Brain Metastasis Growth Kinetics: A Novel Prognosticator for Stereotactic Radiotherapy.

AIMS: The rate of size change in brain metastasis may have clinical implications on tumour biology and prognosis for patients who receive stereotactic radiotherapy (SRT). We analysed the prognostic value of brain metastasis size kinetics and propose a model for patients with brain metastases treated with linac-based SRT in predicting overall survival. MATERIALS AND METHODS: We analysed the patients receiving linac-based SRT between 2010 and 2020. Patient and oncological factors, including the changes in sizes of brain metastasis between the diagnostic and stereotactic magnetic resonance imaging, were collected. The associations between prognostic factors and overall survival were assessed using Cox regression with least absolute selection and shrinkage operator (LASSO) checked by 500 bootstrap replications. Our prognostic score was calculated by evaluating the most statistically significant factors. Patients were grouped and compared according to our proposed score, Score Index for Radiosurgery in Brain Metastases (SIR) and Basic Score for Brain Metastases (BS-BM). RESULTS: In total, 85 patients were included. We developed the prognostic model based on the most important predictors of overall survival: growth kinetics, i.e. percentage change in brain metastasis size per day between the diagnostic and stereotactic magnetic resonance imaging (hazard ratio per 1% increase, 1.32; 95% confidence interval 1.06-1.65), extracranial oligometastatic diseases (≤5 involvements) (hazard ratio 0.28; 95% confidence interval 0.16-0.52) and the presence of neurological symptoms (hazard ratio 2.99; 95% confidence interval 1.54-5.81). Patients with scores 0, 1, 2 and 3 had a median overall survival of 44.4 (95% confidence interval 9.6-not reached), 20.4 (95% confidence interval 15.6-40.8), 12.0 (95% confidence interval 7.2-22.8) and 2.4 (95% confidence interval 1.2-not reached) years, respectively. The optimism-corrected c-indices for our proposed model, SIR and BS-BM were 0.65, 0.58 and 0.54, respectively. CONCLUSIONS: Brain metastasis growth kinetics is a valuable metric for survival outcomes of SRT. Our model is useful in identifying patients with brain metastasis treated with SRT with different overall survival.

Sensorineural Hearing Loss in Nasopharyngeal Carcinoma Survivors in the Modern Treatment Era - The Early and Late Effects of Radiation and Cisplatin.

AIMS: Hearing loss is a common debilitating complication in nasopharyngeal carcinoma (NPC) survivors. The aim of the present study was to investigate the impact of inner ear/cochlear radiation dose and cisplatin use on early and late sensorineural hearing loss (SNHL) in NPC patients treated with radiotherapy alone, concurrent chemoradiation (cCRT) and induction chemotherapy followed by cCRT (iCRT) in the intensity-modulated radiotherapy era. MATERIALS AND METHODS: The study included 81 NPC patients treated with intensity-modulated radiotherapy between 2014 and 2016. Pure tone audiometry was carried out at baseline and follow-up. The effects of cochlear/inner ear radiation and cisplatin doses on early (<12 months) and late (≥24 months) SNHL were analysed using multivariable regression after adjusting for important predictors. RESULTS: In total, 156 ears were examined. In early SNHL (n = 136), cisplatin use predicted the incidence of early high-frequency SHNL (HF-SNHL) (odds ratio 6.4, 95% confidence interval 1.7-23.9, P = 0.005). Ninety ears were analysed for late SNHL (median follow-up 38 months). Inner ear/cochlear radiation and cisplatin doses and better pre-treatment hearing were independent predictors of threshold change at 4 kHz. Every 10 Gy increase in inner ear/cochlear Dmean resulted in 5-dB and 6-dB threshold changes, respectively (cochlear Dmean: B = 0.005, 95% confidence interval 0.0004-0.009, P = 0.031; inner ear Dmean: B = 0.006, 95% confidence interval 0.001-0.010, P = 0.014). Cisplatin use was associated with late HF-SNHL (odds ratio 3.74, 95% confidence interval 1.1-12.3, P = 0.031). In the cCRT and iCRT subgroups, no cisplatin dose-dependent ototoxicity was observed. Severe (≥30 dB) late HF-SNHL occurred in 14% and 25% of the patients when the cochlear dose constraints were 40 Gy and 44 Gy, respectively. The radiotherapy-alone group did not develop severe late HF-SNHL. CONCLUSION: Cochlear/inner ear radiation dose and cisplatin use showed differential and independent ototoxicity in early and late SNHL. As cochlear/inner ear dose-dependent ototoxicity was demonstrated, the cochlear dose constraint should be as low as reasonably achievable, especially when cisplatin is also administered.

Prevalences of levofloxacin resistance and pncA mutation in isoniazid-resistant Mycobacterium tuberculosis in Hong Kong.

INTRODUCTION: In 2018, the World Health Organization recommended a 6-month treatment regimen that included levofloxacin and pyrazinamide for isoniazid-resistant Mycobacterium tuberculosis without rifampicin resistance (Hr-TB). Susceptibility testing for both drugs is not routinely performed for Hr-TB in Hong Kong. This study examined the prevalences of levofloxacin and pyrazinamide resistances in Hr-TB and explored associated risk factors. METHODS: All Hr-TB isolates archived during 2018 were retrieved. Isolates were de-duplicated to identify unique cases. Levofloxacin susceptibility testing was performed using the MGIT 960 System; pncA gene sequencing was used as a surrogate indicator of pyrazinamide susceptibility. Previous laboratory records for each case were analysed. RESULTS: In total, 160 phenotypic Hr-TB cases were identified from among 3411 patients with tuberculosis (4.7%). Among these, 157 were analysed, revealing 0.6% (n=1) levofloxacin resistance and 4.5% (n=7) pyrazinamide resistance, respectively. Independent risk factors associated with pncA mutations included history of tuberculosis in the affected patient and isoniazid poly-resistance (ie, double and triple resistances), but not mono-resistance. CONCLUSION: For Hr-TB in Hong Kong, levofloxacin resistance is rare and pyrazinamide resistance-associated pncA mutations are uncommon. Routine susceptibility testing for these drugs is not indicated unless related risk factors are identified.

Health system responsiveness in Hong Kong: a comparison between South Asian and Chinese patients' experiences.

OBJECTIVES: Health system responsiveness is related to the way and the environment in which individuals are treated during their health system interaction. Generally, patients who are members of ethnic minority (EM) groups encounter more challenges in receiving healthcare services and bear a disproportionate burden of diseases compared with most counterparts. We aimed to compare the health system responsiveness perceived by South Asian (SA) EM people with that of local Chinese people in Hong Kong. STUDY DESIGN: The cross-sectional survey sample comprised 575 SA and 494 Chinese individuals. The health system responsiveness module of the World Health Survey 2002 was used for data collection. METHODS: We used propensity score weighting method to balance the two groups. Simple and multiple regressions were used to compare the perceived outpatient and inpatient health system responsiveness between SA and Chinese participants, respectively, before and after adjustment for demographics. All estimates were accompanied by 95% confidence intervals, and two-sided tests were conducted with significance concluded by a P value < 0∙05. RESULTS: Compared with the Chinese participants, the SA participants reported generally lower health system responsiveness for outpatient and inpatient services. The top three mean score difference (SA-Chinese) for outpatient care included autonomy (-0.78, P < 0.001), communication (-0.67, P < 0.001), and choice (-0.53, P < 0.001), and the top three mean score difference for inpatient care included communication (-0.90, P < 0.001), autonomy (-0.82, P < 0.001), and choice (-0.61, P < 0.01). In addition, SA participants also experienced lower responsiveness in access to community support (-0.81, P < 0.001) during hospitalization but perceived higher quality of basic amenities (0.29, P < 0.001) and confidentiality (0.44, P < 0.01) in outpatient settings. CONCLUSION: SA participants in an urbanized Chinese-oriented society reported generally lower health system responsiveness compared with the local Chinese group; however, SA participants perceived higher confidentiality and quality of basic amenities in their outpatient experience. Concerted efforts from healthcare providers and policymakers are required to improve the existing healthcare system for users of members of EM groups.

New Service Model for Common Mental Disorders in Hong Kong: a Retrospective Outcome Study.

OBJECTIVE: To review the first 8-month outcome of the Common Mental Disorder Clinic model in Hong Kong in terms of patient exit status and improvement in depressive and anxiety symptoms. METHODS: During the first appointment, patients were interviewed by a multidisciplinary team comprising a psychiatrist, a psychiatric nurse, and an occupational therapist. A multidisciplinary case conference was conducted to discuss clinical observations, diagnosis, issues of concern, and the optimal individualised treatment plan. Low-intensity interventions by nurses and/or occupational therapists were provided, as were optional, time-limited, protocol-based interventions by clinical psychologists for those with mild to moderate depressive and anxiety symptoms. Pharmacological intervention may be used when indicated. Upon completion of the treatment plan, patients were reassessed by the treating psychiatrist. Discharge options included discharge without psychiatric follow-up, step-up to psychiatric outpatient clinics, and step-down services. The self-administered Patient Health Questionnaire-9 (PHQ-9) and Generalised Anxiety Disorder 7-item scale (GAD-7) were used to assess the past 2 weeks' depressive and anxiety symptoms, respectively, at baseline and at each session. RESULTS: From July 2015 to February 2016, 1325 Chinese patients received the new service. Of them, 170 men and 363 women (mean age, 52.6 years) completed the treatment plan. After treatment, their mean PHQ-9 score decreased from 11.06 to 7.55 (p < 0.001), and the mean GAD-7 score decreased from 9.94 to 6.54 (p < 0.001). After treatment, 42.4% and 48.2% of the patients were within the normal range of PHQ-9 and GAD-7 scores, respectively, compared with 16.9% and 20.8% before treatment. The mean time to implementation of the individualised treatment plan was 82.33 days. Of the patients, 54.4% were discharged without any need for medical or psychiatric follow-up; 28% were stepped up to psychiatric outpatient clinics; and 17.3% were stepped down. The predictors of exit status were whether psychiatric medication was prescribed during initial intake (p = 0.011), whether psychiatric medication was prescribed at last follow-up (p < 0.001), the service period (p = 0.010), and the GAD-7 final score (p = 0.005). CONCLUSIONS: The first 8-month outcome of the new service model was encouraging, with shortened waiting time, reduced severity of symptoms, and better exit status (high recovery and step-down rates).

Ultrasound detection and closure of contralateral patent processus vaginalis in pediatric patients with unilateral inguinal hernia and hydrocele: a longitudinal study to prove efficacy in avoiding contralateral hernia development.

BACKGROUND: Open herniotomy has been the gold standard of pediatric hernia treatment with the advantages of simplicity in surgical technique, fast post operative recovery, and minimal recurrence rate, but its inability to prevent hernia development from a contralateral patent processus vaginalis (PPV) after a unilateral herniotomy is its major drawback. By contrast, laparoscopic hernia repair has the advantage of contralateral internal ring inspection, and, therefore, has become popular in recent years, although open herniotomy is still the favorable surgical technique among many surgeons. A simple and reliable tool to detect contralateral PPV will be valuable to surgeons who practice conventional open hernia surgery on children, although ultrasound has been applied for this purpose, but there is no long-term data to support such application. METHOD: The author performed a preoperative ultrasound on the contralateral groins of children undergoing unilateral herniotomy or PPV ligation. If the ultrasound showed no evidence of contralateral PPV, no contralateral surgery was performed. Those patients were then followed up after a long period of time to see whether contralateral hernia or hydrocele was developed or not. RESULTS: 322 pediatric patients were studied from 2006 to 2012. In 96 of the cases (30%), contralateral PPV were identified with ultrasound, and 95% of which were affirmed intraoperatively. In the remaining 226 patients who were without evidence of contralateral PPV, only unilateral surgeries were offered. One of these patients later developed contralateral hernia and required another surgery. The remaining patients were phoned up after a median period of 9 years. 114 of them could be contacted and none of them had developed contralateral hernia or hydrocele. CONCLUSIONS: Ultrasound groin is a valuable tool as an adjunct in pediatric hernia management by detecting contralateral PPV with high accuracy. Surgeon can offer unilateral or bilateral hernia surgery according to the ultrasound finding, and the incidence of contralateral hernia development is negligible. Preoperative ultrasound groin with selective contralateral PPV closure in children can be an alternative to routine laparoscopic hernia repair in avoiding contralateral hernia or hydrocele development. LEVEL OF EVIDENCE: Level 3. TYPE OF STUDY: Retrospective study.

Subjective wellbeing, suicide and socioeconomic factors: an ecological analysis in Hong Kong.

AIMS: There has recently been an increased interest in mental health indicators for the monitoring of population wellbeing, which is among the targets of Sustainable Development Goals adopted by the United Nations. Levels of subjective wellbeing and suicide rates have been proposed as indicators of population mental health, but prior research is limited. METHODS: Data on individual happiness and life satisfaction were sourced from a population-based survey in Hong Kong (2011). Suicide data were extracted from Coroner's Court files (2005-2013). Area characteristic variables included local poverty rate and four factors derived from a factor analysis of 21 variables extracted from the 2011 census. The associations between mean happiness and life satisfaction scores and suicide rates were assessed using Pearson correlation coefficient at two area levels: 18 districts and 30 quantiles of large street blocks (LSBs; n = 1620). LSB is a small area unit with a higher level of within-unit homogeneity compared with districts. Partial correlations were used to control for area characteristics. RESULTS: Happiness and life satisfaction demonstrated weak inverse associations with suicide rate at the district level (r = -0.32 and -0.36, respectively) but very strong associations at the LSB quantile level (r = -0.83 and -0.84, respectively). There were generally very weak or weak negative correlations across sex/age groups at the district level but generally moderate to strong correlations at the LSB quantile level. The associations were markedly attenuated or became null after controlling for area characteristics. CONCLUSIONS: Subjective wellbeing is strongly associated with suicide at a small area level; socioeconomic factors can largely explain this association. Socioeconomic factors could play an important role in determining the wellbeing of the population, and this could inform policies aimed at enhancing population wellbeing.

JUNO, the receptor of sperm IZUMO1, is expressed by the human oocyte and is essential for human fertilisation.

STUDY QUESTION: Is JUNO protein present at the surface membrane of human oocytes and involved in the fertilisation process? SUMMARY ANSWER: JUNO protein is expressed on the plasma membrane of human oocytes and its inhibition by a monoclonal antibody completely blocks gamete fusion. WHAT IS KNOWN ALREADY: Fusion of gamete membranes is the culminating event of the fertilisation process, but its molecular mechanisms are poorly understood. Until now, three molecules have been shown to be essential: CD9 tetraspanin in the oocyte, Izumo1 protein on the sperm and Juno, its corresponding receptor on the oocyte. Oocyte CD9 and sperm IZUMO1 have been identified in human gametes and their interaction is also well-conserved among several mammalian species. The presence of JUNO on human oocytes, however, has not yet been reported, nor has its role in fertilisation been investigated. STUDY DESIGN, SIZE, DURATION: We selected an anti-human JUNO antibody in order to investigate the presence of JUNO on the oocyte membrane surface and studied its potential involvement in gamete membrane interaction during fertilisation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Monoclonal antibodies against human JUNO (anti-hJUNO mAb) were produced by immunisation of mice with HEK cells transfected with the putative human JUNO sequence (HEK-hJUNO). These antibodies were used for immunostaining experiments and in vitro fertilisation assays with human gametes (GERMETHEQUE Biobank). MAIN RESULTS AND THE ROLE OF CHANCE: Three hybridoma supernatants, verified by immunostaining, revealed specifically HEK-hJUNO cells. The three purified monoclonal antibodies, FJ2E4 (IgG1), FJ8E8 (IgG1) and FJ4F5 (IgG2a), recognised the soluble recombinant human JUNO protein and, in a western blot of HEK-hJUNO extracts, a protein with an expected MW of 25 kDa. In addition, soluble recombinant human IZUMO protein inhibited the binding of anti-hJUNO mAbs to cells expressing hJUNO. Using these anti-hJUNO mAbs in immunostaining, we identified the presence of JUNO protein at the plasma membrane of human oocytes. Furthermore, we revealed a progressive expression of JUNO according to oocyte maturity. Finally, we showed that human zona-free oocytes, inseminated in the presence of anti-hJUNO mAb, were not fertilised by human sperm. These results suggest that, as seen in the mouse, JUNO is indeed involved in human gamete membrane fusion during fertilisation. LARGE-SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: In accordance with French bioethics laws, functional tests were performed using zona-free oocytes, which of course does not fully encompass all normal in vivo physiological conditions. However, these in vitro tests do provide direct information regarding sperm-oocyte membrane interactions. WIDER IMPLICATIONS OF THE FINDINGS: Mechanisms of gamete fusion appear to be homologous between mice and humans. However, some differences do exist and analysing the human mechanisms is essential. In fact, this is the first report describing the presence of JUNO on human oocytes and its involvement in human fertilisation. This discovery allows further examination of the understanding of molecular mechanisms that drive gamete fusion: a crucial challenge at a time when infertility affects 16% of reproductively active couples. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Agence Nationale pour la Recherche, Grant no. ANR-13-BVS5-0004, and by Association Institut du Cancer et d'Immunogénétique (ICIG). There are no competing interests.

Pre-operative anaemia, intra-operative hepcidin concentration and acute kidney injury after cardiac surgery: a retrospective observational study.

Acute kidney after cardiac surgery is more common in anaemic patients, whereas haemolysis during cardiopulmonary bypass may lead to iron-induced renal injury. Hepcidin promotes iron sequestration by macrophages: hepcidin concentration is reduced by anaemia and increased by inflammation. We analysed the associations in 525 patients between pre-operative anaemia (haemoglobin < 130 g.l-1 in men and < 120 g.l-1 in women), intra-operative hepcidin concentration and acute kidney injury (dialysis or > 26.4 µmol.l-1 or > 50% creatinine increase during the first two days after cardiac surgery. Rates of pre-operative anaemia and postoperative kidney injury were 109/525 (21%) and 36/525 (7%), respectively. The median (IQR [range]) intra-operative hepcidin concentration was 20 (10-33 [0-125]) µg.l-1 and was lower in anaemic patients than those who were not: 15 (4-28 [0-125]) µg.l-1 vs. 21 (12-33 [0-125]) µg.l-1 , respectively, p = 0.002. Four variables were independently associated with postoperative kidney injury, for which the beta-coefficients (SE) were: minutes on cardiopulmonary bypass, 0.016 (0.004), p < 0.001; intra-operative hepcidin concentration, 0.032 (0.008), p < 0.001; pre-operative anaemia, 1.97 (0.56), p < 0.001; and Cleveland clinic risk score, 0.88 (0.35), p = 0.005. Contrary to generally increased rates of kidney injury in patients with higher hepcidin concentrations, rates of kidney injury in anaemic patients were lower in patients with higher hepcidin concentrations, beta-coefficient (SE) -0.037 (0.01), p = 0.007. In cardiac surgical patients the rate of postoperative acute kidney injury predicted by the Cleveland risk score might be adjusted for pre-operative anaemia and intra-operative cardiopulmonary bypass time and hepcidin concentration. Pre-operative correction of anaemia, reduction in intra-operative bypass time and modification of iron homeostasis and hepcidin concentration might reduce acute kidney injury.

Normothermic Ex Vivo Kidney Perfusion Following Static Cold Storage-Brief, Intermediate, or Prolonged Perfusion for Optimal Renal Graft Reconditioning?

Normothermic ex vivo kidney perfusion (NEVKP) demonstrated superior results compared to hypothermic storage in donation after circulatory death (DCD) kidney transplantation. It is unknown whether an optimal perfusion time exists following hypothermic storage to allow for the recovery of renal grafts from cold ischemic injury. In a porcine model of DCD kidney autotransplantation, the impact of initial static cold storage (SCS) (8 h) followed by various periods of NEVKP recovery was investigated: group A, 8 hSCS only (control); group B, 8 hSCS + 1 hNEVKP (brief NEVKP); group C, 8 hSCS + 8 hNEVKP (intermediate NEVKP); and group D, 8 hSCS + 16 hNEVKP (prolonged NEVKP). All grafts were preserved and transplanted successfully. One animal in group D was sacrificed and excluded by postoperative day 3 due to hind limb paralysis, but demonstrated good renal function. Postoperative graft assessment during 8 days' follow-up demonstrated lowest levels of peak serum creatinine for intermediate (C) and prolonged (D) NEVKP (p = 0.027). Histological assessment on day 8 demonstrated a significant difference in tubular injury (p = 0.001), with highest values for group B. These results suggest that longer periods of NEVKP following SCS are feasible and safe for postponing surgical transplant procedure and superior to brief NEVKP, reducing the damage caused during cold ischemic storage of renal grafts.

Continuous Normothermic Ex Vivo Kidney Perfusion Is Superior to Brief Normothermic Perfusion Following Static Cold Storage in Donation After Circulatory Death Pig Kidney Transplantation.

Hypothermic preservation is known to cause renal graft injury, especially in donation after circulatory death (DCD) kidney transplantation. We investigated the impact of cold storage (SCS) versus short periods of normothermic ex vivo kidney perfusion (NEVKP) after SCS versus prolonged, continuous NEVKP with near avoidance of SCS on kidney function after transplantation. Following 30 min of warm ischemia, kidneys were removed from 30-kg Yorkshire pigs and preserved for 16 h with (A) 16 h SCS, (B) 15 h SCS + 1 h NEVKP, (C) 8 h SCS + 8 h NEVKP, and (D) 16 h NEVKP. After contralateral kidney resection, grafts were autotransplanted and pigs followed up for 8 days. Perfusate injury markers such as aspartate aminotransferase and lactate dehydrogenase remained low; lactate decreased significantly until end of perfusion in groups C and D (p < 0.001 and p = 0.002). Grafts in group D demonstrated significantly lower serum creatinine peak when compared to all other groups (p < 0.001) and 24-h creatinine clearance at day 3 after surgery was significantly higher (63.4 ± 19.0 mL/min) versus all other groups (p < 0.001). Histological assessment on day 8 demonstrated fewer apoptotic cells in group D (p = 0.008). In conclusion, prolonged, continuous NEVKP provides superior short-term outcomes following DCD kidney transplantation versus SCS or short additional NEVKP following SCS.

In vivo PET imaging of the neuroinflammatory response in rat spinal cord injury using the TSPO tracer [(18)F]GE-180 and effect of docosahexaenoic acid.

PURPOSE: Traumatic spinal cord injury (SCI) is a devastating condition which affects millions of people worldwide causing major disability and substantial socioeconomic burden. There are currently no effective treatments. Modulating the neuroinflammatory (NI) response after SCI has evolved as a major therapeutic strategy. PET can be used to detect the upregulation of the 18-kDa translocator protein (TSPO), a hallmark of activated microglia in the CNS. We investigated whether PET imaging using the novel TSPO tracer [(18)F]GE-180 can be used as a clinically relevant biomarker for NI in a contusion SCI rat model, and we present data on the modulation of NI by the lipid docosahexaenoic acid (DHA). METHODS: A total of 22 adult male Wistar rats were subjected to controlled spinal cord contusion at the T10 spinal cord level. Six non-injured and ten T10 laminectomy only (LAM) animals were used as controls. A subset of six SCI animals were treated with a single intravenous dose of 250 nmol/kg DHA (SCI-DHA group) 30 min after injury; a saline-injected group of six animals was used as an injection control. PET and CT imaging was carried out 7 days after injury using the [(18)F]GE-180 radiotracer. After imaging, the animals were killed and the spinal cord dissected out for biodistribution and autoradiography studies. In vivo data were correlated with ex vivo immunohistochemistry for TSPO. RESULTS: In vivo dynamic PET imaging revealed an increase in tracer uptake in the spinal cord of the SCI animals compared with the non-injured and LAM animals from 35 min after injection (P < 0.0001; SCI vs. LAM vs. non-injured). Biodistribution and autoradiography studies confirmed the high affinity and specific [(18)F]GE-180 binding in the injured spinal cord compared with the binding in the control groups. Furthermore, they also showed decreased tracer uptake in the T10 SCI area in relation to the non-injured remainder of the spinal cord in the SCI-DHA group compared with the SCI-saline group (P < 0.05), supporting a NI modulatory effect of DHA. Immunohistochemistry showed a high level of TSPO expression (38 %) at the T10 injury site in SCI animals compared with that in the non-injured animals (6 %). CONCLUSION: [(18)F]GE-180 PET imaging can reveal areas of increased TSPO expression that can be visualized and quantified in vivo after SCI, offering a minimally invasive approach to the monitoring of NI in SCI models and providing a translatable clinical readout for the testing of new therapies.

Plasma uric acid effects on glomerular haemodynamic profile of patients with uncomplicated Type 1 diabetes mellitus.

AIMS: Increased plasma uric acid (PUA) levels are associated with impaired renal function in patients with Type 1 diabetes, but the mechanisms are not well understood. Our aim was to evaluate whether higher PUA levels are associated with increased afferent arteriolar resistance in patients with Type 1 diabetes vs. healthy controls, thereby influencing renal function. METHODS: PUA, GFR (inulin) and effective renal plasma flow (ERPF; para-aminohippurate) were measured in 70 otherwise healthy patients with Type 1 diabetes and 60 healthy controls. Gomez's equations were used to estimate afferent (RA ) and efferent (RE ) arteriolar resistances, glomerular hydrostatic pressure (PGLO ) and filtration pressure (ΔPF ). The relationships between PUA and glomerular haemodynamic parameters were evaluated by univariable linear regression correlation coefficients. RESULTS: In patients with Type 1 diabetes, higher PUA correlated with lower PGLO (P = 0.002) and ΔPF (P = 0.0007), with higher RA (P = 0.001), but not with RE (P = 0.55). These associations were accompanied by correlations between higher PUA with lower GFR (P = 0.0007), ERPF (P = 0.008), RBF (P = 0.047) and higher RVR (P = 0.021). There were no significant correlations between PUA and renal haemodynamic parameters in the healthy controls. CONCLUSIONS: The association between higher PUA with lower GFR and lower ERPF in patients with Type 1 diabetes is driven by alterations in the estimated RA . PUA-mediated RA may be caused by increased tone or thickening of the afferent renal arteriole, which might potentiate renal injury by causing ischaemia to the renal microcirculation.

Heart rate and suicide: findings from two cohorts of 533 000 Taiwanese and 75 000 Norwegian adults.

OBJECTIVE: To investigate the association of resting heart rate with suicide in two large cohorts. METHOD: The MJ cohort (Taiwan) included 532 932 adults from a health check-up programme (1994-2008). The HUNT cohort (Norway) included 74 977 adults in the Nord-Trøndelag County study (1984-1986), followed up to 2004. In both cohorts heart rate was measured at baseline, and suicide was ascertained through linkage to cause-of-death registers. Risk of suicide was estimated using Cox proportional hazards models. RESULTS: There were 569 and 188 suicides (average follow-up period of 8.1 and 16.9 years) in the MJ and HUNT cohorts respectively. Sex- and age-adjusted hazard ratio for every 10 beat increase in heart rate per minute was 1.08 (95% Confidence Interval 1.00-1.16) and 1.24 (1.12-1.38) in the MJ and HUNT cohorts, respectively. In the MJ cohort this association was confined to individuals with a history of heart diseases vs. those without such a history (P for interaction = 0.008). In the HUNT cohort the association did not differ by history of heart diseases and was robust to adjustment for health-related life style, medication use, and symptoms of anxiety and depression. CONCLUSION: Elevated resting heart rate may be a marker of increased suicide risk.

A 12-year review on the aetiology and surgical outcomes of paediatric rhegmatogenous retinal detachments in Hong Kong.

PURPOSE: To evaluate the aetiology, clinical features, and surgical outcomes of paediatric rhegmatogenous retinal detachments (RRD) in Hong Kong.Patients and methodsThis is a retrospective consecutive case series of all patients aged 18 or under who underwent primary retinal detachment repair in the Hong Kong Eye Hospital from January 2000 to December 2012.ResultsForty-nine eyes of 47 patients were included. The mean age was 14, and the mean follow-up duration was 6.2 years. The most common aetiology for RRD was idiopathic (28.6%), followed by high myopia (24.5%), atopic dermatitis (AD) (18.4%), congenital and developmental abnormalities (16.3%), trauma (8.2%), and intraocular inflammation (4.1%). The mean preoperative visual acuity was LogMAR 1.0±0.8 (Snellen equivalent 6/60). The primary anatomical success rate in this series was 65.3%, and the final anatomical success rate was 85.7%. The mean postoperative visual acuity was LogMAR 0.9±1.2 (Snellen equivalent 6/48). Patients with congenital and developmental abnormalities or AD had worse anatomical and functional outcomes than patients who had no predisposing factor or high myopia. CONCLUSIONS: The primary and overall anatomical success rates in our series were comparable with existing literature. High myopia is the most commonly identifiable risk factor in Hong Kong and AD is associated with a higher re-detachment rates and a poor visual outcome.

Human albumin eye drops as a therapeutic option for the management of keratoconjunctivitis sicca secondary to chronic graft-versus-host disease after stem-cell allografting.

BACKGROUND: Keratoconjunctivitis sicca from chronic graft-versus-host disease (cgvhd) after allogeneic stem cell transplantation is common, leading to severe corneal damage and blindness if not treated. We retrospectively examined the efficacy and safety of pooled human albumin eye drops (haeds) for symptom relief in 40 stem-cell transplantation patients after other alternatives had failed. METHODS: The Common Terminology Criteria for Adverse Events (version 4.0) and the cgvhd grading scale were used to compare response in the patients during January 2000 and July 2013. In addition, on days 1 and 30, the haeds were subjected to quality assurance testing for sterility, oncotic pressure, albumin measurement, viscosity, pH, and purity by protein electrophoresis. RESULTS: Use of haeds resulted in symptom relief for 37 patients (92.5%); 3 patients (7.5%) failed to improve with use of haeds (p ≤ 0.0001). Of the 37 patients having symptom relief, 7 (19%) improved from grade 3 to no dry eye symptoms. Proportionately, post-treatment symptom improvement by two grade levels, from 3 to 1 (70%), was significantly higher than improvement by one grade level, from 3 to 2 (11%) or from 2 to 1 (19%, p ≤ 0.0001). Time to symptom relief ranged from 2 weeks to 28 weeks. Of the 40 patients, 38 (95%) had no adverse reactions. Days 1 and 30 quality assurance testing results were equivalent. CONCLUSIONS: Complications of keratoconjunctivitis sicca were well managed and well tolerated with haeds when other remedies failed. Quality assurance testing confirmed that haeds were safe and stable in extreme conditions.

Glomerular haemodynamic profile of patients with Type 1 diabetes compared with healthy control subjects.

AIMS: To evaluate the glomerular haemodynamic profile of patients with Type 1 diabetes with either renal hyperfiltration (GFR ≥ 135 ml/min/1.73 m2 ) or renal normofiltration (GFR 90-134 ml/min/1.73 m2 ) during euglycaemic and hyperglycaemic conditions, and to compare this profile with that of a similar group of healthy control subjects. METHODS: Gomez's equations were used to derive afferent and efferent arteriolar resistances, glomerular hydrostatic pressure and filtration pressure. RESULTS: At baseline, during clamped euglycaemia, patients with Type 1 diabetes and hyperfiltration had lower mean ± sd afferent arteriolar resistance than both those with Type 1 diabetes and normofiltration (914 ± 494 vs. 2065 ± 597 dyne/s/cm5 ; P < 0.001) and healthy control subjects (1676 ± 707 dyne/s/cm(5) ; p < 0.001). By contrast, efferent arteriolar resistance was similar in the three groups. Patients with Type 1 diabetes and hyperfiltration also had higher mean ± sd glomerular hydrostatic pressure than both healthy control subjects and patients with Type 1 diabetes and normofiltration (66 ± 6 vs. 60 ± 3 vs. 55 ± 3 mmHg; P < 0.05). Similar findings for afferent arteriolar resistance, efferent arteriolar resistance, glomerular hydrostatic pressure and filtration pressure were observed during clamped hyperglycaemia. CONCLUSION: Hyperfiltration in Type 1 diabetes is primarily driven by alterations in afferent arteriolar resistance rather than efferent arteriolar resistance. Renal protective therapies should focus on afferent renal arteriolar mechanisms through the use of pharmacological agents that target tubuloglomerular feedback, including sodium-glucose cotransporter 2 inhibitors and incretins.

Interaction of fluorescent dyes with DNA and spermine using fluorescence spectroscopy.

Oligonucleotides labelled with fluorescent dyes are widely used as probes for the identification of DNA sequences in detection methods using optical spectroscopies such as fluorescence and surface enhanced Raman scattering (SERS). Spermine is widely used in surface enhanced based assays as a charge reduction and aggregating agent as it interacts strongly with the phosphate backbone and has shown to enhance the signal of a labelled oligonucleotide. The fluorescence intensity of two commonly used labels, FAM and TAMRA, were compared when spermine was added under different experimental conditions. There was a marked difference upon conjugating the free dye to an oligonucleotide, when FAM was conjugated to an oligonucleotide there was around a six fold decrease in emission, compared to a six fold increase when TAMRA was conjugated to an oligonucleotide. Dye labelled single and double stranded DNA also behaved differently with double stranded DNA labelled with FAM being a much more efficient emitter in the mid pH range, however TAMRA becomes increasingly less efficient as the pH rises. Upon addition of the base spermine, signal enhancement from the FAM labelled oligonucleotide is observed. Increasing probe concentrations of TAMRA oligonucleotide above 0.5 µM led to signal reduction most likely through quenching, either by an interaction with guanine, or through self-quenching. By using different bases for comparison, spermine and triethylamine (TEA), different affects were observed in the measured fluorescence signals. When TEA was added to FAM, a reduction in the pH dependence of fluorescence was observed, which may be useful for mid pH range assays. With the drive to increase information content and decrease time and complexity of DNA assays it is likely that more assays will be carried out in complex media such as extracted DNA fragments and PCR product. This model study indicates that dye DNA and dye spermine interactions are dye specific and that extreme care with conditions is necessary particularly if it is intended to determine the concentrations of multiple analytes using probes labelled with different dyes.