Impact of Exercise and Cognitive Stimulation Therapy on Physical Function, Cognition and Muscle Mass in Pre-Frail Older Adults in the Primary Care Setting: A Cluster Randomized Controlled Trial.

OBJECTIVES: Multicomponent exercise program have shown to improve function and cognition in older adults but studies on pre-frail older adults in the primary care setting are limited. This study aimed i) to evaluate impact of 6 months exercise (Ex) versus complementary effect of 3 months of cognitive stimulation therapy (CST) to 6 months of Ex (Ex+CST) on physical function, muscle mass and cognition versus control group at 3, 6 and 12 months ii) inflammatory biomarkers such as Interleukin-6 (IL-6) and Tumor Necrosis Factor Alpha (TNF-α). DESIGN: Cluster randomised control trial. SETTING AND INTERVENTION: Pre-frail older adults ≥ 65 years attending primary care clinic. Two intervention groups i) Ex 6 months ii) CST 3 months with Ex 6 months. MEASUREMENTS: At 0, 3, 6 and 12 months, questionnaires (on demographics, physical function, cognition, and depression) were administered and physical function assessment (gait speed, short physical performance battery (SPPB) test, handgrip strength, five times sit-to-stand (5x-STS)) was conducted. Muscle mass and its surrogates such as phase angle and body cell mass were measured using bioelectrical impedance analysis machine. Inflammatory biomarkers were measured at 0 and 3 months. RESULTS: Data from 190 participants was analysed at 3 months (111 control, 37 Ex and 41 Ex+CST). At 3 months, significant improvement in cognition was seen only in the Ex+CST group whereas improvements in depression, gait speed, SPPB and 5x-STS were seen in both the Ex and Ex+CST groups. At 6 months, the Ex+CST group improved in cognition and depression whereas improvement in frailty and muscle mass indices were seen in both the interventions groups. At 12 months, both the interventions groups had better perceived health, gait speed and less decline in muscle mass compared with control groups. Both the Ex and Ex+CST had significant association with TNF-α at 3 months (ß -2.71 (95% CI -4.80 - -0.62); p = 0.012 and ß -1.74 (95% CI -3.43 - -0.06); p = 0.043 respectively). CONCLUSION: Combined Ex+CST had significant improvement in cognition whereas the intervention groups improved in depression, physical function, muscle mass, frailty, perceived health and TNF-α levels. With growing evidence of the benefits of multicomponent interventions at primary care level, incorporating it into mainstream care with action plans on long-term sustainability and scalability should be a priority for every country.

Impact of the COVID-19 pandemic on a tertiary care public hospital in Singapore: resources and economic costs.

BACKGROUND: The COVID-19 pandemic has prompted hospitals to respond with stringent measures. Accurate estimates of costs and resources used in outbreaks can guide evaluations of responses. We report on the financial expenditure associated with COVID-19, the bed-days used for COVID-19 patients and hospital services displaced due to COVID-19 in a Singapore tertiary hospital. METHODS: We conducted a retrospective cost analysis from January to December 2020 in the largest public hospital in Singapore. Costs were estimated from the hospital perspective. We examined financial expenditures made in direct response to COVID-19; hospital admissions data related to COVID-19 inpatients; and the number of outpatient and emergency department visits, non-emergency surgeries, inpatient days in 2020, compared with preceding years of 2018 and 2019. Bayesian time-series was used to estimate the magnitude of displaced services. RESULTS: USD $41.96 million was incurred in the hospital for COVID-19-related expenses. Facilities set-up and capital assets accounted for 51.6% of the expenditure; patient-care supplies comprised 35.1%. Of the 19,611 inpatients tested for COVID-19 in 2020, 727 (3.7%) had COVID-19. The total inpatient- and intensive care unit (ICU)-days for COVID-19 patients in 2020 were 8009 and 8 days, respectively. A decline in all hospital services was observed from February following a raised disease outbreak alert level; most services quickly resumed when the lockdown was lifted in June. CONCLUSION: COVID-19 led to an increase in healthcare expenses and a displacement in hospital services. Our findings are useful for informing economic evaluations of COVID-19 response and provide some information about the expected costs of future outbreaks.

Predictors of responses to immune checkpoint blockade in advanced melanoma.

Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel.The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma.

Nanoscratch testing for the assessment of enamel demineralization under conditions simulating wine erosion.

BACKGROUND: Erosive tooth wear and dentinal hypersensitivity are common problems affecting professional wine tasters. By using nanoscratch testing, the aim of this in vitro study was to assess enamel softening under conditions simulating 10 one-minute episodes of wine erosion. METHODS: Ten enamel specimens were bathed in artificial saliva for 2 hours before being eroded for 10 episodes, with each episode comprising one minute of wine erosion followed by one minute of remineralization in artificial saliva. Nanoscratches were placed with a spherical tip (20 µm radius) in a nanoindenter under a load of 100 mN at baseline (stage 1), after a one-erosion episode (stage 2) and after 10-erosion episodes (stage 3). RESULTS: There were significant effects of erosion stages on both scratch depth (p<0.001) and surface roughness (p<0.001). Post hoc tests showed significant differences in both scratch depths and surface roughness between stages 1 and 3 (p<0.001), and between stages 2 and 3 (p<0.01). CONCLUSIONS: Enamel softening occurs at an early stage of wine tasting, emphasizing the need to implement early preventive strategies in professional wine tasters. Further research elucidating the fundamental mechanisms involved in early stages of erosion has the potential to lead to development of more effective preventive strategies.

Ministry of Health clinical practice guidelines: depression.

The Ministry of Health (MOH) have updated the clinical practice guidelines on Depression to provide doctors and patients in Singapore with evidence-based treatment for depression. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on Depression, for the information of readers of the Singapore Medical Journal. 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/home/Publications/guidelines/cpg/2012/depression.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.

Ministry of Health clinical practice guidelines: schizophrenia.

The Ministry of Health (MOH) has updated the clinical practice guidelines on Schizophrenia to provide doctors and patients in Singapore with evidence-based treatment for schizophrenia. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on Schizophrenia, for the information of readers of the Singapore Medical Journal. 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/mohcorp/publications.aspx?id=26138. 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.

Co-amplified genes at 8p12 and 11q13 in breast tumors cooperate with two major pathways in oncogenesis.

Co-amplification at chromosomes 8p11-8p12 and 11q12-11q14 occurs often in breast tumors, suggesting possible cooperation between genes in these regions in oncogenesis. We used high-resolution array comparative genomic hybridization (array CGH) to map the minimal amplified regions. The 8p and 11q amplicons are complex and consist of at least four amplicon cores at each site. Candidate oncogenes mapping to these regions were identified by combining copy number and RNA and protein expression analyses. These studies also suggested that CCND1 at 11q13 induced expression of ZNF703 mapping at 8p12, which was subsequently shown to be mediated by the Rb/E2F pathway. Nine candidate oncogenes from 8p12 and four from 11q13 were further evaluated for oncogenic function. None of the genes individually promoted colony formation in soft agar or collaborated with each other functionally. On the other hand, FGFR1 and DDHD2 at 8p12 cooperated functionally with MYC, whereas CCND1 and ZNF703 cooperated with a dominant negative form of TP53. These observations highlight the complexity and functional consequences of the genomic rearrangements that occur in these breast cancer amplicons, including transcriptional cross-talk between genes in the 8p and 11q amplicons, as well as their cooperation with major pathways of tumorigenesis.

Pulmonary function and exercise capacity in survivors of severe acute respiratory syndrome.

The aim of this study was to investigate pulmonary function and exercise capacity in a group of survivors of the severe acute respiratory syndrome (SARS). At 3 months after hospital discharge, 46 survivors of SARS underwent the following evaluation: spirometry, static lung volumes and carbon monoxide transfer factor (TL,CO). In total, 44 of these patients underwent cardiopulmonary exercise testing. No abnormalities were detected in the pulmonary function tests in 23 (50%) of the patients. Abnormalities of forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC and TL,CO were detected in seven (15%), 12 (26%), one (2%) and 18 (39%) patients, respectively. All of these abnormalities were mild except in one case. In 18 patients (41%), the maximum aerobic capacity was below the lower limit of the normal range. Breathing reserve was low in four patients and significant oxygen desaturation was detected in a further four patients. Comparison of the measured exercise capacity with resting pulmonary function tests showed many cases of discordance in impairment. In conclusion, pulmonary function defects were detected in half of the recovered severe acute respiratory syndrome patients 3 months after hospital discharge, but the impairment was mild in almost all cases. Many patients had reduced exercise capacity that cannot be accounted for by impairment of pulmonary function.

Functional analysis and intracellular localization of p53 modified by SUMO-1.

p53 tumor suppressor is a subject of several post-translational modifications, including phosphorylation, ubiquitination and acetylation, which regulate p53 function. A new covalent modification of p53 at lysine 386 by SUMO-1 was recently identified. To elucidate the function of sumoylated p53, we compared the properties of wild type p53 and sumoylation-deficient p53 mutant, K386R. No differences were found between wild type p53 and K386R mutant of p53 in transactivation or growth suppression assays. Moreover, overexpression of SUMO-1 has no effect on p53-regulated transcription. Biochemical fractionation showed that sumoylated p53 is localized in the nucleus and is tightly bound to chromatin structures. p53 and SUMO-1 co-localized in PML nuclear bodies in 293 cells and the nucleoli in MCF7 and HT1080 cells. However, sumoylation-deficient p53 mutant showed a similar pattern of intranuclear localization, suggesting that SUMO-1 does not target p53 to subnuclear structures. These data indicate that SUMO-1 modification of p53 at lysine 386 may not be essential for p53's cellular localization, transcriptional activation, or growth regulation.

p53 is involved in tumor necrosis factor-alpha-induced apoptosis in the human prostatic carcinoma cell line LNCaP.

The human prostatic carcinoma cell line LNCaP is sensitive to TNF-alpha treatment and expresses wild-type p53. To analyse the possible role of p53 in TNF-alpha-mediated apoptosis, we generated a derivative of LNCaP, LN-56, expressing a dominant-negative element of p53, GSE56. P53 inactivation in LN-56 was associated with an increased resistance to apoptosis induced by TNF-alpha. Surface expression of TNF-alpha receptors was unchanged in LN-56 compared to LNCaP. TNF-alpha treatment resulted in accumulation of p53 in LNCaP and upregulation of p21/WAF1. Activation of caspase-7 and PARP proteolysis were delayed in LN-56 under TNF-alpha treatment. TNF-alpha-induced apoptosis in LNCaP cells was accompanied by caspase-dependent proteolysis of p21/WAF1 and Rb, which was significantly attenuated in LN-56. Cytochrome c release was induced by TNF-alpha treatment in both cell lines, but caspase-9 was not activated. LNCaP and LN-56 were injected s.c. in nude mice and tumors were identified in all LN-56, but not LNCaP, bearing mice indicating that p53 plays an important role in growth control of prostatic neoplasms. Interestingly, accumulation of p53 in TNF-alpha-treated LNCaP cells was decreased in the presence of the caspase inhibitor Z-VAD-FMK, suggesting a new role of activated caspases in acceleration of p53 response. In summary, these results indicate that p53 is involved in TNF-alpha-mediated apoptosis in LNCaP.

Structure and regulation of the mouse ing1 gene. Three alternative transcripts encode two phd finger proteins that have opposite effects on p53 function.

The human ING1 gene encodes nuclear protein p33(ING1), previously shown to cooperate with p53 in cell growth control (Garkavtsev, I., Grigorian, I. A., Ossovskaya, V. S., Chernov, M. V., Chumakov, P. M., and Gudkov, A. V. (1998) Nature 391, 295-298). p33(ING1) belongs to a small family of proteins from human, mouse, and yeast of approximately the same size that show significant similarity to one another within the C-terminal PHD finger domain and also contain an additional N-terminal region with subtle but reliably detectable sequence conservation. Mouse ing1 is transcribed from three differently regulated promoters localized within a 4-kilobase pair region of genomic DNA. The resulting transcripts share a long common region encoded by a common exon and differ in their 5'-exon sequences. Two transcripts are translated into the same protein of 185 amino acids, the mouse equivalent of the human p33(ING1), while the third transcript encodes a longer protein that has 94 additional N-terminal amino acids. Overexpression of the longer protein interferes with the accumulation of p53 protein and activation of p53-responsive promoters after DNA damage. Between the two products of ing1, only the longer one forms a complex with p53 detectable by immunoprecipitation. These results indicate that a single gene, ing1, encodes both p53-suppressing and p53-activating proteins that are regulated by alternative promoters.

Suppression of apoptosis by bcl-2 does not prevent p53-mediated control of experimental metastasis and anchorage dependence.

Mutations in the p53 tumor suppressor gene are frequently associated with the metastatic stage of tumor progression. Inactivation of p53 was shown to promote metastasis under experimental conditions. To determine the p53 functions that are involved in the control of tumor metastasis, we compared properties of three types of transformed mouse fibroblasts: with intact p53, with p53-mediated apoptosis suppressed by bcl-2 and with p53 inactivated by dominant negative mutants. Although expression of bcl-2 blocked apoptosis in detached cells and increased tumor cell survival in the blood circulation, it was insufficient to affect the ability of p53 to cause cell cycle arrest in detached cells and suppress experimental metastasis. For the suppression of metastasis complete inactivation of p53 was required. We conclude that the apoptotic function of p53 is dispensable for the p53-dependent suppression of experimental metastasis that is presumably achieved by controlling anchorage dependence. These data provide a possible explanation to dramatic differences in values of bcl-2 and mutant p53 as prognostic markers in human cancer.