Simeprevir plus sofosbuvir for eight or 12 weeks in treatment-naïve and treatment-experienced hepatitis C virus genotype 4 patients with or without cirrhosis.

The OSIRIS study investigated efficacy and safety of simeprevir plus sofosbuvir for eight or 12 weeks in hepatitis C virus (HCV) genotype 4-infected patients with METAVIR F0-F4 fibrosis. Sixty-three patients (33 treatment-naïve and 30 peg-interferon/ribavirin (Peg-IFN/RBV)-experienced) enrolled in a partly randomized, open-label, multicentre, phase IIa study. Patients with F0-F3 fibrosis were randomized (1:1) into two groups (A1 and A2), stratified according to treatment experience and METAVIR score, to receive either eight weeks (Group A1, n=20) or 12 weeks (Group A2, n=20) of treatment. Patients with compensated cirrhosis (METAVIR F4) received 12 weeks of treatment (Group B, n=23). Treatment comprised simeprevir 150 mg and sofosbuvir 400 mg daily. The primary efficacy endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12). Safety and tolerability were assessed throughout. Overall, 92% (95% CI: 82-97) of patients achieved SVR12; 75% (15/20) in Group A1 and 100% in groups A2 and B. Patients who did not achieve SVR12 (n=5) experienced viral relapse during the first 32 days following treatment and were all prior Peg-IFN/RBV null responders. The most commonly reported treatment-emergent adverse events (TEAEs) were asymptomatic lipase increase (14%), pruritus (14%), headache (13%) and hyperbilirubinaemia (11%). No patients discontinued due to TEAEs. In conclusion, simeprevir plus sofosbuvir for 12 weeks achieved a 100% SVR rate in HCV genotype 4-infected patients with or without compensated cirrhosis (ClinicalTrials.gov: NCT02278419). The AE and laboratory profile were favourable and consistent with previous data for simeprevir plus sofosbuvir in eight- and 12-week regimens.

The assessment of surgical and non-surgical treatment of stage II medication-related osteonecrosis of the jaw.

BACKGROUND: Non-surgical treatment has generally been recommended for stage II medication-related osteonecrosis of the jaw (MRONJ) in preference to surgery. However, non-surgical treatment is not empirically effective. The aim of this study was to evaluate whether surgical or non-surgical treatment leads to better outcomes for stage II MRONJ. MATERIAL AND METHODS: In this retrospective study, surgery was performed in a total of 28 patients while 24 patients underwent non-surgical treatment. The outcomes of both treatment approaches after 6 months were evaluated and statistically compared. In addition, risk factors for surgical and non-surgical treatments were assessed for each. RESULTS: Surgical treatment in 25 patients (89.3%) resulted in success, with failure in 3 patients (10.7%). Non-surgical treatment was successful for 8 patients (33.3%) and failed in 16 patients (66.7%). There was therefore a significant difference between surgical and non-surgical treatment outcomes (P<0.01). Regarding risk factors, in non-surgical treatment primary diseases, medications, and drug holiday had a significant effect on outcomes (P<0.01). Risk factors for surgical treatment could not be clarified. CONCLUSIONS: Surgical treatment is more effective than non-surgical treatment for stage II MRONJ, and drug holiday, primary disease, and medication constitute risk factors in non-surgical treatment.

Relationship between clinical factors and severity of esophageal candidiasis according to Kodsi's classification.

Severe Candida esophagitis (CE) may lead to development of strictures, hemorrhage, esophagotracheal fistula, and a consequent decrease in quality of life. Although the severity of CE has been classified based on macroscopic findings on endoscopy, the clinical significance remains unknown. The aim of the study was to elucidate the predictive clinical factors for endoscopic severity of CE. Patients who underwent upper endoscopy and answered questionnaires were prospectively enrolled. Smoking, alcohol, human immunodeficiency virus (HIV) infection, diabetes mellitus, chronic renal failure, liver cirrhosis, systemic steroids use, proton pump inhibitor use, H2 blocker use, and gastrointestinal (GI) symptoms were assessed on the same day of endoscopy. GI symptoms including epigastric pain, heartburn, reflux, hunger cramps, nausea, dysphagia, and odynophagia were assessed on a 7-point Likert scale. Endoscopic severity was classified as mild (Kodsi's grade I/II) or severe (grade III/IV). Of 1855 patients, 71 (3.8%) were diagnosed with CE (mild, n = 48; severe, n = 23). In the CE patients, 50.0% (24/48) in the mild group and 23.1% (6/23) in the severe group did not have any GI symptoms. In HIV-infected patients (n = 17), a significant correlation was found between endoscopic severity and declining CD4 cell count (Spearman's rho = -0.90; P < 0.01). Multivariate analysis revealed that GI symptoms (odds ratio [OR], 3.32) and HIV infection (OR, 3.81) were independently associated with severe CE. Patients in the severe group experienced more epigastric pain (P = 0.02), reflux symptoms (P = 0.04), dysphagia (P = 0.05), and odynophagia (P < 0.01) than those in the mild group. Of the GI symptoms, odynophagia was independently associated with severe CE (OR 9.62, P = 0.02). In conclusion, the prevalence of CE in adults who underwent endoscopy was 3.8%. Silent CE was found in both mild and severe cases. Endoscopic severity was associated with characteristic GI symptoms and comorbidity of HIV infection. A decline in immune function correlated with CE disease progression.

The development and initial validation of a virtual dripping sweat rate and a clothing wetness ratio for use in predictive heat strain models.

This paper applies the heat balance equation (HBE) for clothed subjects as a linear function of mean skin temperature (t sk ) by a new sweating efficiency (η sw ) and an approximation for the thermoregulatory sweat rate. The equation predicting t sk in steady state conditions was derived as the solution of the HBE and used for a predictive heat strain scale. The heat loss from the wet clothing (WCL) area was identified with a new variable of 'virtual dripping sweat rate VDSR' (S wdr ). This is a subject's un-evaporated sweat rate in dry clothing from the regional sweat rate exceeding the maximum evaporative capacity, and adds the moisture to the clothing, reducing the intrinsic clothing insulation. The S wdr allowed a mass balance analysis of the wet clothing area identified as clothing wetness (w cl ). The w cl was derived by combining the HBE at the WCL surface from which the evaporation rate and skin heat loss from WCL region are given. Experimental results on eight young male subjects wearing typical summer clothing, T-shirt and trousers verified the model for predicting t sk with WCL thermal resistance (R cl,w ) identified as 25 % of dry clothing (R cl,d ).

Prediction of mean skin temperature for use as a heat strain scale by introducing an equation for sweating efficiency.

The present paper made the heat balance equation (HBE) for nude or minimally clad subjects a linear function of mean skin temperature (t(sk)) by applying new equations for sweating efficiency (η(sw)) and thermoregulatory sweat rate (S(wR)). As the solution of the HBE, the equation predicting t(sk) was derived and used for a heat strain scale of subjects. The η(sw) was proportional to the reciprocal of S(w)/E(max) (S(w), sweat rate; E(max) maximum evaporative capacity) and the S(wR) was proportional to t(sk) with a parameter of the sweating capacity of the subject. The errors of predicted t(sk) from observations due to the approximation of η(sw) were examined based on experimental data conducted on eight young male subjects. The value of errors of t(sk) was -0.10 ± 0.42 °C (mean ± sample standard deviation (SSD)). We aim to apply the predicted t(sk) of a subject at a level of sweating capacity as a heat strain scale of a function of four environmental factors (dry- and wet-bulb temperatures, radiation, and air velocity) and three human factors (metabolic rate, sweating capacity, and clothing (≤0.2clo)).

Using indocyanine green angiography to achieve complete engraftment of pectoralis major myocutaneous flaps.

Although the pectoralis major myocutaneous (PMMC) flap is among the useful reconstructive materials following oral cancer ablation, this flap has an unstable blood circulation that could result in partial necrosis of the skin paddle. This report describes the usefulness of indocyanine green angiography (ICGA) to achieve complete engraftment of the PMMC flap. Five patients with oral cancer underwent reconstruction with a PMMC flap after cancer ablation. During the skin paddle design and flap elevation, the blood supply to the flap was assessed by ICGA. Areas of the skin paddle that showed no ICG fluorescence were excised. Consequently, prior to transfer to the recipient site, the blood supply to all flaps was confirmed with indocyanine green visible at the edge of the skin paddle, and complete engraftment was achieved without partial necrosis. Based on the results observed, ICGA would make a useful contribution to complete engraftment of the PMMC flap.

TB preventive treatment among pregnant women with HIV.

BACKGROUND: The WHO recommends TB preventive treatment (TPT) for people living with HIV, including pregnant women. Uptake of this policy recommendation in this subpopulation and country alignment with WHO guidance is unclear.METHODS: We conducted a policy review in 38 WHO high TB and TB-HIV burden countries to assess if the uptake of TPT policy among pregnant women living with HIV was in line with the WHO´s 2018 Updated and Consolidated Guidelines for Programmatic Management for LTBI. Data sources included TB national guidelines and HIV/AIDS/ART national guidelines, complemented by results from a previous survey on policy uptake held at the WHO.RESULTS: Uptake of WHO policy to provide TB preventive treatment among women with HIV accessing antenatal care was moderate: 64% (23 of 36 countries) explicitly recommended at least one clinical guideline or policy recommendation on screening, testing or treatment of LTBI among pregnant women living with HIV. There was considerable variation between countries on the stages in pregnancy that TPT should be provided. Two countries (5%) provided clinical monitoring recommendations for pregnant women.CONCLUSIONS: There is moderate uptake of TPT policy for pregnant women with HIV. Failure to provide TPT as part of antenatal or prevention of mother-to-child services is a missed opportunity for TB control.

Clinical standards for the diagnosis, treatment and prevention of TB infection.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT.METHODS: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement.RESULTS: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care.CONCLUSION: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI.

Therapeutic indications for sinonasal topical steroid treatment and its effects on eosinophilic chronic rhinosinusitis after endoscopic sinus surgery.

OBJECTIVE: This study evaluated the post-operative indications for sinonasal topical steroid treatment using a corticosteroid (steroid)-eluting, sinus-bioabsorbable device and its effects in patients with eosinophilic chronic rhinosinusitis. METHOD: Post-operative courses were investigated in two groups: group A with patients who underwent sinonasal topical steroid treatment, and group B with control patients who did not. RESULTS: Group A was significantly younger than group B (p < 0.01), and the pre-operative computed tomography score was significantly higher in group A than in group B (p < 0.05). In the post-operative stage, the nasal symptoms questionnaire component of olfactory loss and the post-operative endoscopic appearance score were significantly worse in group A than in group B (p < 0.01). CONCLUSION: These data suggest that younger age, more severe rhinosinusitis and post-operative olfactory loss led to the need for sinonasal topical steroid treatment to prevent relapsing inflammation after functional endoscopic sinus surgery in patients with eosinophilic chronic rhinosinusitis.

Initial analysis of relationship between plasma platinum concentration and hematological adverse reaction associated with weekly chemotherapy using nedaplatin in combination with radiotherapy for cervical carcinoma.

PURPOSE: Established therapeutic guidelines for cervical carcinoma recommend concurrent chemo- and radiotherapy as standard treatment for locally advanced cervical carcinoma. Nedaplatin (CDGP) is a platinum agent developed in Japan that is less nephrotoxic than cisplatin (CDDP), but with equivalent antitumor potency. In the standard dosage regimen for cervical carcinoma, CDGP is administered once every four weeks (monthly regimen). We investigated the efficacy and safety of a new dosage regimen, in which CDGP was administered once weekly for five weeks (weekly regimen). METHODS: We measured plasma platinum concentration of patients after administration of CDGP, and analyzed the relationship between plasma platinum concentration and hematological adverse reactions such as thrombocytopenia and leucopenia. RESULTS: The relative rates of change in platelet and white blood cell counts tended to increase as the plasma concentration of platinum increased. Furthermore, the rate of change in platelet counts in relation to the area under the curve was greater for the monthly regimen as compared to weekly. On the other hand, the relative rates of change in WBC were nearly the same between the regimens. CONCLUSIONS: These findings indicate that when using chemotherapy with CDGP for a patient with a cervical carcinoma, a weekly regimen might reduce the severity of thrombocytopenia, while still exhibiting the same therapeutic efficacy as the monthly regimen.

Early detection of Niemann-pick disease type C with cataplexy and orexin levels: continuous observation with and without Miglustat.

STUDY OBJECTIVES: Niemann-Pick type C (NPC) is an autosomal recessive and congenital neurological disorder characterized by the accumulation of cholesterol and glycosphingolipids. Symptoms include hepatosplenomegaly, vertical supranuclear saccadic palsy, ataxia, dystonia, and dementia. Some cases frequently display narcolepsy-like symptoms, including cataplexy which was reported in 26% of all NPC patients and was more often recorded among late-infantile onset (50%) and juvenile onset (38%) patients. In this current study, we examined CSF orexin levels in the 10 patients of NPC with and without cataplexy, which supports previous findings. METHODS: Ten patients with NPC were included in the study (5 males and 5 females). NPC diagnosis was biochemically confirmed in all 10 patients, from which 8 patients with NPC1 gene were identified. We compared CSF orexin levels among NPC, narcoleptic and idiopathic hypersomnia patients. RESULTS: Six NPC patients with cataplexy had low or intermediate orexin levels. In 4 cases without cataplexy, their orexin levels were normal. In 5 cases with Miglustat treatment, their symptoms stabilized or improved. For cases without Miglustat treatment, their conditions worsened generally. The CSF orexin levels of NPC patients were significantly higher than those of patients with narcolepsy-cataplexy and lower than those of patients with idiopathic hypersomnia, which was considered as the control group with normal CSF orexin levels. DISCUSSION: Our study indicates that orexin level measurements can be an early alert of potential NPC. Low or intermediate orexin levels could further decrease due to reduction in the neuronal function in the orexin system, accelerating the patients' NPC pathophysiology. However with Miglustat treatment, the orexin levels stabilized or improved, along with other general symptoms. Although the circuitry is unclear, this supports that orexin system is indeed involved in narcolepsy-cataplexy in NPC patients. CONCLUSION: The NPC patients with cataplexy had low or intermediate orexin levels. In the cases without cataplexy, their orexin levels were normal. Our study suggests that orexin measurements can serve as an early alert for potential NPC; furthermore, they could be a marker of therapy monitoring during a treatment.

Screening tools to exclude active pulmonary TB in high TB burden countries: systematic review and meta-analysis.

To examine the use of symptoms, chest X-ray (CXR) abnormalities, and combinations of symptoms and CXR in excluding active pulmonary tuberculosis (TB) before treating for latent tuberculous infection (LTBI) in high TB burden countries. We updated a systematic review and meta-analysis of studies on the sensitivities, specificities, predictive values, diagnostic odds ratios and areas under the curve for index tests. The analysis was conducted using the hierarchical summary receiver operating characteristic method in R software. We included 24 publications in the systematic review and meta-analysis. 'Any CXR abnormality' had the highest sensitivity (94.1%, 95%CI 85.8-97.7) among all index tests. 'CXR abnormality suggestive of TB' had a higher specificity (92.2%, 95%CI 89.7-94.1) than 'any CXR abnormality' (86.8%, 95%CI 79.7-91.7). The sensitivity for 'any TB symptom' was 73.0% (95%CI 64.1-80.4), while 'prolonged cough' of ≥2 weeks had a specificity of 94.3% (95%CI 92.2-95.9). There was no significant difference in the sensitivity and specificity of all screening tools stratified by human immunodeficiency virus (HIV) settings, with the exception of 'CXR abnormality suggestive of TB', which had a significantly higher sensitivity in low than in high HIV prevalence settings (effect estimate 2.26, 95%CI 0.69-3.82; P = 0.002). In countries with a high TB burden, the absence of any TB symptom and any CXR abnormality can be used to exclude active pulmonary TB before initiating treatment for LTBI in household contacts aged ≥5 years of patients with bacteriologically confirmed pulmonary TB. .

Evidence of different climatic adaptation strategies in humans and non-human primates.

To understand human evolution it is critical to clarify which adaptations enabled our colonisation of novel ecological niches. For any species climate is a fundamental source of environmental stress during range expansion. Mammalian climatic adaptations include changes in size and shape reflected in skeletal dimensions and humans fit general primate ecogeographic patterns. It remains unclear however, whether there are also comparable amounts of adaptation in humans, which has implications for understanding the relative importance of biological/behavioural mechanisms in human evolution. We compare cranial variation between prehistoric human populations from throughout Japan and ecologically comparable groups of macaques. We compare amounts of intraspecific variation and covariation between cranial shape and ecological variables. Given equal rates and sufficient time for adaptation for both groups, human conservation of non-human primate adaptation should result in comparable variation and patterns of covariation in both species. In fact, we find similar amounts of intraspecific variation in both species, but no covariation between shape and climate in humans, contrasting with strong covariation in macaques. The lack of covariation in humans may suggest a disconnect in climatic adaptation strategies from other primates. We suggest this is due to the importance of human behavioural adaptations, which act as a buffer from climatic stress and were likely key to our evolutionary success.

The carboxyl third of tau is tightly bound to paired helical filaments.

To obtain definitive evidence that tau is a component of paired helical filaments (PHF) in Alzheimer's disease, we fractionated and sequenced PHF-derived peptides according to a previously described procedure. In the PHF digest, we found four independent tau peptides that were located in the carboxyl third of tau. Subsequent extensive analysis of the PHF digest did not provide any other tau peptides. The conventional PHF antiserum and a new antiserum directed toward formic acid-denatured PHF reacted with the distinct CNBr fragments of tau localized on the carboxy-terminal portion of tau by protein sequencing. From these observations, we conclude that the carboxyl third of tau is tightly bound to PHF.