Standardized approach to extract candidate outcomes from literature for a standard outcome set: a case- and simulation study.

AIMS: Standard outcome sets enable the value-based evaluation of health care delivery. Whereas the attainment of expert opinion has been structured using methods such as the modified-Delphi process, standardized guidelines for extraction of candidate outcomes from literature are lacking. As such, we aimed to describe an approach to obtain a comprehensive list of candidate outcomes for potential inclusion in standard outcome sets. METHODS: This study describes an iterative saturation approach, using randomly selected batches from a systematic literature search to develop a long list of candidate outcomes to evaluate healthcare. This approach can be preceded with an optional benchmark review of relevant registries and Clinical Practice Guidelines and data visualization techniques (e.g. as a WordCloud) to potentially decrease the number of iterations. The development of the International Consortium of Health Outcome Measures Heart valve disease set is used to illustrate the approach. Batch cutoff choices of the iterative saturation approach were validated using data of 1000 simulated cases. RESULTS: Simulation showed that on average 98% (range 92-100%) saturation is reached using a 100-article batch initially, with 25 articles in the subsequent batches. On average 4.7 repeating rounds (range 1-9) of 25 new articles were necessary to achieve saturation if no outcomes are first identified from a benchmark review or a data visualization. CONCLUSION: In this paper a standardized approach is proposed to identify relevant candidate outcomes for a standard outcome set. This approach creates a balance between comprehensiveness and feasibility in conducting literature reviews for the identification of candidate outcomes.

Nitrosative stress and cytokines are linked with the severity of sepsis and organ dysfunction.

OBJECTIVE: An imbalance in oxidant-antioxidant status may impact the severity of sepsis. We hypothesised links between nitrosative stress and pro-inflammatory cytokines and their correlation with the severity of sepsis and associated organ dysfunction. METHODS: The hypothesis was tested in 110 patients with sepsis (in whom a disease severity score (APACHE II) and assessment of organ failure score (SOFA) were determined) and 55 healthy volunteers. Neutrophil inducible nitric oxide synthase (iNOS) expressions at mRNA and protein levels were estimated by real-time PCR and immuno-precipitation followed by Western blotting, respectively. Nitric oxide (NO) content was assessed in neutrophils by confocal microscopy, plasma nitrite by the Griess reaction and inflammatory cytokines (TNF-α, IFN-γ and IL-8) by ELISA (in plasma) and real-time PCR (in neutrophils). Serum bilirubin and creatinine were determined by routine methods and lung function by the PaO2/FiO2 ratio. RESULTS: Increased neutrophil iNOS expression and NO content, plasma total nitrite content and pro-inflammatory cytokines were present in sepsis patients (all P < 0.001). Plasma nitrite correlated with cytokines, APACHE II, SOFA, PaO2/FiO2 ratio, serum bilirubin and creatinine clearance (all r2 0.63-0.85, P < 0.001). Cytokines correlated with nitrite, APACHE II, SOFA, PaO2/FiO2 ratio, serum bilirubin and creatinine clearance (all r2 0.35-0.85, P < 0.001). CONCLUSION: Neutrophils iNOS expression, NO content, plasma nitrite and cytokines have a role in the assessment of the severity of sepsis and organ toxicity.

Evaluation of oxidative stress and antioxidant status: Correlation with the severity of sepsis.

Sepsis is a condition caused by infection followed by unregulated inflammatory response which may lead to the organ dysfunction. During such condition, over-production of oxidants is one of the factors which contribute cellular toxicity and ultimately organ failure and mortality. Antioxidants having free radicals scavenging activity exert protective role in various diseases. This study has been designed to evaluate the levels of oxidative and antioxidative activity in sepsis patients and their correlation with the severity of the sepsis. A total of 100 sepsis patients and 50 healthy controls subjects were enrolled in this study from the period October 2016 to June 2017. The investigation included measurements of oxidative enzyme, myeloperoxidase (MPO), antioxidant enzymes including superoxide dismutase activity (SOD) and catalase activity (CAT) and cytokines (TNF-α, IL-8 and IFN-γ). Furthermore, the level of these activities was correlated with severity of sepsis. Augmented levels of oxidants were found in sepsis as demonstrated by DMPO nitrone adduct formation and plasma MPO level activity (1.37 ± 0.51 in sepsis vs 0.405 ± 0.16 in control subjects). Cytokines were also found to be increased in sepsis patients. However, plasma SOD and CAT activities were significantly attenuated (P < .001) in the sepsis patients compared with controls subjects. Moreover, inverse relation between antioxidant enzymes (SOD and CAT) and organ failure assessment (SOFA), physiological score (APACHE II), organ toxicity specific markers have been observed as demonstrated by Pearson's correlation coefficient. This study suggests that imbalance between oxidant and antioxidant plays key role in the severity of sepsis.

Performance of medical students in final professional examination: Can in-course continuous assessments predict students at risk?

Background: Assessment drives students' learning. It measures the level of students' understanding. We aimed to determine whether performance in continuous assessment can predict failure in the final professional examination results. Methods: We retrieved the in-course continuous assessment (ICA) and final professional examination results of 3 cohorts of medical students (n = 245) from the examination unit of the International Medical University, Seremban, Malaysia. The ICA was 3 sets of composite marks derived from course works, which includes summative theory paper with short answer questions and 1 of the best answers. The clinical examination includes end-of-posting practical examination. These examinations are conducted every 6 months in semesters 6, 7 and 8; they are graded as pass/fail for each student. The final professional examination including modified essay questions (MEQs), 1 8-question objective structured practical examination (OSPE) and a 16-station objective structured clinical examination (OSCE), were graded as pass/fail. Failure in the continuous assessment that can predict failure in each component of the final professional examination was tested using chi-square test and presented as odds ratio (OR) with 95% confidence interval (CI). Results: Failure in ICA in semesters 6-8 strongly predicts failure in MEQs, OSPE and OSCE of the final professional examination with OR of 3.8-14.3 (all analyses p< 0.001) and OR of 2.4-6.9 (p<0.05). However, the correlation was stronger with MEQs and OSPE compared to OSCE. Conclusion: ICA with theory and clinical examination had a direct relationship with students' performance in the final examination and is a useful assessment tool.

Calculation of free and bioavailable vitamin D and its association with bone mineral density in Malaysian women.

INTRODUCTION: Low 25-hydroxyvitamin D [25(OH)D] levels have not been consistently associated with bone mineral density (BMD). It has been suggested that calculation of the free/bioavailable 25(OH)D may correlate better with BMD. We examined this hypothesis in a cohort of Malaysian women. MATERIALS AND METHODS: A cross-sectional study of 77 patients with rheumatoid arthritis (RA) and 29 controls was performed. Serum 25(OH)D was measured using the Roche Cobas E170 immunoassay. Serum vitamin D binding protein (VDBP) was measured using a monoclonal enzyme-linked immunosorbent assay (ELISA). Free/bioavailable 25(OH)D were calculated using both the modified Vermuelen and Bikle formulae. RESULTS: Since there were no significant differences between RA patients and controls for VDBP and 25(OH)D, the dataset was analysed as a whole. Calculated free 25(OH)D by Vermeulen was strongly correlated with Bikle (r = 1.00, p < 0.001). A significant positive correlation was noted between measured total 25(OH)D with free/bioavailable 25(OH)D (r = 0.607, r = 0.637, respectively, p < 0.001). Median free/bioavailable 25(OH)D values were significantly higher in Chinese compared with Malays and Indians, consistent with their median total 25(OH)D. Similar to total 25(OH)D, the free/bioavailable 25(OH)D did not correlate with BMD. CONCLUSION: In this first study of a multiethnic female Malaysian population, free/bioavailable 25(OH)D were found to reflect total 25(OH)D, and was not superior to total 25(OH)D in its correlation with BMD. Should they need to be calculated, the Bikle formula is easier to use but only calculates free 25(OH)D. The Vermuelen formula calculates both free/bioavailable 25(OH)D but is more complex to use.

A scoping review of the uses of the care index in children.

OBJECTIVE: To conduct a scoping review of literature to describe how the care index (CI) and restorative index (RI) are used in child populations and to determine whether they are fit for purpose. BASIC RESEARCH DESIGN: Scoping review conducted using the Arksey and O'Malley (2005) framework. METHOD: Electronic and manual literature searches (1980-2015) were conducted. Titles and abstracts were screened, full-texts of potential studies were reviewed two reviewers extracted data independently, followed by data charting and summarising. RESULTS: Out of 104 articles meeting all criteria, most were cross-sectional (92%), and 56% were conducted in UK and Brazil. Most commonly (63%) studies used CI and RI to obtain epidemiological data on dental care levels. Of the studies that defined CI and RI, most used and specified the standard definition. The CI and RI scores varied either due to patient related factors such as age, gender or dental care related factors including, cost of treatment and method of provider remuneration. CONCLUSION: Overall, it is recommended that future studies should clearly state the definitions and thresholds used to obtain CI and RI, which would enable comparison between communities and allow temporal trends to be studied. Additionally, deriving separate CI and RI scores for groups based on caries extent would help to highlight inequalities in the provision of care. Further research is needed to explore the applicability of CI and RI to changing approaches to caries management with current care recommendations emphasising on minimal treatment and secondary prevention.

Relevance of hepatitis B surface antigen levels in patients with chronic hepatitis B during 5 year of tenofovir treatment.

The role of quantitative hepatitis B surface antigen (HBsAg) levels in patients receiving highly potent oral antiviral therapy is controversial, and here, we determined the HBsAg response in 121 chronic hepatitis B patients treated with tenofovir 300 mg daily. During tenofovir treatment, HBsAg decline of ≥ 1.0 log from baseline was seen in 16.1%, 16.3%, 18.4%, 34.6%, 36.4% and 11.8%, 15.2%, 14.8%, 28.6%, 20% at years 1, 2, 3, 4, 5 for HBeAg-positive and HBeAg-negative patients, respectively. Early decline in HBsAg levels at week 4 was predictive of subsequent significant HBsAg level decline. HBeAg seroconversion occurred in 29.9% of HBeAg-positive patients. On multinomial logistic regression, HBsAg level decline from baseline at week 4 and week 12 or any time subsequently did not correlate with HBeAg seroconversion and HBV DNA level decline from baseline at week 4 and week 12 (OR = 3.704; 95% CI = 1.511-9.076; P = 0.006 and OR = 1.732; 95% CI = 1.032-2.867; P = 0.037, respectively) was significantly predictive of seroconversion. A small proportion of chronic HBV-infected patients treated with tenofovir exhibit a significant (≥ 1.0 log) decline in HBsAg levels. Early decline in HBsAg levels at week 4 was predictive of subsequent and significant HBsAg level decline. The HBsAg decline did not correlate with HBeAg seroconversion in HBeAg-positive patients. Reduction in HBV DNA levels at week 4 and 12 correlated with seroconversion.

Chronic pelvic ischemia: etiology, pathogenesis, clinical presentation and management.

Overactive bladder (OAB) and bladder pain syndrome (BPS) although common, are vaguely defined and difficult to diagnose and manage etiologies of storage-type lower urinary tract symptoms (LUTS). The lack of optimal management options is a direct consequence of deficient understanding of the pathophysiologic mechanisms underlying these conditions. These conditions are especially prevalent in females, and cumulative contemporary epidemiological, clinical and laboratory evidence implicates ischemia as one of the key players in the pathophysiologic foundation of both these disorders. Taken together they make up "the" diagnostic as well as therapeutic black-hole in urologic practice. Much akin to chronic ischemic heart disease, chronic ischemia-reperfusion has been shown to cause degenerative changes at cellular and subcellular level in the bladder mucosa, smooth muscle fibers, and vesical neural and microvascular structures leading to a hypersensitive, hyperactive bladder initially, which with time invariably progresses into a failed, fibrotic and pressurized bladder. Diagnosis and management of these diseases are currently symptom focused and remains a source of much frustration. Consideration of role of ischemia connotates hope and could lead to a paradigm shift in the management of these patients with a completely new therapeutic armamentarium attacking the pathology itself. The aim of the current review is to provide a clinical thought perspective on the etiology/pathophysiology of chronic pelvic ischemia and its role as a precursor to the aforementioned conditions, and shed some light upon the potential management strategies to consider.

Hepatitis B vaccination with or without hepatitis B immunoglobulin at birth to babies born of HBsAg-positive mothers prevents overt HBV transmission but may not prevent occult HBV infection in babies: a randomized controlled trial.

Vertical transmission of Hepatitis B virus HBV can result in a state of chronic HBV infection and its complications. HBV vaccination with or without hepatitis B immunoglobulin (HBIG) prevents transmission of overt infection to the babies. However, whether it also prevents occult HBV infection in babies is not known. Consecutive pregnant women of any gestation found to be HBsAg positive were followed till delivery, and their babies were included in the study. Immediately after delivery, babies were randomized to receive either HBIG or placebo in addition to recombinant HBV vaccine (at 0, 6, 10 and 14 weeks). The primary end-point of the study, assessed at 18 weeks of age, was remaining free of any HBV infection (either overt or occult) plus the development of adequate immune response to vaccine. The babies were further followed up for a median of 2 years of age to determine their eventual outcome. Risk factors for HBV transmission and for poor immune response in babies were studied. Of the 283 eligible babies, 259 were included in the trial and randomized to receive either HBIG (n=128) or placebo (n=131) in addition to recombinant HBV vaccine. Of the 222 of 259 (86%) babies who completed 18 weeks of follow-up, only 62/222 (28%) reached primary end-point. Of the remaining, 6/222 (3%) developed overt HBV infection, 142/222 (64%) developed occult HBV infection, and 12/222 (5%) had no HBV infection but had poor immune response. All 6 overt infections occurred in the placebo group (P=0.030), while occult HBV infections were more common in the HBIG group (76/106 [72%] vs. 66/116 [57%]; P=0.025). This may be due to the immune pressure of HBIG. There was no significant difference between the two groups in frequency of babies developing poor immune response or those achieving primary end-point. The final outcome of these babies at 24 months of age was as follows: overt HBV infection 4%, occult HBV infection 42%, no HBV infection but poor immune response 8% and no HBV infection with good immune response 28%. Women who were anti-HBe positive were a low-risk group, and their babies were most likely to remain free of HBV infection (occult or overt) and had good immune response to the vaccine. Maternal HBeAg-positive status and negativity for anti-HBe predicted not only overt but also any infection (both overt and occult) in babies. In addition, high maternal HBV DNA and treatment with vaccine alone were significant factors for overt HBV infection in babies. The current practice of administration of vaccine with HBIG at birth to babies born of HBsAg-positive mothers is not effective in preventing occult HBV infection in babies, which may be up to 40%. Because the most important risk factors for mother-to-baby transmission of HBV infection are the replicative status and high HBV DNA level in mothers; it will be worthwhile investigating the role of antivirals and HBIG administration during pregnancy to prevent mother-to-child transmission of HBV infection.

Functional role of iNOS-Rac2 interaction in neutrophil extracellular traps (NETs) induced cytotoxicity in sepsis.

BACKGROUND: Recent reports from this lab have demonstrated a higher incidence of NETs, nitrosative, as well as oxidative stress, and have a direct correlation with the severity of sepsis and organ damage. However, the mechanistic perspective of NETs induced organ damage has not been understood at the cellular and molecular level. Interaction of inducible nitric oxide synthase (iNOS) with Rac2 in regulating reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation and its implications in microbial killing has been reported. This study was, therefore, undertaken in neutrophils of sepsis patients to investigate the functional importance of iNOS-Rac2 interaction in ROS/ RNS, peroxynitrite generation, NETs generation, and NETs mediated cell death. METHODS: The study was conducted on 100 patients with sepsis and 50 healthy volunteers. Interaction between iNOS and Rac2 was performed using co-immunoprecipitation and co-immunolabeling assay. Free radicals involving ROS and RNS were evaluated using cytochrome c reduction assay. NETs formation was evaluated by fluorescence microscopy. The cytotoxic effect of NETs was assessed on lung carcinoma cell line (A549) using colorimetric Alamar blue assay. RESULTS: Enhanced interaction between iNOS and Rac2 was found in sepsis neutrophils in comparison with control. This was accompanied by an increased level of superoxide (O2.-), nitric oxide (NO), and peroxynitrite (ONOO-) which were decreased in the presence of NAC, DPI, and 1400 W, signifying the role of iNOS-Rac2 interaction. Enhanced NETs release from activated sepsis neutrophils were abrogated in the presence of DPI. NETs from sepsis neutrophils exert a cytotoxic effect on lung epithelial cells (A549) in a concentration-dependent manner. CONCLUSION: Our findings exhibit the functional role of iNOS-Rac2 interaction in ROS/RNS, peroxynitrite generation, NETs generation, and NETs mediated cell death.

NSAID use and risk of leukaemia: a population-based case-control study.

PURPOSE: The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of developing colorectal and lung cancer. Studies suggesting similar associations in leukaemia have been small and underpowered. We have conducted a large population-based case-control study to determine whether the use of NSAIDs is associated with a reduced risk of acute and chronic leukaemias, and whether their use has any impact on survival in these patients. METHODS: We identified all the incident cases of leukaemia in 'The Health Improvement Network' (THIN) general practice dataset, along with at least four matched controls per case. We used conditional logistic regression to determine odds ratios for NSAID prescription rates and the risk of developing several leukaemia sub-types. We then used Cox regression to determine the association between NSAID prescription rate and risk of death in leukaemia. Hazard ratios were adjusted for gender, age at diagnosis, smoking status and Townsend Score. RESULTS: The risk of leukaemia overall appears to increase marginally with increased use of NSAIDs prior to diagnosis. This is not seen when individual leukaemia sub-types are examined, however, except perhaps in CLL where patients who had received 2-5 prescriptions/year are 34% more likely to be diagnosed with CLL than those who had not had any NSAID prescriptions (O.R. 1.34, p = 0.03, 95% C.I. 1.02-1.74). There was no statistically significant association between exposure to NSAIDs prior to leukaemia diagnosis and survival. CONCLUSION: The use of NSAIDs does not reduce the risk of developing leukaemia, nor do they improve survival.

Are Indians and females less tolerant to pain? An observational study using a laboratory pain model.

In Malaysia, it is a common belief among health care workers that females and Indians have lower pain threshold. This experience, although based on anecdotal experience in the healthcare setting, does not allow differentiation between pain tolerance, and pain expression. To determine whether there is a difference in the tolerance to pain between the three main ethnic groups, namely the Malays, Chinese and Indians as well as between males and females. This was a prospective study, using a laboratory pain model (ischaemic pain tolerance) to determine the pain tolerance of 152 IMU medical students. The mean age of the students was 21.8 years (range 18-29 years). All of them were unmarried. The median of ischaemic pain tolerance for Malays, Chinese and Indians were 639s, 695s and 613s respectively (p = 0.779). However, statistically significant difference in ischaemic pain tolerance for males and females Indian students were observed. Possible ethnic difference in pain tolerance in casual observation is not verified by this laboratory pain model. Difference in pain tolerance between genders is shown only for Indians.

Lithoclast(®) Master in Intracorporeal Lithotripsy during Percutaneous Nephrolithotomy : Our Experience.

BACKGROUND: This study was carried out to compare the efficacy of Lithoclast(®) Master with pneumolithotriptor during percutaneous nephrolithotomy (PNL) in the treatment of renal staghorn calculi. METHODS: In this prospective study, 60 patients suffering from partial or complete staghorn renal stones were included. Patients were divided randomly in two groups : Groups I and II and underwent PNL for removal of stones. In Group I patients, standard pneumolithotriptor and in Group II, Lithoclast(®) Master was used for stone fragmentation. The patients were evaluated for rate of fragmentation/clearance, presence of residual fragments by KUB radiograph/ultrasound. Result was analyzed by Chi-square test. RESULT: The rate of fragmentation using Swiss Lithoclast(®) Master was more effective and quicker in comparison to standard pneumolithotriptor. The average time taken for fragmentation and clearance in Group I using pneumolithotriptor was 65 minutes, whereas it was 58 minutes using Lithoclast® Master, which was statistically significant (p< 0.01). Only 4% patients had significant residual fragments (> 4mm) in Group II and 16 (53%) patients in Group I, which was significant (p < 0.01). The complications in both the modalities were insignificant; one (1.33%) patient had bleeding and three (10%) patients had urine leak in Group I; whereas three(10%) patients had bleeding and five (16.7%) urine leak in Group II. CONCLUSION: Lithoclast(®) Master is an effective intracorporeal lithotripter during percutaneous nephrolithotomy in the treatment of renal staghorn calculi for stone fragmentation/clearance with minimal residual fragments and complications.

Hepatitis C Virus-associated Membranoproliferative Glomerulonephritis Treated with Directly Acting Antiviral Therapy.

Hepatitis C virus (HCV) infection has been shown to affect kidneys with various histopathological pattern on the kidney biopsy. These commonly include a membranoproliferative glomerulonephritis (MPGN) pattern with mixed cryoglobulinemia (CG), thrombotic microangiopathy, membranous nephropathy, and vasculitis affecting medium and small vessels of the kidneys causing polyarteritis nodosa. It has been rarely associated with MPGN without detectable CG. We present one such patient who presented to us with HCV-associated MPGN without detectable CG, who recovered completely with directly acting antiviral therapy without any immunosuppression.

High dose melphalan or intermediate dose melphalan can be well tolerated and result in good response rates in selected elderly patients with myeloma.

We have used two strategies for treating myeloma patients aged 65-75 years. Those fit enough underwent Cyclophosphamide mobilisation and PBSCT using melphalan 200mg/m(2) (HDM) (n=15, median 67 years). Those less fit were mobilised with G-CSF and received melphalan 70mg/m(2) (IDM) (n=15, median 69 years). Where possible sufficient PBSC were collected so that patients not in CR after their first IDM, underwent a second IDM procedure (n=6). The treatment was well tolerated with zero day+100 TRM. Median cell dose was 4.85x10(6)CD34+cells/kg and 2.7x10(6) in the HDM and IDM groups, respectively. Neutrophil engraftment was faster in the HDM group but despite this there was a trend to earlier discharge in the IDM group (13 days versus 15 days) and lower antibiotic and anti-fungal usage, suggesting better tolerability. Response rates were similar with CRs achieved in 7/15 patients receiving HDM and 9/15 receiving IDM (6 after the first and 3 after the second procedure). Three patients did not undergo a second IDM due to insufficient cells. In the IDM group 11/15 remain alive at a median follow up of 14 months with 5 in CR, whilst in the HDM group 12/15 are alive with 5 in CR at a median follow up of 15.5m. We conclude both approaches have comparable efficacy but that IDM may be better tolerated in an older age group.

The C terminus of the Saccharomyces cerevisiae alpha-factor receptor contributes to the formation of preactivation complexes with its cognate G protein.

Binding of the alpha-factor pheromone to its G-protein-coupled receptor (encoded by STE2) activates the mating pathway in MATa yeast cells. To investigate whether specific interactions between the receptor and the G protein occur prior to ligand binding, we analyzed dominant-negative mutant receptors that compete with wild-type receptors for G proteins, and we analyzed the ability of receptors to suppress the constitutive signaling activity of mutant Galpha subunits in an alpha-factor-independent manner. Although the amino acid substitution L236H in the third intracellular loop of the receptor impairs G-protein activation, this substitution had no influence on the ability of the dominant-negative receptors to sequester G proteins or on the ability of receptors to suppress the GPA1-A345T mutant Galpha subunit. In contrast, removal of the cytoplasmic C-terminal domain of the receptor eliminated both of these activities even though the C-terminal domain is unnecessary for G-protein activation. Moreover, the alpha-factor-independent signaling activity of ste2-P258L mutant receptors was inhibited by the coexpression of wild-type receptors but not by coexpression of truncated receptors lacking the C-terminal domain. Deletion analysis suggested that the distal half of the C-terminal domain is critical for sequestration of G proteins. The C-terminal domain was also found to influence the affinity of the receptor for alpha-factor in cells lacking G proteins. These results suggest that the C-terminal cytoplasmic domain of the alpha-factor receptor, in addition to its role in receptor downregulation, promotes the formation of receptor-G-protein preactivation complexes.

Synchronous primary triple neoplasia (renal cell carcinoma and prostate cancer in combination with thyroid neoplasm). Report of an unusual case.

We report a very rare case of triple primary neoplasia synchronously originating in the prostate, kidney and thyroid, in a 79-year-old male who presented with hematuria and continuous pain at the right hip. Examination revealed an enlarged nodular thyroid, while digital rectal examination showed prostatic enlargement with elevated PSA (16.7 ng/mL). Plain radiography showed an osteolytic lesion in the right ischium. Ultrasonography and CT scan of left kidney suggested renal cell carcinoma (RCC), which was subsequently confirmed on histopathology of the left radical nephrectomy specimen. Biopsies from prostate showed adenocarcinoma, along with deposits in ischial biopsy. Fine needle aspiration cytology (FNAC) of neck swellings suggested deposits from thyroid follicular carcinoma, which was subsequently confirmed by histopathology of the near-total thyroidectomy specimen. Currently, the patient is on regular follow-up since the past 24 months.

Development and Testing of a Cognitive Behavioral Therapy Resource for Children's Dental Anxiety.

Cognitive Behavioral Therapy (CBT) is an evidence-based treatment for dental anxiety; however, access to therapy is limited. The current study aimed to develop a self-help CBT resource for reducing dental anxiety in children, and to assess the feasibility of conducting a trial to evaluate the treatment efficacy and cost-effectiveness of such an intervention. A mixed methods design was employed. Within phase 1, a qualitative "person-based" approach informed the development of the self-help CBT resource. This also employed guidelines for the development and evaluation of complex interventions. Within phase 2, children, aged between 9 and 16 y, who had elevated self-reported dental anxiety and were attending a community dental service or dental hospital, were invited to use the CBT resource. Children completed questionnaires, which assessed their dental anxiety and health-related quality of life (HRQoL) prior to and following their use of the resource. Recruitment and completion rates were recorded. Acceptability of the CBT resource was explored using interviews and focus groups with children, parents/carers and dental professionals. For this analysis, the authors adhered to the Mixed Methods Appraisal Tool criteria. There were 24 families and 25 dental professionals participating in the development and qualitative evaluation of the CBT resource for children with dental anxiety. A total of 56 children agreed to trial the CBT resource (66% response rate) and 48 of these children completed the study (86% completion rate). There was a significant reduction in dental anxiety (mean score difference = 7.7, t = 7.9, df = 45, P < 0.001, Cohen's d ES = 1.2) and an increase in HRQoL following the use of the CBT resource (mean score difference = -0.03, t = 2.14, df = 46, P < 0.05, Cohen's d ES = 0.3). The self-help approach had high levels of acceptability to stakeholders. These findings provide preliminary evidence for the effectiveness and acceptability of the resource in reducing dental anxiety in children and support the further evaluation of this approach in a randomized control trial. Knowledge Transfer Statement: This study details the development of a guided self-help Cognitive Behavioral Therapy resource for the management of dental anxiety in children and provides preliminary evidence for the feasibility and acceptability of this approach with children aged between 9 and 16 y. The results of this study will inform the design of a definitive trial to examine the treatment- and cost-effectiveness of the resource for reducing dental anxiety in children.

Review of global regulations concerning biowaivers for immediate release solid oral dosage forms.

The regulations with respect to biowaivers for immediate release (IR) solid oral dosage forms in the USA, the EU, Japan and from the World Health Organization (WHO) are summarized and compared. Two case studies are presented, one from our own files and one from the open literature, showing the similarities and the differences among the qualification requirements of the four systems. The regulatory experience gained up to now is reviewed and expected future trends are discussed.