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Hypophosphatasia (HPP) is a rare and intractable metabolic bone disease caused by mutations in the ALPL gene. Here, we undertook a nationwide survey of HPP in Japan, specifically regarding the prominent genetic and dental manifestations of odonto (n = 16 cases) and other (termed "non-odonto") (n = 36 cases) types. Mean serum alkaline phosphatase (ALP) values in odonto-type patients were significantly greater than those of non-odonto-type patients (P<0.05). Autosomal dominant and autosomal recessive inheritance patterns were detected, respectively, in 89% of odonto-type and 96% of non-odonto-type patients. The ALPL "c.1559delT" mutation, associated with extremely low ALP activity, was found in approximately 70% of cases. Regarding dental manifestations, all patients classified as odonto-type showed early exfoliation of the primary teeth significantly more frequently than patients classified as non-odonto-type (100% vs. 56%; P<0.05). Tooth hypomineralisation was detected in 42% of non-odonto-type patients, but not in any odonto-type patients (0%; P<0.05). Collectively, these results suggest that genetic and dental manifestations of patients with odonto-type and non-odonto-type HPP are significantly different, and these differences should be considered during clinical treatment of patients with HPP. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinases 4 and 6 (CDK4/6) play critical roles in the G1 to S checkpoint of the cell cycle and have been shown to be overactive in several human cancers. Small-molecule inhibitors of CDK4/6 have demonstrated significant efficacy against many solid tumors. Since CDK4/6 inhibition is thought to induce cell cycle arrest at the G1/S checkpoint, much interest has been focused on combining CDK4/6 inhibitors with cytotoxic agents active against the S or M phase of the cell cycle to enhance therapeutic efficacy. However, it remains unclear how best to combine these two classes of drugs to avoid their potentially antagonistic effects. Here, we test various combinations of highly selective and potent CDK4/6 inhibitors with commonly used cytotoxic drugs in several cancer cell lines derived from lung, breast and brain cancers, for their cell-killing effects as compared to monotherapy. All combinations, either concurrent or sequential, failed to enhance cell-killing effects. Importantly, in certain schedules, especially pre-treatment with a CDK4/6 inhibitor, combining these drugs resulted in reduced cytotoxicity of cytotoxic agents. These findings urge cautions when combining these two classes of agents in clinical settings. [ABSTRACT FROM AUTHOR]

Two recent reports suggested that the less common, less virulent enterococcal species, Enterococcus gallinarum and E. casseliflavus, with low-level vancomycin resistance due to chromosomally encoded vanC1 and vanC2/3, may influence host immunity. We reported that peri-transplant gut colonization with E. gallinarum and E. casseliflavus is associated with lower mortality after allogeneic hematopoietic cell transplantation (HCT). Because most acute leukemia patients undergoing HCT have received intensive chemotherapy (usually requiring prolonged hospitalization) for their underlying disease before HCT, we hypothesized that some may have acquired vanC-positive enterococci during chemotherapy. Therefore, we evaluated the presence of the vanC gene cluster using vanC1 and vanC2/3 qPCR in thrice-weekly collected stool samples from 20 acute leukemia patients undergoing intensive chemotherapy. We found that an unexpectedly large proportion of patients have detectable vanC1 and vanC2/3 (15% and 35%, respectively) in at least one stool sample. Comparing qPCR results with 16S rRNA gene sequencing results suggested that E. gallinarum may reach high abundances, potentially persisting into HCT and influencing transplant outcomes. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate the diagnostic accuracy of breast MRI for detecting residual tumor and the tumor size whether it would be affected after neoadjuvant chemotherapy. Methods: Total 109 patients with NAC and 682 patients without NAC were included in this retrospective study. Measurement of the largest diameter of tumors at pathology was chosen as gold standard and compared with preoperative breast MRI. A concordance threshold of ±25% of maximal tumor size was used. The accuracy of MRI was graded as concordant, underestimation, or overestimation rate. Further subgroup analysis with tumor stages, histologic subgroups and intrinsic subtypes was performed. Results: The post-NAC MRI was associated with 92.5% sensitivity, 55.2% specificity, 85.1% positive predictive value, 72.7% negative predictive value, and overall 82.6% accuracy for detecting residual tumor. In determining tumor size, the overall concordance rates of the non-NAC group and the NAC group were 43.5% and 41.3%, respectively (p = 0.678). But the overestimation rate and underestimation rate were 26.6% and 32.1% for NAC group, and 52.9% and 3.5% for the non-NAC group (p<0.001). While in the subgroups analysis, the concordance rate of the NAC group (26.7%) was lower than that of the non-NAC group (82.1%) at T3 stage (p<0.001). There were no statistically significant differences between different tumor histologic subgroups and intrinsic subtypes. Conclusions: The overall accuracy of MRI in predicting tumor size was not affected by NAC; however, it tends to underestimate tumor size after NAC, especially in patients with T3 lesions and above. [ABSTRACT FROM AUTHOR]

Introduction: Videolaryngoscopy (VL) as a new airway management technique has evolved in recent decades, and a large number of videolaryngoscopes are now available on the market. Most recent major guidelines already recommend the immediate availability and use of VL in difficult airway management scenarios. However, national data on the availability of VL, introduction into practice and patterns of use are rarely published. Therefore, the current study aimed to provide data on VL in Hungary. Materials and methods: An electronic survey was designed and popularized with the help of the Hungarian Society of Anaesthesiology and Intensive Therapy to explore the availability, use, and practice of and attitudes toward VL among Hungarian anesthesiologists. The survey was conducted between 01.01.2018 and 31.12.2018. Results: In total, 324 duly completed forms were returned and analyzed. Responders were mainly males (58%), specialists (80%) and those involved mainly in anesthesia practice (68%) in the public sector. Two hundred and ten (65%) responders had access to various videolaryngoscopes and were mainly from surgery, intensive care and traumatology units. No responders reported the availability of eight videolaryngoscopes out of the eighteen listed devices, and 32% of the responders had never used any videolaryngoscope in clinical settings. The most commonly available devices were KingVision, MacGrath Mac and Airtraq. Most of the responders reported using videolaryngoscopes mainly for difficult airway management and reported using a fiberscope as the first alternative device. Popular methods for selecting videolaryngoscopes included the following: short clinical trial (n = 67/324), decision of the departmental lead (n = 65/324) and price (n = 54/324). The majority of responders had some training prior to clinical application, but training was mainly voluntary. Overall, 98% of the responders considered videolaryngoscopes beneficial. Conclusions: Approximately two-thirds of Hungarian anesthesiologists have immediate access to videolaryngoscopes, which are used mainly for difficult airway management. The overall attitude towards VL is positive, and many videolaryngoscopes are known and have been used by Hungarian anesthesiologists. However, only a few devices on the market are used commonly. Based on the results, further improvement might be recommended regarding VL training and availability. [ABSTRACT FROM AUTHOR]

Background: The extent of medication adherence in patients with type 2 diabetes mellitus (T2DM) several years after starting treatment with hypoglycemic agents remains unknown. Most previous work on medication adherence targeting this group of patients has been undertaken across a single year or is questionnaire based. This study aimed to determine medication adherence status and factors affecting adherence 3 years after initiation of hypoglycemic agents, using a nationwide medical claim-based database in Japan. Methods: This retrospective study was conducted on data from 884 subjects with T2DM to better understand medication adherence, the effects of polypharmacy, and other factors. We also investigated the effects of medication nonadherence on hemoglobin A1c levels. Proportion of days covered was defined as the number of days for which a hypoglycemic agent was prescribed and in the patient’s possession to the number of days in the observation period. A proportion of days covered ≥0.8 were considered adherent, and those with a value <0.8 as nonadherence. Polypharmacy was defined as taking ≥5 medications. Results: Of the 884 patients investigated, 440 were considered adherent during the study period. Significant factors related to adherence included number of medications (3 or 4, or ≥5), male sex, age 50–<60 years, and total number of visits ≥17. Medication adherence was also a factor related to patients with hemoglobin A1c values < 7.0% at the end of the observation period. Conclusions: We surveyed medication adherence for 3 years with post medication initiation, and found that subjects aged 50–<60 years, those with ≥3 concomitant medications, and those with a total number of visits ≥17 were more likely to be adherent and persistent, and more likely to continue their hypoglycemic agents. A high degree of medication adherence was found to have a positive influence on hemoglobin A1c levels. [ABSTRACT FROM AUTHOR]

Background: Oral anticoagulant therapy (VKA) is nowadays the mainstay of treatment in primary and secondary stroke prevention in patients with atrial fibrillation. Given the limited risk-benefit ratio of vitamin K antagonists, pharmacological research has been directed towards the development of products that could overcome these limits, new oral anticoagulants were recently introduced: dabigatran, rivaroxaban, apixaban, and edoxaban. Aim: Scope of the present study was to examine patterns of use, effectiveness, safety and mean annual cost per patient of anticoagulant treatment for non-valvular AF in real clinical practice. Methods: A retrospective observational cohort study, by using administrative databases (drugs, hospitalizations, clinical visits, lab tests, population registry), was conducted in the Local Health Unit (LHU) of Treviso, Italy, from January 1, 2012 to December 31, 2016. Results: 5597 subjects were selected, 2171 of which satisfied all inclusion criteria. In particular 1355 patients were treated with VKA, 577 patients were treated with NOAC, and 239 patients were treated initially with VKA and subsequently switched to NOAC (switch group). NOAC treatment showed to be superior to VKA and this superiority was statistically significant on both end-points: patients in the NOAC group reported less cardiovascular events (9,9%) and less bleeding episodes (5,5%) versus VKA patients (14,6% and 11,4%; p<,0001 and p = 0,0049, respectively). The mean cost per patient per year was respectively € 1323,9 for patients treated with NOAC versus € 1003,3 for patients treated with VKA. Cost difference appears to be largely driven by drug cost (€ 767,9 for NOAC versus € 17,7 for VKA patients) and by specialist visits and laboratory tests (€ 318,4 for NOAC versus € 733,4 for VKA patients). Conclusion: In this retrospective real-world study treatment with NOAC showed to be associated with significant reductions of CV events and bleeding events compared to VKA use, albeit at a higher NHS’ direct cost per patient/year, mainly due to higher drug therapy cost. [ABSTRACT FROM AUTHOR]

Background: We aim to examine the trend in the use of antimuscarinics and off-label alpha-adrenergic blockers for treatment of lower urinary tract symptoms (LUTS) in a Taiwanese Women Cohort between 2007 and 2012. Methods: This population-based National Health Insurance Research Database (NHIRD) was used to examine the trends in the use of antimuscarinics or off-label alpha-adrenergic blockers in Taiwan. A sample of 1,000,000 individuals randomly drawn from the whole population of 23 million individuals who were registered in the NHI in 2005. From 2007 through 2012, women aged over 18 years whose claim record contained prescriptions of either of the two drugs for treatment of any of the LUTS-related diagnoses were identified and analyzed. The annual usage of the two drug classes were calculated by defined daily dose (DDD). Results: From 2007–2012, there was a 0.80 fold (69676.8 to 125104.3) increase in DDD of antimuscarinics in our cohort. The overall healthcare seeking prevalence of LUTS was 7.33% in 2007 and 12.38% in 2012, in a rising trend. The prevalence of antimuscarinics-treated LUTS in our cohort increased from 2.53 in 2007 to 3.41 per 1000 women in 2012. The prevalence of LUTS treated by antimuscarinics increased especially for those older than 60 years during the study period. Conclusions: This 6-year observational study provided the epidemiologic information of clinically significant LUTS of Asian female population. Moreover, there was a rising trend in the use of antimuscarinics and off-label alpha-adrenergic blockers in the population-based cohort. [ABSTRACT FROM AUTHOR]

Background: Excellent adherence to tuberculosis (TB) treatment is critical to cure TB and avoid the emergence of resistance. Wirelessly observed therapy (WOT) is a novel patient self-management system consisting of an edible ingestion sensor (IS), external wearable patch, and paired mobile device that can detect and digitally record medication ingestions. Our study determined the accuracy of ingestion detection in clinical and home settings using WOT and subsequently compared, in a randomized control trial (RCT), confirmed daily adherence to medication in persons using WOT or directly observed therapy (DOT) during TB treatment.Methods and Findings: We evaluated WOT in persons with active Mycobacterium tuberculosis complex disease using IS-enabled combination isoniazid 150 mg/rifampin 300 mg (IS-Rifamate). Seventy-seven participants with drug-susceptible TB in the continuation phase of treatment, prescribed daily isoniazid 300 mg and rifampin 600 mg, used IS-Rifamate. The primary endpoints of the trial were determination of the positive detection accuracy (PDA) of WOT, defined as the percentage of ingestions detected by WOT administered under direct observation, and subsequently the proportion of prescribed doses confirmed by WOT compared to DOT. Initially participants received DOT and WOT simultaneously for 2-3 weeks to allow calculation of WOT PDA, and the 95% confidence interval (CI) was estimated using the bootstrap method with 10,000 samples. Sixty-one participants subsequently participated in an RCT to compare the proportion of prescribed doses confirmed by WOT and DOT. Participants were randomized 2:1 to receive WOT or maximal in-person DOT. In the WOT arm, if ingestions were not remotely confirmed, the participant was contacted within 24 hours by text or cell phone to provide support. The number of doses confirmed was collected, and nonparametric methods were used for group and individual comparisons to estimate the proportions of confirmed doses in each randomized arm with 95% CIs. Sensitivity analyses, not prespecified in the trial registration, were also performed, removing all nonworking (weekend and public holiday) and held-dose days. Participants, recruited from San Diego (SD) and Orange County (OC) Divisions of TB Control and Refugee Health, were 43.1 (range 18-80) years old, 57% male, 42% Asian, and 39% white with 49% Hispanic ethnicity. The PDA of WOT was 99.3% (CI 98.1; 100). Intent-to-treat (ITT) analysis within the RCT showed WOT confirmed 93% versus 63% DOT (p < 0.001) of daily doses prescribed. Secondary analysis removing all nonworking days (weekends and public holidays) and held doses from each arm showed WOT confirmed 95.6% versus 92.7% (p = 0.31); WOT was non-inferior to DOT (difference 2.8% CI [-1.8%, 9.1%]). One hundred percent of participants preferred using WOT. WOT associated adverse events were <10%, consisting of minor skin rash and pruritus associated with the patch. WOT provided longitudinal digital reporting in near real time, supporting patient self-management and allowing rapid remote identification of those who needed more support to maintain adherence. This study was conducted during the continuation phase of TB treatment, limiting its generalizability to the entire TB treatment course.Conclusions: In terms of accuracy, WOT was equivalent to DOT. WOT was superior to DOT in supporting confirmed daily adherence to TB medications during the continuation phase of TB treatment and was overwhelmingly preferred by participants. WOT should be tested in high-burden TB settings, where it may substantially support low- and middle-income country (LMIC) TB programs.Trial Registration: ClinicalTrials.gov NCT01960257. [ABSTRACT FROM AUTHOR]

Background: Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax.Methods and Findings: Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7-49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1-12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40-24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48-0.84), p = 0.0013 and 0.83 (0.73-0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99-1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01-0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10-0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01-0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups.Conclusions: In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis. [ABSTRACT FROM AUTHOR]

Background: Military anesthesia meets unique logistical, technical, tactical, and human constraints, but to date limited data have been published on anesthesia management during military operations. Objective: This study aimed to describe and analyze French anesthetic activity in a deployed military setting. Methods: Between October 2015 and February 2018, all patients managed by Sainte-Anne Military Hospital anesthesiologists deployed in mission were included. Anesthesia management was described and compared with the same surgical procedures in France performed by the same anesthesia team (hernia repair, lower and upper limb surgeries). Demographics, type of surgical procedure, and surgical activity were also described. The primary endpoint was to describe anesthesia management during the deployment of forward surgical teams (FST). The secondary endpoint was to compare anesthesia modalities during FST deployment with those usually used in a military teaching hospital. Results: During the study period, 1547 instances of anesthesia were performed by 11 anesthesiologists during 20 missions, totaling 1237 days of deployment in nine different theaters. The majority consisted of regional anesthesia, alone (43.5%) or associated with general anesthesia (21%). Compared with France, there was a statistically significant increase in the use of regional anesthesia in hernia repair, lower and upper limb surgeries during deployment. The majority of patients were civilians as part of medical support to populations. Conclusion: In the context of an austere environment, the use of regional anesthesia techniques predominated when possible. These results show that the training of military anesthetists must be complete, including anesthesia, intensive care, pediatrics, and regional anesthesia. [ABSTRACT FROM AUTHOR]

Purpose: The effects of gravity on bevacizumab or the recommended head position after intraocular bevacizumab injection have not been reported. To evaluate the effect of gravity on bevacizumab in vitro, we added bevacizumab to the upper part of a test tube filled with balanced salt solution (BSS) and examined its distribution over time. Materials and methods: Sixty-four test tubes were divided equally into two groups; group 1 (32, collected from upper part of the tube) and group 2 (32, collected from lower part of the tube). Each test tube was filled with 5 mL BSS before bevacizumab (1.25 mg/0.05 mL) was added, and then stored at 36°C. Bevacizumab concentration in 8 test tubes from each group was measured at 12, 24, 48, and 168 h using an enzyme-linked immunosorbent analysis (ELISA) kit. Mann–Whitney and Jonckheere–Terpstra tests were used for statistical analysis. Results: Bevacizumab concentration was significantly higher in Group 2 than in Group 1 at 12, 24, 48, and 168 h (12, 24, 48, and 168 h; P < 0.01 each; Mann–Whitney test). The mean change in bevacizumab concentration over time tended to increase in Group 1 (P < 0.01; Jonckheere–Terpstra test), but tended to decrease in Group 2 (P < 0.01; Jonckheere–Terpstra test). Conclusions: The significant differences in concentration between the upper and lower parts even after a considerable amount of storage time showed that bevacizumab did not dissolve immediately and diffused evenly throughout the solution. It appeared that more bevacizumab settled in the lower part of the tube than in the upper part because of gravitational force. However, the concentration difference between the upper and lower parts decreased as bevacizumab gradually diffused over time, indicating that the difference in concentration due to gravity was more significant at the beginning of bevacizumab injection. [ABSTRACT FROM AUTHOR]

Background: Patients with cirrhosis and acute myocardial infarction (AMI) present dilemma whether dual antiplatelet therapy (DAPT) should be used. Methods: Electronic medical records between 2001–2013 were retrieved from Taiwan National Health Insurance Research Database. Patients were excluded for missing information, age <20 years old, history of AMI, liver transplant, autoimmune disease, coagulopathy, taking DAPT 3 months before index date, follow-up <3 months, anticoagulation user, without DAPT, and events of myocardial infarction (MI), ischemic stroke, major bleeding, and heart failure within 3-month of enrollment. Primary outcomes were 1-year all-cause mortality, recurrent MI, major bleeding, and gastrointestinal bleeding. Results: A total of 150,887 patients with AMI retrieved. After exclusion criteria and propensity score-matching, 914 cirrhotic and 3,656 non-cirrhotic patients with AMI on DAPT were studied. During 1-year follow-up, there was significantly increased mortality in cirrhotic patients compared to non-cirrhotic patients (HR = 1.49, 95% CI = 1.28–1.74). There was significantly decreased recurrent MI in cirrhotic patients compared to non-cirrhotic patients (subdistribution HR [SHR] = 0.71, 95% CI = 0.54–0.92). However, non-significantly increased major bleeding (SHR = 1.23, 95% CI = 0.87–1.73) and significantly increased gastrointestinal bleeding (SHR = 1.49, 95% CI = 1.31–1.70). Conclusions: In cirrhotic patients with AMI, DAPT offers benefit with decreased recurrent MI at the expense of increased gastrointestinal bleeding. [ABSTRACT FROM AUTHOR]

Background: Discontinuous electroencephalographic activity in children is thought to reflect brain inactivation. Discontinuity has been observed in states of pathology, where it is predictive of adverse neurological outcome, as well as under general anesthesia. Though in preterm-infants discontinuity reflects normal brain development, less is known regarding its role in term children, particularly in the setting of general anesthesia. Here, we conduct a post-hoc exploratory analysis to investigate the spectral features of discontinuous activity in children under general anesthesia. Methods: We previously recorded electroencephalography in children less than forty months of age under general anesthesia (n = 65). We characterized the relationship between age, anesthetic depth, and discontinuous activity, and used multitaper spectral methods to compare the power spectra of subjects with (n = 35) and without (n = 30) discontinuous activity. In the subjects with discontinuous activity, we examined the amplitude and power spectra associated with the discontinuities and analyzed how these variables varied with age. Results: Cumulative time of discontinuity was associated with increased anesthetic depth and younger age. In particular, age-matched children with discontinuity received higher doses of propofol during induction as compared with children without discontinuity. In the tens of seconds preceding the onset of discontinuous activity, there was a decrease in high-frequency power in children four months and older that could be visually observed with spectrograms. During discontinuous activity, there were distinctive patterns of amplitude, spectral edge, and power in canonical frequency bands that varied with age. Notably, there was a decline in spectral edge in the seconds immediately following each discontinuity. Conclusion: Discontinuous activity in children reflects a state of a younger or more deeply anesthetized brain, and characteristic features of discontinuous activity evolve with age and may reflect neurodevelopment. [ABSTRACT FROM AUTHOR]

Background: Active management of third stage of labor is the most indispensable intervention to avert post-partum hemorrhage which is one of the typical causes of maternal morbidity and mortality. Therefore, the aim of the study was to assess practice and factors associated with active management of third stage of labor among obstetric care providers in referral hospitals. Methods: Institution based cross-sectional study design was conducted from April 1–30, 2018. Simple random sampling technique was used to select a total of 356 obstetric care providers. Data were collected using pretested, structured and self-administered questionnaires. Data were entered to Epi data version 3.1 statistical software and exported to SPSS 23 for analysis. Bivariate and multivariate logistic regression analyses were performed to identify associated factors. P value <0.05 with 95% confidence level were used to declare statistical significance. Result: This study revealed that practice of active management of third stage of labor was 61.2%. Age group of 20–30 years [AOR = 1.95 (95%CI;1.13–3.38)], Being male obstetric care provider [AOR = 1.74 (95%CI;1.03–2.94)], having work experience ≥2 years [AOR = 1.95(95%CI;1.13–3.38)], availability of oxytocin [AOR = 5.46 (95%CI; 2.41–12.3)], having exposure to manage third stage of labor [AOR = 2.91(95%CI; 1.55–5.48)], and having good knowledge [AOR = 2.67 (95%CI; 1.46–4.90)], were the factors associated with practice. Conclusion: This study showed that practice of active management of third stage of labor was high. Age group between 20–30 years, being a male obstetric care provider, having ≥2years work experience, availability of oxytocin, exposure to third stage management and having good knowledge were factors associated with practice. Therefore, all referral hospitals and concerned bodies need efforts to focus on providing training to increase health care provider’s knowledge so as to sustain good practice through appropriate interventions. [ABSTRACT FROM AUTHOR]

Intracranial germinoma sometimes present as bifocal germinoma, and whether bifocal germinoma should be treated as a synchronous or disseminated disease remains unclear. This study aimed to determine the optimal treatment modality for bifocal germinoma. Patients with bifocal germinoma who received radiotherapy (RT) from March 1990 to August 2017 were included for analysis. A total of 21 patients were included. The median follow-up period was 76.2 months (range, 6.2–305.4 months). There were 17 patients who received cranio-spinal irradiation (CSI) with local RT; 3, whole ventricular RT (WVRT) with local RT; and 1, local RT only. Three recurrences occurred (1 patient each among those who underwent CSI, WVRT, and local RT). Recurrence in the patient who received CSI and who received WVRT occurred in the right thalamus and right frontal convexity, respectively. Meanwhile, the patient who received local RT showed not only a recurred lesion in the hypothalamus, but also cerebrospinal fluid seeding. For this patient, salvage CSI was performed and complete response was achieved after treatment. However, after 9 years and 6 months, he was diagnosed with glioblastoma and expired. As for toxicity, although 17 patients showed decrease in complete blood count levels during treatment, all patients recovered soon after treatment completion. Our findings suggest that bifocal germinoma may be considered as a disseminated disease when considering the patterns of failure according to RT fields. In addition, patients who received CSI showed low acute toxicity rates. However, further studies are necessary to confirm these findings. [ABSTRACT FROM AUTHOR]

Introduction: While Kedah has recorded the highest prevalence of diabetes among all the states in Malaysia, the information on the practice and effectiveness of disease management in public health institutions remains limited. This study aimed to evaluate the management and glycemic control of patients with type-2 diabetes mellitus (T2DM) at the primary care level in Kedah. Methods: All T2DM patients, who made at least one visit to any of the 58 public health clinics in Kedah during August 2016 and July 2017, were included in this study. The sample was selected from the National Diabetes Registry using the stratified random sampling method. The information on the demographic and clinical characteristics, laboratory findings and pharmacological treatment was gathered from medical records of patients. The differences in mean HbA1C levels across subgroups of each variable were tested using the general linear model. The evaluation of the appropriateness of treatment was performed based on the recommendations of the latest Clinical Practice Guidelines for T2DM. Results: The patients (n = 23,557) were mainly female (63.4%), of Malay ethnicity (80.1%) and middle-aged (62.2%), with a mean duration of T2DM of 6.2±7.16 years. Only 15.6% of them had a HbA1C level <6.5%, and 28.6% did not have their HbA1C levels tested over the 12-month period. Yet, the underutilization of combination treatment (≥2 antidiabetic agents) and insulin in the patients with a poor glycemic control was evident. Retinopathy emerged as the most prevalent diabetes-related complication (12.6%). Along with those with a longer duration of T2DM, the patients who were younger, female and of Indian ethnicity were found to generally have a poorer glycemic control. Conclusion: This study discloses the suboptimal T2DM management at the primary care level in Kedah, which warrants a statewide plan for improvement. [ABSTRACT FROM AUTHOR]

Background and objective: Trial registration is widely endorsed as it is considered not only to enhance transparency and quality of reporting but also to help safeguard against outcome reporting bias and probably spin, known as specific reporting that could distort the interpretation of results thus mislead readers. We planned to investigate the current registration status of recently published randomized controlled trials (RCTs) of acupuncture, outcome reporting bias in the prospectively registered trials, and the association between trial registration and presence of spin and methodological factors in acupuncture RCTs. Methods: Acupuncture RCTs published in English in recent 5 years (January 2013 to December 2017) were searched in PubMed, Cochrane Central Register of Controlled Trials, and EMBASE. Trial registration records identified in the publications and trial registries were classified into prospectively registered, retrospectively registered, or unregistered. Primary outcomes were identified and the direction of the results was judged as statistically significant (positive) or statistically nonsignificant (negative). We compared registered and published primary outcomes to assess outcome reporting bias and assessed whether discrepancies favored statistically significant outcomes. Frequency and strategies of spin in published reports with statistically nonsignificant results for primary outcomes were then identified. We also analyzed whether the trial registration status was associated with spin and quality of methodological factors. Results: Of the 322 included RCTs, 41.9% (n = 135) were prospectively registered. Among 64 studies that were prospectively registered and specified primary outcomes, 25 trials had the discrepancies between the registered and published primary outcomes and 60% of them (15 trials) favored the statistically significant findings. Among 169 studies that specified primary outcomes, trial registration status was not associated with the direction of results, i.e., statistically significant or not. Spin was identified in 56.4% out of 78 studies with statistically nonsignificant primary outcomes and claiming efficacy with no consideration of statistically nonsignificant primary outcomes was the most common strategy for spin. Trial registration status was not statistically different between studies with and without spin. Conclusion: While trial registration seemed to have improved over time, primary outcomes in registered records and publications were often inconsistent, tending to favor statistically significant findings and spin was common in studies with statistically nonsignificant primary outcomes. Journal editors and researchers in this field should be alerted to still prevalent reporting bias and spin. [ABSTRACT FROM AUTHOR]

Cognitive impairments are a common consequence of traumatic brain injury (TBI). The hippocampus is a subcortical structure that plays a key role in the formation of declarative memories and is highly vulnerable to TBI. The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in the hippocampus and reduced expression and function of this receptor are linked with cognitive impairments in Alzheimer’s disease and schizophrenia. Positive allosteric modulation of α7 nAChRs with AVL-3288 enhances receptor currents and improves cognitive functioning in naïve animals and healthy human subjects. Therefore, we hypothesized that targeting the α7 nAChR with the positive allosteric modulator AVL-3288 would enhance cognitive functioning in the chronic recovery period of TBI. To test this hypothesis, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury or sham surgery. At 3 months after recovery, animals were treated with vehicle or AVL-3288 at 30 min prior to cue and contextual fear conditioning and the water maze task. Treatment of TBI animals with AVL-3288 rescued learning and memory deficits in water maze retention and working memory. AVL-3288 treatment also improved cue and contextual fear memory when tested at 24 hr and 1 month after training, when TBI animals were treated acutely just during fear conditioning at 3 months post-TBI. Hippocampal atrophy but not cortical atrophy was reduced with AVL-3288 treatment in the chronic recovery phase of TBI. AVL-3288 application to acute hippocampal slices from animals at 3 months after TBI rescued basal synaptic transmission deficits and long-term potentiation (LTP) in area CA1. Our results demonstrate that AVL-3288 improves hippocampal synaptic plasticity, and learning and memory performance after TBI in the chronic recovery period. Enhancing cholinergic transmission through positive allosteric modulation of the α7 nAChR may be a novel therapeutic to improve cognition after TBI. [ABSTRACT FROM AUTHOR]

Background: Linezolid has shown strong antimicrobial activity against multidrug-resistant (MDR)/rifampin-resistant strains of Mycobacterium tuberculosis. Linezolid achieves clinical efficacy mainly through area under the concentration time curve/minimum inhibitory concentration ratio in the infected lesion site. Previous studies mainly focused on the relationship between linezolid concentrations in the blood and infected bone tissue when the blood drug concentration reached the peak 2 h after administration. However, we do not know whether linezolid can maintain the same bone/plasma ratio in infected bone tissue when the blood concentration reaches the trough level. Therefore, this study aimed to evaluate the penetrability of linezolid into bone tissue 24 h after administration in patients with MDR spinal tuberculosis (TB). Methods: Nine MDR spinal TB patients, who received a treatment regimen including linezolid and underwent surgery, were enrolled prospectively from April 2017 to March 2019. Blood and diseased bone tissue specimens were collected simultaneously during operations 24 h after taking 600 mg of linezolid orally. Linezolid concentrations in plasma and diseased bone tissue specimens were determined by high-performance liquid chromatography–tandem mass spectrometry. Results: Following a 600 mg oral administration of linezolid 24 h before surgery, median concentrations of linezolid in plasma and diseased bone tissue for the 9 patients were 1.98 mg/L (range 0.30–3.44 mg/L) and 0.60 mg/L (range 0.18–2.13 mg/L), respectively, at resection time. The median diseased bone/plasma linezolid concentration ratio was 0.48 (range 0.30–0.67). Pearson’s correlation analysis showed that linezolid concentrations in the plasma were positively related to those in diseased bone tissue (r = 0.949, p < 0.001). Conclusions: After 24 h of medication, linezolid still had good penetrability into diseased bone tissue in patients with MDR spinal TB. [ABSTRACT FROM AUTHOR]

Background: It remains unknown which is the optimal first-line treatment regimen for patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). We performed a network meta-analysis to address this important issue. Methods: PubMed, Embase, Cochrane Library, Web of Science and major international scientific meetings were searched for relevant randomized controlled trials (RCTs). Progression-free survival (PFS) data was the primary outcome of interest, and overall survival (OS) and serious adverse events (SAEs) were the secondary outcomes of interests, reported as hazard ratio (HR) or odds ratio (OR) and 95% confidence intervals (CIs). Results: 25 RCTs with a total of 5005 patients randomized to receive seven treatments were included in the meta-analysis. Third-generation tyrosine kinase inhibitor (TKI) (osimertinib) and first-generation TKIs (F-TKIs) in combination with chemotherapy (F-TKIs+CT) were more effective than F-TKIs alone in terms of PFS (HR = 0.46, 95% CI: 0.22–0.93; P = 0.031 and HR = 0.62, 95% CI: 0.39–0.98; P = 0.041) and OS (HR = 0.63, 95% CI: 0.43–0.91; P = 0.014 and HR = 0.73, 95% CI: 0.57–0.92; P = 0.008). Second-generation TKIs (S-TKIs) showed significant OS advantage over F-TKIs (HR = 0.83, 95% CI: 0.70–0.99; P = 0.04). Based on treatment ranking in terms of PFS and OS, osimertinib had the highest probability of being the most effective treatment (89% and 86%) and with the best tolerability. F-TKIs+CT was ranked the second-most effective regimen, but with relatively high risk of SAEs. Conclusions: Osimertinib seemed to be the most preferable first-line treatment in advanced EGFR-mutated NSCLC. However, limitations of the study including a single RCT investigating osimertinib and immature OS data need to be considered. [ABSTRACT FROM AUTHOR]

Background: Patients with diabetes are at high risk of drug therapy problems (DTPs), as they are receiving multiple medications. To date, studies regarding DTPs in patients with diabetes in Ethiopia are limited. The aim of this study was to assess prevalence of DTPs, medication adherence and treatment satisfaction of patients with diabetes at Tikur Anbessa Specialized Hospital (TASH). Method: A cross-sectional study was conducted on randomly selected 418 participants who fulfilled the inclusion criteria. Data were collected using structured questionnaire and patients’ chart review. Cipolle’s classification system was used to determine DTPs. Modified Morisky’s Adherence Scale (MMAS-8) was used to measure patients’ adherence to their medication. Treatment Satisfaction with Medicines Questionnaire (SATMED-Q) patient satisfaction assessment questionnaire was used to assess patients’ treatment satisfaction. Results: A total of 207 DTPs in 177 (42.3%) of participants were identified. Commonly identified DTPs were dosage too low (58, 28.0%), ineffective drug therapy (54, 26.1%), and need additional drug therapy (52, 25.1%). Factors associated with DTPs were female gender (Adjusted Odds Ratio [AOR] = 2.31,95% CI:1.30–4.12); ≥3comorbidities (AOR = 3.61, 95% CI:1.19–10.96); ever married (AOR = 2.58,95% CI:1.23–5.48); type 2 diabetes (AOR = 5.62, 95% CI:1.21–26.04); non-adherence (AOR = 5.26,95% CI:2.51–11.04) and residence out of Addis Ababa (AOR = 0.30, 95% CI:0.12–0.73). Twenty four percent of participants were non-adherent to their drug therapies. Factors associated with non-adherence were diabetes complications (AOR = 2.00, 95% CI: 1.2–3.32), the female gender (AOR = 1.67, 95%CI: 1.01–2.8) and level of education (AOR = 0.42, 95%CI: 0.18–0.96). Eighty one percent of participants were satisfied with the current treatment. Conclusion: A significant proportion of patients were satisfied with their treatment and a quarter of the study participants were non-adherent to their medications at TASH diabetic clinic. However, DTPs were considerably higher among the study participants. Hence, future interventions targeting prevention and resolution of DTPs deemed to be necessary. [ABSTRACT FROM AUTHOR]

Purpose: Development of a supervised machine-learning model capable of predicting clinically relevant molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) from diffusion-weighted-imaging-derived radiomic features. Methods: The retrospective observational study assessed 55 surgical PDAC patients. Molecular subtypes were defined by immunohistochemical staining of KRT81. Tumors were manually segmented and 1606 radiomic features were extracted with PyRadiomics. A gradient-boosted-tree algorithm was trained on 70% of the patients (N = 28) and tested on 30% (N = 17) to predict KRT81+ vs. KRT81- tumor subtypes. A gradient-boosted survival regression model was fit to the disease-free and overall survival data. Chemotherapy response and survival were assessed stratified by subtype and radiomic signature. Radiomic feature importance was ranked. Results: The mean±STDEV sensitivity, specificity and ROC-AUC were 0.90±0.07, 0.92±0.11, and 0.93±0.07, respectively. The mean±STDEV concordance indices between the disease-free and overall survival predicted by the model based on the radiomic parameters and actual patient survival were 0.76±0.05 and 0.71±0.06, respectively. Patients with a KRT81+ subtype experienced significantly diminished median overall survival compared to KRT81- patients (7.0 vs. 22.6 months, HR 4.03, log-rank-test P = <0.001) and a significantly improved response to gemcitabine-based chemotherapy over FOLFIRINOX (10.14 vs. 3.8 months median overall survival, HR 2.33, P = 0.037) compared to KRT81- patients, who responded significantly better to FOLFIRINOX over gemcitabine-based treatment (30.8 vs. 13.4 months median overall survival, HR 2.41, P = 0.027). Entropy was ranked as the most important radiomic feature. Conclusions: The machine-learning based analysis of radiomic features enables the prediction of subtypes of PDAC, which are highly relevant for disease-free and overall patient survival and response to chemotherapy. [ABSTRACT FROM AUTHOR]

Background: TB/HIV coinfection is a serious public health issue in Brazil, and patients with coinfection have difficulty adhering to treatments. Directly observed treatment (DOT) has been recommended by the World Health Organization, considering the vulnerability of those affected. The purpose is to investigate the occurrence of DOT and associated factors compared to conventional treatment in Porto Alegre, Brazil. Methods: A retrospective cohort study was carried out with all patients with coinfection from 2009 to 2013 in the city of Porto Alegre, Brazil, the state capital with the highest rate of coinfection in Brazil. The data came from national health information systems. The dependent variable was the performance of DOT. Bivariate and multivariable models were used to determine factors associated with DOT. The percentage of cure and death was verified in a period of two years, comparing patients who received and did not receive DOT. Results: 2,400 cases of coinfection were reported, with 1,574 males and 826 females and a mean age of 38 years ± 9.91 years. The occurrence of DOT was 16.9%. In the multivariable analysis, factors independently associated to DOT were the year (with greater chances of being received in 2012 and 2013), place of origin, non-white race (OR = 1.29, 95% CI = 1.08–1.54), cases of relapse (OR = 1.33; 95% CI = 1.03–1.73), readmission after abandonment (OR = 1.48, 95% CI = 1.20–1.83), transfer (OR = 2.04; 95% CI = 1.40–2.98), acid-fast bacilli (AFB) test with positive result in first sample (OR = 1.73, 95% CI = 1.24–2.42), alcohol abuse (OR = 1.39; 95% CI = 1.16–1.67), and mental disorders (OR = 1.83; 95% CI = 1.38–2.44.) Of the 532 cases of death, occurring in two years, 10.2% were in patients who underwent DOT and 89.8% in patients who did not undergo DOT (p<0.001). O percentual de óbitos em pessoas que receberam DOT foi de 13% e o percentual de óbitos para pessoas que receberam tratamento convencional foi de 24%. Conclusions: There was an increase in the percentage of DOT over the years in the scenario studied, and the predictors for DOT were related to social vulnerability. In relation to death within two years, a lower proportion was found in patients who underwent DOT, suggesting a protective effect of the strategy. [ABSTRACT FROM AUTHOR]

Background: Several studies have examined the risk and health outcomes related to polypharmacy among the elderly. However, information regarding polypharmacy among pediatric patients is lacking. Objective: The aim of this study was to investigate the prevalence of polypharmacy and its related factors among the pediatric population of South Korea. Methods: We used national claim data from the Health Insurance Review and Assessment Service—Pediatric Patients Sample (HIRA-PPS) in Korea originating from 2012 through 2016. Polypharmacy was defined as a daily average of two or more drugs used yearly. Complex chronic conditions (CCCs) were examined to evaluate concomitant chronic diseases in pediatric patients. Age-specific contraindications and potential drug-drug interactions were assessed according to criteria established by the Korea Institute of Drug Safety & Risk Management (KIDS). Descriptive statistics and logistic regression were conducted to analyze the status of polypharmacy and its associated risk factors in pediatric patients. Results: The 5-year prevalence of pediatric polypharmacy in pediatric patients was 3.7%. The prevalence of polypharmacy was much higher in younger pediatric patients: 9.5% for patients between the ages of 1–7 years, 0.9% for ages 6–11 years, and 1.1% for ages 12–19 years. Pediatric patients with CCCs, Medical Aid benefits, or a hospital admission history had a significantly higher prevalence of polypharmacy when compared to their counterparts without those conditions. The most commonly prescribed drugs were respiratory agents (29%) followed by anti-allergic drugs (18.7%), central nervous system agents (15.9%), antibiotics (10.1%), and gastrointestinal drugs (7.7%). There was a positive correlation between the daily average number of inappropriate prescriptions and the degree of polypharmacy, especially in pediatric patients between the ages of 1–7 years. Contraindications and potential drug-drug interactions occurred in 11.0% and 10.1% of patients exposed to polypharmacy, respectively. Conclusions: One in ten pediatric patients under the age of 7 years was prescribed two or more concurrent drugs on average per day. Furthermore, pediatric patients exposed to polypharmacy showed an increased risk of inappropriate drug use. The implementation of a medication review system that considers pediatric patient polypharmacy exposure would reduce inappropriate drug use and prevent unwanted adverse outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Vacuolization is a frequently found morphological feature in acute myeloid leukemia (AML) blasts. Subcellular origin and biological function as well as prognostic impact are currently unknown. The aim of this study was to evaluate whether vacuolization correlates with clinically relevant AML features. Materials & methods: Bone marrow smears of patients diagnosed with AML at the University Hospital Frankfurt between January 2011 and August 2013 were analyzed for blast vacuolization and correlated with clinically relevant AML features. Patients undergoing standard induction chemotherapy were further analyzed for molecular and cytogenetic features as well as treatment response and survival. Results: 14 of 100 patients diagnosed with AML receiving standard induction chemotherapy had evidence of blast vacuolization. Positivity for vacuolization correlated with a CD15 positive immunophenotype and with a higher incidence of high-risk AML according to the European LeukemiaNet risk stratification. AML patients with blast vacuolization had a poor blast clearance after standard induction chemotherapy and poor survival. Discussion: In conclusion, our findings demonstrate that vacuolization can easily be determined in myeloid leukemia blasts and may be a useful biomarker to predict AML risk groups as well as early treatment response rates and survival. [ABSTRACT FROM AUTHOR]

Background: Pulmonary embolism (PE) is correlated with increased mortality among patients with lung cancer (LC). The characteristics of patients with LC presenting with PE have not been fully established, and our meta-analysis aims to comprehensively investigate the clinical characteristics associated with PE in patients with LC to help physicians identify PE earlier in these patients. Methods: Multiple databases were searched, including PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure and Wanfang. Odds ratios (ORs) and weighted mean differences (WMDs) with 95% confidence intervals (95% CIs) were used as effect measures for dichotomous and continuous variables, respectively. Moreover, Egger’s test, Begg’s test and a sensitivity analysis were performed to assess the publication bias and reliability of the articles. Results: In total, 16 studies were included in our meta-analysis. The results indicated that history of chronic obstructive pulmonary disease (OR = 2.59, 95% CI: 1.09, 6.15; P = 0.03), adenocarcinoma (OR = 2.28, 95% CI: 1.88, 2.77; P < 0.01), advanced tumour stage (TNM III-IV vs. I-II, OR = 2.38, 95% CI: 1.99, 2.86; P < 0.01), history of central venous catheter (OR = 1.95, 95% CI: 1.36, 2.78; P < 0.01), history of chemotherapy (OR = 2.32, 95% CI: 1.80, 2.99, P < 0.01), high levels of D-dimer (WMD = 4.31, 95% CI: 2.53, 6.10; P < 0.01) and carcinoembryonic antigen (WMD = 10.30, 95% CI: 9.95, 10.64; P < 0.01) and a low level of partial pressure of oxygen (WMD = -25.97, 95% CI: -31.31, -20.62; P < 0.01) were clinical features of LC patients with PE compared to those without PE. Conclusions: These results reveal that LC patients with PE have specific clinical features, including but not limited to several cancer- and treatment-related factors, that may help their early identification. [ABSTRACT FROM AUTHOR]

Seizures can induce endoplasmic reticulum (ER) stress, and sustained ER stress contributes to neuronal death after epileptic seizures. Despite the recent debate on whether inhibiting ER stress can reduce neuronal death after seizures, whether and how ER stress impacts neural activity and seizures remain unclear. In this study, we discovered that the acute ER stress response functions to repress neural activity through a protein translation-dependent mechanism. We found that inducing ER stress promotes the expression and distribution of murine double minute-2 (Mdm2) in the nucleus, leading to ubiquitination and down-regulation of the tumor suppressor p53. Reduction of p53 subsequently maintains protein translation, before the onset of translational repression seen during the latter phase of the ER stress response. Disruption of Mdm2 in an Mdm2 conditional knockdown (cKD) mouse model impairs ER stress-induced p53 down-regulation, protein translation, and reduction of neural activity and seizure severity. Importantly, these defects in Mdm2 cKD mice were restored by both pharmacological and genetic inhibition of p53 to mimic the inactivation of p53 seen during ER stress. Altogether, our study uncovered a novel mechanism by which neurons respond to acute ER stress. Further, this mechanism plays a beneficial role in reducing neural activity and seizure severity. These findings caution against inhibition of ER stress as a neuroprotective strategy for seizures, epilepsies, and other pathological conditions associated with excessive neural activity. [ABSTRACT FROM AUTHOR]

Background: An earlier open label, prospective, non-randomized, non-comparative, multi-centric study conducted within public health facilities in Bihar, India (CTRI/2012/08/002891) measured the field effectiveness of three new treatment regimens for visceral leishmaniasis (VL): single dose AmBisome (SDA), and combination therapies of AmBisome and miltefosine (AmB+Milt) and miltefosine and paromomycin (Milt+PM) up to 6 months follow-up. The National Vector Borne Disease Control Program (NVBDCP) recommended an extended follow up at 12 months post-treatment of the original study cohort to quantify late relapses. Methods: The 1,761 patients enrolled in the original study with the three new regimens were contacted and traced between 10 and 36 months following completion of treatment to determine their health status and any occurrence of VL relapse. Results: Of 1,761 patients enrolled in the original study, 1,368 were traced at the extended follow-up visit: 711 (80.5%), 295 (83.2%) and 362 (71.5%) patients treated with SDA, AmB+Milt and Milt+PM respectively. Of those traced, a total of 75 patients were reported to have relapsed by the extended follow-up; 45 (6.3%) in the SDA, 25 (8.5%) in the AmB+Milt and 5 (1.4%) in the Milt+PM arms. Of the 75 relapse cases, 55 had already been identified in the 6-months follow-up and 20 were identified as new cases of relapse at extended follow-up; 7 in the SDA, 10 in the AmB+Milt and 3 in the Milt+PM arms. Conclusion: Extending follow-up beyond the standard 6 months identified additional relapses, suggesting that 12-month sentinel follow-up may be useful as a programmatic tool to better identify and quantify relapses. With limited drug options, there remains an urgent need to develop effective new chemical entities (NCEs) for VL. [ABSTRACT FROM AUTHOR]

Background: Chagas disease (CD) affects over 300,000 people in the United States, but fewer than 1% have been diagnosed and less than 0.3% have received etiological treatment. This is a significant public health concern because untreated CD can produce fatal complications. What factors prevent people with CD from accessing diagnosis and treatment in a nation with one of the world’s most advanced healthcare systems? Methodology/Principal findings: This analysis of barriers to diagnosis and treatment of CD in the US reflects the opinions of the authors more than a comprehensive discussion of all the available evidence. To enrich our description of barriers, we have conducted an exploratory literature review and cited the experience of the main US clinic providing treatment for CD. We list 34 barriers, which we group into four overlapping dimensions: systemic, comprising gaps in the public health system; structural, originating from political and economic inequalities; clinical, including toxicity of medications and diagnostic challenges; and psychosocial, encompassing fears and stigma. Conclusions: We propose this multidimensional framework both to explain the persistently low numbers of people with CD who are tested and treated and as a potential basis for organizing a public health response, but we encourage others to improve on our approach or develop alternative frameworks. We further argue that expanding access to diagnosis and treatment of CD in the US means asserting the rights of vulnerable populations to obtain timely, quality healthcare. [ABSTRACT FROM AUTHOR]

Trazodone is an antidepressant drug with considerable affinity for 5-HT1A receptors and α1-adrenoceptors for which the drug is competitive agonist and antagonist, respectively. In this study, we used cell-attached or whole-cell patch-clamp recordings to characterize the effects of trazodone at somatodendritic 5-HT1A receptors (5-HT1AARs) and α1-adrenoceptors of serotonergic neurons in rodent dorsal raphe slices. To reveal the effects of trazodone at α1-adrenoceptors, the baseline firing of 5-HT neurons was facilitated by applying the selective α1-adrenoceptor agonist phenylephrine at various concentrations. In the absence of phenylephrine, trazodone (1–10 μM) concentration-dependently silenced neurons through activation of 5-HT1AARs. The effect was fully antagonized by the selective 5-HT1A receptor antagonist Way-100635. With 5-HT1A receptors blocked by Way-100635, trazodone (1–10 μM) concentration-dependently inhibited neuron firing facilitated by 1 μM phenylephrine. Parallel rightward shift of dose-response curves for trazodone recorded in higher phenylephrine concentrations (10–100 μM) indicated competitive antagonism at α1-adrenoceptors. Both effects of trazodone were also observed in slices from Tph2-/- mice that lack synthesis of brain serotonin, showing that the activation of 5-HT1AARs was not mediated by endogenous serotonin. In whole-cell recordings, trazodone activated 5-HT1AAR-coupled G protein-activated inwardly-rectifying (GIRK) channel conductance with weak partial agonist efficacy (~35%) compared to that of the full agonist 5-CT. Collectively our data show that trazodone, at concentrations relevant to its clinical effects, exerts weak partial agonism at 5-HT1AARs and disfacilitation of firing through α1-adrenoceptor antagonism. These two actions converge in inhibiting dorsal raphe serotonergic neuron activity, albeit with varying contribution depending on the intensity of α1-adrenoceptor stimulation. [ABSTRACT FROM AUTHOR]

Background: Knowledge of antibiotic prescription practices in low- and middle-income countries is limited due to a lack of adequate surveillance systems. Objective: To assess the prescription of antibiotics for the treatment of acute respiratory tract infections (ARIs) in primary care. Method: An explanatory sequential mixed-methods study was conducted in 4 private not-for-profit outreach clinics located in slum areas in Nairobi, Kenya. Claims data of patients who received healthcare between April 1 and December 27, 2016 were collected in real-time through a mobile telephone-based healthcare data and payment exchange platform (branded as M-TIBA). These data were used to calculate the percentage of ARIs for which antibiotics were prescribed. In-depth interviews were conducted among 12 clinicians and 17 patients to explain the quantitative results. Results: A total of 49,098 individuals were registered onto the platform, which allowed them to access healthcare at the study clinics through M-TIBA. For 36,210 clinic visits by 21,913 patients, 45,706 diagnoses and 85,484 medication prescriptions were recorded. ARIs were the most common diagnoses (17,739; 38.8%), and antibiotics were the most frequently prescribed medications (21,870; 25.6%). For 78.5% (95% CI: 77.9%, 79.1%) of ARI diagnoses, antibiotics were prescribed, most commonly amoxicillin (45%; 95% CI: 44.1%, 45.8%). These relatively high levels of prescription were explained by high patient load, clinician and patient perceptions that clinicians should prescribe, lack of access to laboratory tests, offloading near-expiry drugs, absence of policy and surveillance, and the use of treatment guidelines that are not up-to-date. Clinicians in contrast reported to strictly follow the Kenyan treatment guidelines. Conclusion: This study showed successful quantification of antibiotic prescription and the prescribing pattern using real-world data collected through M-TIBA in private not-for-profit clinics in Nairobi. [ABSTRACT FROM AUTHOR]

Objective: Soft tissue sarcoma (STS) is a rare cancer type that when locally advanced or metastatic, is predominantly treated with palliative chemotherapy with the aim of improving both quantity and quality of life. Given modest survival data after commencing first line chemotherapy, this study examines (i) what constitutes health related quality of life (HRQoL), (ii) whether the most commonly used HRQoL assessment tool measures this and (iii) to what extent HRQoL, and its components, change during and after treatment. Design: Mixed-methods longitudinal study of 66 sarcoma patients living with STS (42 commencing chemotherapy, 24 under surveillance after completing chemotherapy) involving serial EORTC QLQ-C30 questionnaires and nested-qualitative semi-structured interviews with a sub-sample of participants. EORTC QLQ-C30 score change from baseline to primary evaluation point was examined using a paired t-test. Interviews were analysed using the framework approach before both datasets were integrated. Results: Five main factors, including control of pain, were identified by study participants as important components of HRQoL; these are examined within the EORTC QLQ-C30. However, others e.g. independence loss and common causes of anxiety, are not. Whilst social and psychological domains are addressed by the EORTC QLQ-C30, the quantitative change over time did reflect qualitative descriptions of decline. The mean overall EORTC QLQ-C30 HRQoL score deteriorated from baseline (60.4) to the primary evaluation point (50.2) [change of -10.2, t-test: -2.70, p = 0.01] for those receiving chemotherapy; this was in concordance with patients’ qualitative accounts. Baseline overall HRQoL scores were higher in the surveillance group suggesting a correlation with chemotherapy response and longer-term improvement in HRQoL. The evidence from both HRQoL scores and qualitative accounts indicated that the presence and control of physical symptoms were particularly important in maintaining HRQoL. Whilst fatigue deteriorated on chemotherapy (baseline 41.7 to 52.8; change of +11.1, t-test +2.51, p<0.05), pain (baseline 41.5 to 32.1; change -9.4, t-test -2.06 p<0.05) and sleep disturbance (43.1 to 28.5; change -14.6, t-test –3.05, p<0.05) both improved. Conclusion: A key finding was that the EORTC QLQ-C30 assesses some but not all of the patient-reported components of HRQoL in sarcoma patients highlighting the need for either STS specific modules within the EORTC QLQ-C30 or a completely new STS specific HRQoL tool. First line palliative chemotherapy improves specific symptoms known to be prevalent and to influence HRQoL in this patient group which in some patients may translate to sustained improvement in HRQoL: further exploration and validation of these findings in larger prospective studies are warranted. [ABSTRACT FROM AUTHOR]

The objective of this study was to identify, understand and generate a Taguchi orthogonal array model for the formation of 10–50 μm microparticles with applications in topical/ocular controlled drug delivery. Poly(lactic-co-glycolic acid) (PLGA) microparticles were fabricated by the single emulsion oil-in-water method and the particle size was characterized using laser diffraction and scanning electronic microscopy (SEM). Sequential Taguchi L12 and L18 orthogonal array (OA) designs were employed to study the influence of ten and eight parameters, respectively, on microparticle size (response). The first optimization step using the L12 design showed that all parameters significantly influenced the particle size of the prepared PLGA microparticles with exception of the concentration of poly(vinyl alcohol) (PVA) in the hardening bath. The smallest mean particle size obtained from the L12 design was 54.39 μm. A subsequent L18 design showed that the molecular weight of PLGA does not significantly affect the particle size. An experimental run comprising of defined parameters including molecular weight of PLGA (89 kDa), concentration of PLGA (20% w/v), concentration of PVA in the emulsion (0.8% w/v), solvent type (ethyl acetate), organic/aqeuous phase ratio (1:1 v/v), vortexing speed (9), vortexing duration (60 seconds), concentration of PVA in hardening bath (0.8% w/v), stirring speed of hardening bath (1200 rpm) and solvent evaporation duration (24 hours) resulted in the lowest mean particle size of 23.51 μm which was predicted and confirmed by the L18 array. A comparable size was demonstrated during the fabrication of BSA-incorporated microparticles. Taguchi OA design proved to be a valuable tool in determining the combination of process parameters that can provide the optimal condition for microparticle formulation. Taguchi OA design can be used to correctly predict the size of microparticles fabricated by the single emulsion process and can therefore, ultimately, save time and costs during the manufacturing process of drug delivery formulations by minimising experimental runs. [ABSTRACT FROM AUTHOR]

Objectives: A lack of physician training is a major obstacle for effective tobacco dependence treatment. This study assessed the feasibility of an active learning training program and its effects on smoking cessation counselling skills of medical residents in Armenia, an Eastern European country with high smoking prevalence. Study design: The study used a pre-post assessment of smoking cessation counselling activities and a course evaluation survey to assess the feasibility of the intervention in a different environment. Methods: We adapted an active learning training model developed in Switzerland. Residents were trained in Yerevan, Armenia, using video-taped counselling sessions, role plays, standardized patients (actors), group discussions and immediate feedback. The training evaluation was done using a semi-structured anonymous questionnaire. The study assessed the physicians’ self-reported smoking cessation counselling activities before and 6 months after the training. A non-parametric Mann-Whitney test was used to assess pre-post differences in physicians’ counselling skills measured on ordinal scale. Results: Of the 37 residents trained, 75% were female, 89% aged 20–29 years and 83% were never-smokers. Twenty-eight trainees (76%) returned the course evaluation survey and 32 (86%) answered a questionnaire on skills self-assessment at 6 months follow-up. The majority agreed the course was successful in achieving its learning objectives (64%-96%) and increased their confidence in assisting their patients to quit (74%). After 6 months, the physicians were more likely than at baseline to adhere to evidence-based counselling strategies, including assessing the smoking status and dependence and matching the advice to the patient motivation. The training did not, however, improve the prescription of tobacco dependence medications. Conclusions: Six months after the training, several self-reported smoking cessation counselling activities had significantly improved compared to baseline. This training model is acceptable for medical residents in Yerevan, Armenia and offers a promising approach in addressing the lack of physician counselling skills in similar settings and populations. [ABSTRACT FROM AUTHOR]

Objective: Pakistan has a high pediatric burden of tuberculosis, but few studies describe the treatment experience of children with tuberculosis in Pakistan. We sought to identify risk factors for unsuccessful treatment outcomes in children with drug-susceptible tuberculosis identified in eight hospitals in Karachi, Pakistan. Design: We conducted a retrospective cohort study among children (<15 years old) treated with first-line anti-tuberculosis drugs for presumed or confirmed drug-susceptible tuberculosis between 2016 and 2017. We assessed risk factors for experiencing an unsuccessful treatment outcome through multivariable logistic regression analysis. Results: In total, 1,665 children initiated tuberculosis treatment, including 916 (55.0%) identified through intensified case finding. Unsuccessful treatment outcomes were experienced by 197 (11.8%) children, comprising 27 (1.6%) deaths, 16 (1.0%) treatment failures, and 154 (9.3%) lost to follow-up. An additional 47 (2.8%) children had outcomes not evaluable. In multivariable analysis, children 0–4 years old (OR: 1.80, 95% CI: 1.07–3.04), males (OR: 1.48, 95% CI: 1.04, 2.11), and those with bacteriologic confirmation of disease (OR: 3.39, 95% CI: 1.98, 5.80) had increased odds of experiencing an unsuccessful treatment outcome. Conclusion: Our findings suggest a need to deploy strategies to identify children earlier in the disease process and point to the need for interventions tailored for young children once treatment is initiated. [ABSTRACT FROM AUTHOR]

The role of state anxiety and state fear in placebo effects is still to be determined. We aimed to investigate the effect of fear of movement-related pain (FMRP) and contextual pain related anxiety (CPRA) on the magnitude of placebo analgesia induced by verbal suggestion. Fifty-six female participants completed a modified voluntary joystick movement paradigm (VJMP) where half participated in a predictable pain condition (PC), in which one of the joystick movements is always followed by pain and the other movement is never followed by pain, and half in an unpredictable pain condition (UC), in which pain was delivered unpredictably. By varying the level of pain predictability, FMRP and CPRA were induced in PC and UC respectively. Colour stimuli were presented at the beginning of each trail. Half of the participants were verbally informed that the green or red colour indicated less painful stimuli (experimental groups), the other half did not receive any suggestion (control groups). We measured self-reported pain intensity, expectancy of pain intensity (PC only), pain related fear and anxiety (eyeblink startle response and self-ratings) and avoidance behaviour (movement-onset latency and duration). The results indicate that the placebo effect was successfully induced in both experimental conditions. In the PC, the placebo effect was predicted by expectancy. Despite the fact that FMRP and CPRA were successfully induced, no difference was found in the magnitude of the placebo effect between PC and UC. Concluding, we did not find a divergent effect of fear and anxiety on placebo analgesia. [ABSTRACT FROM AUTHOR]

Ewing Sarcoma (ES) is characterized by recurrent translocations between EWSR1 and members of the ETS family of transcription factors. The transcriptional activity of the fusion oncoprotein is dependent on interaction with the nucleosome remodeling and deactylase (NuRD) co-repressor complex. While inhibitors of both histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1) subunits of the NuRD complex demonstrate single agent activity in preclinical models, combination strategies have not been investigated. We selected 7 clinically utilized chemotherapy agents, or active metabolites thereof, for experimentation: doxorubicin, cyclophosphamide, vincristine, etoposide and irinotecan as well as the HDAC inhibitor romidepsin and the reversible LSD1 inhibitor SP2509. All agents were tested at clinically achievable concentrations in 4 ES cell lines. All possible 2 drug combinations were then tested for potential synergy. Order of addition of second-line conventional combination therapy agents was tested with the addition of SP2509. In two drug experiments, synergy was observed with several combinations, including when SP2509 was paired with topoisomerase inhibitors or romidepsin. Addition of SP2509 after treatment with second-line combination therapy agents enhanced treatment effect. Our findings suggest promising combination treatment strategies that utilize epigenetic agents in ES. [ABSTRACT FROM AUTHOR]

Introduction: Prader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual disability, behavioral problems, and growth hormone deficiency. This study evaluated the safety and efficacy of orally administered Diazoxide Choline Controlled-Release Tablets (DCCR) in subjects with PWS. Method: This was a single-center, Phase II study and included a 10-week Open-Label Treatment Period during which subjects were dose escalated, followed by a 4-week Double-Blind, Placebo-Controlled Treatment Period. Results: Five female and eight male overweight or obese, adolescent and adult subjects with genetically-confirmed PWS with an average age of 15.5±2.9 years were enrolled in the study. There was a statistically significant reduction in hyperphagia at the end of the Open-Label Treatment Period (-4.32, n = 11, p = 0.006). The onset of effect on hyperphagia was rapid and greater reductions in hyperphagia were seen in subjects with moderate to severe Baseline hyperphagia (-5.50, n = 6, p = 0.03), in subjects treated with the highest dose (-6.25, n = 4, p = 0.08), and in subjects with moderate to severe Baseline hyperphagia treated with the highest dose (-7.83, n = 3, p = 0.09). DCCR treatment resulted in a reduction in the number of subjects displaying aggressive behaviors (-57.1%, n = 10, p = 0.01), clinically-relevant reductions in fat mass (-1.58 kg, n = 11, p = 0.02) and increases in lean body mass (2.26 kg, n = 11, p = 0.003). There was a corresponding decrease in waist circumference, and trends for improvements in lipids and insulin resistance. The most common adverse events were peripheral edema and transient increases in glucose. Many of the adverse events were common medical complications of PWS and diazoxide. Conclusion: DCCR treatment appears to address various unmet needs associated with PWS, including hyperphagia and aggressive behaviors in this proof-of-concept study. If the results were replicated in a larger scale study, DCCR may be a preferred therapeutic option for patients with PWS. [ABSTRACT FROM AUTHOR]

Background: The country of Kiribati is a small Pacific island nation which had a new case detection rate of 191 per 100,000 in 2016, and is one of the few countries yet to reach the WHO leprosy elimination goal. Chemoprophylaxis of household contacts of new cases, or to the whole population in a highly endemic areas have been found to be effective in reducing new case rates. This study investigated the potential impact of different chemoprophylaxis strategies on future cases in South Tarawa, the main population centre of Kiribati. Methodology: The microsimulation model SIMCOLEP was calibrated to simulate the South Tarawa population and past leprosy control activities, and replicate annual new cases from 1989 to 2016. The impact of six different strategies for delivering one round of single dose rifampicin (SDR) chemoprophylaxis to household contacts of new cases and/or one or three rounds of SDR to the whole population was modelled from 2017 to 2030. Principal Findings: Our model predicted that continuing the existing control program of high levels of public awareness, passive case detection, and treatment with multidrug treatment would lead to a substantial reduction in cases but this was less effective than all modelled intervention scenarios. Mass chemoprophylaxis led to a faster initial decline in cases than household contact chemoprophylaxis alone, however the decline under the latter was sustained for longer. The greatest cumulative impact was for household contact chemoprophylaxis with three rounds of mass chemoprophylaxis at one-year intervals. Conclusions: The results suggest that control of leprosy would be achieved most rapidly with a combination of intensive population-based and household chemoprophylaxis. These findings may be generalisable to other countries where crowding places social contacts as well as household contacts of cases at risk of developing leprosy. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most common cancer affecting women in Ethiopia with increasing burden, and chemotherapy treatment produces a detrimental effect on individual wellbeing. Since last few years quality of life has been the primary goal of cancer treatment, yet little research has been conducted on quality of life of breast cancer patients under chemotherapy. Objective: To determine the quality of life and associated factors among patients with breast cancer under chemotherapy at Tikur Anbessa specialized hospital, Addis Ababa, Ethiopia. Methods: Institution based cross-sectional study was conducted on 404 patients with breast cancer, who took at least one cycle of chemotherapy treatment using face to face interview at oncology unit of Tikur Anbessa specialized hospital day care center from February to April 2018. The validated Amharic version of European organization for research and treatment of cancer core 30 (EORTC QLQ-C30) and quality of life questionnaire specific to breast (QLQ-BR23) was used to measure health related quality of life. Both descriptive and inferential statistics were used. For the purpose of interpretation quality of life score was dichotomized in to two using the calculated mean score, which is 53 as a cutoff point, then, bi-variable and multivariable logistic regression was used to describe association between dependent and independent variables. Hence, patients who score above 53 for quality of life were considered to have good quality of life. Result: Of the total sample, overall response rate was 99.77%. The average quality of life score of patients with breast cancer under chemotherapy treatment was 52.98 (SD = 25.61). Majority of patients had scored poor in emotional functioning, sexual functioning, and financial difficulties. Educational status of college and above, being divorced, higher household income, higher scores of physical and social functioning were associated with significantly improved (better) quality of life. Lower scores of fatigue, insomnia, financial difficulties and systemic therapy side effects all were associated with better scores of quality of life of breast cancer patients. Whereas, patients receiving < = 2 cycles of chemotherapy had significantly lower scores of quality of life. Conclusion and recommendation: Quality of life of breast cancer patients under chemotherapy treatment is poor in comparison with the reference data and international findings. Therefore, quality of life assessment should be incorporated in patient’s treatment protocol. And financial aids may significantly improve the quality of life of breast cancer patients under chemotherapy treatment. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer is often diagnosed in advanced stages, when survival is poor. Treatment advances have been made, but are inconsistently implemented. Our purpose was to project the maximum life expectancy gains that could be achieved in women with stage IIIC epithelial ovarian cancer if the implementation of available chemotherapy regimens could be optimized. Methods: We used a microsimulation model to estimate life expectancy benefits associated with “optimized” implementation of four post-operative chemotherapy options: standard intravenous chemotherapy; intraperitoneal + intravenous chemotherapy; bevacizumab + intravenous chemotherapy; and hyperthermic intraperitoneal chemotherapy + intravenous chemotherapy. Optimized implementation was defined as follows. Patients triaged to primary cytoreductive surgery received intraperitoneal + intravenous chemotherapy if optimally or completely cytoreduced, and bevacizumab + intravenous chemotherapy if suboptimally cytoreduced. Patients triaged to neoadjuvant chemotherapy received hyperthermic intraperitoneal chemotherapy at interval cytoreductive surgery if optimally or completely cytoreduced, and standard IV chemotherapy if suboptimally cytoreduced. Life expectancy associated with optimized implementation was compared with that of current utilization practices, estimated using published literature and the National Cancer Database. Effects of model uncertainty were evaluated in sensitivity analyses. Results: Life expectancy associated with optimized implementation vs. current practice was 76.7 vs. 64.5 months (life expectancy gain = 12.2 months). Providing intraperitoneal + intravenous chemotherapy to all eligible patients was the largest driver of life expectancy gains, due to both the potential benefit conferred by intraperitoneal + intravenous chemotherapy and the proportion of eligible women who do not receive intraperitoneal + intravenous chemotherapy in current practice. Conclusion: Population-level life expectancy in stage IIIC epithelial ovarian cancer could be substantially improved through greater uptake of available chemotherapy regimens. [ABSTRACT FROM AUTHOR]

Background: Little is known about outpatient health services use following critical illness and intensive care. We examined the association of intensive care with outpatient consultations and quality of life in a population-based sample. Methods: Cross-sectional analysis of data from 6,686 participants of the Study of Health in Pomerania (SHIP), which consists of two independent population-based cohorts. Statistical modeling was done using Poisson regression, negative binomial and generalized linear models for consultations, and a fractional response model for quality of life (EQ-5D-3L index value), with results expressed as prevalence ratios (PR) or percent change (PC). Entropy balancing was used to adjust for observed confounding. Results: ICU treatment in the previous year was reported by 139 of 6,686 (2,1%) participants, and was associated with a higher probability (PR 1.05 [CI:1.03;1.07]), number (PC +58.0% [CI:22.8;103.2]) and costs (PC +64.1% [CI:32.0;103.9]) of annual outpatient consultations, as well as with a higher number of medications (PC +37.8% [CI:17.7;61.5]). Participants with ICU treatment were more likely to visit a specialist (PR 1.13 [CI:1.09; 1.16]), specifically internal medicine (PR 1.67 [CI:1.45;1.92]), surgery (PR 2.42 [CI:1.92;3.05]), psychiatry (PR 2.25 [CI:1.30;3.90]), and orthopedics (PR 1.54 [CI:1.11;2.14]). There was no significant effect regarding general practitioner consultations. ICU treatment was also associated with lower health-related quality of life (EQ-5D index value: PC -13.7% [CI:-27.0;-0.3]). Furthermore, quality of life was inversely associated with outpatient consultations in the previous month, more so for participants with ICU treatment. Conclusions: Our findings suggest that ICU treatment is associated with an increased utilization of outpatient specialist services, higher medication intake, and impaired quality of life. [ABSTRACT FROM AUTHOR]

Metronomic chemotherapy using the 5-FU prodrug uracil-tegafur (UFT) and cyclophosphamide (CTX) was previously shown to only modestly delay primary tumor growth, but nevertheless markedly suppressed the development of micro-metastasis in an orthotopic breast cancer xenograft model, using the metastatic variant of the MDA-MB-231 cell line, 231/LM2-4. Furthermore, a remarkable prolongation of survival, with no toxicity, was observed in a model of postsurgical advanced metastatic disease. A question that has remained unanswered is the seemingly selective anti-metastatic mechanisms of action responsible for this treatment. We assessed the in vivo effect of metronomic UFT, CTX or their combination, on vascular density, collagen deposition and c-Met (cell mediators or modulators of tumor cell invasion or dissemination) via histochemistry/immunohistochemistry of primary tumor sections. We also assessed the effect of continuous exposure to low and non-toxic doses of active drug metabolites 5-fluorouracil (5-FU), 4-hydroperoxycyclophosphamide (4-HC) or their combination, on 231/LM2-4 cell invasiveness in vitro. In the in vivo studies, a significant reduction in vascular density and p-Met[Y1003] levels was associated with UFT+CTX treatment. All treatments reduced intratumoral collagen deposition. In the in vitro studies, a significant reduction of collagen IV invasion by all treatments was observed. The 3D structures formed by 231/LM2-4 on Matrigel showed a predominantly Mass phenotype under treated conditions and Stellate phenotype in untreated cultures. Taken together, the results suggest the low-dose metronomic chemotherapy regimens tested can suppress several mediators of tumor invasiveness highlighting a new perspective for the anti-metastatic efficacy of metronomic chemotherapy. [ABSTRACT FROM AUTHOR]

Objective: Healthcare workers (HCWs) are one of the target groups for systematic testing and treatment of latent tuberculosis infection (LTBI) in a setting of low TB incidence. We performed this study to describe the testing of HCWs for LTBI and analyse the acceptance and completion of treatment of LTBI. Methods: This retrospective cohort study was conducted in four university-affiliated hospitals between January 1 and December 31, 2018. HCWs with positive interferon-gamma release assay (IGRA) during LTBI screening were analysed. We assessed the acceptance and completion of LTBI treatment. Results: Overall, 893 HCWs were IGRA positive. Among them, 609 HCWs visited the clinic for evaluation of LTBI. Of 609 HCWs who were evaluated, 302 (49.6%) were offered treatment for LTBI. The proportion of acceptance for treatment was 64.5% (195 of 302 HCWs). The treatment course was completed by 143 of 195 HCWs (73.3%). Three months of isoniazid and rifampin (3HR) was used in 137 HCWs (70.3%) and 4 months of rifampin (4R) in 58 (29.7%). 72 HCWs (36.9%) experienced at least one adverse drug events, but there was no different characteristics between completer and non-completer. Conclusion: The acceptance and completion of LTBI treatment were unsatisfactory. Subjective perspective regarding obstacles to treatment of LTBI needs to be explored to increase compliance to LTBI treatment. [ABSTRACT FROM AUTHOR]

Purpose: Triple negative breast cancer (TNBC) patients frequently receive neoadjuvant chemotherapy (NAC). Only 50% will achieve pathological complete response (pCR). In this retrospective study, we evaluated TNBC outcomes with NAC vs. AC. Methods: Patients with stages II and III TNBC treated with NAC or AC between 2010 and 2013 were identified from the National Cancer Database. Baseline characteristics were compared with χ2 and two sample t tests. Kaplan-Meier survival analyses were computed in patients treated with NAC or AC, and log-rank tests used to examine differences. Unadjusted analyses of trends in proportions over time were performed using Cochran–Armitage tests. Log-binomial models were applied to estimate relative risks of non-pCR following NAC. Results: Of 19,151 patients, 5,621 (29.4%) received NAC, 13,530 (70.6%) received AC. NAC treated patients had worse OS compared to AC treated patients (73.4% vs. 76.8%; p<0.0001). pCR rate following NAC was 47.4%, and was associated with improved 5 year OS compared to non-pCR (86.2% vs. 62.3%; p<0.0001). In patients who received NAC, age, black race, clinical stage, diagnosis year, and Charlson-Deyo comorbidity score predicted non-pCR status. Use of NAC increased over the study period from 2010 to 2013 (27.8% - 31.2%; p = 0.0002). Conclusions: NAC may be inferior to AC in TNBC, likely related to the high frequency of non-pCR following NAC. It is unclear if removing the primary tumor prior to chemotherapy will have a beneficial biologic impact on therapeutic efficacy. These data should be considered hypothesis-generating as it is possible that the findings are due to selection bias, as physicians may use NAC for TNBC patients with more advanced local disease. Although, NAC still has a role in TNBC, developing biomarkers to identify patients likely to achieve pCR and benefit from NAC is an urgent need. [ABSTRACT FROM AUTHOR]

Objectives: This systematic review aimed to evaluate the therapeutic effects and safety of Chinese herbal medicine (CHM) formulae for managing menopausal hot flushes (MHF). Methods: Seven English and Chinese databases were searched for studies from respective inceptions to February 2019. Randomized controlled trials investigating the clinical effects and safety of CHM formulae on MHF were considered for inclusion. The outcomes of subjective feelings (MHF and quality of life), objective changes (hormones and peripheral blood flow) and safety were analyzed. The most frequently prescribed formulae and herbs were summarized. Results: Nineteen randomized clinical trials involving 2469 patients were included. When compared to menopausal hormone therapy, CHM had similar effects to menopausal hormone therapy on total effectiveness rate (OR 1.41, 95% CI 0.84 to 2.35) and total Kupperman index (KI) score (SMD -0.13, 95% CI -0.61 to 0.36), and could significantly reduce vasomotor symptom score (MD -0.43, 95% CI -0.55 to -0.31) and upper-body peripheral blood flow (MD -3.56, 95% CI -5.14 to -1.98 under the jaw, MD -7.10, 95% CI -11.01 to -3.19 in the fingertip). When compared to placebo, CHM could reduce MHF severity (MD -0.70, 95% CI-1.00 to -0.40) and improve total KI score (MD -12.61, 95% CI -15.21 to -10.01). However, no statistically significant changes to hormone levels were detected. Most commonly seen adverse events were mild gastrointestinal tract reactions. The most popularly studied formula was Kun Tai capsule and the most frequently prescribed herb was Bai shao (Paeoniae Radix Alba, Paeonia lactiflora Pall.). More than 50% included studies had low risks of bias in the domains of selection, performance, attrition and reporting. Conclusions: This review indicated that CHM formulae were safe to be applied in MHF females and able to improve MHF-related symptom scores as well as the peripheral blood flow. Further studies should focus on specific formulae. [ABSTRACT FROM AUTHOR]

Antenatal corticosteroids (ACS) are standard of care for women at risk of preterm delivery, although choice of drug, dose or route have not been systematically evaluated. Further, ACS are infrequently used in low resource environments where most of the mortality from prematurity occurs. We report proof of principle experiments to test betamethasone-phosphate (Beta-P) or dexamethasone-phosphate (Dex-P) given orally in comparison to the clinical treatment with the intramuscular combination drug beta-phosphate plus beta-acetate in a Rhesus Macaque model. First, we performed pharmacokinetic studies in non-pregnant monkeys to compare blood levels of the steroids using oral dosing with Beta-P, Dex-P and an effective maternal intramuscular dose of the beta-acetate component of the clinical treatment. We then evaluated maternal and fetal blood steroid levels with limited fetal sampling under ultrasound guidance in pregnant macaques. We found that oral Beta is more slowly cleared from plasma than oral Dex. The blood levels of both drugs were lower in maternal plasma of pregnant than in non-pregnant macaques. Using the pharmacokinetic data, we treated groups of 6–8 pregnant monkeys with oral Beta-P, oral Dex-P, or the maternal intramuscular clinical treatment and saline controls and measured pressure-volume curves to assess corticosteroid effects on lung maturation at 5d. Oral Beta-P improved the pressure-volume curves similarly to the clinical treatment. Oral Dex-P gave more variable and nonsignificant responses. We then compared gene expression in the fetal lung, liver and hippocampus between oral Beta-P and the clinical treatment by RNA-sequencing. The transcriptomes were largely similar with small gene expression differences in the lung and liver, and no differences in the hippocampus between the groups. As proof of principle, ACS therapy can be effective using inexpensive and widely available oral drugs. Clinical dosing strategies must carefully consider the pharmacokinetics of oral Beta-P or Dex-P to minimize fetal exposure while achieving the desired treatment responses. [ABSTRACT FROM AUTHOR]

Objective: Previous reports have highlighted the suboptimal utilization and prescription of statin therapy among patients with type 2 diabetes mellitus (T2DM) in the Malaysian clinical practice. This study aims to test the impact of a pharmacist-led academic detailing program on improving the overall statin therapy prescribing in Malaysian hospital and primary care settings. Methods: As a quasi-experimental design with a control group and pre-tests., we examined 1,598 medical records of T2DM subjects in six healthcare facilities in the state of Pahang, Malaysia. In all study sites, there was a pre and post-intervention assessment of the percentage of appropriate statin therapy prescribing that complied with the clinical guidelines with no potential safety issues. The intervention was an academic detailing program offered to the health care providers in three study sites, while the other three sites served as the control group. A comparison of the overall percentage of appropriate statin therapy prescribing before and after the academic detailing was performed in all intervention and control sites. Results: Overall, 797 medical records were examined in the pre-intervention phase, and 801 records were evaluated in the post-intervention phase. The academic detailing program was associated with a statistically significant difference in the proportion of appropriate statin therapy prescribing between the post-intervention phase compared to the pre-intervention phase (n = 246, 61.7% versus n = 188, 47.1%), p = 0.001. Whereas, the appropriate statin therapy prescribing in the control study sites experienced a modest change from 53.8% (214/398) to 56.7% (228/402), p = 0.220. The academic detailing showed significant increases in the proportions of appropriate statin therapy prescribing in both hospital and primary care settings. Conclusions: The academic detailing program was found to be significantly associated with a positive impact on the overall statin therapy prescribing among patients with T2DM in Malaysian hospital and primary care settings. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is one of the most common malignancies among women. However, there remains no consensus in current literature on the incidence of autoimmune diseases among breast cancer patients. The purpose of this study was to evaluate the risks of major autoimmune diseases (MAD) including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome (SS) and dermatomyositis (DMtis)/polymyositis (PM) in female breast cancer patients. Methods: Using the Taiwanese National Health Insurance Research Database (NHIRD) records from 2003 to 2013, we identified newly-diagnosed female breast cancer patients and randomly selected females without breast cancer in the period 2007 to 2013 into a control group. We matched the two cohorts using a 1:4 ratio based on age, and the year of index date for comparison of the risk of major autoimmune diseases. We estimated and compared the relative risks of autoimmune diseases in female breast cancer patients and females without breast cancer. Results: A total of 54,311 females with breast cancer and 217,244 matched females without breast cancer were included in this study. For SLE, the incidence rates were 2.3 (breast cancer group) vs. 10.0 (control group) per 100,000 women years; for RA rates were 19.3 (breast cancer group) vs. 42.7 (control group) per 100,000 women years; and for SS rates were 20.5 (breast cancer group) vs. 38.2 (control group) per 100,000 women years. After adjusting for potential confounders, the hazard ratios (95% confidence intervals) for female breast cancer patients vs. control group were 0.04 (0.01–0.24) for SLE; 0.03 (0.02–0.04) for RA; and 0.21 (0.09–0.48) for SS. Conclusion: Female breast cancer patients had lower risks of SLE, RA and SS when compared to female individuals without breast cancer. However, there was no significant difference in the risk of developing DMtis/PM between both groups. [ABSTRACT FROM AUTHOR]