The pharmacokinetics (PK) of RO7049389, a new hepatitis B virus (HBV) core protein allosteric modulator of class I, and of its active metabolite M5 were studied in fasted and fed conditions after single and multiple once-a-day and twice-a-day doses in healthy subjects and patients with HBV. The nonlinearity of the pharmacokinetics, the large variability, the small sample size per dose arms, the higher plasma exposure in Asians, and the heterogeneity in patient baseline characteristics seen in phase I studies made the ethnic sensitivity assessment and the selection of the recommended phase II dose difficult. A population PK model, simultaneously modeling RO7049389 and M5, was developed to characterize the complex PK, quantify ethnicity (i.e., Asian vs. non-Asian) and gender effects on the PK of RO7049389 and M5, and infer the quantity of RO7049389 in liver relative to plasma. Exposures in the liver are of particular importance for dose selection since the liver is the site of action of the compound. The model described and reproduced the population PK profiles as well as the between-subject variability of RO7049389 and its metabolite. It could show that the PK is similar between healthy subjects and in HBV patients, once the ethnicity and gender effects are accounted for. The model predicts that, despite a large difference in the plasma exposure of RO7049389 between Asians and non-Asians, the exposure in the liver is comparable, allowing the use of the same dose to treat Asian and non-Asian patients. This model provides a valuable basis to develop this new anti-HBV drug and to define optimal dosing.
  The aims of the study were to estimate the frequency of epiphora and to identify factors associated with epiphora after orbital-sparing maxillectomy via modified Weber-Ferguson incision with lower blepharoplasty (OSOSM-MWFILB).
 
  We performed a retrospective cohort study enrolling a sample derived from the patient population undergoing OSM-MWFILB over a 7-year period. The predictor variables were grouped into demographic, related health status, anatomic, tumor-specific, and therapeutic categories. The primary outcome variable was the presence of postmaxillectomy epiphora (PME). Descriptive, univariate, and multivariate regression mixed-effect models were computed.
 
  The study sample was composed of 134 patients (46.3% females; 71.6% squamous cell carcinomas) with a mean age of 64.7 ± 12.2 years. There were 23 (17.2%) PME events, which were significantly associated with eight variables male gender, poor general health (ASA III-IV), large vertical defect (Brown and Shaw's class III-IV), squamous cell carcinoma tumor type, big tumor size (T3-4), cervical lymph node metastasis (N1-2), long operating time > 3 h, and adjuvant radio(chemo)therapy in both univariate mixed regression and multivariate Cox hazards analyses. Healing of PME in irradiated patients was significantly delayed.
 
  Ophthalmologic consequences in patients undergoing OSM-MWFILB require particular attention, especially in case of advanced tumors, multiple comorbidities, or long surgery with postoperative radio(chemo)therapy.  https://www.selleckchem.com/products/evobrutinib.html  This emphasizes the importance of appropriate cooperation between the surgeons and ophthalmic colleagues.
 Ophthalmologic consequences in patients undergoing OSM-MWFILB require particular attention, especially in case of advanced tumors, multiple comorbidities, or long surgery with postoperative radio(chemo)therapy. This emphasizes the importance of appropriate cooperation between the surgeons and ophthalmic colleagues.
  In patients with serious illness, use of specialist palliative care may result in improved quality of life, patient and caregiver satisfaction and advance care planning, as well as lower health care utilization. However, evidence of efficacy is limited for patients with dementia, particularly in the setting of an acute hospitalization.
 
  To determine whether implementation of hospital-based specialist palliative care was associated with differences in treatment intensity outcomes for hospitalized patients with dementia.
 
  Retrospective cohort study.
 
  Fifty-one hospitals in New York State that either did or did not implement a palliative care program between 2008 and 2014. Hospitals that consistently had a palliative care program during the study period were excluded.
 
  Hospitalized patients with dementia.
 
  The primary outcome of this study was discharge to hospice from an acute hospitalization. Secondary outcomes included hospital length of stay, use of mechanical ventilation and dialysis, and days in intementation of a specialist palliative care program was associated with an increase in discharge to hospice following acute hospitalization in patients with dementia.The value of model-based translation in drug discovery and development is now effectively being recognized in many disease areas and among various stakeholders. Such quantitative approaches are expected to facilitate the selection on which compound to prioritize for successful development, predict the human efficacious dose based on preclinical data with adequate precision, guide design, and de-risk later development stages. The importance of time-dependencies, which are typically species-dependent due to different turnover rates of biological processes, is, however, often neglected. For bacterial infections, the choice of dosing regimen is typically relying on preclinical pharmacokinetic (PK) and pharmacodynamic (PD) data, because the bacterial load and disease severity, and consequently the PK/PD relationship, cannot be quantified well on clinical data, given the low-information end points used. It is time to recognize the limitations of using time-collapsed approaches for translation (i.e., methods where targets are based on summary measures of exposure and response). Models describing the full time-course captures important quantitative information of drug distribution, bacterial growth, antibiotic killing, and resistance development, and can account for species-differences in the PK profiles driving the killing. Furthermore, with a model-based approach for translation, we can take a holistic approach in development of a joint model for in vitro, in vivo, and clinical data, as well as incorporating information on the contribution of the immune system. Such advancements are anticipated to facilitate rational decision making during various stages of drug development and in the optimization of treatment regimens for different groups of patients.