Protein engineering of a nanoCLAMP antibody mimetic scaffold as a platform for producing bioprocess-compatible affinity capture ligands.

Protein A affinity chromatography is widely used for the large-scale purification of antibodies because of its high yield, selectivity, and compatibility with NaOH sanitation. A general platform to produce robust affinity capture ligands for proteins beyond antibodies would improve bioprocessing efficiency. We previously developed nanoCLAMPs (nano Clostridial Antibody Mimetic Proteins), a class of antibody mimetic proteins useful as lab-scale affinity capture reagents. This work describes a protein engineering campaign to develop a more robust nanoCLAMP scaffold compatible with harsh bioprocessing conditions. The campaign generated an improved scaffold with dramatically improved resistance to heat, proteases, and NaOH. To isolate additional nanoCLAMPs based on this scaffold, we constructed a randomized library of 1 × 1010 clones and isolated binders to several targets. We then performed an in-depth characterization of nanoCLAMPs recognizing yeast SUMO, a fusion partner used for the purification of recombinant proteins. These second-generation nanoCLAMPs typically had a Kd of <80 nM, a Tm of >70 °C, and a t1/2 in 0.1 mg/ml trypsin of >20 h. Affinity chromatography resins bearing these next-generation nanoCLAMPs enabled single-step purifications of SUMO fusions. Bound target proteins could be eluted at neutral or acidic pH. These affinity resins maintained binding capacity and selectivity over 20 purification cycles, each including 10 min of cleaning-in-place with 0.1 M NaOH, and remained functional after exposure to 100% DMF and autoclaving. The improved nanoCLAMP scaffold will enable the development of robust, high-performance affinity chromatography resins against a wide range of protein targets.

Age-specific associations between the number of co-morbidities, all-cause mortality and public direct medical costs in patients with type 2 diabetes: A retrospective cohort study.

AIM: To evaluate the association between the number of co-morbidities, all-cause mortality and public health system expenditure in patients with type 2 diabetes (T2D) across different age groups. MATERIALS AND METHODS: A retrospective observational study of T2D patients using electronic health records in Hong Kong was conducted. Patients were stratified by age (< 50, 50-64, 65-79, ≥ 80 years) and the number of co-morbidities (0, 1, 2, 3, ≥ 4), defined using the Charlson Comorbidity Index and prevalent chronic diseases identified in local surveys. The association between the number of co-morbidities, all-cause mortality and direct medical costs was examined using Cox proportional hazard regression and the gamma generalized linear model with log link function. RESULTS: A total of 262 212 T2D patients with a median follow-up of 10 years were included. Hypertension and dyslipidaemia were the most common co-morbidities in all age groups. After age stratification, cardiovascular diseases dominated the top pair of co-morbidities in the older age groups (65-79 and ≥ 80 years), while inflammatory and liver disease were predominant among younger individuals. Compared with co-morbidity-free T2D patients, the hazard ratios (95% CI) of death for patients aged younger than 50 and 80 years or older with two co-morbidities were 1.31 (1.08-1.59) and 1.25 (1.15-1.36), respectively, and increased to 3.08 (2.25-4.21) and 1.98 (1.82-2.16), respectively, as the number of co-morbidities increased to four or more. Similar trends were observed for medical costs. CONCLUSIONS: Age-specific co-morbidity patterns were observed for patients with T2D. A greater number of co-morbidities was associated with increased mortality and healthcare costs, with stronger relationships observed among younger patients.

The Use of Close Friends on Instagram, Help-Seeking Willingness, and Suicidality Among Hong Kong Youth: Exploratory Sequential Mixed Methods Study.

BACKGROUND: Social networking sites (SNSs) have gained popularity in recent years for help seeking and self-distress expression among adolescents. Although online suicidal expression is believed to have major benefits, various concerns have also been raised, particularly around privacy issues. Understanding youths' help-seeking behavior on SNSs is critical for effective suicide prevention; however, most research neglects the impacts of the private SNS context. OBJECTIVE: This study aims to examine youths' private SNS use via the new Instagram feature, Close Friends, and its association with both online and offline help-seeking willingness as well as youths' suicidality. METHODS: This study employed an exploratory sequential mixed methods approach with a combination of explorative qualitative interviews and a systematic quantitative survey, targeting youth aged 15-19 years in Hong Kong. The motivations for utilizing Close Friends and concerns regarding online expression were addressed in the focus group and individual interviews (n=40). A cross-sectional survey (n=1676) was conducted subsequently with eligible secondary school students to examine the prevalence of Close Friends usage, their online and offline help-seeking willingness, and suicide-related experiences. RESULTS: A total of 3 primary motives for using Close Friends were identified during interviews, including (1) interaction and help seeking, (2) release of negative emotions, and (3) ventilation and self-expression. Most participants also highlighted the privacy concerns associated with public online communication and the importance of contacting close friends for emotional support. Survey results showed that use of Close Friends was quite prevalent among adolescents (1163/1646, 70.66%), with around 46% (754/1646, 45.81%) of respondents being frequent users. Differences by gender and school academic banding were also revealed. Regarding help-seeking intentions, youths were generally positive about seeking help from peers and friends offline (1010/1266, 79.78%) yet negative about seeking assistance from online friends or professionals with whom they had not yet developed a real-world connection (173/1266, 13.67%). Most notably, frequencies of Close Friends usage were differentially associated with online and offline help-seeking willingness and youths' suicidality. Compared with nonusers, those who had ever used the feature were more likely to seek offline support (adjusted odds ratios [AORs] 1.82-2.36), whereas heavy use of Close Friends was associated with increased odds of online help-seeking willingness (AOR 1.76, 95% CI 1.06-2.93) and a higher risk of suicidality (AOR 1.53, 95% CI 1.01-2.31). CONCLUSIONS: The popularity of Close Friends reflects the increasing need for private online expression among youth. This study demonstrates the importance of Close Friends for self-expression and private conversation and inadequacy of peer support for suicidal adolescents. Further research is needed to identify the causal relationship between Close Friends usage and help-seeking willingness to guide the advancement of suicide prevention strategies. Researchers and social media platforms may cooperate to co-design a risk monitoring system tailored to the private SNS context, assisting professionals in identifying youth at risk of suicide.

Metastatic melanoma patient outcomes since introduction of immune checkpoint inhibitors in England between 2014 and 2018.

Immune checkpoint inhibitors (CPIs) have radically changed outcomes for patients diagnosed with metastatic melanoma globally in the last 10 years, based on evidence of overall survival (OS) benefits generated from international randomised controlled trials (RCTs). Since RCTs do not always reflect real-world prescribing, we interrogated established national databases to track prescribing of CPIs approved for first line treatment of metastatic melanoma patients in England since 2014 and determined patient outcomes associated with OS, as well as treatment-related toxicity. Between April 2014 and March 2018, 5465 melanoma patients were diagnosed and treated with systemic anticancer therapy (SACT), 2322 of which received first-line CPIs. There was good 3-year OS concordance with RCT outcomes for ipilimumab (32%), ipinivo (56%) and nivolumab (51%), but OS was lower than expected for pembrolizumab (40%). Comparing patients prescribed ipinivo with those prescribed pembrolizumab, ipinivo-treated patients were younger (88% vs 49% patients <70 years, P < .001) and fitter (60% vs 38% patients with Eastern Cooperative Oncology Group [ECOG] performance status 0, P < .0001). Emergency hospital admission rates from the earliest and last treatment dates were higher for patients prescribed ipinivo (37% and 55%) compared to those prescribed pembrolizumab (17% and 29%). The 30-day mortality rates favoured ipinivo patients (3.8% ipinivo, 9.1% pembrolizumab, P < .0001) and likely reflected marked differences in median treatment durations: 63 (range 7-440) days for ipinivo and 192 (range 5-943) days for pembrolizumab. The dominant treatment-related condition linked to hospital admission was colitis, recorded for 25% of patients prescribed ipinivo compared to 4% of patients prescribed pembrolizumab. Our population data has demonstrated that RCT outcomes can be achieved in routine care settings with careful patient selection.

Prediction models and nomograms for 10-year risk of end-stage renal disease in Chinese type 2 diabetes mellitus patients in primary care.

AIMS: To develop and validate 10-year risk prediction models, nomograms and charts for end-stage renal disease (ESRD) in Chinese patients with type 2 diabetes mellitus (T2DM) in primary care, in order to guide individualized treatment. MATERIALS AND METHODS: This was a 10-year population-based observational cohort study. A total of 141 516 Chinese T2DM patients without history of cardiovascular disease or ESRD who were managed in public primary care clinics in 2008 were included and followed up until December 2017. Two-thirds of these patients were randomly selected to develop sex-specific ESRD risk prediction models using Cox regressions. The validity and accuracy of the models were tested on the remaining third of patients using Harrell's C-index. We selected variables based on their clinical and statistical importance to construct the nomograms and charts. RESULTS: The median follow-up period was 9.75 years. The cumulative incidence of ESRD was 6.0% (men: 6.1%, women: 5.9%). Age, diabetes duration, systolic blood pressure (SBP), SBP variability, diastolic blood pressure, triglycerides, glycated haemoglobin (HbA1c), HbA1c variability, urine albumin to creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR) were significant predictors for both sexes. Smoking and total cholesterol to HDL cholesterol ratio were additional significant predictors for men and women, respectively. The models showed Harrell's C-statistics of 0.889/0.889 (women/men). Age, eGFR, UACR, SBP and HbA1c were selected for both sexes to develop nomograms and charts. CONCLUSIONS: Using routinely available variables, the 10-year ESRD risk of Chinese T2DM patients in primary care can be predicted with approximately 90% accuracy. We have developed different tools to facilitate routine ESRD risk prediction in primary care, so that individualized care can be provided to prevent or delay ESRD in T2DM patients.

Associations between demographic factors and psychological distress among Chinese residents in Hong Kong: beyond socioeconomic classes.

Most studies highlighted the association between psychological distress and socioeconomic status (SES). There were weaker explanations for distress found in the middle classes, especially in Asian countries. We conducted a questionnaire survey with 1626 adult Chinese primary-care attenders from 13 private and 6 public clinics in different districts of Hong Kong. Their demographic background and distress level measured by GHQ-12 were analysed. We found that respondents with younger age, better education, and lower income were more likely to be distressed. In a multiple logistic regression model, age and income, but not education, were significant predictors for distress. Highest rates of distress were found among the unemployed (45.5%) and the students (37.1%), followed by service workers and shop sales workers (33.0%), associate professionals (32.0%), and clerks (29.2%). Craftworkers (9.1%), plant and machine operators (11.5%), and retired people (12.8%) were least likely to be distressed, followed by professionals (21.0%). Apart from SES, the findings suggest that young age, academic and job stressors, and low self-esteem are significant factors for distress. These factors may be intensified in a Chinese context by peer comparison resulting in a state of relative deprivation.

I-O Optimise: a novel multinational real-world research platform in thoracic malignancies.

Aim: To describe I-O Optimise, a multinational program providing real-world insights into lung cancer management. Materials & methods: Real-world data source selection for I-O Optimise followed a structured approach focused on population coverage, key variable capture, continuous/consistent data availability, record duration and data latency, and database expertise. Results: As of 31 October 2018, seven real-world data sources were included in I-O Optimise, providing data on characteristics, treatment patterns and clinical outcomes from more than 45,000 patients/year with non-small-cell lung cancer, small-cell lung cancer and mesothelioma across Denmark, Norway, Portugal, Spain, Sweden and the UK. Conclusion: The ongoing I-O Optimise initiative has the potential to provide a broad, robust and dynamic research platform to continually address numerous research objectives in the lung cancer arena.

Views of Hong Kong Chinese primary care attenders on psychological distress: causes, management and recovery.

Background: Most of the previous studies of help seeking for psychological distress were conducted in Western countries. Chinese studies have had a stronger emphasis on psychosis. Objective: This study aims to understand how Hong Kong Chinese primary care attenders see psychological distress, including its causes, management approaches and recovery, and whether their views are different from Western views. Method: Nine focus groups and six individual interviews were conducted in Hong Kong among Chinese primary care attenders with/without known distress, patients' significant others and the general public, and a questionnaire survey was conducted with 1626 primary care attenders recruited from 13 private clinics and 6 public clinics. Results: More survey respondents agreed with psychological counselling (95.3%) than drugs (69.0%) to relieve psychological distress. Despite the belief in self-resilience (77.7%), only 34.8% respondents agreed that psychological distress could get better without professional help. Respondents with younger ages, better education and higher incomes tended to have stronger trust in counselling and self-resilience than drugs. Qualitative interviews revealed that although participants regarded psychological distress as a common problem in modern societies, distressed patients might be seen as being weak and troublesome. Some distressed patients found their recovery process painful because of discouragement from family and personnel at their workplace. Conclusions: Hong Kong Chinese patients' views of the causes and management approaches of psychological distress are similar to Western findings. However, help seeking and recovery are of greater concern in a Chinese context where patients may receive limited empathy for their conditions of psychological distress.

Do patients with and without a regular primary care physician have their psychological distress looked after differently?

BACKGROUND: While qualitative studies suggested that continuity of care by primary care physicians (PCPs) facilitated consultations for psychological problems, there was limited quantitative evidence. This survey compared management of psychological distress between patients with and without a regular PCP. METHODS: A questionnaire survey was conducted with 1626 adult primary care attenders from 13 private and 6 public clinics in Hong Kong. Management of psychological distress between respondents with a regular PCP and those without were compared. Effects of demographic factors were adjusted for by multivariable logistic regression. RESULTS: Among the 1626 respondents, 650 (40.0%) reported that they had ever experienced psychological distress. Of the 650 respondents experienced distress, 307 (47.2%) had a regular PCP. A significantly higher proportion of patients with a regular PCP than those without reported: (i) their PCPs sometimes/often asked about psychological problems [37.7 versus 20.1%, adjusted OR = 2.241]; (ii) they sometimes/often mentioned their psychological problems to PCPs [45.2 versus 24.9%, adjusted OR = 2.503]; and (iii) their distress had been treated by PCPs [22.1 versus 13.4%, adjusted OR = 1.702]. CONCLUSION: Patients with a regular PCP have around double odds of receiving mental health care. Continuity of care by PCPs should be emphasized in mental health care delivery.

Combined nicotine patch with gum versus nicotine patch alone in smoking cessation in Hong Kong primary care clinics: a randomised controlled trial.

BACKGROUND: The prevalence of daily cigarette smoking has dropped to 10% in Hong Kong (HK) in 2017, however, smoking still kills 5700 persons per year. Studies suggest that abstinence rates are higher with combined NRT than single NRT, although local data on safety and benefits of combined NRT are lacking. The aim of this study is to compare the effectiveness of combined NRT with single NRT among HK Chinese. METHODS: This is a one-year, two-arm, parallel randomised trial. Five hundred sixty smokers, who smoked ≥10 cigarettes/day for ≥1 year, were randomized to combined and single NRT. Combined NRT group received counseling and nicotine patch & gum. Single NRT group received counselling and nicotine patch. Primary outcome was abstinence rate measured as self-reported 7-day point prevalence with CO validated at 52 weeks. Secondary outcomes included smoking abstinence rates at 4, 12, & 26 weeks. Crude odds ratio and p-value were reported from logistic regression without adjustment; for trend analysis, adjusted odds ratio (AOR) and p-value were reported from Generalized Estimating Equation (GEE) (controlling for time). All AORs were adjusted for age, sex, baseline CO and clusters. RESULTS: Abstinence rates at 4, 12, 26 and 52 weeks were all higher in the combined NRT group (35.8, 21.9, 16.8, 20.1%) compared with the single NRT group (28, 16.8, 11.2, 14.3%). At 4 weeks, combined NRT group was more likely to quit smoking (OR 1.43, 95% CI, 1.00 to 2.05) than the single NRT group. From GEE analysis, combined NRT group had a significantly higher abstinence rate (23.6%) than the single NRT group (17.6%) across repeated measures at all-time points. Combined NRT group was more likely to quit smoking (OR 1.43, 95% CI, 1.15 to 1.77). No significant difference in the side effect profile was detected between groups. CONCLUSIONS: Smokers given 8 weeks of combined NRT were more likely to quit smoking at 4, 12, 26 and 52 weeks compared with single NRT. Combined NRT was as well tolerated as single NRT and it should be further promoted in our community. TRIAL REGISTRATION: NCT03836560 from ClinicalTrial.gov , 9 Feb 2019.

Treating Subthreshold Depression in Primary Care: A Randomized Controlled Trial of Behavioral Activation With Mindfulness.

PURPOSE: We undertook a randomized controlled trial to assess the efficacy of group-based behavioral activation with mindfulness (BAM) for treating subthreshold depression in primary care in Hong Kong. METHODS: We recruited adult patients aged 18 years or older with subthreshold depression from public primary care clinics and randomly assigned them to a BAM intervention group or a usual care group. The BAM group was provided with eight 2-hour weekly BAM sessions by trained allied health care workers. Patients in the usual care group received usual medical care with no additional psychological interventions. The primary outcome was depressive symptoms measured by the Beck Depression Inventory-II at 12 months. Secondary outcomes included incidence of major depressive disorder at 12 months. We assessed quality of life, activity and circumstances change, functional impairment, and anxiety at baseline, end of intervention, 5 months, and 12 months. RESULTS: We randomly allocated 115 patients to the BAM intervention and 116 patients to usual care. At 12 months, compared with usual care peers, BAM patients had a slightly more favorable change in levels of depressive symptoms on the Beck Depression Inventory-II (between-group mean difference in score = -3.85; 95% CI, -6.36 to -1.34; Cohen d = -0.46, 95% CI, -0.76 to -0.16). Incidence of major depressive disorder was lower with BAM (10.8% vs 26.8%, P = .01), whereas groups did not differ significantly on other secondary outcomes at 12 months. CONCLUSIONS: Group BAM appears to be efficacious for decreasing depressive symptoms and reducing the incidence of major depression among patients with subthreshold depression in primary care, although generalizability of our findings may be limited.

Adolescent Seizure in the Emergency Department Due to Concomitant Brugada Syndrome.

Brugada syndrome is an increasingly discussed entity in the emergency medicine and cardiology literature. However, there are few cases reported in the pediatric population. Seizure is a presentation common to pediatric emergency departments. This case report describes the clinical course, workup, and differential diagnosis of a 15-year-old male adolescent with first-time seizure and Brugada pattern on electrocardiogram. A brief review of the literature follows the case presentation.

Condensation on Highly Superheated Surfaces: Unstable Thin Films in a Wickless Heat Pipe.

A wickless heat pipe was operated on the International Space Station to provide a better understanding of how the microgravity environment might alter the physical and interfacial forces driving evaporation and condensation. Traditional heat pipes are divided into three zones: evaporation at the heated end, condensation at the cooled end, and intermediate or adiabatic in between. The microgravity experiments reported herein show that the situation may be dramatically more complicated. Beyond a threshold heat input, there was a transition from evaporation at the heated end to large-scale condensation, even as surface temperatures exceeded the boiling point by 160 K. The hotter the surface, the more vapor was condensed onto it. The condensation process at the heated end is initiated by thickness and temperature disturbances in the thin liquid film that wet the solid surface. Those disturbances effectively leave the vapor "superheated" in that region. Condensation is amplified and sustained by the high Marangoni stresses that exist near the heater and that drive liquid to cooler regions of the device.

Development of polyol-responsive antibody mimetics for single-step protein purification.

The purification of functional proteins is a critical pre-requisite for many experimental assays. Immunoaffinity chromatography, one of the fastest and most efficient purification procedures available, is often limited by elution conditions that disrupt structure and destroy enzymatic activity. To address this limitation, we developed polyol-responsive antibody mimetics, termed nanoCLAMPs, based on a 16 kDa carbohydrate binding module domain from Clostridium perfringens hyaluronidase. nanoCLAMPs bind targets with nanomolar affinity and high selectivity yet release their targets when exposed to a neutral polyol-containing buffer, a composition others have shown to preserve quaternary structure and enzymatic activity. We screened a phage display library for nanoCLAMPs recognizing several target proteins, produced affinity resins with the resulting nanoCLAMPs, and successfully purified functional target proteins by single-step affinity chromatography and polyol elution. To our knowledge, nanoCLAMPs constitute the first antibody mimetics demonstrated to be polyol-responsive.

30-day mortality after systemic anticancer treatment for breast and lung cancer in England: a population-based, observational study.

BACKGROUND: 30-day mortality might be a useful indicator of avoidable harm to patients from systemic anticancer treatments, but data for this indicator are limited. The Systemic Anti-Cancer Therapy (SACT) dataset collated by Public Health England allows the assessment of factors affecting 30-day mortality in a national patient population. The aim of this first study based on the SACT dataset was to establish national 30-day mortality benchmarks for breast and lung cancer patients receiving SACT in England, and to start to identify where patient care could be improved. METHODS: In this population-based study, we included all women with breast cancer and all men and women with lung cancer residing in England, who were 24 years or older and who started a cycle of SACT in 2014 irrespective of the number of previous treatment cycles or programmes, and irrespective of their position within the disease trajectory. We calculated 30-day mortality after the most recent cycle of SACT for those patients. We did logistic regression analyses, adjusting for relevant factors, to examine whether patient, tumour, or treatment-related factors were associated with the risk of 30-day mortality. For each cancer type and intent, we calculated 30-day mortality rates and patient volume at the hospital trust level, and contrasted these in a funnel plot. FINDINGS: Between Jan 1, and Dec, 31, 2014, we included 23 228 patients with breast cancer and 9634 patients with non-small cell lung cancer (NSCLC) in our regression and trust-level analyses. 30-day mortality increased with age for both patients with breast cancer and patients with NSCLC treated with curative intent, and decreased with age for patients receiving palliative SACT (breast curative: odds ratio [OR] 1·085, 99% CI 1·040-1·132; p<0·0001; NSCLC curative: 1·045, 1·013-1·079; p=0·00033; breast palliative: 0·987, 0·977-0·996; p=0·00034; NSCLC palliative: 0·987, 0·976-0·998; p=0·0015). 30-day mortality was also significantly higher for patients receiving their first reported curative or palliative SACT versus those who received SACT previously (breast palliative: OR 2·326 99% CI 1·634-3·312; p<0·0001; NSCLC curative: 3·371, 1·554-7·316; p<0·0001; NSCLC palliative: 2·667, 2·109-3·373; p<0·0001), and for patients with worse general wellbeing (performance status 2-4) versus those who were generally well (breast curative: 6·057, 1·333-27·513; p=0·0021; breast palliative: 6·241, 4·180-9·319; p<0·0001; NSCLC palliative: 3·384, 2·276-5·032; p<0·0001). We identified trusts with mortality rates in excess of the 95% control limits; this included seven for curative breast cancer, four for palliative breast cancer, five for curative NSCLC, and seven for palliative NSCLC. INTERPRETATION: Our findings show that several factors affect the risk of early mortality of breast and lung cancer patients in England and that some groups are at a substantially increased risk of 30-day mortality. The identification of hospitals with significantly higher 30-day mortality rates should promote review of clinical decision making in these hospitals. Furthermore, our results highlight the importance of collecting routine data beyond clinical trials to better understand the factors placing patients at higher risk of 30-day mortality, and ultimately improve clinical decision making. Our insights into the factors affecting risk of 30-day mortality will help treating clinicians and their patients predict the balance of harms and benefits associated with SACT. FUNDING: Public Health England.

Thermocapillary phenomena and performance limitations of a wickless heat pipe in microgravity.

A counterintuitive, thermocapillary-induced limit to heat- pipe performance was observed that is not predicted by current thermal-fluid models. Heat pipes operate under a number of physical constraints including the capillary, boiling, sonic, and entrainment limits that fundamentally affect their performance. Temperature gradients near the heated end may be high enough to generate significant Marangoni forces that oppose the return flow of liquid from the cold end. These forces are believed to exacerbate dry out conditions and force the capillary limit to be reached prematurely. Using a combination of image and thermal data from experiments conducted on the International Space Station with a transparent heat pipe, we show that in the presence of significant Marangoni forces, dry out is not the initial mechanism limiting performance, but that the physical cause is exactly the opposite behavior: flooding of the hot end with liquid. The observed effect is a consequence of the competition between capillary and Marangoni-induced forces. The temperature signature of flooding is virtually identical to dry out, making diagnosis difficult without direct visual observation of the vapor-liquid interface.

Task-Shifting: An Approach to Decentralized Hepatitis C Treatment in Medically Underserved Areas.

BACKGROUND: Despite the availability of safe and effective direct-acting antiviral drugs (DAAs), the vast majority of patients with chronic hepatitis C (HCV) in the USA remain untreated, in part due to lack of access to specialist providers. AIMS: To determine the effectiveness of DAA-based treatment in medically underserved areas in California, in a healthcare model dependent on task-shifting--wherein a visiting hepatologist assesses patients for treatment eligibility, but subsequent routine follow-up evaluation of patients prescribed treatment is devolved to a part-time licensed vocational nurse under remote supervision of the hepatologist. METHODS: We retrospectively determined rates of sustained virologic response 12 weeks after treatment completion (SVR-12), adverse events, and treatment discontinuations in patients who received sofosbuvir-based DAA regimens between December 2013 and November 2014. RESULTS: Despite limited specialist provider involvement in medically underserved areas, all but two of 58 patients completed treatment, and 88 % of patients achieved the curative endpoint of undetectable HCV RNA 12 weeks after completing treatment (sustained virologic response, SVR-12). Almost 80 % of patients with cirrhosis and 85 % of patients with prior treatment experience achieved SVR-12. CONCLUSIONS: Treatment effectiveness with sofosbuvir-based regimens in medically underserved areas utilizing task-shifting from a specialist to a mid-level provider is comparable to those achieved in pivotal clinical trials for these regimens, and to "real-world" experiences of tertiary care centers in the USA.

Acquired localised hypertrichosis in a Chinese child after cast immobilisation.

Hypertrichosis refers to excessive hair growth that is independent of any androgen effect. Hypertrichosis could be congenital or acquired, localised or generalised. The phenomenon of acquired localised hypertrichosis following cast application for a fracture is well known to orthopaedic surgeons, but is rarely encountered by primary care physicians. We describe a 28-month-old Chinese boy who had fracture of right leg as a result of an injury. He had a cast applied by an orthopaedic surgeon as treatment. On removal of the cast 6 weeks later, he was noticed to have significant hair growth on his right leg compared with the left leg. The patient was reassessed 3 months after removal of the cast. The hypertrichosis resolved completely with time. This patient was one of the youngest among the reported cases of acquired localised hypertrichosis after cast application. We illustrate the significance of management of post-cast-acquired localised hypertrichosis in the primary care setting.

Histologic changes in liver tissue from patients with chronic hepatitis B and minimal increases in levels of alanine aminotransferase: a meta-analysis and systematic review.

BACKGROUND & AIMS: The level of alanine aminotransferase (ALT) is a marker of hepatitis B severity and response to treatment. However, measurements of ALT level may be of limited use during the immune clearance phase of chronic hepatitis B (CHB) and can be affected by age, weight, and concomitant liver disease. We performed a literature review to determine the proportion of CHB patients with ALT levels of 1- to 2-fold the upper limit of normal who also had significant underlying liver fibrosis (stage ≥2). METHODS: We performed a Medline search of original articles published before June 2012, and their references; we also searched abstracts from the 2010 and 2011 annual meetings of the American Association for the Study of Liver Diseases and the 2011 and 2012 Digestive Disease Weeks. Studies were included that had 20 or more consecutive treatment-naive CHB patients with 6 months or more of follow-up evaluation, histologic data, and levels of ALT 1- to 2-fold the upper limit of normal. Study heterogeneity was assessed by a Forest plot and Q and I(2) analyses. Sensitivity was measured using 1-study removed analysis. RESULTS: Our analysis included 8 articles and 1 abstract, comprising 683 patients. Based on random-effects modeling, 48% of patients had stage 2 or higher fibrosis (95% confidence interval, 36%-61%). In a sensitivity analysis, exclusion of the study that caused the greatest deflection of the pooled estimate produced a revised estimate of 43%. A subgroup of hepatitis B e antigen-positive and hepatitis B e antigen-negative patients (n = 168 and 170, respectively) showed similar rates of fibrosis (41% vs 47%; P = nonsignificant). CONCLUSIONS: Despite heterogeneity in the literature, a substantial proportion of patients with slight increases in ALT level have significant fibrosis. Given the possibility of advanced liver disease, the threshold for antiviral treatment must be individualized. Further studies are needed to investigate patients with modest increases in ALT level.

Current practices, attitudes, and perceived barriers for treating smokers by Hong Kong dentists.

OBJECTIVES: To assess the attitudes of dentists towards smoking cessation advice, as well as to investigate their current practice and perceived barriers to giving such advice and the relationships among their peers regarding such activity. DESIGN: Cross-sectional survey. SETTING: Hong Kong. PARTICIPANTS: Self-reporting questionnaires were mailed to 330 dentists in Hong Kong by systematic sampling. Information on their attitudes, practices, and perceived barriers towards smoking cessation advice and relevant background information was collected. RESULTS: A total of 218 questionnaires were returned (response rate, 66%). The majority (97%) reported that they would enquire into every patient's smoking status, yet only around half of them did so routinely. Most (95%) of the dentists who always enquired about smoking status would actually offer smoking cessation advice to their patients. Multiple logistic regression of the results revealed that government dentists (odds ratio=2.7; 95% confidence interval, 1.4-5.1), those who received training in smoking cessation advice (2.5; 1.2-5.1), and those aged over 40 years (1.9; 1.0-3.4) were significantly more likely to enquire about smoking status. In most practices (93%), smoking cessation advice was offered by the dentists themselves rather than by other team members. "Lack of training", "unlikely to be successful", and "possibility of losing patients" were the three barriers regarded as "very important" by dentists. CONCLUSIONS: Dentists in Hong Kong generally had positive attitudes towards smoking cessation advice. The dental team is in a very good position to help smokers quit. However, training and guidelines designed specifically for dental teams are paramount to overcome barriers in delivering smoking cessation advice by dental professionals.