Palliative Prognostic Index as a predictor of mortality among geriatric patients with advanced chronic medical conditions.

INTRODUCTION: This study is to validate Palliative Prognostic Index (PPI) as a tool for six months prognostication in geriatric patients with advanced chronic medical conditions and to identify other independent prognostic markers of survival. METHODS: This was a prospective and observational study of 108 geriatric patients conducted at Pusat Jantung Hospital Umum Sarawak (PJHUS) Kota Samarahan and Sarawak General Hospital (SGH). The PPI scores were calculated and determined at the time of admission. Mortality is considered as the primary outcome. Sensitivity and specificity analysis were conducted to test the accuracy of PPI. The ideal cut-off value for PPI and other associated markers were determined based on the highest value of Youden Index. Cox regression analysis and survival analysis were applied to test the association between potential markers within six months. RESULTS: PPI score has a significant association with survival within six months based on univariate and multivariate analyses (p<0.05). Total PPI had a hazard ratio of 1.56 (95% Confidence Interval (95%CI): 1.33,1.57). The study shows PPI reported area under the curve-ROC of 0.945 with p<0.001. PPI score with cut-off value of six reports the highest accuracy in predicting death within six months with sensitivity and specificity of 88.6% and 90.6%, respectively. Total PPI score of >6 with serum albumin level ≤25, the sensitivity and specificity tested were 100.0%. CONCLUSION: PPI has the potential to be a useful and significant predictor of mortality within six months in the geriatric population with an advanced chronic medical condition. This study also re-emphasised the strong prognostic role of other markers such as Palliative Performance Scale, Barthel Index, and serum albumin level. This study has identified that hypoalbuminemia cut-off value of 25g/dL analysed against PPI score of >5 revealed extremely high accuracy of prognostication for mortality.

A retrospective cross-sectional study on the risk factors and survival outcome of End Stage Kidney Disease patients receiving regular maintenance haemodialysis with COVID-19 infection in Hospital Enche' Besar Hajjah Khalsom, Kluang.

INTRODUCTION: COVID-19 pandemic has affected healthcare services around the globe as hospitals were turned into designated hospitals to accommodate high risk groups of patients with COVID-19 infection including end stage kidney disease (ESKD) patients. In Malaysia, there was insufficient data on COVID-19 infection among ESKD patients. This study aims to determine factors and survival outcomes associated with COVID-19 infection among ESKD patients in a designated COVID-19 hospital in Malaysia. METHODS AND MATERIALS: A retrospective cross-sectional study involving 80 haemodialysis (HD) patients recruited from March 2020 till March 2021. Patients' information and results was retrieved and evaluated. Risk factors affecting the COVID-19 mortality were analysed using a one-way analysis of variance (ANOVA) and binary logistic regression. RESULTS: The mean age of the patients was 54 years who were predominantly Malays (87.5%) and living in rural areas. Majority of them had comorbidities such as diabetes mellitus (71%) and hypertension (90%). The most common presentations were fever (46%) and cough (54%) with chest radiographs showing bilateral lower zone ground glass opacities (45%). A quarter of the study population were admitted to the intensive care unit, necessitating mechanical ventilation. This study found that 51% of the patients were given steroids and 45% required oxygen supplementation. The COVID-19 infection mortality among the study population was 12.5%. Simple logistic regression analysis showed that albumin, Odd Ratio, OR=0.85 (95% Confidence Interval, 95%CI: 0.73, 0.98)) and absolute lymphocyte count OR=0.08 (95%CI: 0.11, 0.56) have inverse association with COVID-19 mortality. C-reactive protein OR=1.02 (95%CI: 1.01, 1.04), lactate dehydrogenase OR=1.01 (95%CI: 1.00, 1.01), mechanical ventilation OR=17.21 (95%CI: 3.03, 97.67) and high dose steroids OR=15.71 (95%CI: 1.80, 137.42) were directly associated with COVID-19 mortality. CONCLUSION: The high mortality rate among ESKD patients receiving HD was alarming. This warrants additional infection control measures to prevent the spread of COVID- 19 infection among this vulnerable group of patients. Expediting vaccination efforts in this group of patients should be advocated to reduce the incidence of complications from COVID-19 infection.

A rare presentation of ectopic thyroid gland at right axilla.

The thyroid gland and its hormones play important roles in organ development and in the homeostatic control of physiological mechanisms in human beings. As a result of embryogenic descent of thyroid gland, it commonly resides along the midline - from tongue to mediastinum (90%). Ectopic thyroid gland is a rare occurrence, with extra-lingual ectopic thyroid gland being even rarer. Thus, there is a concern for malignant metastasis. Madam H, a 56-year-old healthy woman presented to the Hospital Sultanah Nora Ismail, Johor, Malaysia in April 2020 with an increasing size of right axilla mass and history of weight loss. She was having right axilla mass for the previous 7 years but only noticed the increase in size about 1 year ago. She has no other constitutional symptoms. A tru-cut biopsy performed demonstrated a benign ectopic thyroid tissue. Thyroid function test showed primary hypothyroidism. Serum Chromogranin A and other thyroid antibodies were within the normal value. Further radiological imaging showed the normal thyroid gland at neck, with no signs of distant malignancy. There was no other axillary, mediastinal or hilar lymph node enlargement. She was started on regular T. L Thyroxine 100mcg daily and given regular follow-up in endocrine clinic. Benign ectopic thyroid gland is an unusual finding. As such, follow up is needed with possibility of carcinomatous transformation such as papillary carcinoma should be considered.

Hypothalamic-pituitary fungal infection causing panhypopituitarism.

Madam LPS, a 69 years old lady complained of left eye blurring of vision since January 2017. It was associated with left orbital swelling with chemosis, eye redness, epiphora, several episodes of self-limiting epistaxis and bilateral ophthalmoplegia. Other neurological examinations and cerebellar systems were intact. Magnetic Resonance Imaging (MRI) Brain and Orbit were performed, depicting a sellar mass with suprasellar extension with blood investigations results showed panhypopituitarism. She underwent bilateral orbital decompression. Trans-nasal endoscopic biopsy showed suppurative granulomatous lesion, which cultured Candida Albicans and Candida Galbrata. She was started on antifungal and hormonal replacement therapy for panhypopituitarism. Unfortunately, she did not respond well to treatment as repeated MRI Brain on December 2018 showed increase in size of sellar mass causing obstructive hydrocephalus and increasing size of left orbital lesion. She was counselled for another debulking surgery with a ventriculoperitoneal (VP) shunt. HPE taken were reported as chronic inflammatory process in favour to fungal infection. Pituitary infections may mimic pituitary mass. Some may exhibit symptoms of panhypopituitarism as well. Thus, physical examination, MRI brain imaging as well as HPE of biopsy are important aids to achieve diagnosis. Optimal treatment of fungal pituitary abscess includes transsphenoidal surgery combined with antifungal therapy.

Gamma delta tocotrienols reduce hepatic triglyceride synthesis and VLDL secretion.

AIM: Present study aimed to elucidate the suppression of serum lipids by gamma- and delta-tocotrienol (γδT3). METHODS: The lipid-lowering effects of γδT3 were investigated using HepG2 liver cell line, hypercholesterolemic mice and borderline-high cholesterol patients. RESULTS: In-vitro results demonstrated two modes of action. First, γδT3 suppressed the upstream regulators of lipid homeostasis genes (DGAT2, APOB100, SREBP1/2 and HMGCR) leading to the suppression of triglycerides, cholesterol and VLDL biosyntheses. Second, γδT3 enhanced LDL efflux through induction of LDL receptor (LDLr) expression. Treatment of LDLr-deficient mice with 1 mg/day (50 mg/kg/day) γδT3 for one-month showed 28%, 19% reduction in cholesterol and triglyceride levels respectively, whereas HDL level was unaltered. The lipid-lowering effects were not affected by alpha-tocopherol (αTP). In a placebo-controlled human trial using 120 mg/day γδT3, only serum triglycerides were lowered by 28% followed by concomitant reduction in the triglyceride-rich VLDL and chylomicrons. In contrast, total cholesterol, LDL and HDL remained unchanged in treated and placebo groups. The discrepancies between in-vitro, in-vivo and human studies may be attributed to the differential rates of post-absorptive γδT3 degradation and LDL metabolism. CONCLUSION: Reduction in triglycerides synthesis and transport may be the primary benefit caused by ingesting γδT3 in human.

In vivo evidence of gamma-tocotrienol as a chemosensitizer in the treatment of hormone-refractory prostate cancer.

gamma-Tocotrienol (gammaT3) is known to selectively kill prostate cancer (PCa) cells and to sensitize the cells to docetaxel (DTX)-induced apoptosis. In the present study, the pharmacokinetics of gammaT3 and the in vivo cytotoxic response of androgen-independent prostate cancer (AIPCa) tumor following gammaT3 treatment were investigated. Here, we investigated these antitumor effects for PCa tumors in vivo. The pharmacokinetic and tissue distribution of gammaT3 after exogenous gammaT3 supplementation were examined. Meanwhile, the response of the tumor to gammaT3 alone or in combination with DTX were studied by real-time in vivo bioluminescent imaging and by examination of biomarkers associated with cell proliferation and apoptosis. After intraperitoneal injection, gammaT3 rapidly disappeared from the serum and was selectively deposited in the AIPCa tumor cells. Administration of gammaT3 alone for 2 weeks resulted in a significant shrinkage of the AIPCa tumors. Meanwhile, further inhibition of the AIPCa tumor growth was achieved by combined treatment of gammaT3 and DTX (p < 0.002). The in vivo cytotoxic antitumor effects induced by gammaT3 seem to be associated with a decrease in expression of cell proliferation markers (proliferating cell nuclear antigen, Ki-67 and Id1) and an increase in the rate of cancer cell apoptosis [cleaved caspase 3 and poly(ADP-ribose) polymerase]. Additionally, the combined agents may be more effective at suppressing the invasiveness of AIPCa. Overall, our results indicate that gammaT3, either alone or in combination with DTX, may provide a treatment strategy that can improve therapeutic efficacy against AIPCa while reducing the toxicity often seen in patients treated with DTX.

Gastric adenocarcinoma occurring in a young patient with common variable immunodeficiency syndrome.

Patients with common variable immunodeficiency syndrome (CVID) have an increased risk of gastric adenocarcinoma. We describe a case of gastric adenocarcinoma in a 29-year-old man with CVID. He complained of dyspepsia and weight loss. Endoscopy showed an antral lesion. He underwent subtotal gastrectomy with postoperative adjuvant chemoradiation, and remained disease-free for three years. CVID is a predisposing factor for gastric adenocarcinoma. Gastric complaints are common among these patients and should be viewed seriously. Endoscopy is performed to detect any pathology. Premalignant conditions like chronic atrophic gastritis, intestinal metaplasia and dysplasia require regular endoscopic surveillance in these high-risk patients.

Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways.

Tocotrienol-rich fraction (TRF) has demonstrated antiproliferative effect on prostate cancer (PCa) cells. To elucidate this anticancer property in PCa cells, this study aimed, first, to identify the most potent isomer for eliminating PCa cells; and second, to decipher the molecular pathway responsible for its activity. Results showed that the inhibitory effect of gamma-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of pro-caspases and the presence of sub-G(1) cell population. Examination of the pro-survival genes revealed that the gamma-tocotrienol-induced cell death was associated with suppression of NF-kappaB, EGF-R and Id family proteins (Id1 and Id3). Meanwhile, gamma-tocotrienol treatment also resulted in the induction of JNK-signalling pathway and inhibition of JNK activity by a specific inhibitor (SP600125) was able to partially block the effect of gamma-tocotrienol. Interestingly, gamma-tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and gamma-catenin expression, which was associated with suppression of cell invasion capability. Furthermore, a synergistic effect was observed when cells were co-treated with gamma-tocotrienol and Docetaxel. Our results suggested that the antiproliferative effect of gamma-tocotrienol act through multiple-signalling pathways, and demonstrated for the first time the anti-invasion and chemosensitisation effect of gamma-tocotrienol against PCa cells.

Testing the hypothesis of a recombinant origin of the SARS-associated coronavirus.

The origin of severe acute respiratory syndrome-associated corona-virus (SARS-CoV) is still a matter of speculation, although more than one year has passed since the onset of the SARS outbreak. In this study, we implemented a 3-step strategy to test the intriguing hypothesis that SARS-CoV might have been derived from a recombinant virus. First, we blasted the whole SARS-CoV genome against a virus database to search viruses of interest. Second, we employed 7 recombination detection techniques well documented in successfully detecting recombination events to explore the presence of recombination in SARS-CoV genome. Finally, we conducted phylogenetic analyses to further explore whether recombination has indeed occurred in the course of coronaviruses history predating the emergence of SARS-CoV. Surprisingly, we found that 7 putative recombination regions, located in Replicase 1ab and Spike protein, exist between SARS-CoV and other 6 coronaviruses: porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), bovine coronavirus (BCoV), human coronavirus 229E (HCoV), murine hepatitis virus (MHV), and avian infectious bronchitis virus (IBV). Thus, our analyses substantiate the presence of recombination events in history that led to the SARS-CoV genome. Like the other coronaviruses used in the analysis, SARS-CoV is also a mosaic structure.

Factors limiting large-scale localisation.

The mechanisms mediating relative spatial localisation in the visual system are still unclear. There is a growing amount of evidence that this capability is not merely limited by the processing of the front-end visual system. Models of localisation should, therefore, include higher-level processing stages. A careful study of the sources of error in localisation tasks may further our understanding of the nature of these processes. A study is reported in which the possible role of higher-order processing in relative spatial localisation is explicitly addressed. For this purpose the error sources of threshold performance were investigated for two similar relative-spatial-localisation tasks: two-dot separation discrimination and two-dot orientation discrimination. Fovea-centered stimuli with large dot separations were used. The front-end processing for these stimuli is probably identical in both tasks. Hence, differential effects of the variation of the experimental parameters on threshold performance for both tasks may reveal the characteristics of the higher-level processing involved. The effects of dot separation, stimulus orientation, and experimental procedure (single-stimulus binary forced choice versus two-alternative forced choice) on threshold performance for both tasks are reported. The results show that thresholds for both tasks increase proportionally with dot separation. However, separation-discrimination thresholds are always significantly higher than orientation-discrimination thresholds. Thresholds for separation discrimination are independent of stimulus orientation. In contrast, orientation-discrimination thresholds show an oblique effect: thresholds are consistently lower for horizontal stimuli. Both tasks also show a different dependency of threshold behaviour on the experimental procedure. For a horizontal stimulus orientation, separation discrimination is better with an explicit (physical) reference standard, whereas orientation discrimination is better with an implicit referent. These differential effects cannot be explained by any of the known characteristics of the front-end visual system. They suggest that large-scale spatial-localisation performance is probably limited at a processing level at which spatial relations are explicitly represented.

Operative cholangiography.

Retrospective analysis of 174 operative cholangiograms done over a 3-year period confirms its substantial benefit when used selectively in patients with clinical criteria for common bile duct exploration. A low incidental ductal stone rate of 1.6%, together with a 3.3% false positive cholangiogram rate and a case of bile duct injury resulting from the procedure makes its routine application appear superfluous.

Fixational drift and nasal-temporal pursuit asymmetries in strabismic amblyopes.

This study evaluated to what extent inaccurate and asymmetric smooth pursuit in strabismic amblyopic eyes is attributable to abnormally high-velocity eye drifts that these eyes exhibit during monocular fixation. Smooth pursuit gains (peak eye velocity/peak target velocity) were determined in the amblyopic and nonamblyopic eyes of 11 strabismics for nasalward and temporalward motion; the target oscillated across 6 degrees of the horizontal meridian at frequencies ranging from 0.0625 to 1 Hz. In general, pursuit gains were higher for nasalward than temporalward motion, for both amblyopic and nonamblyopic eyes. Correction for each eye's mean velocity of fixational drift eliminated this nasal-temporal pursuit asymmetry for most of the nonamblyopic eyes, but not for the amblyopic eyes. Compared to the nonamblyopic eyes, corrected pursuit gains of the amblyopic eyes averaged about 0.2 lower nasalward and about 0.4 lower temporalward, but substantial variation occurred among individuals. We suggest that the overall reduction of pursuit gain in strabismic amblyopic eyes (after correction is made for fixational drift bias) stems from the use of a nonfoveal (eccentric fixation) locus for tracking; the further reduction of temporalward gain may result from a nasal-temporal asymmetry in processing motion signals.

Spatial-filter selection in large-scale spatial-interval discrimination.

Spatial-interval discrimination thresholds were measured for a pair of bars in the presence of other parallel bars placed far enough from the targets as to be outside the range of neural and optical blurring. Thresholds were elevated when the targets were embedded in an array of four parallel bars (two between and two flanking the targets), but not when there were only two parallels, whether the parallels were between the target bars or flanking them. The threshold elevation was larger with a 100-msec than with a 500-msec exposure duration. Attenuating the high spatial frequencies magnified the threshold elevation. The data indicate that the process responsible for spatial-interval discrimination automatically selects which spatial filters to use; it does not have to scan through all ranges of spatial filters.

Spatiotemporal limitations in bisection and separation discrimination.

Exposure duration was found to have a different effect on bisection thresholds than on separation-discrimination thresholds. Bisection thresholds were higher than separation discrimination thresholds between 33 and 150 msec but equal to or lower than them at longer durations. Experiments in which stimulus contrast was manipulated showed that the effect of exposure duration on separation-discrimination and bisection thresholds could not be attributed primarily to temporal contrast integration. The data could be accounted for by a model in which bisection is done by encoding the two separations in bisection sequentially.

Two mechanisms for localization? Evidence for separation-dependent and separation-independent processing of position information.

The Weber function for separation--i.e. delta s as a function of separation s--is typically measured using a pair of targets presented roughly symmetrically relative to the fovea. With this paradigm, as the separation increases, the eccentricity of the individual targets increases also. To disentangle the effects of separation and eccentricity on the Weber function for separation, we systematically examined each of these variables and also examined the effects of target size and exposure duration. Separation discrimination thresholds were measured for average separations from 3 to 6 deg across a wide range of eccentricities, and for eccentricities of 2.5-10 deg for a range of separations. The dependence of threshold on target size was measured by varying the length of the stimuli from 1 to 120 min arc; the dependence on exposure duration was measured using durations of 100 and 500 msec at 10 deg eccentricity for comparison with data collected previously at smaller eccentricities. We found that for separations less than the eccentricity of the targets, thresholds depend primarily on separation; for larger separations, thresholds depend solely on eccentricity. In general, unless the targets are very small or quite brief, the spatial and temporal characteristics of the targets are not major contributors to the slope of the Weber function. Two mechanisms are proposed to account for thresholds in the two regions, one separation-dependent and one separation-independent.

Peripheral positional acuity: retinal and cortical constraints on 2-dot separation discrimination under photopic and scotopic conditions.

The precision of discriminating the separation of two dots was measured as a function of separation for eccentricities of 0-10 deg under photopic and scotopic conditions. At each eccentricity, the 2-dot separation discrimination thresholds showed a V-shaped dependence on separation. For separations less than approximately twice the resolution threshold, performance deteriorated from photopic to scotopic conditions and appeared to be limited by ganglion cell receptive field size or spacing. For separations smaller than 10% of the effective eccentricity (eccentricity + 0.6 deg), the photopic 2-dot separation discrimination thresholds were significantly better than 3-dot bisection thresholds previously measured under similar experimental conditions, supporting the hypothesis that 3-dot bisection suffers from spatial interference for these separations. Interestingly, under scotopic conditions, 2-dot separation discrimination thresholds were better than resolution for a range of separations at each eccentricity, implying that cone input was not necessary for hyperacuity performance. 2-dot separation discrimination thresholds for large separations were little changed from photopic to scotopic luminance conditions.

"Weber's law" for position: unconfounding the role of separation and eccentricity.

Bisection thresholds are approximately proportional to the separation/eccentricity of the targets. This "Weber's law" for position has been invoked over the past century. It is the separation of the reference targets, or their eccentricity which determines the threshold? In previous studies separation and eccentricity are confounded. In the present report we have pitted separation against eccentricity. Bisection thresholds were measured for stimuli presented on an isoeccentric arc, so that separation could be varied while holding the eccentricity of the test lines constant. We used a 5-fold range of separations from 2-10 deg. In this regime, the present results provide strong evidence against Weber's law. When separation is varied but eccentricity held constant, there is no Weber's law. Rather the thresholds are approximately constant. Our results suggest that the judgement of the separation of widely separated objects is similar to a distance measurement using a ruler on the cortex, in that the error of measurement is independent of the separation between objects. The results imply that when we attempt to gauge the distance between widely separated objects it is unlikely that we do so on the basis of the outputs of large spatial filters; rather it appears that we make such judgements by estimating the cortical distance which separates the targets of interest.

Peripheral hyperacuity: three-dot bisection scales to a single factor from 0 to 10 degrees.

Performance of three-dot bisection was determined as a function of the feature separation at eccentricities of 0-10 deg along the inferior vertical field meridian by using dot stimuli scaled in size to compensate for eccentricity. For these briefly flashed dot stimuli, the entire function of three-dot bisection acuity against dot separation worsens away from the fovea with a single scaling factor that is compatible with the change of the cortical magnification factor in area V1. When the presentation duration of the stimulus was lengthened from 150 msec to 1 sec, the improvement was much greater in the fovea than at 10-deg eccentricity for closely separated stimuli. We attribute this difference to a luminance cue (detection of a brightness change) that is present for a long stimulus duration at small separations in the fovea, but not in the periphery.

Peripheral hyperacuity: isoeccentric bisection is better than radial bisection.

Performance of three-dot bisection was determined as a function of orientation for a variety of feature separations and field meridians at eccentricities of 0-10 deg for two observers. The dot stimuli and separations were scaled in size to compensate for eccentricity. The precision of three-dot bisection was found to depend on the direction of test-feature offset. In the fovea, horizontal and vertical bisections were better than oblique bisections, while at eccentricities of 5-20 deg, isoeccentric (on a tangent to a circle of a given eccentricity) bisection was better than radial bisection. The direction of offset was more important than the orientation of the stimulus. Large separations showed a stronger effect than small separations. The anisotropy of bisection appears different from the meridional effect for resolution and is unlikely to be simply related to a local anisotropy of the cortical magnification factor.