivers. Four townships were selected as the intervention groups (approximate population size of 607 872 residents as of 2022), wherein interventions that combined ITT with SIT over the course of the study period were conducted. Townships were subject to releases of wAlbB-SG male A aegypti mosquitoes twice a week. Data were assessed over the course of epidemiological weeks (EWs), which provide the finest temporal resolution of recorded Wolbachia release schedule and mosquito abundance data. A novel synthetic control framework was then developed to account for the non-randomised and staggered adoption setting of the intervention across trial sectors to identify the direct suppressive effectiveness of IIT-SIT on female A aegypti populations, the spillover effects in non-release areas, and the effect of the intervention on other mosquito populations such as Aedes albopictus. Furthermore, we recalculated effectiveness in terms of calendar time, time since intervention, and over multiple sites to examine heterogeneities in IIT-SIT effectiveness. FINDINGS: Between EW27 2018 and EW26 2022, Wolbachia releases were conducted across 117 sectors, of which 97 had sufficient trap data, which were collected between EW8 2019 and EW26 2022. We found that Wolbachia-based IIT-SIT reduced wild-type female A aegypti populations by a mean of 62·01% (95% CI 60·68 to 63·26) by 3 months, 78·40% (77·56 to 79·18) by 6 months, and 91·32% (90·95 to 91·66) by at least 18 months of releases. We also found a smaller but non-negligible spillover suppression effect that gradually increased over time (mean spillover intervention effectiveness 61·02% [95% CI 57·89 to 63·72] in adjacent, non-intervention sectors). Although no consistent change in A albopictus populations was seen across the four intervention townships after Wolbachia releases, the average intervention effectiveness on the A albopictus population across all release sectors was -25·80% (95% CI -30·93 to -21·05), which was driven by increases in two towns. INTERPRETATION: Our results demonstrate the potential of IIT-SIT for strengthening long-term, large-scale vector control in tropical cities, where dengue burden is the greatest. The effect of these interventions in different geographical settings should be assessed in future work. FUNDING: Singapore's Ministry of Finance, Ministry of Sustainability and the Environment, National Environment Agency, and National Robotics Program.

Gut metagenomes of Asian octogenarians reveal metabolic potential expansion and distinct microbial species associated with aging phenotypes.

While rapid demographic changes in Asia are driving the incidence of chronic aging-related diseases, the limited availability of high-quality in vivo data hampers our ability to understand complex multi-factorial contributions, including gut microbial, to healthy aging. Leveraging a well-phenotyped cohort of community-living octogenarians in Singapore, we used deep shotgun-metagenomic sequencing for high-resolution taxonomic and functional characterization of their gut microbiomes (n = 234). Joint species-level analysis with other Asian cohorts identified distinct age-associated shifts characterized by reduction in microbial richness, and specific Alistipes and Bacteroides species enrichment (e.g., Alistipes shahii and Bacteroides xylanisolvens). Functional analysis confirmed these changes correspond to metabolic potential expansion in aging towards alternate pathways synthesizing and utilizing amino-acid precursors, vis-à-vis dominant microbial guilds producing butyrate in gut from pyruvate (e.g., Faecalibacterium prausnitzii, Roseburia inulinivorans). Extending these observations to key clinical markers helped identify >10 robust microbial associations to inflammation, cardiometabolic and liver health, including potential probiotic species (e.g., Parabacteroides goldsteinii) and pathobionts (e.g., Klebsiella pneumoniae), highlighting the microbiome's role as biomarkers and potential targets for promoting healthy aging.

Knowledge, attitudes, and perceptions of residents towards Hospital-at-Home (HaH) and its role in residency training.

BACKGROUND: With the proliferation of Hospital at Home (HaH) programmes globally, there is a need to equip junior doctors with the skills necessary for provision of HaH care. The ideal training structure and clinical requirements for junior doctors to be considered competent in providing HaH care is still poorly understood. This study examines the perceptions of junior doctors towards HaH, and aims to determine the learning needs that might be helpful for future curriculum planning. METHODS: We conducted a cross-sectional study of residents at the National University Health System (NUHS) Singapore. Using a 45-item questionnaire, we explored the knowledge, attitudes and perceptions of residents towards HaH, and their interest in participating in HaH as part of residency training. RESULTS: One hundred six residents responded. Overall knowledge and attitudes were mostly average. Perceptions were neutral but comparatively lower in the domains of safety, efficiency and equity. 69% of residents showed a positive attitude and interest to participate in HaH as part of residency rotations. 80% of respondents were keen to have a 2-4 week rotation incorporated into routine training. Demographic factors that influenced higher scores in various domains included type of residency programme and years of work experience. CONCLUSION: Our findings suggest that residents are interested in participating in HaH. Incorporation of HaH rotations in residency training will allow juniors doctors to receive greater exposure and training in the skills specific to provision of HaH care. Further studies on the introduction of a HaH curriculum and Entrustable Professional Activities (EPAs) specific for HaH in residency training may be useful to to ensure that we have a competent HaH workforce that can support and keep up with the growth of HaH globally.

Long-term outcomes of subthalamic nucleus deep brain stimulation for Parkinson's disease in Singapore.

Introduction: Subthalamic nucleus deep brain stimulation (STN-DBS) is a proven treatment modality for Parkinson's disease (PD), reducing dyskinesia and time spent in the "OFF" state. This study evaluates the long-term outcomes of STN-DBS in PD patients up to 10 years post-surgery in Singapore. Method: We conducted a retrospective review of Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores, activities of daily living (ADLs), disease milestones, dopaminergic drug prescriptions, and adverse events in patients before and after STN-DBS surgery. Results: A total of 94 PD patients who underwent bilateral STN-DBS were included. STN-DBS reduced time in the "OFF" state by 36.9% at 1 year (P=0.034) and 40.9% at 5 years (P=0.006). Time with dyskinesia did not significantly change. Levodopa equivalent daily dose was reduced by 35.1% by 5 years (P<0.001). MDS-UPDRS-II and III scores increased from 5 years post-DBS by 40.5% and 35.4%, respectively. Independence in ADLs decreased, though not significantly. The prevalence of frequent falls increased at 5 years. Surgery- and device-related adverse events were uncommon and generally mild. Conclusion: STN-DBS provides sustained relief from motor complications and reduced medication requirements in PD patients in Singapore. This study highlights STN-DBS as an effective treatment option, significantly enhancing the quality of life for those with PD.

Repetitive transcranial magnetic stimulation for major depression and obsessive-compulsive disorders in Singapore.

Introduction: Repetitive transcranial magnetic stimulation (rTMS) is used for treatment-resistant major depressive disorder (MDD) and obsessive-compulsive disorder (OCD), but there are few studies on patient outcomes in Southeast Asia. In this study, we describe the clinical profile and outcome of patients with MDD and OCD treated with rTMS in Singapore. Method: A naturalistic retrospective study of 71 patients (inpatient and outpatient) who received rTMS treatment between June 2018 and April 2023 was conducted. The depressive and obsessive outcome rating scales used were clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS), Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Clinical Global Impressions-Severity (CGI-S) and self-rated Depression Anxiety and Stress Scale-21 (DASS-21). Results: Clinician-rated and self-rated mood and general condition improved significantly. MADRS mean score improved from 28.1 (standard deviation [SD] 7.3) to 20.7 (SD 10.1) (P<0.0001) (20.8% response rate/17% remission rate). CGI-S mean 4.6 (SD 0.8) improved to 3.3 (SD 1.2) (P<0.0001). DASS-21 total mean improved from 67.3 (SD 24.6) to 49.6 (SD 28.0) (P<0.0001). Y-BOCS mean score displayed a trend towards improvement from 30.1 (SD 7.5) to 27.2 (SD 6.9) (P=0.799). However, 44.4% of patients with OCD responded with a minimal 20% reduction in baseline Y-BOCS. Moreover, the subgroup of 35.8% of patients with less than 30 rTMS sessions had contributed disproportionately to nonresponse (85.7%). Patients who received rTMS treatment (>30 sessions) had a trend of larger improvement of MADRS score when compared to patients with (≤30 sessions) (9.4 [SD 9.7] versus 3.8 [SD 12.3] [P=0.078]). Conclusion: Response and remission rates for MDD and OCD suggest patients have a good response to rTMS treatment. Dosing longer rTMS sessions after an acute course helps to maximise effectiveness. Further research to determine predictors of outcome and characterise clinical features of late responders to target treatment more effectively is recommended.

Patients' Expectations of Doctors' Clinical Competencies in the Digital Health Care Era: Qualitative Semistructured Interview Study Among Patients.

BACKGROUND: Digital technologies have impacted health care delivery globally, and are increasingly being deployed in clinical practice. However, there is limited research on patients' expectations of doctors' clinical competencies when using digital health care technologies (DHTs) in medical care. Understanding these expectations can reveal competency gaps, enhance patient confidence, and contribute to digital innovation initiatives. OBJECTIVE: This study explores patients' perceptions of doctors' use of DHTs in clinical care. Using Singapore as a case study, it examines patients' expectations regarding doctors' communication, diagnosis, and treatment skills when using telemedicine, health apps, wearable devices, electronic health records, and artificial intelligence. METHODS: Findings were drawn from individual semistructured interviews with patients from outpatient clinics. Participants were recruited using purposive sampling. Data were analyzed qualitatively using thematic analysis. RESULTS: Twenty-five participants from different backgrounds and with various chronic conditions participated in the study. They expected doctors to be adept in handling medical data from apps and wearable devices. For telemedicine, participants expected a level of assessment of their medical conditions akin to in-person consultations. In addition, they valued doctors recognizing when a physical examination was necessary. Interestingly, eye contact was appreciated but deemed nonessential by participants across all age bands when electronic health records were used, as they valued the doctor's efficiency more than eye contact. Nonetheless, participants emphasized the need for empathy throughout the clinical encounter regardless of DHT use. Furthermore, younger participants had a greater expectation for DHT use among doctors compared to older ones, who preferred DHTs as a complement rather than a replacement for clinical skills. The former expected doctors to be knowledgeable about the algorithms, principles, and purposes of DHTs such as artificial intelligence technologies to better assist them in diagnosis and treatment. CONCLUSIONS: By identifying patients' expectations of doctors amid increasing health care digitalization, this study highlights that while basic clinical skills remain crucial in the digital age, the role of clinicians needs to evolve with the introduction of DHTs. It has also provided insights into how DHTs can be integrated effectively into clinical settings, aligning with patients' expectations and preferences. Overall, the findings offer a framework for high-income countries to harness DHTs in enhancing health care delivery in the digital era.

Screen time and social-emotional skills in preschoolers with developmental, behavioural or emotional issues in Singapore.

Introduction: This study aimed to determine patterns of screen viewing time (SVT) in preschool children with developmental, behavioural or emotional (DBE) issues, and to identify its relationship with social-emotional development. Method: This cross-sectional study involved children aged 0-5 years who were referred to a developmental paediatric clinic for DBE issues. Parents completed a screen time questionnaire, and the Devereux Early Childhood Assessment-Clinical (DECA-C) question-naire which assessed the social-emotional competence of the children. Data were analysed using logistic regression, correlational analyses and tests of comparison. Results: Among 225 children (mean age: 32.4 months), mean daily SVT was 138 minutes. More than half (51.1%) of the children had clinical features of language delay, while 26.6% had features suggestive of autism spectrum disorder. Screen time was first introduced at a mean age of 13.8 months, with 32.4% of children previously experiencing higher SVT. Compared to SVT introduction after 1 year of age, SVT in the first 12 months was primarily to facilitate feeding (P<0.05). Children with higher past SVT had poorer attention, more aggression, and increased behavioural concerns. Children with DBE issues have significantly more screen time than same-aged peers. Conclusion: Children with DBE issues are exposed to SVT at a very young age and have significantly more screen time than their peers. It is crucial to guide parents to reduce SVT in early childhood, particularly around mealtimes.

Trends in fluid overload-related hospitalisations among patients with diabetes mellitus The impact of chronic kidney disease.

Introduction: Fluid overload is a known complication in patients with diabetes mellitus, particularly those with cardiovascular and/or chronic kidney disease (CKD). This study investigates the impact of fluid overload on healthcare utilisation and its association with diabetes-related complications. Method: Electronic medical records from the SingHealth Diabetes Registry (2013-2022) were analysed. Hospitalisations due to fluid overload were identified using International Classification of Diseases, 10th Revision (ICD-10) discharge codes. Trends were examined using Joinpoint regression, and associations were assessed with generalised estimating equation models. Results: Over a period of 10 years, 259,607 individuals treated at primary care clinics and tertiary hospitals were studied. The incidence of fluid overload-related hospitalisations decreased from 2.99% (n=2778) in 2013 to 2.18% (n=2617) in 2017. However, this incidence increased from 2.42% (n=3091) in 2018 to 3.71% (n=5103) in 2022. The strongest associations for fluid overload-related hospitalisation were found with CKD stages G5 (odds ratio [OR] 6.61, 95% confidence interval [CI] 6.26-6.99), G4 (OR 5.55, 95% CI 5.26-5.86) and G3b (OR 3.18, 95% CI 3.02-3.35), as well as with ischaemic heart disease (OR 3.97, 95% CI 3.84-4.11), acute myocardial infarction (OR 3.07, 95% CI 2.97-3.18) and hypertension (OR 3.90, 95% CI 3.45-4.41). Additionally, the prevalence of stage G5 CKD among patients with fluid overload increased between 2018 and 2022. Conclusion: Our study revealed a significant increase in fluid overload-related hospitalisations and extended lengths of stay, likely driven by severe CKD. This underscores an urgent need for initiatives aimed at slowing CKD progression and reducing fluid overload-related hospitalisations in diabetes patients.

Demographic diversity of participants in clinical trials conducted in Singapore.

Introduction: The under-representativeness of participants in clinical trials limits the generalisability of results. This review evaluates the representative-ness within pharmaceutical randomised controlled trials (RCTs) in Singapore. Method: Four bibliographic databases were searched for papers on pharmaceutical RCTs which included Singapore adults (≥18 years old), published between 2017 and 2022. The demographic characteristics of study participants were compared against the population in the 2020 Singapore census. Recruitment strategies and authors' comments on the generalisa-bility of their findings were reviewed. Results: Thirty-three publications were included (19 Singapore-only studies and 14 multiregional trials which included Singapore). Where data were available, we found that females and Indians were under-represented compared to the census (41.3% versus [vs] 51.1%, P<0.05; 7.3% vs 9.0%, P<0.05). Ethnic diversity varied between individual studies, and almost half (46.2%) of Singapore-only studies achieved census levels. However, more than one-third of the trials provided no data (31.6%) or partial data (5.3%) on ethnicity. Half of the multiregional publications stated the number of participants recruited from Singapore, but only 1 reported any detail beyond Asian participants. Recruitment strategies were mentioned in fewer than half (42.4%), and less than a quarter (24.2%) commented on sample representative-ness or the external validity of the evidence generated. Conclusion: There is room for improvement regarding the recruitment of RCT participants in Singapore, with particular attention to female gender and Indian ethnicity. Demographic data should also be presented in full. RCTs should be designed and reported such that clinicians can ascertain the generalisability to the Singapore population and the potential benefits from the studied interventions in clinical practice.