Targeting the DNA damage response in hematological malignancies.

Deregulation of the DNA damage response (DDR) plays a critical role in the pathogenesis and progression of many cancers. The dependency of certain cancers on DDR pathways has enabled exploitation of such through synthetically lethal relationships e.g., Poly ADP-Ribose Polymerase (PARP) inhibitors for BRCA deficient ovarian cancers. Though lagging behind that of solid cancers, DDR inhibitors (DDRi) are being clinically developed for haematological cancers. Furthermore, a high proliferative index characterize many such cancers, suggesting a rationale for combinatorial strategies targeting DDR and replicative stress. In this review, we summarize pre-clinical and clinical data on DDR inhibition in haematological malignancies and highlight distinct haematological cancer subtypes with activity of DDR agents as single agents or in combination with chemotherapeutics and targeted agents. We aim to provide a framework to guide the design of future clinical trials involving haematological cancers for this important class of drugs.

Trends in surgical management of spinal metastases in a Singaporean tertiary referral center: a 17-year retrospective review.

Introduction: Surgical treatment is increasingly the treatment of choice in cancer patients with epidural spinal cord compression and spinal instability. There has also been an evolution in surgical treatment with the advent of minimally invasive surgical (MIS) techniques and separation surgery. This paper aims to investigate the changes in epidemiology, surgical technique, outcomes and complications in the last 17 years in a tertiary referral center in Singapore. Methods: This is a retrospective study of 383 patients with surgically treated spinal metastases treated between January 2005 to January 2022. Patients were divided into 3 groups, patients treated between 2005 - 2010, 2011-2016, and 2017- 2021. Demographic, oncological, surgical, patient outcome and survival data were collected. Statistical analysis with univariate analysis was performed to compare the groups. Results: There was an increase in surgical treatment (87 vs 105 vs 191). Lung, Breast and prostate cancer were the most common tumor types respectively. There was a significant increase in MIS(p<0.001) and Separation surgery (p<0.001). There was also a significant decrease in mean blood loss (1061ml vs 664 ml vs 594ml) (p<0.001) and total transfusion (562ml vs 349ml vs 239ml) (p<0.001). Group 3 patients were more likely to have improved or normal neurology (p=<0.001) and independent ambulatory status(p=0.012). There was no significant change in overall survival. Conclusion: There has been a significant change in our surgical practice with decreased blood loss, transfusion and improved neurological and functional outcomes. Patients should be managed in a multidisciplinary manner and surgical treatment should be recommended when indicated.

Menopausal symptoms in midlife Singaporean women: Prevalence rates and associated factors from the Integrated Women's Health Programme (IWHP).

OBJECTIVE: Menopausal symptoms can substantially impact quality of life. We studied somatic, psychological, and urogenital symptoms and their associated factors. DESIGN: Cross-sectional study of healthy midlife Singaporean women from three major Asian ethnic groups. METHODS: In 2014-16, women aged 45 to 69 attending well-woman clinics at the National University Hospital Singapore completed the Menopause Rating Scale (MRS). Sociodemographic, reproductive, medical, anthropometric, body composition, and physical performance characteristics were assessed using validated questionnaires and strict protocols. We analysed sub-scales and total scores by median split, and adjusted odds ratios using multivariable logistic regression. RESULTS: Of the 1054 eligible women, 62.6 % reported at least one moderate to extremely severe symptom. The top five menopausal symptoms were joint and muscle discomfort, sleep problems, vaginal dryness, physical and mental exhaustion, and hot flushes. Higher total scores on the MRS were associated with moderate disability (adjusted odds ratio: 9.80, 95 % confidence interval: 2.88-33.34), poorer self-rated health status (2.18, 1.60-2.97), menstrual irregularity at 25 years (1.63, 1.07-2.49), and slower chair stands (1.49, 1.09-2.03). Age ≥65 (0.54, 0.30-0.94) and a lower level of education (0.45, 0.26-0.76) had significant inverse associations with total MRS score. CONCLUSIONS: Menopausal symptoms were associated with disability, poorer health status, and weaker lower-body muscle strength. These data add to the limited Asian evidence and raise the profile of this important area of health.

The right turn around: Penrose tourniquet application in paediatrics.

INTRODUCTION: Commercially available tourniquets are ill-suited for paediatric patients with limb circumferences smaller than the required mechanism, forcing surgeons to improvise. This study aimed to quantify pressures exerted by the Penrose tourniquet when applied on a phantom model and evaluate the intra-/inter-rater reproducibility of the technique previously proposed. METHODS: Eight calibrated pressure sensors were distributed evenly along the inner and outer circumference of a silicon-based model. A 30cm-by-3.2 cm ARGYLE Penrose drain, 4-by-4 gauze, marker and ruler were used. The optimal interval for arterial occlusion was determined to be 70% of limb circumference. The tourniquet was secured using two half-knots formed by gauze. RESULTS: Two-turns of the tourniquet about the model generated mean pressures (SD) of 209.43 (SD:35.98 mmHg) (95%CI: 195.85-224.00 mmHg) (outer-sensor) and 246.32 (SD:61.92 mmHg) (95%CI: 221.02-273.49 mmHg) (inner-sensor). Three-turns generated mean pressures of 302.07 (SD:23.98 mmHg) (95%CI: 292.29-312.53 mmHg) (outer-sensor) and 314.44 (SD:56.70 mmHg) (95%CI: 291.25-338.25 mmHg) (inner-sensor). CONCLUSION: The Penrose tourniquet has clinical utility, particularly for patients where commercially available tourniquets are not suitable. Current application techniques generate inconsistent pressures. Using the existing model, further refinement can be done to improve the consistency and safety of the application. We recommend using intervals of slightly more than 70% of limb circumference and only two turns of the Penrose tourniquet during application. LEVEL OF EVIDENCE: V.

Health inequity and social determinants of healthcare utilization in the disadvantaged community of Hong Kong.

Access to appropriate healthcare among disadvantaged populations in countries with universal healthcare requires a critical understanding of the relationships between poverty, social exclusion and health in the local context. The qualitative study explored the experiences of healthcare utilization in an inner-city impoverished community living in slum conditions in Hong Kong. Interviews with 40 slum residents in one of the poorest neighbourhoods in the city explored the following domains: experience and perceptions of the community, housing conditions, informal social capital and support system, interactions with community workers, and experiences in utilizing social and healthcare services. Framework analysis was conducted to identify local themes under the model of healthcare utilization: approachability, acceptability, availability and accommodation, affordability and appropriateness. Despite the subsidized public healthcare system, multiple barriers were identified. Low literacy of healthcare systems was prevalent. Specifically, structural barriers relating mainly to the availability, accommodation and affordability of health services were salient to impede access to healthcare. The barriers related to healthcare providers primarily stemmed from the interactions of healthcare providers, perceived stigma and the lack of patient-centred care. In addition, poverty-related sociocultural norms and personal beliefs of healthcare were found to be significant barriers to healthcare access. Despite the well-established subsidized public healthcare system, healthcare inequity was evident. Lack of quality healthcare access needs to be addressed by providing social and educational resources that facilitate collective efficacy for healthcare, community engagement from public sectors and person-centred care with healthcare providers.

Access to appropriate healthcare among disadvantaged populations in countries with universal healthcare requires a critical understanding of the relationships between poverty, social exclusion and health in the local context. This study explored the experiences and views of healthcare access among residents living in slum conditions in an inner-city impoverished community in Hong Kong. The findings indicated that in addition to low functional health literacy that is rooted in structural barriers of public resources, a lack of patient-centred care was prevalent due to stigma attached to poverty. Poor quality interactions with healthcare providers and systems resulted in fatalistic beliefs in health promotion. Social and educational resources should be provided to the disadvantaged to enhance collective efficacy to build a resilient health community.

Hallux valgus with second metatarsalgia: Is second metatarsal Weil osteotomy necessary?

BACKGROUND: The role of concomitant Weil osteotomy to address second toe metatarsalgia during hallux valgus correction is unclear. We aimed to critically analyse outcomes of an additional Weil osteotomy versus isolated Scarf osteotomy.in the management of hallux valgus and second metatarsalgia. METHODS: Patients with second toe metatarsalgia who underwent first metatarsal Scarf osteotomy for hallux valgus were enrolled retrospectively. Demographics, radiographic measurements and functional outcomes were assessed at baseline, 6-months and 2-years postoperatively. Between-group significance was established with Fisher exact test, Chi-square or Mann-Whitney U test. Within-group changes from baseline were assessed with paired t-test and Wilcoxon signed-rank test. RESULTS: 48 feet (34 isolated Scarf, 14 concomitant Weil osteotomy) were included. Both cohorts demonstrated significant improvements across all measures of functional outcome. However, patients with additional Weil osteotomy reported poorer short-term outcomes. CONCLUSION: Superiority of additional Weil osteotomy versus isolated Scarf osteotomy in addressing second toe metatarsalgia or improving functional outcomes was not demonstrated.

Hip survivorship following the Bernese periacetabular osteotomy for the treatment of acetabular dysplasia: A systematic review and meta-analysis.

INTRODUCTION: The Bernese periacetabular osteotomy (PAO) is a popular joint-preservation technique aimed at addressing the structural and biomechanical abnormalities associated with acetabular dysplasia. However, the prognostic factors and long-term survivorship of the native hip, with failure defined as conversion to total hip arthroplasty (THA), is poorly understood. Our study aims to address the following: (1) What is the estimated duration of survival of the native hip post-PAO, (2) What are some prognostic factors of functional outcome and (3) What is the complication rate and complications associated with PAO. HYPOTHESIS: The Bernese PAO is able to result in favourable mid- to long-term outcomes conditional on a stringent patient selection criteria. MATERIALS AND METHODS: A systematic review was performed using the PRISMA guidelines. All studies that reported on the outcomes of isolated Bernese PAO for the treatment of acetabular dysplasia were included. RESULTS: A total of 24 studies (3471 patients, 3655 hips) were included at a mean follow-up duration of 54.2months (range: 1-336months). In total, 208 hips (6.03%; 95% CI: 5.25-6.94%) converted to THA at a mean duration of 4.71years (range: 1-240months). Univariate analysis identified advanced age beyond a follow-up duration of 6years (p=0.001) and preoperative Tönnis grade 2 and above (p<0.001) to be the most significant negative prognostic factors. Beyond a follow-up duration of 2years, intraoperative fluoroscopy proved to be a significant positive prognostic factor (p<0.001). Indications for PAO, obesity and gender were not found to be significant predictors of failure. Our study found the complication rate to be 23.5% (95% CI: 21.6-25.6%). The most common complications detailed are transient lateral femoral cutaneous nerve dysesthesia (8.24%; 95% CI: 7.02-9.65%), stress fracture (5.28%; 95% CI: 4.31-6.89%) and the delayed union, non-union or pseudoarthrosis of the ramus not necessitating surgical correction (3.73%, 95% CI: 2.93-4.75%). DISCUSSION: PAO alters the natural history of the dysplastic hip with a 10- and 20-year survivorship of approximately 75.9% and 36.5% of patients respectively. The ideal patient should be below 40years old, with a preoperative Tönnis grade of 0 or 1. Intraoperative fluoroscopy is able to guide a better precision when re-orientating the acetabulum. LEVEL OF EVIDENCE: IV; systematic review and meta-analysis.

Enoxaparin Versus Direct Oral Anticoagulants for Venous Thromboembolism in Asians Undergoing Total Knee Arthroplasty: A Meta-Analysis and Systematic Review.

BACKGROUND: The introduction of direct oral anticoagulants (DOACs) shows promise for their role as a chemoprophylaxis agent after total knee arthroplasty (TKA) for the prevention of venous thromboembolism (VTE). However, existing studies are largely based on Western populations that do not account for the different risk profiles and lower rates of VTE in Asians. This systematic review and meta-analysis aimed to evaluate the efficacy of DOACs compared with enoxaparin in an Asian-based population study. METHODS: The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. All studies that compared outcomes between enoxaparin and DOACs as VTE prophylaxis after TKA in the Asian population were included. RESULTS: Five studies with 121,153 patients were included. DOACs demonstrated a convincing benefit over enoxaparin in overall VTE prevention (odds ratio [OR] = 0.42, 95% confidence interval [CI]: 0.24-0.74). However, although the OR trended in favor of DOACs for the reduction of deep vein thrombosis events (OR = 0.54, 95% CI: 0.20-1.48) and pulmonary embolism (OR = 0.75, 95% CI: 0.07-8.20), statistical significance was not reached. In terms of bleeding complications, both arms had similar rates of major (0.91% vs 0.20%), clinically relevant nonmajor (3.28% vs 2.94%), and minor bleeding complications (12.8 vs 13.3%). A nonsignificance advantage of enoxaparin over DOACs was revealed in the OR for major bleeding (OR = 3.17; 95% CI: 0.81-12.43), whereas DOACs were favored to reduce risk of clinically relevant nonmajor (OR = 0.82; 95% CI: 0.01-91.51) and minor bleeding (OR = 0.76; 95% CI: 0.11-5.33). CONCLUSION: DOACs confer a significantly reduced rate of overall VTE compared with enoxaparin in Asians after TKA. No significant differences in deep vein thrombosis, pulmonary embolism, and rates of bleeding complications exist.

Periacetabular osteotomy for acetabular retroversion: A systematic review and meta-analysis.

INTRODUCTION: The evidence for periacetabular osteotomy (PAO) when used in the management of acetabular retroversion remain limited. The review aims to answer the following questions: (1) What are the indications for an anteverting PAO for acetabular retroversion? (2) When are other concomitant procedures required when performing anteverting PAO for acetabular retroversion? (3) To what extent is an anteverting PAO able to correct acetabular retroversion? (4) What are the clinical outcomes for an anteverting PAO when used in acetabular retroversion? (5) What is the estimated survival for anteverting PAO when used in the treatment of acetabular retroversion, before other procedures need to be performed? (6) What are the complications and the complication rates when an anteverting PAO is performed? (7) How do the outcomes of an anteverting PAO compare to other surgical procedures used in the management of acetabular retroversion? MATERIAL AND METHODS: The systematic review was conducted using the PRISMA guidelines. The search was conducted using PubMed Medical Literature Analysis and Retrieval System Online (MEDLINE) and Cumulative Index to Nursing and Allied Health Literature (CINAHL) from inception through 1 May 2020. The keywords used were "periacetabular osteotomy". All studies that reported the outcomes of periacetabular osteotomy for acetabular retroversion were included. Each study's data was then retrieved individually. The study design, surgical technique, indications, outcomes and complications of each study were analysed. RESULTS: Seven studies with 225 hips were included. The pooled odds ratio (OR) for a positive crossover sign and posterior wall sign preoperatively as compared to postoperatively were 456.31 (95% CI: 99.57 to 2091.28) and 53.45 (95% CI: 23.05 to 123.93) respectively. The pooled weighted mean difference (WMD) for studies with their mean preoperative LCEA and AI in the dysplastic range were 12.61 (95% CI: 6.54 to 18.68) and-15.0 (95% CI: -19.40 to -11.80) respectively, while the pooled WMD for studies with their mean preoperative LCEA and AI in the normal range were 3.43 (95% CI: 1.08 to 5.77) and -3.56 (95% CI: -5.29 to -1.83) respectively. Other indicators for acetabular retroversion correction, hip dysplasia correction, functional outcomes and range of motion were also significantly improved and sustained up till 11 years postoperatively. Only 7.1% of the hips required subsequent surgical procedures for impingement symptoms or progression of osteoarthritis, and the mean estimate for survival time across the studies was 123.90 months (95% CI: 119.94 to 127.86). The complication rates for low-grade complication were 31.6% while the rate for high-grade complications was 12.0%. DISCUSSION: Anteverting PAO is indicated for symptomatic acetabular retroversion, and when performed, leads to good deformity correction for both acetabular retroversion and hip dysplasia, positive improvement in clinical outcomes sustainable till 11 years postoperatively and a mean estimated survival time of more than 10 years. LEVEL OF EVIDENCE: IV; Systematic review and meta-analysis.

The outcomes of subtalar arthroereisis in pes planus: a systemic review and meta-analysis.

INTRODUCTION: Subtalar arthroereisis has been increasingly accepted as a solution to manage symptomatic pes planus. However, despite the recent developments related to arthroereisis, no other published literature has aimed to review the outcomes in paediatric patients since 2010. This systematic review and meta-analysis, therefore, aims to evaluate the current outcomes of subtalar arthroereisis in the treatment of symptomatic pes planus among the paediatric population. MATERIALS AND METHODS: The review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All studies reported on the clinical outcomes of subtalar arthroereisis in children aged 21 or younger were included. RESULTS: A total of 17 publications were included, with 1536 feet. The average duration of follow-up of the studies included in the review is 43.52 months. The studies consistently reported improvement in the radiological outcomes, approximating that of a normal population. Subtalar arthroereisis has shown to restore the collapsed medial longitudinal arch, supported by the decrease in Meary's angle to 5.267° (95% CI: 4.695°-5.839°, normal: 0°-10.0°) post-operatively and an increased calcaneal pitch of 15.70° (95% CI: 15.41°-15.99°, normal 18.0°-20.0°). Deformities associated with pes planus such as heel valgus was also significantly reduced, evident by the post-operative lateral talocalcaneal angle of 27.19° (95% CI: 26.44°-27.93°, normal: 25.0°-45.0°) and a post-operative Kite's angle of 18.13° (95% CI: 17.73°-18.52°, normal: 15.0°-30.0°). Subjectively, subtalar arthroereisis has generally resulted in an improvement in the grading of outcomes postoperatively from the patient's point of view. CONCLUSIONS: Subtalar arthroereisis could serve as a procedure to correct radiological abnormalities, as well as relieve pain in selected patients with symptomatic pes planus.