bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patterns and early evolution of organ failure in the intensive care unit and their relation to outcome
Authors: Sakr Yasser , Lobo Suzana M , Moreno Rui P , Gerlach Herwig , Ranieri V Marco , Michalopoulos Argyris , Vincent Jean-Louis ,   the SOAP Investigators
Published: November 2012

Abstract
Introduction
Recognition of patterns of organ failure may be useful in characterizing the clinical course of critically ill patients. We investigated the patterns of early changes in organ dysfunction/failure in intensive care unit (ICU) patients and their relation to outcome.

Methods
Using the database from a large prospective European study, we studied 2,933 patients who had stayed more than 48 hours in the ICU and described patterns of organ failure and their relation to outcome. Patients were divided into three groups: patients without sepsis, patients in whom sepsis was diagnosed within the first 48 hours after ICU admission, and patients in whom sepsis developed more than 48 hours after admission. Organ dysfunction was assessed by using the sequential organ failure assessment (SOFA) score.

Results
A total of 2,110 patients (72% of the study population) had organ failure at some point during their ICU stay. Patients who exhibited an improvement in organ function in the first 24 hours after admission to the ICU had lower ICU and hospital mortality rates compared with those who had unchanged or increased SOFA scores (12.4 and 18.4% versus 19.6 and 24.5%, P < 0.05, pairwise). As expected, organ failure was more common in sepsis than in nonsepsis patients. In patients with single-organ failure, in-hospital mortality was greater in sepsis than in nonsepsis patients. However, in patients with multiorgan failure, mortality rates were similar regardless of the presence of sepsis. Irrespective of the presence of sepsis, delta SOFA scores over the first 4 days in the ICU were higher in nonsurvivors than in survivors and decreased significantly over time in survivors.

Conclusions
Early changes in organ function are strongly related to outcome. In patients with single-organ failure, in-hospital mortality was higher in sepsis than in nonsepsis patients. However, in multiorgan failure, mortality rates were not influenced by the presence of sepsis.
Secondary hyperparathyroidism in HIV‐infected patients: relationship with bone remodeling and response to vitamin D supplementation
Authors: Bañon S , Del Palacio M , Pérez Elías M , Moreno A , Moreno S , Dronda F , Casado J 
Published: November 2012

Purpose of the studySecondary hyperparathyroidism (SH) is frequent in HIV‐infected patients. However, the causes and consequences are not well established. The aim of our study was to determine the relationship between parathyroid hormone (PTH), vitamin D and bone mineral density (BMD) in HIV‐infected patients, and the effect of vitamin D replacement on PTH levels.MethodsProspective study of 506 patients with at least two sequential serum determinations of PTH and 25‐hydroxyvitamin D levels. In all cases, a bone dual X‐ray absorptiometry (DEXA) was performed at inclusion. Hyperparathyroidism was defined as a PTH level above 65 pg/ml.Summary of resultsMean age was 44 yrs (24–78), and 75% were male. Mean BMI was 23.7 (17.97–33.11), and only 3% were of black race. Median nadir CD4+ was 200 cells/µL (9–499), and median time of HIV infection was 15.3 yrs (1.7–25.2). At inclusion, 488 patients (86%) were on HAART (31% TDF+PI, 44% TDF+NNRTI, 25% non‐TDF based regimen) for a median of 929.5 days (154–1969), and 40% were HCV‐coinfected. Median eGFR was 97.9 ml/min (62.14–134.08). Overall, mean serum PTH was 56.3 pg/mL (27.2–95.07). SH was observed in 27% of cases, with a marked influence of seasonality (from 44% in January to 10% in August). Mean levels of vitamin D were 17.45 ng/mL (7.6–40.78), with 16% below 10 ng/ml, 59%<20 ng/ml (deficiency), 85%<30 ng/ml (insufficiency). SH was related to vitamin D deficiency (relative risk, RR, 2.44), age (RR 1.04 per year), and a higher decrease in eGFR (RR 1.03 per ml/min), after adjustment by season, antiretroviral therapy, GFR at baseline, and HCV coinfection. DEXA scan showed 18% osteoporosis and 54% osteopenia, and there was an inverse correlation between PTH levels and T and Z score in femoral neck (r=−0.14, p<0.01), higher in those patients below 40 yrs. Vitamin D supplementation in 181 patients produced a significant decrease in serum PTH (57.2 if not treated vs 50.5 pg/ml, p=0.02, 23% continues with SH) and the only factor associated with lack of response was persistent vitamin D deficiency.ConclusionSH is relatively frequent in HIV patients, in close relation with vitamin D deficiency. It is associated with bone resorption, especially in the femoral neck. The use of vitamin D supplementation improves SH when levels above 20 ng/ml are achieved.
Bone turnover markers in HIV‐infected patients before starting antiretroviral therapy
Authors: Martín‐Morales R , Ruiz J , Nuño E , Márquez M , Santos J , Palacios R 
Published: November 2012

PurposeBone turnover markers (BTM) ‐ aminoterminal propeptide of type 1 collagen (P1NP) and C‐terminal telopeptide of type 1 collagen (β‐CTX) ‐ are related to bone density and fracture risk. A high prevalence of osteopenia/osteoporosis and hypovitaminosis D has been reported in HIV patients, however there are few data about BTM in this population. Our aim was to analyse the prevalence of elevated serum levels of BTM in HIV patients before starting antiretroviral therapy (ART), and related factors.MethodsCross‐sectional study of a series of HIV‐patients who started ART during June/11–June/12 in our hospital. Patients with presence of diseases or treatments known to affect bone metabolism were excluded. Epidemiological, clinical, and immunovirological data in addition to serum fasting levels of glucose, lipid profile, calcium, phosphate, alkaline phosphatase, 25‐hydroxyvitamin D3 (25OHD), parathyroid hormone (PTH), P1NP, and β‐CTX were collected. Definitions: hypovitaminosis D if 25OHD<30 ng/ml, vitamin D deficiency if 25OHD<20 ng/ml; elevated levels of BTM if β‐CTX (ng/ml) >0.64 (men<70 years),>0.85 (men >70 years),>0.58 (pre‐menopause women), >0.99 (post‐menopause women), or P1NP (ng/mL)>69.4 (men <60 years), >71.1 (men>60 years), >55.7 (pre‐menopause women), >61.2 (post‐menopause women).Results47 patients were included, 91.5% men, median age 37.1 years (30.0–44.3), and 93.6% sexual transmission of HIV (34 HMX, 10 HTX). Median time since the diagnosis of HIV was 3.4 months (1.4–31.7); there were 7 (14.9%) Aids cases, median CD4 count was 277/mm3 (155–433), and HIV‐VL 4.8 log10 (4.1–5.2). Median serum 25OHD was 29 µg/L (21.9–41.1), with a prevalence of hypovitaminosis of 52.2%, and deficiency of 17.4%. PTH was in range in all cases. Median serum P1NP was 33.3 ng/mL (24.5–52.5) and β‐CTX 0.25 ng/mL (0.20–0.45); five (11.4%) patients presented high levels of BTM: 4 men, median age 37.1 years, median CD4 count 247/mm3, median HIV‐VL 5.18 log10, and one with hypovitaminosis D. Elevated BTM were related with no clinical, analytical, immunovirological parameters nor with serum levels of 25OHD nor PTH.ConclusionsThe prevalence of elevated BTM was high in this series of HIV‐patients, mostly young men, with short time of HIV infection and with no immunovirologic control. BTM were related with no clinical nor analytical data.
Lack of correlation between UGT1A1*6, *28 genotypes, and plasma raltegravir concentrations in Japanese HIV‐1‐infected patients
Authors: Takahashi M , Hirano A , Oishi Y , Sato M , Yoshino M , Ikemura K , Shibata M , Fukushima N , Amioka K , Nomura T , Yokomaku Y , Sugiura W 
Published: November 2012

BackgroundRaltegravir is metabolized by glucuronidation via UGT1A1. Among the genetic polymorphisms of UGT1A1, the *6, *27 and *28 alleles are associated with reduced levels of UGT1A1. In particular, the *28 allele accounts for most of the UGT1A1 polymorphisms, and the level of UGT1A1 activity has been the focus of most studies. On the other hand, among Asians, the *6 and *27 alleles are more commonly found in comparison with white populations. In this study, we aimed to clarify the contribution of UGT1A1 polymorphisms (*6, *27) to plasma raltegravir concentrations in Japanese HIV‐1‐infected patients.Materials & MethodsWe analyzed the presence of genotypic variants (*6, *27 and *28) among the 74 patients recruited at the National Hospital Organization Nagoya Medical Center. Genotyping of *6 and *27 in UGT1A1 was performed using the TaqMan drug metabolism genotyping assay. Genotyping of *28 in UGT1A1 was performed using the primers described by Ehmer et al. Plasma raltegravir concentrations were determined by a LC‐MS method.ResultsAmong the 74 patients, the UGT1A1 genotype in 3 patients (two male, one female) was *6 homozygote. Heterozygous variants were found in 20 patients for *6, and in 14 patients for *28, while all of the patients were found to carry wild‐type sequences at the position corresponding to the *27 allele. The male *6 homozygote patient had modestly higher plasma raltegravir concentration (0.53 µg/ml) than other patients who were wild type (0.12 µg/ml) or heterozygous (0.16 µg/ml) for the *6 polymorphism. The other two UGT1A1*6 homozygote patients had a lower plasma raltegravir concentration (0.03 and 0.05 µg/ml). On the other hand, plasma raltegravir concentrations were 0.12 µg/ml (*6−/− *28−/−; n=37), 0.11 µg/ml (*6−/− *28−/+; n=14), 0.16 µg/ml (*6−/+ *28−/−; n=20). There were no statistically significant differences in the plasma raltegravir concentrations between patients carrying wild‐type alleles and those heterozygous for *6 or *28.ConclusionsPatients heterozygous for the *6 or *28 allele did not display significantly different plasma raltegravir concentrations compared to patients homozygous for the respective wild‐type allele. In this study, we showed that heterozygosity for the reduced‐function *6 and *28 alleles had no significant effect on plasma raltegravir concentrations in Japanese HIV‐1‐infected patients.
Use of antacid preparations with HAART
Authors: Vekeria S , Nelson M 
Published: November 2012

BackgroundConcurrent prescription and consumption of antacid and ulcer healing preparations can affect the absorption of some antiretrovirals (ARV) due to increases in intra‐gastric pH and should therefore be avoided in drugs dependent on gastric pH for absorption.MethodsQuestionnaires were given to consecutive consenting patients presenting to outpatient pharmacy who were receiving antiretroviral therapy (ART) which consisted of either atazanavir (TAZ), darunavir (DRV) or efavirenz (EFV) for greater than 1 year. All patients receiving TAZ are routinely advised on the need for caution with co‐administration of antacid preparations when they commence the drug. Information was gathered on the awareness of potential interactions between ARVs and antacid/ulcer healing medication and the use of such preparations over the past year. Viral load (VL) data was observed for each patient and any VL blips in the preceding year recorded.ResultsA total of 215 patients were questioned, of whom 30% were aware of interactions between ART and antacids/ulcer healing medication; 38% of patients receiving TAZ, 30% on DRV and 25% and on EFV were aware of the drug interaction. 62% of individuals receiving TAZ were therefore unaware of the need not to receive antacid preparations with this drug. 30% (n=66) of patients had either been prescribed or bought antacid/ulcer healing medication in the previous year. 16 out of the 215 patients were recorded as having at least one VL blip in the last year; 9 on TAZ, 6 on DRV and 1 on EFV. 7 of these patients had either bought or been prescribed antacids in the previous year. Four of the patients with viral blips on TAZ had taken antacid preparations.

TAZ
DRV
EFV

n
63
53
99

Aware of interactions with ART
24
16
25

Prescribed PPI/antacid
5
13
9

Bought PPI/antacid
15
15
19

ConclusionThe majority of patients are unaware of potential interactions between ARVs and antacids. However, few patients developed a positive viral load during the period studied. Patients receiving TAZ were not more aware of the potential drug interaction than those receiving other agents. It is essential that information is given to patients at each clinic visit to reinforce interactions between antacids and HAART.
No change of plasma darunavir concentrations by switching from ritonavir soft capsule to tablet
Authors: Shibata M , Takahashi M , Fukushima N , Yamaguchi F , Nomura T , Yokomaku Y , Sugiura W 
Published: November 2012

BackgroundDarunavir, a second‐generation protease inihibitor, is used with a low boosting dose of ritonavir to improve its clinical efficacy. The boosting dose of ritonavir acts as an inhibitor of CYP3A4, thereby increasing darunavir bioavailability. Recently, ritonavir tablet has been on sale in place of soft capsule. However, pharmacokinetic study of darunavir by changing ritonavir form is still not clear. In this study, we aimed to compare with plasma darunavir concentrations by switching ritinavir soft capsule to tablet in Japanese HIV‐1 infected patients.MethodsWe analyzed 34 Japanese HIV‐1 infected patients (32 males: 2 females) recruited at the National Hospital Organization Nagoya Medical Center. All patients had been administered with 800/100 mg darunavir/ritonavir once daily in combination with other antiretrovirals. Plasma darunavir concentrations were determined by an HPLC method. A pared t‐test was used to compare with their concentrations by switching from ritonavir soft capsule to tablet.ResultsThe mean of age, body weight, and duration of antiretroviral therapy for 34 patients were 41.9 (range: 24–62) years, 66.3 (range: 51.4–90.0) kg, and 436 (range: 182–739) days, respectively. The mean±SD darunavir concentration was 3.44±1.78 µg/ml when ritonavir soft capsule was co‐administered. After switching to ritonavir tablet, the mean±SD darunavir concentration was 3.30±2.02 µg/ml. Statistical difference was not found in plasma trough darunavir concentration between ritonavir soft capsule and tablet (P=0.826). On the other hand, the mean of viral load was 78 copies/ml when ritonavir soft capsule was administered. After switching to ritonavir tablet, the mean viral load was 33 copies/ml.ConclusionRecruited all patients have been sustained an ndetectable viral load (less than 40 copies/ml) after switching to ritonavir tablet. In this study, switching to ritonavir tablet had no significant difference on plasma darunavir concentrations in Japanese HIV‐1 infected patients.
Budget impact analysis of switch to darunavir/ritonavir monotherapy in Greece
Authors: Lazanas M , Hill A , Sawyer A , Paparouni K 
Published: November 2012

BackgroundIn virologically suppressed patients, simplifying to darunavir/ ritonavir (DRV/r) monotherapy maintains HIV RNA suppression and could lower treatment costs. Monotherapy is mentioned as an alternative treatment option in the Greek therapeutic guidelines (posted in the Greek Health Authority website), even though it is not included in the label of darunavir or any other PI.MethodsIn the MONET trial 256 patients with HIV RNA<50 copies/mL and no history of virological failure on HAART were switched to DRV/r 800/100 mg once daily, either as monotherapy (n=127) or with 2NRTI (n=129). The three‐year analysis of the MONET trial was used to calculate the overall nationwide cost of switching to DRV/r monotherapy in Greek patients. We used a ‘switch included’ analysis at Week 144 to account for additional antiretrovirals taken after initial treatment failure. Published Greek hospital prices of antiretrovirals were used in this analysis. Data from a local expert panel were used to estimate the number of patients currently receiving NNRTI versus PI‐based treatment in Greece, and the number of patients eligible for DRV/r monotherapy.ResultsIn the ITT switch included analysis, HIV RNA<50 copies/mL by Week 144 was 86.1% versus 84.3% in the DRV/r monotherapy and control arms. No patients developed resistance to DRV as measured by virtual phenotype. Before the trial, the mean annual cost of antiretrovirals was €5,625 for patients on NNRTI‐based HAART, and €6,935 for patients on PI‐based HAART. The mean per‐patient cost in the monotherapy arm was €4,514 in the MONET trial (including the cost of intensification with NRTIs where needed): this annual cost of antiretrovirals was €1,111 lower (20%) than NNRTI‐based treatment, and €2,421 (35%) lower than PI‐based treatment taken before the trial, respectively. According to the local expert panel feedback 5,230 people are treated with antiretrovirals in Greece (40% NNRTI‐based, 60% PI‐based) and 20% of patients (n=1,046) are eligible for PI monotherapy. Based on the MONET results, a switch to DRV/r monotherapy in 20% of patients could reduce the three‐year cost of antiretroviral treatment for these patients, from €20.11 million to €14.26 million.ConclusionsBased on the MONET trial results, if the 1,046 eligible patients were to switch to PI monotherapy the lower cost of DRV/r monotherapy versus triple therapy in Greece would allow a potential saving of up to €5.85 million over three years.
Costs of Drug Development and Research and Development Intensity in the US, 2000-2018
Authors: Sertkaya Aylin , Beleche Trinidad , Jessup Amber , Sommers Benjamin D. 
Published: June 2024

ImportanceUnderstanding the cost of drug development can help inform the development of policies to reduce costs, encourage innovation, and improve patient access to drugs.ObjectiveTo estimate the cost of drug development by therapeutic class and trends in pharmaceutical research and development (R&amp;amp;D) intensity over time.Design, Setting, and ParticipantsIn this economic evaluation study, an analytical model of drug development constructed using public and proprietary sources that collectively cover data from 2000 to 2018 was used to estimate the cost of bringing a drug to market, overall and for specific therapeutic classes. The analysis for the study was completed in October 2020.Main Outcomes and MeasuresThree measures of development cost from nonclinical through postmarketing stages were estimated: mean out-of-pocket cost or cash outlay, mean expected cost, and mean expected capitalized cost. Pharmaceutical R&amp;amp;D intensity, defined as the ratio of R&amp;amp;D spending to total sales, from 2008 to 2019, based on the time frame for available data, was also analyzed.ResultsThe estimated mean cost of developing a new drug was approximately $172.7 million (2018 dollars) (range, $72.5 million for genitourinary to $297.2 million for pain and anesthesia), inclusive of postmarketing studies. The cost increased to $515.8 million when cost of failures was included. When the costs of failures and capital were included, the mean expected capitalized cost of drug development increased to $879.3 million (range, $378.7 million for anti-infectives to $1756.2 million for pain and anesthesia); results varied widely by therapeutic class. The pharmaceutical industry as a whole experienced a decline of 15.6% in sales but increased R&amp;amp;D intensity from 11.9% to 17.7% from 2008 to 2019. By contrast, R&amp;amp;D intensity of large pharmaceutical companies increased from 16.6% to 19.3%, whereas sales increased by 10.0% (from $380.0 to $418.0 billion) over the same 2008 to 2019 period, even though the cost of drug development remained relatively stable or may have even decreased.Conclusions and RelevanceIn this economic evaluation of new drug development costs, even though the cost of drug development appears to have remained stable, R&amp;amp;D intensity of large pharmaceutical companies remained relatively unchanged, despite substantial growth in revenues during this period. These findings can inform the design of drug-related policies and their potential impacts on innovation and competition.
Rome, city of 4: Julio‐Claudian
Authors: Conlin Diane Atnally 
Published: June 2024

Abstract
Following the extensive building programs of Augustus, the Julio‐Claudians enhanced the projects of their predecessor and introduced new themes and occasionally controversial designs in Rome. Tiberius and Claudius commissioned architectural projects to bolster their legitimacy to rule through familial connections and military achievements. Claudius also sponsored civic architecture to associate his reign with the accomplishments of Julius Caesar and Marcus Agrippa. Caligula and Nero, on the other hand, reinforced their concrete claims to dynastic power while also experimenting with innovative buildings and topographical changes in the heart of the capital, most of which were deliberately dismantled by successive rulers.
Ziaelas of Bithynia
Authors: Gabelko Oleg 
Published: June 2024

Abstract

Ziaelas (?–ca. 230
bce
) after the death of his father, Nikomedes I, had to take refuge in Armenia. He came to power after the end of the civil war against his half‐brothers. His subsequent activity involved attempts to expand the area of the kingdom in various directions and fight against Attalos I of Pergamon.
Childhood Arthritis and Rheumatology Research Alliance Biologic Disease‐Modifying Antirheumatic Drug Consensus Treatment Plans for Refractory Moderately Severe Juvenile Dermatomyositis
Authors: Tarvin Stacey E. , Sherman Matthew A. , Kim Hanna , Balmuri Nayimisha , Brown Amanda G. , Chow Albert , Gewanter Harry L. , de Guzman Marietta M. , Huber Adam M. , Kim Susan , Klein‐Gitelman Marisa S , Perron Megan M. , Robinson Angela Byun , Sabbagh Sara E. , Savani Sonia , Shenoi Susan , Spitznagle Jacob , Stingl Cory , Syverson Grant , Tory Heather , Spencer Charles ,   for the Childhood Arthritis and Rheumatology Research Alliance Juvenile Dermatomyositis Workgroup
Published: June 2024

ObjectiveThe objective was to develop consensus treatment plans (CTPs) for patients with refractory moderately severe juvenile dermatomyositis (JDM) treated with biologic disease‐modifying antirheumatic drugs (bDMARDs).MethodsThe Biologics Workgroup of the Childhood Arthritis and Rheumatology Research Alliance JDM Research Committee used case‐based surveys, consensus framework, and nominal group technique to produce bDMARD CTPs for patients with refractory moderately severe JDM.ResultsFour bDMARD CTPs were proposed: tumor necrosis factor α (TNFα) inhibitor (adalimumab or infliximab), abatacept, rituximab, and tocilizumab. Each CTP has different options for dosing and/or route. Among 76 respondents, consensus was achieved for the proposed CTPs (93% [67 of 72]) as well as for patient characteristics, assessments, outcome measures, and follow‐up. By weighted average, respondents indicated that they would most likely administer rituximab, followed by abatacept, TNFα inhibitor, and tocilizumab.ConclusionCTPs for the administration of bDMARDs in refractory moderately severe JDM were developed using consensus methodology. The implementation of the bDMARD CTPs will lay the groundwork for registry‐based prospective comparative effectiveness studies.