Interleukin-18 and COVID-19.

Vulnerability to coronavirus disease (COVID)-19 varies due to differences in interferon gamma (IFNγ) immunity. We investigated whether a key modifiable interferon precursor, interleukin-18, was related to COVID-19, overall and by severity, using Mendelian randomisation. We used four established genome-wide significant genetic predictors of interleukin-18 applied to the most recent genome-wide association study of COVID-19 (June 2021) to obtain Mendelian randomisation inverse variance weighted estimates by severity, i.e. any (cases = 112 612, non-cases = 2 474 079), hospitalised (cases = 24 274, non-cases = 2 061 529) and very severe (cases = 8779, non-cases = 1 001 875) COVID-19. To be comprehensive, we also conducted an exploratory analysis for IFNγ and two related cytokines with less well-established genetic predictors, i.e. interleukin-12 and interleukin-23. Genetically predicted interleukin-18 was associated with lower risk of any COVID-19 (odds ratio (OR) 0.96 per standard deviation, 95% confidence interval (0.94-0.99, P-value 0.004)) and of very severe COVID-19 (OR 0.88, 95% CI 0.78-0.999, P-value 0.048). Sensitivity analysis and a more liberal genetic instrument selection gave largely similar results. Few genome-wide significant genetic predictors were available for IFNγ, interleukin-12 or interleukin-23, and no associations with COVID-19 were evident. Interleukin-18 could be a modifiable target to prevent COVID-19 and should be further explored in an experimental design.

Effects of transforming growth factor-ß1 on plasminogen activation in stem cells from the apical papilla: role of activating receptor-like kinase 5/Smad2 and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signalling.

AIM: To study the effects of TGF-ß1 on the plasminogen activation (PA) system of stem cells from the apical papilla (SCAP) and its signalling. METHODOLOGY: SCAP cells were isolated from the apical papilla of immature permanent teeth extracted for orthodontic reasons. They were exposed to various concentration of TGF-ß1 with/without pretreatment and coincubation by SB431542 (ALK/Smad2/3 inhibitor), or U0126 (MEK/ERK inhibitor). MTT assay, Western blotting and enzyme-linked immunosorbent assay (ELISA) were used to detect their effects on cell viability, and the protein expression of plasminogen activator inhibitor-1 (PAI-1), urokinase-type plasminogen activator (uPA), uPA receptor (uPAR) and their secretion. The paired Student's t-test was used for statistical analysis. RESULTS: TGF-ß1 significantly stimulated PAI-1 and soluble uPAR (suPAR) secretion of SCAP cells (P < 0.05), whereas uPA secretion was inhibited. Accordingly, TGF-ß1 induced both PAI-1 and uPAR protein expression of SCAP cells. SB431542 (an ALK5/Smad2/3 inhibitor) pretreatment and coincubation prevented the TGF-ß1-induced PAI-1 and uPAR of SCAP. U0126 attenuated the TGF-ß1-induced expression/secretion of uPAR, but not PAI-1 in SCAP. SB431542 reversed the TGF-ß1-induced decline of uPA. CONCLUSIONS: TGF-ß1 may affect the repair/regeneration activities of SCAP via differential increase or decrease of PAI-1, uPA and uPAR. These effects induced by TGF-ß1 are associated with ALK5/Smad2/3 and MEK/ERK activation. Elucidation the signalling pathways and effects of TGF-ß1 is useful for treatment of immature teeth with open apex by revascularization/revitalization procedures and tissue repair/regeneration.

Pattern of mortality after menopausal hormone therapy: long-term follow up in a population-based cohort.

OBJECTIVE: To investigate long-term pattern of mortality in menopausal women according to different modalities of hormone therapy. DESIGN: Population-based prospective cohort study. SETTING: Denmark 1993-2013. POPULATION: A total of 29 243 women aged 50-64 years at entry into the Diet, Cancer and Health Cohort, enrolled 1993-97 and followed through 31 December 2013. METHODS: Cox' proportional hazards models for increasingly longer periods of follow-up time were used to estimate mortality pattern according to baseline hormone use adjusted for relevant potential confounders. MAIN OUTCOME(S): All-cause and cause-specific mortality. Outcome information was obtained from the Danish Register of Causes of Death (linkage 99.6%). RESULTS: A total of 4098 women died during a median follow up of 17.6 years. After adjustment for relevant lifestyle risk factors, hormone use had no impact on all-cause mortality, regardless of modality. Among baseline users, lower cardiovascluar disease mortality was only evident after 5 years [hazard ratio (HR) 0.54; 95% CI 0.32-0.92], but dissipated with additional follow up. Conversely, lower colorectal cancer mortality (HR 0.64; 95% CI 0.46-0.89) and higher breast cancer mortality (HR 1.34; 95% CI 1.05-1.72) only became evident after 15 years of follow up. There were no significant associations for mortality from other types of cancer or from stroke. CONCLUSIONS: In this long-term follow-up study, taking hormones during menopause was not associated with overall mortality among middle-aged women. Investigating cause-specific mortality revealed significant, albeit weak, differential associations according to both causes of death and over time, underlining the importance of carefully considering individual risks and duration of treatment when making decisions on hormone therapy. TWEETABLE ABSTRACT: Long-term follow-up study confirms no association between menopausal hormone therapy and overall mortality.

Parental consanguinity in Hong Kong.

INTRODUCTION: Consanguineous union increases the risk of genetic disorders in offspring. The present study aimed to evaluate the prevalence and characteristics of parental consanguinity in Hong Kong, and its effects on pregnancy, perinatal, and child health outcomes. METHODS: Pregnant women in consanguineous unions attending an obstetrics unit at a public hospital in Hong Kong were retrospectively studied. Their pregnancy, perinatal, and child health outcomes were compared with an ethnicity-matched control group of pregnant women in non-consanguineous unions. RESULTS: The overall prevalence of parental consanguinity was 0.6% (first cousins or closer, 78.4%; beyond first cousins, 21.6%). The majority were ethnic Pakistani (85.0%). Women in consanguineous unions were more likely to have an obstetric history of congenital abnormality (10.5%), unexplained intrauterine fetal demise (4.2%) and unexplained neonatal death (4.6%), or family history of congenital abnormality (4.6%). Offspring of consanguineous parents had significantly higher risk of recessive diseases (odds ratio [OR]=8.70, 95% confidence interval [CI]=1.06-71.36), structural abnormalities (OR=4.55, 95% CI=2.17-9.53) and developmental delay (OR=6.72, 95% CI=1.48-30.63), and significantly higher incidence of autistic spectrum disorder (2.1%; P=0.008). CONCLUSIONS: It is essential that information on the increased risks associated with parental consanguinity is included in genetic counselling for consanguineous couples, so that they can make informed decisions.

Uterine Fibroid Symptom and Health-related Quality of Life Questionnaire: a Chinese translation and validation study.

INTRODUCTION: The Uterine Fibroid Symptom and Health-related Quality of Life (UFS-QOL) questionnaire is a validated tool in English language to assess treatment outcomes for women with fibroids. We performed a Chinese (traditional) translation and cultural adaptation of it and evaluated its reliability, validity, and responsiveness. METHODS: Overall, 223 Chinese women aged ≥18 years with uterine fibroids self-administered the UFS-QOL, Short-Form Health Survey-12, pictorial blood loss assessment chart (PBAC), and a visual analogue scale (VAS) on fibroid-related symptom severity. Demographics and haemoglobin levels were recorded; physical examination and ultrasound for size of fibroids were performed. Half of the women were followed up 6 months later for responsiveness. RESULTS: Cronbach's alpha coefficients ranged from 0.706 to 0.937, demonstrating high internal reliability. The intra-class correlation coefficients to measure test-retest reliability implied excellent stability of symptom scores (0.819, P<0.001), health-related quality of life scores (0.897, P<0.001), and all subscales (range 0.721-0.870, P<0.001). Convergent validity was demonstrated by positive correlations between the findings of various symptom severity assessment tools (PBAC, VAS on fibroid-related symptoms severity) and the symptom severity domain of Chinese UFS-QOL. In addition, there were positive correlations between health-related quality of life scores of Chinese UFS-QOL and the corresponding subscales of the Short-Form Health Survey-12. Responsiveness was shown by reduction of symptom severity scores and improvement of health-related quality of life scores after treatment. CONCLUSIONS: The Chinese version of the UFS-QOL is valid, reliable, and responsive to changes after treatment.

Non-surgical treatment of knee osteoarthritis.

Knee osteoarthritis is one of the most common degenerative diseases causing disability in elderly patients. Osteoarthritis is an increasing problem for ageing populations, such as that in Hong Kong. It is important for guidelines to be kept up to date with the best evidence-based osteoarthritis management practices available. The aim of this study was to review the current literature and international guidelines on non-surgical treatments for knee osteoarthritis and compared these with the current guidelines in Hong Kong, which were proposed in 2005. Internationally, exercise programmes for non-surgical management of osteoarthritis have been proven effective, and a pilot programme in Hong Kong for comprehensive non-surgical knee osteoarthritis management has been successful. Long-term studies on the effectiveness of such exercise programmes are required, to inform future changes to guidelines on osteoarthritis management.

The first pilot study of expanded newborn screening for inborn errors of metabolism and survey of related knowledge and opinions of health care professionals in Hong Kong.

INTRODUCTION: Newborn screening is important for early diagnosis and effective treatment of inborn errors of metabolism (IEM). In response to a 2008 coroners' report of a 14-year-old boy who died of an undiagnosed IEM, the OPathPaed service model was proposed. In the present study, we investigated the feasibility of the OPathPaed model for delivering expanded newborn screening in Hong Kong. In addition, health care professionals were surveyed on their knowledge and opinions of newborn screening for IEM. METHODS: The present prospective study involving three regional hospitals was conducted in phases, from 1 October 2012 to 31 August 2014. The 10 steps of the OPathPaed model were evaluated: parental education, consent, sampling, sample dispatch, dried blood spot preparation and testing, reporting, recall and counselling, confirmation test, treatment and monitoring, and cost-benefit analysis. A fully automated online extraction system for dried blood spot analysis was also evaluated. A questionnaire was distributed to 430 health care professionals by convenience sampling. RESULTS: In total, 2440 neonates were recruited for newborn screening; no true-positive cases were found. Completed questionnaires were received from 210 respondents. Health care professionals supported implementation of an expanded newborn screening for IEM. In addition, there is a substantial need of more education for health care professionals. The majority of respondents supported implementing the expanded newborn screening for IEM immediately or within 3 years. CONCLUSION: The feasibility of OPathPaed model has been confirmed. It is significant and timely that when this pilot study was completed, a government-led initiative to study the feasibility of newborn screening for IEM in the public health care system on a larger scale was announced in the Hong Kong Special Administrative Region Chief Executive Policy Address of 2015.

Risk in the "Red Zone": Outcomes for Children Admitted to Ebola Holding Units in Sierra Leone Without Ebola Virus Disease.

We collected data on 1054 children admitted to Ebola Holding Units in Sierra Leone and describe outcomes of 697/1054 children testing negative for Ebola virus disease (EVD) and accompanying caregivers. Case-fatality was 9%; 3/630 (0.5%) children discharged testing negative were readmitted EVD-positive. Nosocomial EVD transmission risk may be lower than feared.

Emergency Department Urinary Antibiograms Differ by Specific Patient Group.

Patients presenting to the emergency department (ED) represent a heterogeneous population comprised of all ages, various backgrounds, such as from the community and skilled-nursing facilities (SNFs), and at various risks for resistant pathogens. The aim of this study was to compare patient group-specific urinary antibiograms in the ED. Adults presented to the ED with an ICD 9/10 code urinary tract infection (UTI) diagnosis during July 2015 to June 2016 were randomly selected (n = 500) to extract relevant demographic, laboratory, and clinical data from the medical record. Urinary Escherichia coli antibiograms were compared between institutional versus ED and among ED patients (male versus female; age of 18 to 64 years versus ≥65 years; female aged 18 to 50 years versus >50 years; home versus SNF; and admitted versus discharged). E. coli grew from 56% (145/259) of the positive urine cultures. Overall ciprofloxacin (CIP), trimethoprim-sulfamethoxazole (SXT), and cefazolin (CFZ) susceptibilities were <71%. Differences in antibiograms were the following: lower CFZ and SXT susceptibilities in ED versus institutional (CFZ, 67% versus 86% [P = 0.001]; SXT, 66% versus 74% [P = 0.02]), lower ampicillin and gentamicin susceptibilities in females aged 18 to 50 years versus >50 years (32% versus 52% [P = 0.04]; 78% versus 93% [P = 0.02]), lower CIP susceptibilities in the elderly (64% versus 81%; P = 0.03), SNF versus home (35% versus 77%; P < 0.001), admitted versus discharged (63% versus 78%; P = 0.04), and lower SXT susceptibilities in patients aged <65 years versus the elderly (58% versus 71%; P = 0.01). Nitrofurantoin showed >80% susceptibility in all groups. Patient group-specific urinary antibiograms revealed distinct differences in E. coli susceptibility and should be developed to better inform empirical UTI therapy selection in the ED.

Reappraisal of endometrial thickness for the detection of endometrial cancer in postmenopausal bleeding: a retrospective cohort study.

OBJECTIVE: To estimate the accuracy of transvaginal ultrasound (TVS) measurement of endometrial thickness (ET) in diagnosing endometrial cancer in postmenopausal women with vaginal bleeding (PMB). DESIGN: Retrospective cohort study. SETTING: One-stop PMB clinic in a Hong Kong teaching hospital. POPULATION: A cohort of 4383 women with PMB. METHODS: Transvaginal ultrasonic measurement of ET and endometrial biopsies were obtained in women presenting with PMB between 2002 and 2013. Endometrial histology was used as the reference standard to calculate accuracy estimates. MAIN OUTCOME MEASURES: Accuracy data for TVS ET presented as sensitivity, specificity, and area under the receiver operator characteristic (ROC) curve. RESULTS: Endometrial cancer was diagnosed in 3.8% of women. The median ET in those with endometrial cancer was significantly higher than those with benign conditions (15.7 versus 3.2 mm, P < 0.001). The area under the ROC curve was 0.92 (95% CI 0.89-0.94). The sensitivity for the detection of endometrial cancer at 3-, 4-, and 5-mm cut-offs were 97.0% (95% CI 94.5-99.6%), 94.1% (95% CI 90.5-97.6%), and 93.5% (95% CI 89.7-97.2%), respectively. The corresponding estimates of specificity at these thresholds were 45.3% (95% CI 43.8-46.8%), 66.8% (65.4-68.2%), and 74.0% (72.7-75.4%). CONCLUSIONS: Transvaginal ultrasound using a 3-mm cut-off has high sensitivity for detecting endometrial cancer and can identify women with PMB who are highly unlikely to have endometrial cancer, thereby avoiding more invasive endometrial biopsy.

Factors affecting the deceased organ donation rate in the Chinese community: an audit of hospital medical records in Hong Kong.

INTRODUCTION: The number of actual donors per million population is the most commonly used metric to measure organ donation rates worldwide. It is deemed inadequate, however, because it does not take into account the potential donor pool. The aim of this study was to determine the true potential for solid organ donation from deceased brain-dead donors and the reasons for non-donation from potential donors in the Chinese community. METHODS: Medical records of all hospital deaths between 1 January and 31 December 2014 at a large regional hospital in Hong Kong were reviewed. Those who were on mechanical ventilation with documented brain injury and aged ≤75 years were classified as possible organ donors. The reasons why some potential organ donors did not become utilised organ donors were recorded and evaluated. RESULTS: Among 3659 patient deaths, 121 were classified as possible organ donors. The mean age of the possible organ donors was 59.4 years and 72.7% of them were male. The majority (88%) were from non-intensive care units. Of the 121 possible organ donors, 108 were classified as potential organ donors after excluding 13 unlikely to fulfil brain death criteria. Finally 11 patients became actual organ donors with an overall conversion rate of 10%. Reasons for non-donation included medical contra-indication (46%), failure to identify and inform organ donation coordinators (14%), failure of donor maintenance (11%), brain death diagnosis not established (18%), and refusal by relatives (11%). CONCLUSIONS: It is possible to increase the organ donation rate considerably by action at different stages of the donation process. Ongoing accurate audit of current practice is necessary.

Evaluation of a Clostridium difficile infection management policy with clinical pharmacy and medical microbiology involvement at a major Canadian teaching hospital.

WHAT IS KNOWN AND OBJECTIVE: Clostridium difficile infection (CDI) represents a spectrum of disease and is a significant concern for healthcare institutions. Our study objective was to assess whether implementation of a regional CDI management policy with Clinical Pharmacy and Medical Microbiology and Infection Control involvement would lead to an improvement in concordance in prescribing practices to an evidence-based CDI disease severity assessment and pharmacological treatment algorithm. METHODS: Conducted at a tertiary care teaching hospital, this two-phase quality assurance study consisted of a baseline retrospective healthcare record review of patients with CDI prior to the implementation of a regional CDI management policy followed by a prospective evaluation post-implementation. RESULTS AND DISCUSSION: One hundred and forty-one CDI episodes in the pre-implementation group were compared to 283 episodes post-implementation. Overall treatment concordance to the CDI treatment algorithm was achieved in 48 of 141 cases (34%) pre-implementation compared with 136 of 283 cases (48·1%) post-implementation (P = 0·01). The median time to treatment with vancomycin was reduced from five days to one day (P < 0·01), with median length of hospital stay decreasing from 30 days to 21 days (P = 0·01) post-implementation. There was no difference in 30-day all-cause mortality. WHAT IS NEW AND CONCLUSION: A comprehensive approach with appropriate stakeholder involvement in the development of clinical pathways, education to healthcare workers and prospective audit with intervention and feedback can ensure patients diagnosed with CDI are optimally managed and prescribed the most appropriate therapy based on CDI disease severity.

PubMed-supported clinical term weighting approach for improving inter-patient similarity measure in diagnosis prediction.

BACKGROUND: Similarity-based retrieval of Electronic Health Records (EHRs) from large clinical information systems provides physicians the evidence support in making diagnoses or referring examinations for the suspected cases. Clinical Terms in EHRs represent high-level conceptual information and the similarity measure established based on these terms reflects the chance of inter-patient disease co-occurrence. The assumption that clinical terms are equally relevant to a disease is unrealistic, reducing the prediction accuracy. Here we propose a term weighting approach supported by PubMed search engine to address this issue. METHODS: We collected and studied 112 abdominal computed tomography imaging examination reports from four hospitals in Hong Kong. Clinical terms, which are the image findings related to hepatocellular carcinoma (HCC), were extracted from the reports. Through two systematic PubMed search methods, the generic and specific term weightings were established by estimating the conditional probabilities of clinical terms given HCC. Each report was characterized by an ontological feature vector and there were totally 6216 vector pairs. We optimized the modified direction cosine (mDC) with respect to a regularization constant embedded into the feature vector. Equal, generic and specific term weighting approaches were applied to measure the similarity of each pair and their performances for predicting inter-patient co-occurrence of HCC diagnoses were compared by using Receiver Operating Characteristics (ROC) analysis. RESULTS: The Areas under the curves (AUROCs) of similarity scores based on equal, generic and specific term weighting approaches were 0.735, 0.728 and 0.743 respectively (p < 0.01). In comparison with equal term weighting, the performance was significantly improved by specific term weighting (p < 0.01) but not by generic term weighting. The clinical terms "Dysplastic nodule", "nodule of liver" and "equal density (isodense) lesion" were found the top three image findings associated with HCC in PubMed. CONCLUSIONS: Our findings suggest that the optimized similarity measure with specific term weighting to EHRs can improve significantly the accuracy for predicting the inter-patient co-occurrence of diagnosis when compared with equal and generic term weighting approaches.

A 5-week whole body vibration training improves peak torque performance but has no effect on stretch reflex in healthy adults: a randomized controlled trial.

AIM: This study aimed to investigate the neuromuscular adaptation following a 5-week high frequency and low amplitude whole body vibration (WBV) exercise training. METHODS: The study is a prospective, double blind, randomized controlled intervention design with a total of 19 subjects volunteered to participate in the study. They were randomly assigned either to WBV exercise training or control group. Both groups participated in a 5-week training program. The intervention group received WBV in semi-squat position on a device with an amplitude of 0.76 mm, frequency of 40Hz, and peak acceleration of 23.9 m/s2. Each vibration training session consisted of 6 series of 60s on with 30s rest period in between. The control group underwent the same statically mini-squatting position without exposure to WBV. The effectiveness of the vibration program was evaluated by vertical jump test and the isokinetic knee extensor peak torque. The possible neural factors that contributed to the improved muscular performance were evaluated by the stretch induced knee jerk reflex. RESULTS: WBV training significantly enhanced the isokinetic knee extensor peak torque performance. Two-way mixed repeated measures analysis of variance revealed significant time effect of the changes in the peak torque (P=0.043) and the effect was significantly different between the intervention and control group (P=0.042). WBV did not affect vertical jump height, reflex latency of VL, EMGVL, and knee jerk angle. CONCLUSION: The results of this study do not support the hypothesis that the improvement in the muscular performance when subjects exposed to WBV training is attributed by neuromuscular efficiency via modulation of the muscle spindle sensitivity.

The association of diabetes and anti-diabetic medications with clinical outcomes in multiple myeloma.

BACKGROUND: Insulin/insulin-like growth factor-1 signalling may underlie the promoting effect of type 2 diabetes on cancer. This study examined the association of diabetes, including steroid-induced diabetes (SID), and the impact of anti-diabetic medication on clinical outcomes of multiple myeloma (MM). METHODS: A retrospective review was conducted of 1240 MM patients. Overall survival (OS) and MM disease status prior to death were analysed. RESULTS: Diabetic patients had a significantly shorter OS than non-diabetic patients (median: 65.4 vs 98.7 months). In multivariate analysis, SID was a significant predictor of decreased OS, along with age, comorbidity, MM stage, and cytogenetic abnormalities. Analyzing only the diabetic MM patients, Cox regression showed that metformin predicted an increased OS, whereas use of insulin/analogues predicted a decreased OS. Competing risk analysis showed that DM was associated with increased cumulative incidence of death with progressive MM. Among the diabetics, multivariate regression showed that insulin/analogues were associated with increased, but metformin with decreased death with progressive MM. Potential immortal time bias was evaluated by landmark analyses. CONCLUSIONS: DM, SID in particular, is associated with poor clinical outcomes in MM. Insulin/analogues are associated with poor outcomes, whereas metformin is associated with improved outcomes. No conclusion about causal relationships can be made at this time. Managing hyperglycaemia with non-insulin regimens should be investigated in randomised trials.

Testosterone concentrations in young healthy US versus Chinese men.

BACKGROUND: Previous small studies examining differences in testosterone concentrations by ethnicity found mixed results for Caucasians and Chinese men, which might be confounded by age differences and living standards. The aim of the present study is to examine the differences in total, free, and bioavailable testosterone concentrations between healthy young men from the United States (US) and from the most economically developed part of China, i.e., Hong Kong (HK). METHODS: Cross-sectional analysis based on 365 young men from the Third National Health and Nutrition examination Survey (NHANES III) in the US and 299 Chinese men recruited from university students. All participants were aged from 18 to 29 years. Main outcome measures were total testosterone (TT) and calculated bioavailable testosterone (Bio T) and free testosterone (FT). RESULTS: In both US and Chinese men, TT, FT, and Bio T concentration peaked at 20-24 years of age, at 23.19, 0.49, and 12.23 nmol/l in US men, and 20.72, 0.48 and 12.59 nmol/l in Chinese men, respectively. Among those aged 18-24 years, after adjusting for age, US men had higher TT (mean, 95% confidence interval: 21.64, 21.31-21.99 versus 20.20, 20.12-20.28 nmol/l), but not FT (0.47, 0.47-0.48 versus 0.47, 0.47-0.47 nmol/l) or Bio T (11.90, 11.83-11.97 versus 12.39, 12.35-12.42 nmol/l) than Chinese men. CONCLUSIONS: TT, but not FT or Bio T concentrations are lower in young healthy Chinese men than US men. These differences apparent in young men may be important in understanding different patterns of diseases between Western and Asian populations.