The SINgapore GERiatric Intervention Study to Reduce Cognitive Decline and Physical Frailty (SINGER): Study Design and Protocol.

BACKGROUND: The SINgapore GERiatric intervention study to reduce cognitive decline and physical frailty (SINGER) randomised controlled trial (RCT) uses a multidomain lifestyle interventions approach, shown to be effective by the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) trial, to delay cognitive decline. OBJECTIVE: To investigate the efficacy and safety of the SINGER multidomain lifestyle interventions in older adults at risk for dementia to delay cognitive decline. PARTICIPANTS: 1200 participants between 60-77 years old, with Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk score ≥6, fulfilling at least one of the following LIBRA index for diet, cognitive activity, physical activity and a Montreal Cognitive Assessment (MoCA) score ≥18, ≤27 points, will be recruited across Singapore. METHODS: SINGER is a 2-year multi-site RCT consisting of multidomain interventions: dietary advice, exercise, cognitive training, and vascular risk factors management. Participants will be randomised into either the Self-Guided Intervention (SGI; general lifestyle and health information and resources) or Structured Lifestyle Intervention (SLI) group. The SLI comprises diet training (6 group and 3 individual sessions over 12 months); exercise (supervised: 1-hour twice weekly for 6 months, unsupervised: 2-3/week for the rest of the study duration); cognitive sessions (15-30 minutes/session, 3/week for 6 months, together with 10 workshops in 24 months). Vascular management takes place every 3-6 months or otherwise as specified by study physicians. The primary outcome is global cognition measured using the modified Neuropsychological Battery assessing performance in various domains, such as episodic memory, executive function and processing speed. Secondary outcome measures include: domain-specific cognition and function, imaging evidence of brain and retinal changes, incidence and progression of chronic diseases, blood biomarkers, quality of life, mental health and cost-benefit analysis. CONCLUSIONS: SINGER is part of the Worldwide-FINGERS international network, which is at the forefront of harmonizing approaches to effective non-pharmacological interventions in delaying cognitive decline in older adults at risk of dementia. By establishing the efficacy of multidomain interventions in preventing cognitive decline, SINGER aims to implement the findings into public health and clinical practices by informing policy makers, and guiding the design of community- and individual-level health promotion initiatives.

A systematic review of nudge theories and strategies used to influence adult health behaviour and outcome in diabetes management.

BACKGROUND: Diabetes is a chronic disease associated with a variety of complications, and nudging may be a potential solution to improve diabetes control. Since nudging is a new concept, no review of literature on nudging diabetic patients into improving their health behaviour has been done. Therefore, we aim to collate a list of nudge intervention and determine the context in which nudging is successful. METHODS: We adopted a two-arm search strategy comprising the search of literature databases and snowballing using relevant search terms. We summarized patient characteristics, the nudge intervention, according to nudging strategies, delivery mode and their outcomes. The conditions present in effective nudge interventions were assessed and reported. RESULTS: We retrieved 11,494 studies from our searches and included 33. An additional five studies were added through snowballing. Studies included utilized framing (n=5), reminders (n=10), gamification (n=2), social modelling (n=5) and social influence (n=16). Studies on reminders and gamification were more likely to have a statistically significant outcome. The targeted health behaviours identified were medication adherence, physical activity, diet, blood glucose monitoring, foot care, self-efficacy, HbA1c and quality of life. Of these, studies with adherence to medication, foot care practice and quality of life as targeted health behaviours were more likely to show a statistically significant outcome. CONCLUSION: Nudging has shown potential in changing health behaviour of patients with diabetes in specific context. We identified two possible factors (delivery mode and patient characteristics) that may affect the effectiveness of nudge intervention.

COVID-19: Four Paediatric Cases in Malaysia.

OBJECTIVE: This is a brief report of 4 paediatric cases of COVID-19 infection in Malaysia BACKGROUND: COVID-19, a coronavirus, first detected in Wuhan, China has now spread rapidly to over 60 countries and territories around the world, infecting more than 85000 individuals. As the case count amongst children is low, there is need to report COVID-19 in children to better understand the virus and the disease. CASES: In Malaysia, until end of February 2020, there were four COVID-19 paediatric cases with ages ranging from 20 months to 11 years. All four cases were likely to have contracted the virus in China. The children had no symptoms or mild flu-like illness. The cases were managed symptomatically. None required antiviral therapy. DISCUSSION: There were 2 major issues regarding the care of infected children. Firstly, the quarantine of an infected child with a parent who tested negative was an ethical dilemma. Secondly, oropharyngeal and nasal swabs in children were at risk of false negative results. These issues have implications for infection control. Consequently, there is a need for clearer guidelines for child quarantine and testing methods in the management of COVID-19 in children.

Atrophy in Neovascular Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report Number 15.

PURPOSE: To identify the development and progression of macular retinal pigment epithelial atrophy in eyes with neovascular (CNV) age-related macular degeneration (AMD) and to correlate with visual acuity (VA). DESIGN: Cohort study. PARTICIPANTS: Age-Related Eye Disease Study 2 (AREDS2) participants with intermediate AMD enrolled in a randomized controlled clinical trial of oral supplements. Analyses were conducted in the subset of AREDS2 participants who were also enrolled in the fundus autofluorescence ancillary (FAF) ancillary study. METHODS: Color photographs and FAF images were evaluated in eyes that developed CNV. Presence of geographic atrophy (GA) prior to the incidence of CNV and the development of macular atrophy following incident CNV were assessed. Areas of hypoautofluorescence representing atrophy were measured for area and macular involvement. Enlargement rate of atrophy and change in visual acuity over time were analyzed. MAIN OUTCOME MEASURES: incidence and enlargement rate of atrophy and VA changes in eyes with incident CNV. RESULTS: Incident CNV developed in 334 (9.2%) of eyes evaluated in the AREDS2 FAF substudy. Of these, 40% had macular atrophy at incidence of CNV with half of these attributable to pre-existing GA. Atrophy developed in 14.7 % of eyes over 4 years of follow-up. Mean area of atrophy was largest in eyes with pre-existing GA and CNV (5.17 mm2, p<0.001), and atrophy involved the center of the macula in > 65% of eyes. Mean VA letter score at the annual visit in which CNV was documented was similar in the three groups with atrophy; eyes with CNV and pre-existing GA, incident atrophy at the first visit with CNV, and atrophy during follow up (60 letters). Enlargement rate of atrophy was also similar in eyes in the three groups (1.23 - 1.86 mm2, p = 0.47). Eyes with macular atrophy lost more visual acuity compared to eyes without atrophy, particularly after 2 years of follow-up (-10.9 vs. - 3.6 letters, p = 0.07). CONCLUSION: Atrophy is commonly seen in neovascular AMD and often can be attributed to pre-existing GA. Macular atrophy and GA appear to be a continuum of the same disease process and are both associated with poor vision.

Ministry of Health Clinical Practice Guidelines: Hypertension.

The Ministry of Health (MOH) has updated the clinical practice guidelines on hypertension to provide doctors and patients in Singapore with evidence-based treatment for hypertension. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on hypertension, for the information of SMJ readers. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov.sg/content/moh_web/healthprofessionalsportal/doctors/guidelines/cpg_medical.html. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

MDR1 deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation.

The multidrug resistance-1 (MDR1) gene encodes an ATP-dependent efflux transporter that is highly expressed in the colon. In mice, loss of MDR1 function results in colitis with similarities to human inflammatory bowel diseases (IBD). Here, we show that MDR1 has an unexpected protective role for the mitochondria where MDR1 deficiency results in mitochondrial dysfunction with increased mitochondrial reactive oxygen species (mROS) driving the development of colitis. Exogenous induction of mROS accelerates, while inhibition attenuates colitis in vivo; these effects are amplified in MDR1 deficiency. In human IBD, MDR1 is negatively correlated to SOD2 gene expression required for mROS detoxification. To provide direct evidential support, we deleted intestinal SOD2 gene in mice and showed an increased susceptibility to colitis. We exploited the genome-wide association data sets and found many (∼5%) of IBD susceptibility genes with direct roles in regulating mitochondria homeostasis. As MDR1 primarily protects against xenotoxins via its efflux function, our findings implicate a distinct mitochondrial toxin+genetic susceptibility interaction leading to mitochondrial dysfunction, a novel pathogenic mechanism that could offer many new therapeutic opportunities for IBD.

The role of carbon chain length in the attachment between microbubbles and aqueous solutions of ionic liquid.

HYPOTHESIS: The effects of varying carbon chain lengths (CCLs) and concentrations of aqueous solutions of imidazolium based ionic liquids on bubble particle attachment (BPA) will provide a better understanding in catering for the varying degrees of surface activities in the application of the flotation technology. The general trends of this study should also be applicable to homologous series of other cationic surfactants and ionic liquids. EXPERIMENTS: Zeta potentials of small air bubbles and bunker oil drops dispersed in aqueous solutions of n-methylimidazolium chloride ionic liquids (n=0, 2, 3, 6, 8, 10, 12) of concentrations ranging from 1000PPM to 8000PPM, as were interfacial tensions of these solutions with bunker oil (180cst) and contact angles made by air bubbles at interfaces between these solutions and thin layers of bunker oil on flat solid surfaces were investigated. Finally, interparticle forces analysis using the Derjaguin-Landau, Verwey-Overbeek (DLVO) theory is also included. FINDINGS: Analysis using the DLVO theory showed attractive forces between the oil particles and micro-bubbles are significantly more prevalent in short CCLs solutions of imidazolium-based ILs in low concentrations, namely [C0mim][Cl] and [C2mim][Cl] at a maximum zeta potential difference of 75.3mV. The results from CA measurements follows similarly whereby low concentrations of ILs with short CCLs were in favor for the bubble-particle attachment process with angles ranging between 93.95° for [C0mim][Cl] and 97.28° for [C2mim][Cl]. IFT which is important in reducing coalescence for the preferential BPA process to occur in flotation decreases with an increase of CCL and concentration of IL.

Biomechanical investigation of 'figure of 8' flexor tendon repair techniques.

This biomechanical study compared the original Al-Qattan repair with other modifications postulated to reduce bulk and friction, thereby potentially improving outcome. A total of 32 cadaveric digits with intact flexor apparatus were used. In each digit, the flexor digitorum profundus and flexor digitorum superficialis tendons were cut cleanly in Zone 2. We tested Al-Qattan's technique along with three modifications using stronger suture material and varying the number of strands across the repair site. Of the four repair techniques, the modified Al-Qattan's technique using two 'figure of 8' 4-0 Fiberwire core sutures (Group 4) had the best balance of ultimate tensile strength (50.9 N), 2 mm gapping force (38 N) and friction. The modified technique provided a stronger repair for early active mobilization and has less friction than the originally described repair.

Temporal dynamics of visual working memory.

The involvement of the human cerebellum in working memory has been well established in the last decade. However, the cerebro-cerebellar network for visual working memory is not as well defined. Our previous fMRI study showed superior and inferior cerebellar activations during a block design visual working memory task, but specific cerebellar contributions to cognitive processes in encoding, maintenance and retrieval have not yet been established. The current study examined cerebellar contributions to each of the components of visual working memory and presence of cerebellar hemispheric laterality was investigated. 40 young adults performed a Sternberg visual working memory task during fMRI scanning using a parametric paradigm. The contrast between high and low memory load during each phase was examined. We found that the most prominent activation was observed in vermal lobule VIIIb and bilateral lobule VI during encoding. Using a quantitative laterality index, we found that left-lateralized activation of lobule VIIIa was present in the encoding phase. In the maintenance phase, there was bilateral lobule VI and right-lateralized lobule VIIb activity. Changes in activation in right lobule VIIIa were present during the retrieval phase. The current results provide evidence that superior and inferior cerebellum contributes to visual working memory, with a tendency for left-lateralized activations in the inferior cerebellum during encoding and right-lateralized lobule VIIb activations during maintenance. The results of the study are in agreement with Baddeley's multi-component working memory model, but also suggest that stored visual representations are additionally supported by maintenance mechanisms that may employ verbal coding.

Single Stage Knee Arthroplasty Revision Surgery: A Systematic Review of the Literature.

Total Knee Arthroplasty is an increasingly common procedure and revision surgery, particularly for infection, is associated with significant morbidity and healthcare costs. The current gold standard is a two stage revision procedure but single stage revision is increasingly being used in some departments to improve patient outcomes. We conducted a systematic review of the literature to determine the up-to-date evidence underlying the use of a single stage knee approach in revision surgery. A total of 12 studies were included in this review amounting to 433 revision surgeries. This is the largest review of single stage knee revision surgery. The procedures described were heterogenous and included the 'two-in-one' technique as well as other single stage revision procedures. There were also differences in implants and antibiotic regimens. The mean re-infection rates described in 10 studies was 9.4% (range 0-19.2%) after a mean follow-up of 40.3 months (range 7-180 months). The re-infection rates in the studies published over the last 30 years are falling, and this is not accounted for by any significant change in duration of follow-up during this period. The outcome scores varied, but patients generally showed an improvement. The Knee Society Score and the Oxford Knee Score were the most commonly used in five and three studies respectively. We conclude that the current evidence for single stage revision is variable and there is a lack of good quality evidence to address whether single stage revisions is thorough enough to eradicate deep infection and is able to restore adequate function. There is a need for larger prospective studies with standardised procedures and protocol, and with adequate follow-up. Till then, patients considered for a single stage approach should be thoroughly assessed and the surgery should be performed by a senior surgeon with experience in single stage knee revisions.

Bipedicled homodigital neurovascular island flap for resurfacing dorsal digital defects amputation.

Critical defects distal to the proximal interphalangeal joint are usually treated by heterodigital or reverse-flow homodigital flaps. Drawbacks of the former are potential donor digit stiffness and scarring, while the latter might be complicated by flap congestion. A bipedicled neurovascular island transposition flap design that preserves both proximal and distal extent of digital nerve and artery was employed to treat critical dorsal skin defect in two patients with encouraging results. Technical details and cadaveric study concepts are presented.

Age-related macular degeneration-clinical review and genetics update.

Age-related macular degeneration (AMD) is the leading cause of central vision impairment in persons over the age of 50 years in developed countries. Both genetic and non-genetic (environmental) factors play major roles in AMD etiology, and multiple gene variants and lifestyle factors such as smoking have been associated with the disease. While dissecting the basic etiology of the disease remains a major challenge, current genetic knowledge has provided opportunities for improved risk assessment, molecular diagnosis and clinical testing of genetic variants in AMD treatment and management. This review addresses the potential of translating the wealth of genetic findings for improved risk prediction and therapeutic intervention in AMD patients. Finally, we discuss the recent advancement in genetics and genomics and the future prospective of personalized medicine in AMD patients.

Nuclear factor κB (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter.

AIMS/HYPOTHESIS: While chronic low-grade inflammation is associated with obesity, acute inflammation reduces food intake and leads to negative energy balance. Although both types of inflammation activate nuclear factor κB (NF-κB) signalling, it remains unclear how NF-κB activation results in opposite physiological responses in the two types of inflammation. The goal of this study was to address this question, and to understand the link between inflammation and leptin signalling. METHODS: We studied the ability of NF-κB to modulate Pomc transcription, and how it impinges on signal transducer and activator of transcription 3 (STAT3)-mediated leptin signalling by using a combination of animal models, biochemical assays and molecular biology. RESULTS: We report that suppression of food intake and physical movement with acute inflammation is not dependent on STAT3 activation in pro-opiomelanocortin (POMC) neurons. Under these conditions, activated NF-κB independently leads to increased Pomc transcription. Electrophoretic mobility shift assay and chromatin immunoprecipitation (ChIP) experiments reveal that NF-κB v-rel reticuloendotheliosis viral oncogene homologue A (avian) (RELA [also known as p65]) binds to the Pomc promoter region between -138 and -88 bp, which also harbours the trans-acting transcription factor 1 (SP1) binding site. We found significant changes in the methylation pattern at this region and reduced Pomc activation under chronic inflammation induced by a high-fat diet. Furthermore, RELA is unable to bind and activate transcription when the Pomc promoter is methylated. Finally, RELA binds to STAT3 and inhibits STAT3-mediated promoter activity, suggesting that RELA, possibly together with forkhead box-containing protein 1 (FOXO1), may prevent STAT3-mediated leptin activation of the Pomc promoter. CONCLUSIONS/INTERPRETATION: Our study provides a mechanism for the involvement of RELA in the divergent regulation of energy homeostasis in acute and chronic inflammation.

Disseminated toxoplasmosis after allogeneic stem cell transplantation in a seronegative recipient.

Toxoplasmosis is increasingly diagnosed after hematopoietic stem cell transplantation (HSCT) and is associated with considerable morbidity and mortality. In the majority of cases, reactivation of latent disease secondary to impaired cellular and humoral immunity after HSCT is believed to be the main pathogenetic mechanism. Hence, primary toxoplasmosis is rarely considered in the differential diagnosis of infections after HSCT in a recipient who is seronegative for Toxoplasma gondii pre-transplant. We herein report a seronegative patient with acute T-cell lymphoblastic leukemia, who developed primary disseminated toxoplasmosis 5 months after HSCT from a seronegative unrelated donor. A review of all reported cases of primary toxoplasmosis after HSCT revealed significantly increased morbidity and mortality. Patients with negative pre-transplant Toxoplasma serology should therefore be considered at risk for toxoplasmosis after allogeneic HSCT. Possible prevention and monitoring strategies for seronegative recipients are reviewed and discussed in detail.

Recurrent bilateral varicose veins secondary to tricuspid regurgitation.

BACKGROUND: Varicose veins are a common condition. We present a case of recurrent veins due to tricuspid regurgitation. CASE HISTORY: A 55-year-old female presented with large bilateral varicosities. On examination these were extensive and pulsatile in nature over both legs. Three and 5 years previously she presented with similar signs and had undergone bilateral venous surgery including Trendelenburg procedure. Past medical history included successful atrial septal defect repair in 1995. Severe tricuspid regurgitation and right heart failure was diagnosed in 2000, followed by annuloplasty 2 years later. Prior to attempting venous surgery the third time an echocardiogram was performed. This demonstrated severe tricuspid regurgitation again and therefore surgery was not undertaken at this time. DISCUSSION: Concurrent valvular disease should be fully investigated and optimised before consideration is given to surgery, with a multidisciplinary approach being essential in its management.

Genome-wide association identifies SKIV2L and MYRIP as protective factors for age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. We conducted a genome-wide association study in a series of families enriched for AMD and completed a meta-analysis of this new data with results from reanalysis of an existing study of a late-stage case-control cohort. We tested the top findings for replication in 1896 cases and 1866 controls and identified two novel genetic protective factors for AMD. In addition to the complement factor H (CFH) (P=2.3 × 10⁻64) and age-related maculopathy susceptibility 2 (ARMS2) (P=1.2 × 10⁻6°) loci, we observed a protective effect at rs429608, an intronic SNP in SKIV2L (P=5.3 × 10⁻¹5), a gene near the complement component 2 (C2)/complement factor B (BF) locus, that indicates the protective effect may be mediated by variants other than the C2/BF variants previously studied. Haplotype analysis at this locus identified three protective haplotypes defined by the rs429608 protective allele. We also identified a new potentially protective effect at rs2679798 in MYRIP (P=2.9 × 10⁻4), a gene involved in retinal pigment epithelium melanosome trafficking. Interestingly, MYRIP was initially identified in the family-based scan and was confirmed in the case-control set. From these efforts, we report the identification of two novel protective factors for AMD and confirm the previously known associations at CFH, ARMS2 and C3.

6-Shogaol, an active constituent of ginger, inhibits breast cancer cell invasion by reducing matrix metalloproteinase-9 expression via blockade of nuclear factor-κB activation.

BACKGROUND AND PURPOSE: Shogaols are reported to possess anti-inflammatory and anticancer activities. However, the antimetastatic potential of shogaols remains unexplored. This study was performed to assess the effects of shogaols against breast cancer cell invasion and to investigate the underlying mechanisms. EXPERIMENTAL APPROACH: The anti-invasive effect of a series of shogaols was initially evaluated on MDA-MB-231 breast cancer cells using the matrigel invasion assay. The suppressive effects of 6-shogaol on phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-9 (MMP-9) gelatinolytic activity and nuclear factor-κB (NF-κB) activation were further determined. KEY RESULTS: Shogaols (6-, 8- and 10-shogaol) inhibited PMA-stimulated MDA-MB-231 cell invasion with an accompanying decrease in MMP-9 secretion. 6-Shogaol was identified to display the greatest anti-invasive effect in association with a dose-dependent reduction in MMP-9 gene activation, protein expression and secretion. The NF-κB transcriptional activity was decreased by 6-shogaol; an effect mediated by inhibition of IκB phosphorylation and degradation that subsequently led to suppression of NF-κB p65 phosphorylation and nuclear translocation. In addition, 6-shogaol was found to inhibit JNK activation with no resulting reduction in activator protein-1 transcriptional activity. By using specific inhibitors, it was demonstrated that ERK and NF-κB signalling, but not JNK and p38 signalling, were involved in PMA-stimulated MMP-9 activation. CONCLUSIONS AND IMPLICATIONS: 6-Shogaol is a potent inhibitor of MDA-MB-231 cell invasion, and the molecular mechanism involves at least in part the down-regulation of MMP-9 transcription by targeting the NF-κB activation cascade. This class of naturally occurring small molecules thus have potential for clinical use as antimetastatic treatments.