bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Expression of Prolyl Endopeptidase Induced by Oxidative Stress in Nucleus Pulposus Cells Aggravates Intervertebral Disc Degeneration
Authors: Zheng Huo-Liang , Xu Wen-Ning , Chen Peng-Bo , Jiang Lei-Sheng , Zheng Xin-Feng , Jiang Sheng-Dan
Published: April 2022

A healthy microenvironment of the intervertebral disc tissue is characterized by hypoxia owing to its sparse vascular distribution. Oxidative stress plays a pivotal role in the pathological development of intervertebral disc degeneration (IVDD). We found that the expression of prolyl endopeptidase (PREP) increased in degenerative nucleus pulposus (NP) tissues. The purpose of this study was to determine whether PREP is involved in oxidative-stress-induced IVDD. Tertbutyl hydroperoxide can inhibit the expression of PREP by activating the PI3K/AKT signaling pathway at low concentrations in NP cells. Knockdown of PREP protected NP cells from apoptosis induced by oxidative stress, whereas overexpression of PREP exacerbated the apoptosis of NP cells. We also investigated the connection between the PI3K/AKT signaling pathway and PREP and found that the activation of the PI3K/AKT signaling pathway downregulated the expression of PREP by inhibiting p53. As a crucial transcription factor, p53 binds to the PREP promoter region and promotes its transcription. Overexpression of PREP also impairs protein secretion in the extracellular matrix of NP cells. Furthermore, the in vivo knockout of PREP could attenuate puncture-induced IVDD. These findings suggested that the downregulation of PREP might maintain the viability of NP cells and attenuate IVDD under oxidative stress.
Intelligent Selection Algorithm of Optimal Logistics Distribution Path Based on Supply Chain Technology
Authors: He Dan
Published: April 2022

How to realize the intelligence of logistics distribution is a hot research topic at present. How to reasonably allocate vehicles, optimize driving routes and travel time, deliver goods to customers on time at the lowest cost, and realize efficient and low-cost operation of the logistics distribution system has always been a problem in academia and industry for many years. Logistics enterprises face problems such as low efficiency of logistics operation, lack of scientific rationality of logistics resource planning, and lack of overall optimization of logistics management operation mode. These are severe tests that steel companies must accept. Under the background of logistics supply chain, the integrated service platform of logistics supply chain has become an urgent research topic. This study takes a steel enterprise as the main research background. On this basis, the two core modules of warehousing and distribution in the logistics business of iron and steel enterprises are qualitatively analyzed, the concept of business process reengineering is proposed, and the logistics supply chain of iron and steel enterprises is established. The concept of comprehensive service platform is realized through RFID technology. In addition, this study conducts a comprehensive analysis and research on the logistics distribution path optimization and vehicle scheduling problem, designs and implements a logistics vehicle scheduling management system, and then adopts the multiobjective method to solve the logistics distribution path planning problem, SMEs. Genetic algorithm and a simulation decision-making subsystem suitable for this problem are designed, which can better solve the problem of route optimization and vehicle scheduling in small-scale distribution.
A Phase Ib/II Study of the CDK4/6 Inhibitor Ribociclib in Combination with Docetaxel plus Prednisone in Metastatic Castration-Resistant Prostate Cancer
Authors: de Kouchkovsky Ivan , Rao Arpit , Carneiro Benedito A. , Zhang Li , Lewis Catriona , Phone Audrey , Small Eric J. , Friedlander Terence , Fong Lawrence , Paris Pamela L. , Ryan Charles J. , Szmulewitz Russell Z. , Aggarwal Rahul
Published: April 2022

Purpose:

Ribociclib, a CDK4/6 inhibitor, demonstrates preclinical antitumor activity in combination with taxanes. We evaluated the safety and efficacy of ribociclib plus docetaxel in a phase Ib/II study in metastatic castration-resistant prostate cancer (mCRPC).

Patients and Methods:

Patients had chemotherapy-naïve mCRPC with progression on ≥ 1 androgen receptor signaling inhibitor (ARSI). The phase II primary endpoint was 6-month radiographic progression-free survival (rPFS) rate, with an alternative hypothesis of 55% versus 35% historical control. Circulating tumor cells (CTC) were collected at baseline and genomically profiled.

Result:

Forty-three patients were enrolled (N = 30 in phase II). Two dose-limiting toxicities were observed (grade 4 neutropenia and febrile neutropenia). The recommended phase II dose (RP2D) and schedule was docetaxel 60 mg/m2 every 21 days plus ribociclib 400 mg/day on days 1–4 and 8–15 with filgrastim on days 5–7. At the RP2D, neutropenia was the most common grade ≥ 3 adverse event (37%); however, no cases of febrile neutropenia were observed. The primary endpoint was met; the 6-month rPFS rate was 65.8% [95% confidence interval (CI): 50.6%–85.5%; P = 0.005] and median rPFS was 8.1 months (95% CI, 6.0–10.0 months). Thirty-two percent of evaluable patients achieved a PSA50 response. Nonamplified MYC in baseline CTCs was associated with longer rPFS (P = 0.052).

Conclusions:

The combination of intermittent ribociclib plus every-3-weeks docetaxel demonstrated acceptable toxicity and encouraging efficacy in ARSI-pretreated mCRPC. Genomic profiling of CTCs may enrich for those most likely to derive benefit. Further evaluation in a randomized clinical trial is warranted.
Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy Presenting with Area Postrema Syndrome-Like Symptoms without Medulla Oblongata Lesions
Authors: Iwami Kosuke , Nomura Taichi , Seo Sho , Nojima Shingo , Tsuzaka Kazufumi , Kimura Akio , Shimohata Takayoshi , Yabe Ichiro
Published: April 2022

Introduction: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a recently described steroid-responsive meningoencephalomyelitis positive for cerebrospinal fluid (CSF) anti-GFAP antibody. Area postrema syndrome (APS) involves intractable hiccups, nausea, and vomiting, which is caused by medulla oblongata (MO) impairment. APS is a characteristic symptom of aquaporin-4 (AQP4) autoimmunity, and it helps to differentiate between AQP4 and GFAP autoimmunity. Conversely, although 6 cases of autoimmune GFAP astrocytopathy with APS and MO lesions have been reported, the association between GFAP autoimmunity and APS is unclear. We report the case of a patient with autoimmune GFAP astrocytopathy presenting with APS-like symptoms without MO lesions and discuss the mechanisms underlying the symptoms. Methods: CSF anti-GFAP antibody was detected using cell-based assays and immunohistochemical assays. Results: A 54-year-old Japanese man developed persistent hiccups, intermittent vomiting, fever, anorexia, and inattention. Brain magnetic resonance imaging (MRI) showed periventricular lesions with radial linear periventricular enhancement, suggesting autoimmune GFAP astrocytopathy. However, no obvious MO lesions were identified on thin-slice images. Spinal cord MRI revealed hazy lesions with patchy enhancement along the cervical and thoracic cord. CSF analysis demonstrated inflammation, with positive results for anti-GFAP antibodies. Anti-AQP4 antibodies in the serum and CSF were negative. Esophagogastroduodenoscopy revealed gastroparesis and gastroesophageal reflux disease, and vonoprazan, mosapride, and rikkunshito were effective only against persistent hiccups. Steroid therapy was initiated, allowing clinical and radiological improvements. Repeated MRIs demonstrated no obvious MO lesions. Conclusion: This report suggests that autoimmune GFAP astrocytopathy presents with APS-like symptoms without obvious MO lesions. The possible causes of hiccups were gastroparesis and cervical cord lesions. Gastroesophageal reflux disease was not considered a major cause of the hiccups. Intermittent vomiting appeared to be associated with gastroparesis, cervical cord lesions, and viral-like symptoms. Testing for anti-GFAP antibodies should be considered in patients with APS-like symptoms in the context of typical clinical-MRI features of autoimmune GFAP astrocytopathy.
Relationship Between Social Vulnerability Indicators and Trial Participant Attrition: Findings From the HYVALUE Trial
Authors: Henderson Kamal H. , Helmkamp Laura J. , Steiner John F. , Havranek Edward P. , Vupputuri Suma X. , Hanratty Rebecca , Blair Irene V. , Maertens Julie A. , Dickinson Miriam , Daugherty Stacie L.
Published: April 2022

Background:

Social vulnerability indicators are associated with health care inequities and may similarly impede ongoing participation in research studies. We evaluated the association of social vulnerability indicators and research participant attrition in a trial focused on reducing health disparities.

Methods:

Self-identified White or Black adults enrolled in the HYVALUE trial (Hypertension and VALUEs), a randomized trial testing a values-affirmation intervention on medication adherence, from February 2017 to September 2019 were included. The self-reported measures of social vulnerability indicators included: (1) Black race; (2) female gender; (3) no health insurance; (4) unemployment; (5) a high school diploma or less; and (6) financial-resource strain. Full attrition was defined as not completing at least one 3- or 6-month follow-up study visit. Log-binomial regression models adjusted for age, gender, race, medical comorbidities, and the other social vulnerability indicators to estimate the relative risk of each social vulnerability indicator with study attrition.

Results:

Among 825 participants, the mean age was 63.3 years (±11.7 years), 60% were women, 54% were Black, and 97% reported at least one social vulnerability. Overall, 21% participants had full attrition after study enrollment. After adjustment for all other social vulnerabilities, only financial-resource strain remained consistently associated with full attrition (relative risk, 1.71 [95% CI, 1.28–2.29]). In a secondary analysis of partial attrition (completed only one follow-up visit), financial-resource strain (relative risk, 1.40 [95% CI, 1.09–1.81]) and being uninsured (relative risk, 1.54 [95% CI, 1.01–2.34]) were associated with partial attrition.

Conclusions:

In a trial aimed at reducing disparities in medication adherence, participants who reported financial-resource strain had a higher risk of participant attrition independent of race or gender. Our findings suggest that efforts to retain diverse populations in clinical trials should extend beyond race and gender to consider other social vulnerability indicators.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03028597.
Stroke Proteomics: From Discovery to Diagnostic and Therapeutic Applications
Authors: Hochrainer Karin , Yang Wei
Published: April 2022

Stroke remains a leading cause of death and disability, with limited therapeutic options and suboptimal tools for diagnosis and prognosis. High throughput technologies such as proteomics generate large volumes of experimental data at once, thus providing an advanced opportunity to improve the status quo by facilitating identification of novel therapeutic targets and molecular biomarkers. Proteomics studies in animals are largely designed to decipher molecular pathways and targets altered in brain tissue after stroke, whereas studies in human patients primarily focus on biomarker discovery in biofluids and, more recently, in thrombi and extracellular vesicles. Here, we offer a comprehensive review of stroke proteomics studies conducted in both animal and human specimen and present our view on limitations, challenges, and future perspectives in the field. In addition, as a unique resource for the scientific community, we provide extensive lists of all proteins identified in proteomic studies as altered by stroke and perform postanalysis of animal data to reveal stroke-related cellular processes and pathways.
White Evangelicals, White Supremacy, and the ‘Born Again’ Identity in a Post-Trump America: A Latino Reading of John 3:1–8
Authors: Estrada Rodolfo Galvan
Published: April 2022

This essay seeks to provide a Latino rereading of the ‘born again’ identity in John 3:1–8. It argues that being ‘born again’ is not a religious identity as popularly understood in American evangelicalism but an anti-racist identity that rejects all notions of racial superiority through the negation of birthing privileges. To champion or support racist policies toward Latin American migrants (or any minoritized community) is contrary to the very identity of a ‘born again’ believer. This Latino reading explores the racial context of the historical milieu of the New Testament and reflects upon the contemporary challenges of white supremacy and white evangelicalism in a post-Trump America.
Anton August Heinrich Lichtenstein’s (1794) Catalogus Rerum Naturalium Rarissimarum, pars secunda. Facsimile edition and annotated translation
Authors: GEIGER DANIEL L.
Published: April 2022

The new species of Lichtenstein’s catalog (1794: part 2) were discussed by Geiger (2003). Here a facsimile edition and full translation of the work is given. Additional insights into select Lichtenstein species are provided. Tentative identifications include Mya papyracea Lichtenstein, 1794 as a member of Thraciidae, Helix porphyrostoma Lichtenstein, 1796 from Ambon as a member of Planorbidae and Helix australasiae Lichtenstein, 1794 from Tahiti as a Partula sp. Trochus tahitiensis Lichtenstein, 1794 is here designated as a nomen oblitum with Trochus histrio Reeve, 1861 [1842 in error] as its nomen protectum. Oliva brasiliensis Chemnitz and Murex galea Chemnitz (now Coralliophila galea) were first made available by Lichtenstein (1794), not by Schumacher (1817) and Dillwyn (1823), respectively. Olivancillaria brasiliensis (Lichtenstein, 1794) is senior synonym of O. urceus (Röding, 1798).
Implications of Participatory Budgeting on Social Justice: Some Theoretical Considerations
Authors: Choi Jung M.
Published: April 2022

Participatory budgeting (PB) is a novel way to understand the ways in which local projects are funded. Citizens engage in direct participation at every level of the project from designing, evaluating, modifying, and eventually disbursing funds. In short, PB is a fair and practical way for citizens to participate in direct democracy, rather than passive engagement through voting and waiting for elected officials to render a decision. In addition, due to its commitment to community-based philosophy, PB represents a radical move toward social justice.
A Virtual Hybrid Care Hotel Model Supports the Recovery of Post-procedural Patients with Mild to Severe Systemic Diseases
Authors: Chadha Ryan M. , Paulson Margaret R. , Avila Francisco R. , Torres-Guzman Ricardo A. , Maita Karla C. , Garcia John P. , Forte Antonio J. , Matcha Gautam V. , Pagan Ricardo J. , Maniaci Michael J.
Published: April 2022

Background

Patients with mild to severe chronic systemic disease undergoing low-risk procedures are often hospitalized for observation. The Care Hotel is a novel virtual medicine hybrid model of care that offers patients a comfortable, out of hospital environment where they can receive both in-person and virtual care after a surgery or procedure. This study aimed to analyze if virtual hybrid post-procedure care in a hotel could be both conducted on and accepted by patients, even those with moderate to severe chronic diseases.

Methods

This retrospective cohort study was conducted between July 23, 2020 and June 4, 2021 at Mayo Clinic in Florida, a 306-bed community academic hospital. We collected the sex, age, race, ethnicity, acceptance rate, ASA score, and primary procedure of patients using the Care Hotel.

Results

Out of 392 patients, 272 (69.4%) opted for care in the program. Median patient age was 61.5 years, 59.56% were males, and 86.40% were white. We found that 50.37% had an ASA score of 2 and 43.4% had an ASA score of 3. Ten different surgical specialties were able to utilize the Care Hotel for care in 47 different procedure types. Urology had the most patients (n=70, 25.7%). Post-electrophysiologic procedures were the most common procedures (n=39, 14.3%).

Conclusion

Our virtual hybrid Care Hotel program was widely accepted by patients and could care for a multitude of post-operative procedures. Additionally, this novel program can care for patients with both mild and severe systemic diseases.
An Evaluation of Pediatric Gastrocutaneous Fistula Closure Through the Punch Excision of Epithelized Tract Procedure
Authors: Stephenson Krista J. , Bonasso Patrick C. , Vasquez Isabel L. , Burford Jeffrey M. , Wyrick Deidre L. , Bhavaraju Avi , Dassinger Melvin S.
Published: April 2022

Background

Persistent gastrocutaneous fistulae frequently complicate gastrostomy tube placement. A minimally invasive technique for tract closure employing balloon catheter retraction and punch excision of the epithelized tract (PEET) was recently reported. We hypothesized the PEET technique of closure would lead to decreased complications without an increased incidence of recurrence.

Methods

We conducted a single-center retrospective cohort study evaluating children who underwent gastrocutaneous fistula (GCF) closure 1/1/2018–12/31/2021, comparing patients who underwent the PEET procedure to those repaired with layered closure. Procedure duration and outcomes were additionally compared to the 2018-2019 National Surgical Quality Improvement Program (NSQIP) Participant Use File (PUF) database.

Results

Sixty-two children underwent operative GCF closure, including 25 with PEET and 37 traditional layered closure. Procedural time was significantly decreased employing PEET (14 vs 26 minutes, P < .0001), less than half the national median by the NSQIP PUF database of 292 GCF closures (14 vs 34.5 minutes, P < .0001). Those repaired with the PEET method experienced no episodes of recurrence, surgical site infection, readmission, reoperation, or mortality within 30 days of the procedure. Conversely, in traditional closure, there was a 24.3% complication rate, including 7 surgical site infections, 1 readmission, and 2 unplanned reoperations. National procedural complication rate by NSQIP PUF was 5.5%, with a 4.8% rate of surgical site infection, .3% reoperation incidence, and .3% mortality.

Discussion

Our study suggests GCF closure employing the PEET procedure is a safe, more efficient method of tract closure than the traditional layered closure technique.
Calculating diffusion coefficients from molecular dynamics simulations for foam extrusion modelling of polypropylene with CO2, N2 and ethanol
Authors: Melzer Felix , Breuer Robert , Dahlmann Rainer , Hopmann Christian
Published: April 2022

In foaming processes, the blowing agent has a significant influence on the material behaviour and the necessary processing parameters. Low-density polypropylene foam sheets are usually produced with aliphatic hydrocarbons or alkanes as physical blowing agent. Due to the necessary safety precautions and the environmental impact, there is great interest in using alternative blowing agents such as CO2. The sole use of CO2 often leads to corrugation, open cells or surface defects on the foam sheet and therefore requires modifications to the process technology. For this reason, blowing agent mixtures based on CO2 and organic solvents are used for the production of foam sheets. For developing a process model describing the melt flow in the extrusion die and the formation of cells, specific material data like diffusion coefficients are necessary. For CO2 and N2 as sole blowing agent, experimental data exist in the literature. Since no experimental data are available for co-blowing agents such as ethanol at elevated temperatures as they occur in the foam process, these data were calculated using molecular dynamics (MD) simulations. The benefit of MD simulations lies in their ability to reduce the experimental effort and, in particular, to provide data in cases where this data is not available through experimental measurements. The calculated diffusion coefficient values are compared to experimental data from the literature and presented for CO2, N2 and ethanol in polypropylene. The calculated diffusion coefficients of CO2 and N2 are compared with literature results and agree well with them. For the ethanol molecules, the diffusion coefficient is compared relative to the both aforementioned ones considered the larger size of the ethanol molecule compared to N2 and CO2. The results of the diffusion coefficients for ethanol are reasonable compared to the values found for the other two molecules.
Forecasting of Future Medical Care Expenditure in Japan Using a System Dynamics Model
Authors: Inoue Sachie , Xu Hua , Maswana Jean-Claude , Kobayashi Makoto
Published: April 2022

Background

The aim of this study was to construct a system dynamics (SD) model to estimate the future medical care expenditure and to address the dynamic issues of health care that should be resolved. In particular, the measures for promoting the spread of generic drug (GE drug) usage in Japan and reducing cancer-related medical expenses were investigated regarding their future impact on medical finances.

Methods

The SD model was constructed from FY 2018 to FY 2050. The change in the future GE drug quantity share was analyzed by using a regression equation. The impact of the increase in medical expense for cancer and the change in the future national medical care expenditure were also estimated.

Results

The annual total medical care expenditure in FY 2050 would arrive at 58.9–64.2 trillion JPY (US$ 535.1–584.0 billion) (1.3–1.5 times higher than that in FY 2018) with different trends in age groups. The cumulative total medical care expenditure was expected to decrease by about 787.0–989.4 billion JPY (US$ 7.2–9.0 billion) if the impact of the spread of GE drug usage was considered. On the other hand, due to the continuous increase in the cancer-related medical expense, the cumulative total medical care expenditure was estimated to increase about 7554.3–11715.0 billion JPY (US$ 68.7–106.5 billion).

Conclusions

If the cancer-related medical expense continues to increase in the future, an increase of 686.4–1104.2 billion JPY (US$ 6.2–10.0 billion) in FY 2050 is expected which suggests that this disease field should be prioritized regarding the measures to maintain medical finances.
Unique Case of Congenital Langerhans Cell Histiocytosis Presenting as Intrauterine Fetal Demise
Authors: Baig Ayesha , Albrecht Steffen , Corredor Andrea Gomez , Fiset Pierre-Olivier , Chen Moy Fong
Published: April 2022

Congenital Langerhans cell histiocytosis (LCH) (formerly called Letterer–Siwe disease) is characterized by a clonal proliferation of Langerhans cells occurring in children at birth and manifests typically with multifocal cutaneous lesions, hepatosplenomegaly, lymphadenopathy, pulmonary lesions, and destructive osteolytic bone lesions. We present a case of LCH involving multiple systems high-risk organs (LCH MS-RO+), in a 32-week stillborn from a 20-year-old G2A1. The fetus was mildly hydropic and pale. Apart from maceration, the skin showed multiple targetoid lesions over the face, trunk, and limbs. There was hepatosplenomegaly and a pale brain. The placenta was large and bulky. Despite severe autolysis, histological examination showed disseminated histiocytes with multinucleated giant cells in the skin, lungs, thymus, mesenteric lymph nodes, spleen, and brain. By immunohistochemistry, the histiocytes were positive for S100, CD1a, and Langerin (CD207), confirming the diagnosis of LCH. There was extramedullary hematopoiesis in the spleen, brain, and placenta. Targeted next-generation sequencing performed on thymic DNA did not show the BRAF p.V600E variant but did show the MAP2K1 p.F53_Q58delinsL. Infants with LCH pose a diagnostic challenge due to their heterogeneous presentations. Our case is unusual in that the newborn presented with severe multiorgan involvement including brain and intrauterine death. LCH is still poorly understood requiring further genetic and molecular studies.
Virtual nexus: Female players’ emotional attachment in a role-playing video game
Authors: Wang Yichen , Hao Xiaofei
Published: April 2022

Casual gaming has become an increasingly important part of leisure in the last decade, and role-playing games (RPGs) are one of the most popular genres. RPGs prompt players to develop emotional attachments, so exploring players’ user emotions toward RPGs is of academic significance. This study applied the qualitative method to examine the development of female user emotional attachment in the RPG Onmyoji. The resulting model of developing user emotions between female players and the game and the three stages of the development are structured. The results indicate that female players can form emotional connections with the game, and they generate an emotional ‘virtual nexus’ in the process.
Frequency of Antiretroviral Drug Resistance Mutations in HIV-1 Strains from Patients Failing Triple Drug Regimens
Authors: Winters Mark A , Baxter John D , Mayers Douglas L , Wentworth Deborah N , Hoover Marie L , Neaton James D , Merigan Thomas C ,   for the Terry Beirn Community Programs for Clinical Research on AIDS
Published: April 2022

The frequency of protease and reverse transcriptase (RT) gene mutations was determined in HIV-1 strains from 153 patients entering the CPCRA 046 (GART) study who were failing triple-drug regimens consisting of one protease inhibitor (PI) and two RT inhibitors. Population-based sequence analyses showed that nearly all patients had similar RT gene mutations regardless of prior drug exposure, although the M184V mutation was significantly less prevalent in patients not recently treated with lamivudine. Whilst typical inhibitor-specific (‘signature’) protease gene mutations were found in patients failing their first PI, these mutations were significantly less likely to be found in patients exposed to two or more PIs. Protease gene mutations associated with multi-PI resistance were more likely to be observed in patients treated with more than one PI. These results suggest sequential treatment with PIs select for a relatively limited number of protease gene mutations that likely originated during early PI therapy. These protease gene mutations and a similarly limited set of RT gene mutations appear to be responsible for treatment failure in antiretroviral therapy.
The Relation between Baseline HIV Drug Resistance and Response to Antiretroviral Therapy: Re-Analysis of Retrospective and Prospective Studies Using a Standardized Data Analysis Plan
Authors: DeGruttola Victor , Dix Lynn , D'Aquila Richard , Holder Dan , Phillips Andrew , Ait-Khaled Mounir , Baxter John , Clevenbergh Philippe , Hammer Scott , Harrigan Richard , Katzenstein David , Lanier Randall , Miller Michael , Para Michael , Yerly Sabine , Zolopa Andrew , Murray Jeffrey , Patick Amy , Miller Veronica , Castillo Steven , Pedneault Louise , Mellors John
Published: April 2022

To assess the relation between resistance to antiretroviral drugs for treatment of HIV-1 infection and virological response to therapy, results from 12 different studies were re-analysed according to a standard data analysis plan. These studies included nine clinical trials and three observational cohorts. The primary end-point in our analyses was virological failure by week 24. Baseline factors that were investigated as predictors of virological failure were plasma HIV-1 RNA, the number and type of new antiretroviral drugs in the regimen, and viral susceptibility to the drugs in the regimen, determined by genotyping or phenotyping methods. These analyses confirmed the importance of both genotypic and phenotypic drug resistance as predictors of virological failure, whether these factors were analysed separately or adjusted for other baseline confounding factors. In most of the re-analysed studies, the odds of virological failure were reduced by about twofold for each additional drug in the regimen to which the patient's virus was sensitive by genotyping methods, and by about two- to threefold for each additional drug that was sensitive by phenotyping.
Additive Antiviral Effects of Lamivudine and α-Interferon in Chronic Hepatitis B Infection
Authors: Mutimer David , Dowling Damien , Cane Pat , Ratcliffe Daina , Tang Howard , O'Donnell Katharina , Shaw Jean , Elias Elwyn , Pillay Deenan
Published: April 2022

α-Interferon has limited efficacy against chronic hepatitis B virus (HBV) infection. Nucleoside analogues may confer greater benefits, however, it is likely that combination therapies will be required for effective control of this infection. We investigated the antiviral effect of lamivudine and interferon therapy in eight patients with high HBV-DNA levels. Six patients received lamivudine/interferon combination therapy followed, after a 6-month drug-free period, with lamivudine monotherapy. Mean HBV viral load (copies/ml) reduction was significantly greater after 4 months of combination therapy (4.3x103) compared to an equivalent period of lamivudine monotherapy (2.9x102) ( P=0.03). Two patients were given 6 months of lamivudine/interferon combination therapy followed immediately by lamivudine monotherapy. Cessation of interferon in these patients led to a rapid 1–2 log10 increase in HBV viral load. These findings suggest that α-interferon has a direct antiviral effect on chronic HBV infection, which may be additive to, or synergistic with lamivudine.
Adherence over 48 Weeks in An Antiretroviral Clinical Trial: Variable within Patients, Affected by Toxicities and Independently Predictive of Virological Response
Authors: Nieuwkerk Pythia , Gisolf Elisabeth , Sprangers Mirjam , Danner Sven ,   Prometheus Study Group, Gisolf EH , Reiss P , Weverling GJ , Duurvoort M , Krijger E , Brouwer E , Visser GR , Klotz A , Benschop C , Wulfert F , Danner SA , de Wolf F , Jurriaans S , Portegies P , Colebunders R , Pelgrom J , Wijnants H , de Roo A , Keersmaekers K , Vandenbruane M , van den Brande D , James T , van Wanzeele F , van der Gucht B , van der Ende ME , Nouwen J , Deenenkamp R , van der Meyden D , Koopmans PP , Brinkman K , ter Hofstede H , Zomer B , Blok WL , Ruissen C , Sprenger H , Law G , van der Meulen P , ten Veen C , Juttmann JR , van der Heul C , Santegoets R , van der Ven B , Gasthuis Kennemer , haarlem  , ten Kate RW , Schoemaker M , Kauffmann RH , Henrichs JM , Maat A , Prins E , ten Napel CH , Pogany K , Duyts T , Lansink T , Simons P , Lacor P , de Waele A , van Wijngaarden E , Lejeune M , Scholte R , Dijkman J
Published: April 2022

Objectives

To investigate adherence to antiretroviral therapy over 48 weeks, to investigate the association between adherence and treatment-related symptoms and to investigate the impact of adherence on virological response over 48 weeks among established predictors of treatment success.

Methods

One-hundred-and-sixty HIV-1 infected protease inhibitor- and stavudine-naive patients participating in a trial of ritonavir/saquinavir versus ritonavir/saquinavir/ stavudine completed an adherence questionnaire and a symptom checklist at weeks 12, 24, 36 and 48. We calculated odds ratios between experienced symptoms and non-adherence. Regression models were used to determine predictors of HIV-1 RNA below 400 copies/ml at week 48, and of the area about the change from baseline over 48 weeks (ACFB) in serum HIV-1 RNA.

Results

The percentage of patients reporting missing medication, deviation from time schedule, and dietary prescriptions at separate time-points ranged from 12 to 15%, 32 to 35% and 17 to 22%, respectively. The percentage that changed their level of adherence during 48 weeks ranged from 29% for skipping medication to 48% for deviation from time-schedule. Experienced side-effects were associated with an increased likelihood of non-adherence. Not skipping medication was an independent predictor of both having a serum HIV-1 RNA below 400 copies/ml at week 48 and the ACFB over 48 weeks in serum HIV-1 RNA.

Conclusions

Adherence was an independent predictor of virological response over 48 weeks. The level of adherence is variable within patients over time. This suggests the need for continued adherence monitoring in all patients as part of standard medical practice.
A Rational Approach to the Selection and Sequencing of Nucleoside/Nucleotide Analogues: A New Paradigm
Authors: Lange Joep
Published: April 2022

While the value of highly active antiretroviral therapy (HAART) is unquestionable, its use as a life-long therapy will require a more structured and strategic approach to the sequential use of antiretroviral agents than has previously been the case. A complex cocktail of factors influences the durability of a given regimen, but the durability of HAART requires a carefully planned approach to the selection of agents across multiple regimens from first-line onwards, based on considerations of drug cross-resistance and sequenceability at regimen failure. Despite considerable ongoing interest in sequencing protease inhibitors and even non-nucleoside reverse transcriptase inhibitors, there has been little study into the optimal sequence of nucleoside reverse transcriptase inhibitor (NRTI) drugs in consecutive regimens. Historical practice, clinical experience and force of habit have all emphasized the use of thymidine analogue-based first-line combinations and the frequent retention of a thymdine analogue at all subsequent stages until a salvage situation is reached. Emerging data clearly associates thymidine analogue-derived reverse transcriptase mutations with loss of drug susceptibility and clinical response to other members of the NRTI class, particularly when present alongside other NRTI-associated mutations. Any approach to strategic therapy across multiple treatment lines will require, as a basic tenet, that agents with the greatest potential for cross-resistance be used later in therapy rather than earlier. To this end, a move away from the universal use of the thymidine analogues in first-line therapy is likely as strategic thinking becomes more integrated into clinical management in HIV disease. However, more clinical investigation is required into both the performance of alternative first-line NRTI combinations and the individual sequenceability of NRTI drugs, in the absence of the class reductions in susceptibility conferred by accumulations of thymidine analogue mutations that are the corollary to most current definitions of ‘treatment-experienced’. Another basic tenet of strategic therapy is that while drugs with high potency in treatment-experienced individuals, and favourable cross-resistance profiles, are urgently required for the salvage of patients with limited options, constraining such agents to this niche merely cements the bad habits which led to an early salvage situation in the first place. Potent drugs with low cross-resistance should be investigated at all stages of therapy, including first-line, for their potential to provide not only individual regimen durability but also to extend the number of effective, successive treatment lines. Just as highly cross-resistant agents are best used later in therapy, poorly cross-resistant agents may provide an even greater strategic advantage in first- or second-line regimens than they do when used where little else is likely to work.
Therapy for Recurrent Respiratory Papillomatosis
Authors: Auborn Karen J
Published: April 2022

Human papillomaviruses types 6 or 11 are aetiological agents of recurrent respiratory papillomatosis, a disease characterized by benign exophytic tumours usually on the vocal cords. Surgery debulks the tumours, but these growths generally recur at regular intervals. Adjunct medical treatments, aimed at containing the virus and growth of tumours, include indole-3-carbinol or its dimer diindolylmethane, interferon, photodynamic therapy and others. Preventive and therapeutic vaccines hold promise for eliminating the virus.
Persistence of Viral HLA-DR- CD4 T-Cell Reservoir during Prolonged Treatment of HIV-1 Infection with a Five-Drug Regimen
Authors: van Rij Ronald P , van Praag Rieneke ME , Prins Jan M , Rientsma Ronald , Jurriaans Suzanne , Lange Joep MA , Schuitemaker Hanneke
Published: April 2022

During sustained suppression of plasma viraemia using a standard triple-drug regimen, replication-competent HIV-1 can still be recovered from resting memory CD4 T cells. In an attempt to accelerate the clearance of this pool of infected CD4 T cells, eight antiretroviral therapy-naive HIV-1-infected patients were treated with a five-drug regimen. While plasma HIV-1 RNA levels generally remained below the level of detection (<5 copies/ml), replication competent HIV-1 was isolated from HLA-DR- CD4 T cells from all patients on multiple occasions throughout treatment. Decay slopes of infected CD4 T cells ranged from -0.061/week (half-life=2.6 months) to +0.003/week (half-life=infinite). Virus was still detectable at the last time point analysed (80–173 weeks) in all patients. Although more intensive treatment results in improved suppression of plasma viraemia compared with standard drug regimens, it does not result in clearance of the viral reservoir in this timeframe. Strategies other than treatment with a combination of five of the currently available drugs need to be pursued in order to achieve eradication of HIV-1 from this cellular reservoir.
Hyperlactataemia in HIV-Infected Patients: The Role of NRTI-Treatment
Authors: Vrouenraets Saskia ME , Treskes Marco , Regez Rosa M , Troost Nancy , Smulders Yvo M , Weigel Hugo M , Frissen PH Jos , Brinkman Kees
Published: April 2022

Background

Long-term treatment with nucleoside reverse transcriptase inhibitors (NRTIs) can induce mitochondrial dysfunction, most severely represented by lactic acidosis. Diagnostic tests for mitochondrial dysfunction are lacking, although persistently elevated serum lactate might be a surrogate marker.

Objectives

To determine the occurrence of hyperlactataemia in HIV-infected patients on NRTI-treatment and to evaluate the possible risk factors.

Methods

Cross-sectional analysis of lactic-acid levels in asymptomatic HIV-infected patients. Hyperlactactaemia was considered mild if between 2.0–5 mmol/l, serious if >5 mmol/l and lactic acidosis was defined as lactic acid levels >5 mmol/l with bicarbonate <20 mmol/l. Possible risk factors, such as current and preceding NRTI-treatment as well as treatment with non-nucleoside reverse transcriptase inhibitors or protease inhibitors and concurrent liver disease, were analysed.

Results

Two hundred and twenty three asymptomatic HIV-infected patients were studied, including 174 patients (78%) on NRTI treatment, 12 patients (5%) treated without NRTIs and 37 patients (17%) not treated. Mild hyperlactataemia was found in 42 patients (19%), from whom 38/42 (90%) were NRTI-treated and the remaining patients (4/42, 10%) received no treatment (χ2, P<0.05). The significant risk factors for hyperlactataemia in the univariate analysis were NRTI-treatment as a group ( P=0.03) and elevated ALT ( P=0.008). In multivariate analysis NRTI use ( P=0.05) and ALT level ( P=0.03) remained a significant determinant of hyperlactataemia. Among the different individual NRTIs, a stavudine-containing ( P=0.004) and a zalcitabine-containing ( P=0.07) regimen were most notably associated with the development of hyperlactataemia, whereas for the combinations of NRTIs, such association was only found for stavudine/lamivudine ( P=0.05).

Conclusions

A correlation between hyperlactataemia and NRTI treatment was found, but the value of routine lactate measurement for individual treatment monitoring remains uncertain.
Divergent Distribution of HIV-1 Drug-Resistant Variants on and off Antiretroviral Therapy
Authors: Venturi Giulietta , Romano Laura , Carli Tiziana , Corsi Paola , Pippi Luigi , Valensin Pier E , Zazzi Maurizio
Published: April 2022

Objective

To investigate the distribution of drug-resistant HIV-1 variants in plasma RNA and peripheral blood monuclear cell (PBMC) DNA at treatment failure while on therapy and after stopping therapy.

Design

Fifty-eight patients failing their first highly active antiretroviral treatment while on therapy and 50 patients after a median of 18.6 weeks after treatment interruption following multiple treatment failures were analysed.

Methods

Paired plasma HIV-1 RNA and PBMC HIV-1 DNA were used for genotypic antiretroviral resistance testing. Drug resistance was computed by using the Stanford on-line genotype interpretation system.

Results

The extent of drug resistance was larger in plasma RNA than in PBMC DNA in the on-therapy group ( P=0.004) and in PBMC DNA than in plasma RNA in the off-therapy group ( P=0.04). Interpretation of genotype based on PBMC DNA and plasma RNA in the on-therapy and in the off-therapy group would have missed detection of resistance to one or more drugs in 21 and 22% of the patients, respectively, compared to interpretation based on the other blood compartment. In a subset of 27 patients for whom a sample before stopping therapy was available, there was a significant decrease in the number of RNA (mean 8.1 to 5.3, P=0.004), but not DNA (mean 6.8 to 5.7, P=0.143), resistance mutations following treatment interruption.

Conclusion

While plasma RNA is the material of choice for early detection of drug resistance while on therapy, analysis of PBMC DNA may additionally support and possibly improve sensitivity of resistance testing in the absence of therapy.
Single-Dose Pharmacokinetics of Enteric-Coated Didanosine in HIV-Infected Children
Authors: King Jennifer R , Nachman Sharon , Yogev Ram , Hodge Janice , Aldrovandi Grace , Damle Bharat , Smith Elizabeth , Wiznia Andrew , Acosta Edward P
Published: April 2022

Didanosine remains a cornerstone nucleoside analogue for the treatment of HIV infection. A potential problem with the buffered formulations of didanosine is the likelihood of interactions with other drugs that require an acidic pH for absorption or can be chelated by cations in the buffer. An encapsulated enteric-coated (EC) bead formulation of didanosine has been approved and is routinely used as an alternative to the chewable/dispersible buffered tablet formulation. The objective of this study was to evaluate the single-dose pharmacokinetics of didanosine EC at 240 mg/m2 in 10 HIV-infected children. Didanosine EC was administered at time 0 on an empty stomach with no other concomitant medications. Blood samples were collected at pre-dose, 0.5, 1, 2, 4, 8 and 12 h post-dose. Didanosine was measured in plasma using radioimmunoassay. Ten subjects completed the intensive pharmacokinetic evaluation; data are available for eight participants. Plasma concentrations of didanosine following EC administration were analysed using non-compartmental methods. Median (range) AUC∞, Cmax, Tmax and CL/F for didanosine following EC administration were 2385 (1291, 3966) ngxh/ml, 854 (300, 1799) ng/ml, 3.0 (1.0, 8.1) h and 3.3 (2.7–6.4) l/h/kg, respectively. Results from this study indicate that the didanosine Cmax is decreased and Tmax is prolonged, but total exposure of didanosine in plasma following didanosine EC administration appears similar to previous data collected in HIV-infected children following buffered didanosine administration.
Reduced Fitness of HIV-1 Resistant to Cxcr4 Antagonists
Authors: Armand-Ugón Mercedes , Quiñones-Mateu Miguel E , Gutiérrez Arantxa , Barretina Jordi , Blanco Julià , Schols Dominique , De Clercq Erik , Clotet Bonaventura , Esté José A
Published: April 2022

HIV-1 strains with a syncytium-inducing phenotype that use CXCR4 (X4 strains) have been associated with faster disease progression and AIDS. Antiviral agents designed to block CXCR4 may prevent the emergence of X4 HIV strains but resistant strains that maintain the X4 phenotype can be raised by sequential passage in cell cultures. We have demonstrated that a laboratory adapted strain (NL4-3) and a cloned clinical isolate (CI-1) of HIV-1 cultured in the presence of the CXCR4 antagonist, AMD3100, became resistant to the compound without a change in co-receptor use. These strains became resistant through divergence with respect to the wild-type virus. Conversely, a clinical isolate made resistant to AMD3100 switched co-receptor use from X4 to R5 through a change in diversity from the original virus population. When dual infection competition/heteroduplex tracking assays were performed, all AMD3100-resistant strains, regardless of co-receptor use showed a significantly diminished fitness compared with the wild-type virus. Single virus infections, at a similar multiplicity of infection, also indicated that the wild-type strains possess better replicative ability than their corresponding resistant strains. Thus, viral resistance development to a CXCR4 antagonist such as AMD3100 is associated with reduced viral fitness.
Persistent Brain Abnormalities in Antiretroviral-Naive HIV Patients 3 Months after Haart
Authors: Chang Linda , Ernst Thomas , Witt Mallory D , Ames Nina , Walot Irwin , Jovicich Jorge , DeSilva Menaka , Trivedi Neha , Speck Oliver , Miller Eric N
Published: April 2022

Background

Proton magnetic resonance spectroscopy (1H-MRS) and neuropsychological tests may be useful for monitoring the effectiveness of highly active antiretroviral therapy (HAART) in HIV-associated brain injury. We aimed to evaluate whether brain abnormalities will improve 3 months after HAART.

Method

Thirty-three HIV patients naive to antiretroviral medications were evaluated before and 3 months after HAART using 1H-MRS and neuropsychological tests; results were compared with those of 26 seronegative control subjects.

Results

Despite significant improvement in CD4 counts, and suppression of plasma and cerebrospinal fluid (CSF) viral loads, elevated brain metabolites (choline compounds and myoinositol in the frontal lobes) and neuropsychological tests abnormalities (including the computerized tests [CalCAP®]) persisted after 3 months of HAART. In the basal ganglia, choline and myoinositol became elevated only after treatment. No interaction effect was observed between the number of CSF-penetrating drugs (one vs two) and changes (baseline vs 3 months) in any of the brain metabolites, cognitive performance or CSF viral load.

Conclusions

The persistent brain abnormalities suggest ongoing repair or reactive inflammatory processes in the brain after 3 months of HAART. Regimens with two CSF-penetrating antiretroviral medications do not appear to be more effective than those with one CSF-penetrating drug in treating HIV brain injury at 3 months.