Exploration of patients' preference for modalities of care among peritoneal dialysis patients in Singapore: a single-center experience.

INTRODUCTION: Peritoneal dialysis (PD) is home-based dialysis therapy and therefore a suitable modality for kidney failure patients, particularly, during the COVID-19 pandemic. The present study examined patients' preferences for different PD-related services. METHODS: This was a cross-sectional survey study. Anonymized data from PD patients followed up at a single center in Singapore were collected using an online platform. The study focused on telehealth services, home visits, and monitoring of quality-of-life (QoL). RESULTS: A total of 78 PD patients responded to the survey. The majority of participants were Chinese (76%), married (73%), and between 45 and 65 years old (45%). The in-person visit was preferred over teleconsultation for consultation with nephrologists (68% versus 32%), counseling for kidney disease and dialysis by renal coordinators (59%), whereas the telehealth service was favored over in-person visit for dietary counseling (60%) and medication counseling (64%). Most participants (81%) preferred medication delivery over self-collection, and the acceptable turnaround time was 1 week. Sixty percent would like to have a regular home visit, but 23% refused such visits. The preferred frequency of home visits was one-to-three visits within the first 6 months (74%) and then 6 monthly for subsequent visits (40%). The majority of participants (87%) agreed with QoL monitoring, and the preferred frequency of monitoring varied between 6 monthly (45%) and yearly (40%). Participants also indicated three key areas in research to improve QoL, such as the development of artificial kidneys, portable PD devices, and simplification of PD procedure. Participants also would like to see improvement in two main areas of PD services, such as delivery service for PD solutions and social (instrumental, informational, and emotional) support. CONCLUSIONS: Most PD patients preferred in-person visits with nephrologists or renal coordinators; however, they favored telehealth services with dieticians and pharmacists. PD patients also welcomed home visit service and QoL monitoring. Future studies should confirm these findings.

PRMT5 and CDK4/6 inhibition result in distinctive patterns of alternative splicing in melanoma.

Drugs targeting cyclin-dependent kinases 4 and 6 (CDK4/6) are promising new treatments for melanoma and other solid malignancies. In studies on CDK4/6 inhibitor resistance, protein arginine methyltransferase 5 (PRMT5) regulation of alternative splicing was shown to be an important downstream component of the CDK4/6 pathway. However, the full effects of inhibition of CDK4/6 on splicing events in melanoma and the extent to which they are dependent on PRMT5 has not been established. We performed full-length mRNA sequencing on CHL1 and A375 melanoma cell lines treated with the CDK4/6 inhibitor palbociclib and the PRMT5 inhibitor GSK3326595 and analysed data for differential gene expression and differential pre-mRNA splicing induced by these agents. Changes in gene expression and RNA splicing were more extensive under PRMT5 inhibition than under CDK4/6 inhibition. Although PRMT5 inhibition and CDK4/6 inhibition induced common RNA splicing events and gene expression profiles, the majority of events induced by CDK4/6 inhibition were distinct. Our findings indicate CDK4/6 has the ability to regulate alternative splicing in a manner that is distinct from PRMT5 inhibition, resulting in divergent changes in gene expression under each therapy.

Modeling Methods in Craniofacial Virtual Surgical Planning.

Despite the widespread use of virtual surgical planning (VSP), few papers describe the modeling methods used to generate the digital simulations that underpin VSP. This paper aims to review the modeling methods that are currently available for use in VSP and the implications of their use in clinical practice. A literature review was undertaken of the two broad categories of modeling techniques; contour-based planning-namely mirroring from the contralateral side, templating from a normative database, and extrapolation from surrounding landmarks-and occlusal-based planning (OBP). The indications for each modeling method were discussed, including mandibular/maxillary reconstruction, pediatric craniofacial surgery, and orthognathic, as well as the limitations to the accuracy of modeling types. Unilateral defects of the upper/midface, wherein contour accuracy is paramount, are best reconstructed using mirroring methods, whereas bilateral defects-or cases with asymmetry due to craniofacial dysmorphology-are most suited to normative-data-based methods. Cases involving resection of the alveolar margin, in which functional occlusion is the primary outcome are best managed with OBP. Similarly, orthognathic surgery typically uses OBP, although complex cases involving asymmetry, such as clefts, may benefit from a combination of OBP and normative data methods. The choice of modeling methods is, therefore, largely driven by the defect type and the goals of reconstruction.

Denosumab for central giant cell granuloma in an Australian tertiary paediatric centre.

BACKGROUND: Central giant cell granulomas (CGCG) are rare osteolytic, benign but often locally aggressive tumours of bone. Surgical curettage may not be possible in extensive lesions and resection carries high morbidity, especially in growing children, and previous medical therapies have had variable efficacy and high recurrence rates. Interruption of receptor activator of nuclear factor-kappa B ligand (RANKL) signalling holds promise as an effective therapeutic strategy for these tumours. AIMS: To evaluate the efficacy and safety of our protocol for denosumab treatment of CGCG in children. METHODS: Retrospective review of 4 patients treated with denosumab using a standardised protocol for CGCG in a tertiary paediatric centre. Denosumab 70 mg/m2 was given 4-weekly, followed by 2 doses of zoledronate 0.025 mg/kg, aimed at preventing rebound hypercalcaemia. RESULTS: Treatment of CGCG resulted in metabolic remission in all patients, but recurrence, detected by positron emission tomography (PET), occurred at 6 months in three patients and 12 months in one patient. Three patients developed symptomatic hypercalcaemia 4-5 months and one patient asymptomatic hypercalcaemia 7 months after cessation of denosumab, with 3 requiring additional bisphosphonate treatment. CONCLUSIONS: Denosumab produced a radiological and metabolic response in our patients, but metabolic recurrence occurred in all patients. PET imaging was effective for monitoring treatment response and early detection of recurrence. Incidence of rebound hypercalcaemia in this paediatric cohort was high. We present proposed changes to our protocol with the aim of producing sustained remission and preventing rebound hypercalcaemia.

Clinical and Radiologic Response of Central Giant Cell Granuloma to Denosumab: A 6-Year Prospective Observational Study.

Central giant cell granuloma (CGCG) is a rare lesion of the jaw occurring in young adults and adolescents. Surgery, the traditional mainstay of therapy, is associated with significant morbidity. Denosumab, a humanised monoclonal antibody to RANKL, is effective in a related entity, giant cell tumour of bone (GCTB), but experience in the more indolent CGCG is limited. This prospective observational study of all denosumab-treated CGCG at a tertiary referral centre (2015-2021) aimed to evaluate the safety, efficacy and recurrence risk using denosumab in CGCG at lower-frequency dosing than used for GCTB. All received standardised, time-limited courses of denosumab 120 mg with stepwise increase in dosing interval based on response. They were followed for up to 75 months using a radiation-minimising protocol: 3-monthly clinical, biochemical and radiological assessment (orthopantomograms, cone beam CT). Eight patients, median age 20.5 years [IQR 6], received 13 initial doses [IQR 10] of denosumab 120 mg. Radiologic response was seen after 5.5 doses [IQR 4.5]: ossification in all and size reduction in three. Recurrence occurred in four of seven completing therapy, observed 12 months post-cessation [IQR 6.5]. Larger baseline size, aggressive subtype and fewer than 12 initial doses were more common in the recurrence group. There was no osteonecrosis of the jaw. Hypocalcaemia occurred in one receiving modified dosing. This study represents the largest, most diverse cohort of denosumab-treated CGCG with the longest follow-up in literature. It demonstrates the efficacy of lower-frequency, time-restricted course of denosumab but highlights the risk of recurrence. Long-term follow-up is critical.

Effectiveness and acceptability of a multidisciplinary approach in improving the care of patients with advanced chronic kidney disease: a pilot study.

OBJECTIVE: This study aimed at determining the feasibility of conducting a large-scale pragmatic effectiveness study on the implementation of multidisciplinary care (MDC) program for patients with advanced chronic kidney disease (CKD). METHODS: This is a single-arm pre-post intervention design pilot study over 12 months. Participants with an estimated glomerular filtration rate (eGFR) between 11 and 20 ml/min/1.73m2 were screened and recruited at the initial MDC clinic visit and followed for 12 months. Clinical parameters, KDQOL™-36, questionnaires, and interviews were collected, administered, and analysed for enrolment and completion rates, baseline characteristics, implementation fidelity, adherence to CKD interventions, eGFR decline, CKD complications, health-related quality of life, and participants' acceptability of the program. RESULTS: The study enrolment and completion rates were 43.1% (50/116 screened) and 66.0% (33/50 recruited) respectively. The participants had a mean age of 68.5 years (SD9.0) and a mean eGFR of 15.4 ml/min/1.73m2(3.2). After 12 months of MDC program, there was increased adherence to CKD interventions (difference  - 0.6(1.0), 95%CI  - 1.1,  - 0.1, p = 0.02). There was good participants' acceptability of the program with participants being more satisfied with the waiting time and having a better understanding of kidney failure after attending the program. No difference in the eGFR decline noted (difference 0.0 ml/min/1.73m2(5.3), 95%CI  - 1.9, 1.9, p = 1.00). CONCLUSION: Our pilot data suggest increased adherence to CKD interventions and good acceptability to MDC program, albeit no difference in eGFR decline probably because of the small sample size. However, reasons for overall low enrolment and completion rates need to be explored and addressed while designing a future large-scale randomised controlled trial.

Patient Decision Aid Development for Older Adults With End-Stage Kidney Disease in Singapore.

INTRODUCTION: In managing end-stage kidney disease (ESKD), older adults face a decision regarding whether to undergo dialysis or manage symptoms through kidney supportive care (KSC). This article describes the development of a patient decision aid (PDA) that is designed specifically for older adults with ESKD. METHODS: The decision context of the PDA was to choose a treatment between hemodialysis, peritoneal dialysis, and KSC. The development process used insights obtained from qualitative interviews with patients, informal caregivers, and health care providers. The PDA was then developed in English and Mandarin and was pilot-tested with patients, caregivers, and health care providers. We finalized the PDA based on feedback from pilot testing and performed a preliminary evaluation based on the International Patient Decision Aid Standards (IPDASi v4.0) criteria. RESULTS: The final PDA consists of 2 booklets and a video. During pilot testing, patients and caregivers reported high levels of ease of understanding and usefulness with ≥92.5% providing agree/strongly agree responses for the "Content"-related criteria, and ≥75% providing agree/strongly agree responses for the "Development Process and Effectiveness"-related criteria. The final PDA met 10 of 12 IPDASi v4.0 criteria. CONCLUSIONS: This PDA was found useful during pilot-testing. It will be used during renal counseling in Singapore to help older adults with ESKD and their caregivers make informed decisions on which treatment option is best for the patients.

CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory.

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, whereas their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic, and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunologic T-cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous antitumor T-cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor T cells, and induced a retinoblastoma-dependent T-cell phenotype supportive of favorable responses to immune checkpoint blockade in patients with melanoma. Together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost antitumor T-cell immunity. SIGNIFICANCE: Immunologic memory is critical for sustained antitumor immunity. Our discovery that CDK4/6 inhibitors drive T-cell memory fate commitment sheds new light on their clinical activity, which is essential for the design of clinical trial protocols incorporating these agents, particularly in combination with immunotherapy, for the treatment of cancer.This article is highlighted in the In This Issue feature, p. 2355.

Combined BRAF, MEK, and CDK4/6 Inhibition Depletes Intratumoral Immune-Potentiating Myeloid Populations in Melanoma.

Combined inhibition of BRAF, MEK, and CDK4/6 is currently under evaluation in clinical trials for patients with melanoma harboring a BRAFV600 mutation. While this triple therapy has potent tumor-intrinsic effects, the impact of this combination on antitumor immunity remains unexplored. Here, using a syngeneic BrafV600ECdkn2a-/-Pten-/- melanoma model, we demonstrated that triple therapy promoted durable tumor control through tumor-intrinsic mechanisms and promoted immunogenic cell death and T-cell infiltration. Despite this, tumors treated with triple therapy were unresponsive to immune checkpoint blockade (ICB). Flow cytometric and single-cell RNA sequencing analyses of tumor-infiltrating immune populations revealed that triple therapy markedly depleted proinflammatory macrophages and cross-priming CD103+ dendritic cells, the absence of which correlated with poor overall survival and clinical responses to ICB in patients with melanoma. Indeed, immune populations isolated from tumors of mice treated with triple therapy failed to stimulate T-cell responses ex vivo While combined BRAF, MEK, and CDK4/6 inhibition demonstrates favorable tumor-intrinsic activity, these data suggest that collateral effects on tumor-infiltrating myeloid populations may impact antitumor immunity. These findings have important implications for the design of combination strategies and clinical trials that incorporate BRAF, MEK, and CDK4/6 inhibition with immunotherapy for the treatment of patients with melanoma.

Healthcare professionals' perceptions of the role of a multidisciplinary approach in improving the care of patients with advanced chronic kidney disease.

OBJECTIVE: To explore and understand the experiences of healthcare professionals (HCPs) delivering care in a multidisciplinary care (MDC) clinic for advanced chronic kidney disease (CKD) patients. METHODS: This is a qualitative study based on semi-quantitative questionnaire and semi-structured interviews with thematic analysis and deductive mapping onto the Theoretical Framework of Acceptability. Sixteen HCPs caring for advanced CKD patients in a MDC clinic in a tertiary teaching hospital in Singapore were recruited based on maximum variation sampling procedures. RESULTS: The majority of the HCPs were supportive of a MDC clinic. There was a positive overall opinion of the programme [median 7.0 of 10.0 (IQR 7.0-8.0)], high satisfaction ratings for interaction with other members of team [6.9 (5.3-8.0)] and time spent with patients [7.0 (5.3-7.0)]. Thematic analysis of the interviews identified the value of MDC clinic in the provision of one-stop care, the improvement in communication and collaboration between HCPs, the facilitation of patient activation to make planned kidney care decisions, and the optimisation of medications. The main challenges were lack of continuity of care, manpower constraints, poor patient navigation between HCPs, poor patient attendance with allied HCPs, and the perception of increased cost and time spent by patients in each MDC clinic visit. The proposed interventions were notification of patients beforehand of the MDC clinic schedule and provision of navigation to patients within the MDC clinic. CONCLUSION: A multidisciplinary care clinic for advanced chronic kidney disease patients was viewed positively by the majority of the healthcare professionals, with areas for improvement.

Emotion Regulation and Immune Functioning During Grief: Testing the Role of Expressive Suppression and Cognitive Reappraisal in Inflammation Among Recently Bereaved Spouses.

OBJECTIVE: Losing a spouse is a distressing life event that can negatively affect both mental and physical health. Stress-induced health consequences often include increased risk of cardiovascular disease and altered immune system functioning marked by increased inflammation. Here, we sought to identify individual difference factors that covary with problematic inflammatory outcomes. METHOD: We measured recently bereaved spouses' (n = 99) propensity to use emotion regulation strategies and peripheral inflammation, as measured by levels of proinflammatory cytokines after ex vivo stimulation of peripheral leukocytes with T-cell agonists. Specifically, we measured participants' use of cognitive reappraisal, an adaptive emotion regulation strategy in many contexts, and expressive suppression, a less adaptive emotion regulation strategy that involves actively inhibiting emotions after already experiencing them. RESULTS: Bereaved spouses who self-reported frequently using expressive suppression as an emotion regulation strategy tended to have a more pronounced inflammatory response, as indexed by higher levels of a composite cytokine index consisting of interleukin (IL) 17A, IL-2, IL-6, tumor necrosis factor α, and interferon-γ (b = 0.042), as well as tumor necrosis factor α (b = 0.083) and interferon-γ (b = 0.098) when analyzed individually. Notably, these associations were observed in both unadjusted and adjusted models, with the latter including known covariates of inflammation and other potential confounding variables. CONCLUSIONS: These findings suggest that bereaved spouses' use of emotion regulation strategies is associated with altered immune functioning, and such a link may be an important biological pathway by which interventions targeting affect may improve immune system-related health outcomes.

Biopsychosocial experiences and coping strategies of elderly ESRD patients: a qualitative study to inform the development of more holistic and person-centred health services in Singapore.

BACKGROUND: As the incidence and prevalence rates of end stage renal disease (ESRD) rise globally, a disproportionate increase has been observed in the elderly population. Singapore has the fifth highest incidence of treated ESRD worldwide, with the upward trend of ESRD being most apparent among those aged 70 years and older. Although it is well-documented that ESRD patients suffer an impaired quality of life compared to the general population, there is limited research focusing on the unique experiences and needs of elderly ESRD patients in Asian populations. To address the knowledge gap, this study seeks to explore the impact of ESRD and dialysis on the quality of life of elderly (≥70 years old) ESRD patients in Singapore and examine the coping strategies utilised by these patients. METHODS: This qualitative study involved semi-structured, in-depth interviews with 7 peritoneal dialysis patients, 5 haemodialysis patients, 4 patients on non-dialysis supportive care and 7 caregivers in Singapore. Interviews were conducted in English, Chinese, and Malay and fully transcribed. QSR NVivo 11 software was used for analysis. RESULTS: Participants reported that ESRD and dialysis had an impact on three highly interconnected areas of their quality of life: (a) biological/physical (general symptoms, neuromuscular problems, skin problems and poor sleep quality); (b) psychological (depressive symptoms, anxiety and fears, stress and negative self-perceptions); and (c) social (increased dependence on family and loss of social life). There were four key strategies that participants used to cope with these biopsychosocial challenges: (a) family support (financial, practical and emotional support); (b) religious/spiritual support (experiencing gratitude/contentment, the power of prayer and belonging to a faith community); (c) avoidance (cognitive avoidance and distraction techniques); and (d) acceptance (positive thinking and problem solving). CONCLUSIONS: This study has provided insights into the biopsychosocial impact of ESRD and dialysis, as well as cultural and religious factors that shape the experiences and coping mechanisms of elderly ESRD patients and caregivers in Singapore, which can be used to further the development and implementation of more holistic and person-centred services to help each patient achieve a better quality of life.

Perspectives on decision making amongst older people with end-stage renal disease and caregivers in Singapore: A qualitative study.

BACKGROUND: End-stage renal disease (ESRD) is increasing both globally and in Asia. Singapore has the fifth highest incidence of ESRD worldwide, a trend that is predicted to rise. Older patients with ESRD are faced with a choice of haemodialysis, peritoneal dialysis or conservative management, all of which have their risks and benefits. OBJECTIVE: This study seeks to explore perspectives on decision making amongst older (≥70) Singaporean ESRD patients and their caregivers to undergo (or not to undergo) dialysis. DESIGN: Qualitative study design using semi-structured interviews. SETTING AND PARTICIPANTS: Twenty-three participants were recruited from the largest tertiary hospital in Singapore: seven peritoneal dialysis patients, five haemodialysis patients, four patients on conservative management and seven caregivers. RESULTS: While some patients believed that they had made an independent treatment decision, others reported feeling like they had no choice in the matter or that they were strongly persuaded by their doctors and/or family members to undergo dialysis. Patients reported decision-making factors including loss of autonomy in daily life, financial burden (on themselves or on their families), caregiving burden, alternative medicine, symptoms and disease progression. Caregivers also reported concerns about financial and caregiving burden. DISCUSSION AND CONCLUSION: This study has identified several factors that should be considered in the design and implementation of decision aids to help older ESRD patients in Singapore make informed treatment decisions, including patients' and caregivers' decision-making factors as well as the relational dynamics between patients, caregivers and doctors.

Ameloblastic Carcinoma.

BACKGROUND: Ameloblastic carcinoma secondary type is an extremely rare and aggressive odontogenic neoplasm that exhibits histological features of malignancy in primary and metastatic sites. It arises through carcinomatous de-differentiation of a pre-existing ameloblastoma or odontogenic cyst, typically following repeated treatments and recurrences of the benign precursor neoplasm. Identification of an ameloblastic carcinoma, secondary type presenting with histologic features of malignant transformation from an earlier untreated benign lesion remains a rarity. Herein, we report 1 such case. CASE REPORT: A 66-year-old man was referred for management of a newly diagnosed ameloblastic carcinoma. He underwent radical surgical intervention comprising hemimandibulectomy, supraomohyoid neck dissection, and free-flap reconstruction. Final histologic analysis demonstrated features suggestive of carcinomatous de-differentiation for a consensus diagnosis of ameloblastic carcinoma, secondary type (de-differentiated) intraosseous. CONCLUSIONS: Ameloblastic carcinoma, secondary type represents a rare and challenging histologic diagnosis. Radical surgical resection with adequate hard and soft tissue margins is essential for curative management of localized disease.

The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice.

Heart failure (HF) and atrial fibrillation (AF) share common risk factors, frequently coexist and are associated with high mortality. Treatment of HF with AF represents a major unmet need. Here we show that a small molecule, BGP-15, improves cardiac function and reduces arrhythmic episodes in two independent mouse models, which progressively develop HF and AF. In these models, BGP-15 treatment is associated with increased phosphorylation of the insulin-like growth factor 1 receptor (IGF1R), which is depressed in atrial tissue samples from patients with AF. Cardiac-specific IGF1R transgenic overexpression in mice with HF and AF recapitulates the protection observed with BGP-15. We further demonstrate that BGP-15 and IGF1R can provide protection independent of phosphoinositide 3-kinase-Akt and heat-shock protein 70; signalling mediators often defective in the aged and diseased heart. As BGP-15 is safe and well tolerated in humans, this study uncovers a potential therapeutic approach for HF and AF.