bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trends of Cancer Screenings, Diagnoses, and Mortalities During the COVID-19 Pandemic: Implications and Future Recommendations
Authors: Concepcion Jennifer , Yeager Matthew , Alfaro Sophie , Newsome Kevin , Ibrahim Joseph , Bilski Tracy , Elkbuli Adel 
Published: April 2022

Introduction The impact of the COVID-19 pandemic on cancer screenings and care has yet to be determined. This study aims to investigate the screening, diagnosis, and mortality rates of the top five leading causes of cancer mortality in the United States from 2019 to 2021 to determine the potential impact of the COVID-19 pandemic on cancer care. Methods A retrospective cohort study investigating the impact of the COVID-19 pandemic on screening, diagnoses, and mortality rates of the top five leading causes of cancer death (lung/bronchus, colon/rectum, pancreas, breast, and prostate), as determined by the National Institute of Health (NIH) utilizing The United States Healthcare Cost Institute and American Cancer Society databases from 2019 to 2021. Results Screenings decreased by 24.98% for colorectal cancer and 16.01% for breast cancer from 2019 to 2020. Compared to 2019, there was a .29% increase in lung/bronchus, 19.72% increase in colorectal, 1.46% increase in pancreatic, 2.89% increase in breast, and 144.50% increase in prostate cancer diagnoses in 2020 (all P < .01). There was an increase in the total number of deaths from colorectal, pancreatic, breast, and prostate cancers from 2019 to 2021. Conclusion There was a decrease in the screening rates for breast and colorectal cancer, along with an increase in the estimated incidence and mortality rate among the five leading causes of cancer deaths from 2019 to 2021. The findings suggest that the COVID-19 pandemic is associated with impaired cancer screening, diagnosis, and care, and further emphasizes the need for proactive screening and follow-up to prevent subsequent cancer morbidity and mortality.
Management Strategies of Fibrous Dysplasia Involving the Paranasal Sinus and the Adjacent Skull Base
Authors: Shi Li-li , Xiong Peng , Zhen Hong-tao 
Published: April 2022

Objective Current management of fibrous dysplasia (FD) involving the paranasal sinuses and the adjacent skull base is currently controversial. This study aims to present our experience in the management strategy of FD that involves the paranasal sinuses and the adjacent skull base. Methods Twenty three patients from 2006 to 2019 with monostotic fibrous dysplasia (MFD), polyostotic fibrous dysplasia (PFD), or McCune-Albright syndrome (MAS) involving the paranasal sinuses and the adjacent skull base were retrospectively reviewed. This study series was divided into 3 groups based on management strategies: the observation group, the surgery group, and the optic nerve decompression group. Results The observation group included 9 patients with asymptomatic MFD with stable condition during the follow-up period of 15 to 164 months. The surgery group included 10 symptomatic patients with MFD who had personalized endoscopic endonasal surgery. The symptoms of the patients were relieved after surgery. The optic nerve decompression group included 4 patients with visual loss, who underwent endonasal endoscopic optic nerve decompression (EOND) with the aid of image-guided navigation. Their vision improved after surgery. Conclusions Clinical observation and periodic computed tomography (CT) scan are adopted for asymptomatic patients. Surgery is indicated in symptomatic patients. Optic nerve decompression is recommended as soon as possible if the patient has visual loss, whereas prophylactic decompression is not recommended if the optic nerve is encroached by FD without visual loss. Navigation plays an important role in endoscopic surgery involving the paranasal sinuses and the adjacent skull base, especially in FD resection and optic nerve decompression.
Synovial Fluid Cytokine Profile at the Time of Arthroscopy Explains Intermediate-Term Functional Outcomes
Authors: Kingery Matthew T. , Adams Anngela C. , Manjunath Amit K. , Berlinberg Elyse J. , Markus Danielle H. , Strauss Eric J. 
Published: April 2022

Background: The intra-articular immune response after ligamentous, meniscal, or focal chondral knee injuries likely plays a role in intra-articular healing and the onset and progression of posttraumatic osteoarthritis. Purpose: To evaluate the association of synovial fluid cytokine concentrations measured at the time of knee arthroscopy with intermediate-term functional outcomes after knee arthroscopy based on the Lysholm score. Study Design: Cohort study; Level of evidence, 2. Methods: This was a prospective cohort study of patients undergoing arthroscopic knee surgery. Synovial fluid was aspirated from the injured knee immediately before surgical incision, and the concentrations of 10 cytokines were analyzed using immunoassay. Principal component regression was used to create a model to predict patient-reported Lysholm score at a minimum of 5 years postoperatively. Hierarchical clustering was performed to identify groups of patients with similar synovial fluid inflammatory phenotypes. Lysholm scores and cytokine concentrations were compared between clusters. Results: A total of 26 patients (mean age, 40.33 ± 16.40 years) were included in the analysis. The mean duration between surgery and follow-up was 6.69 ± 0.72 years. A model consisting of 2 principal components (PC1, PC2) explained 62.48% of the variance in the cytokine data and 52.03% of the variance in intermediate-term Lysholm score. Hierarchical clustering resulted in 3 patient clusters based on the principal components used in the regression model. Despite no baseline differences in Lysholm score, cluster 3 demonstrated significantly greater intermediate-term Lysholm score compared with cluster 2 (94.33 vs 76.09, respectively; 95% CI, 5.96-30.52; P = .006) and cluster 1 (94.33 vs 52.33, respectively; 95% CI, 24.09-59.91; P = .003). Cluster 3, when compared with the overall means, was characterized by greater PC1 value (1.01 vs 0.00, respectively; P = .030) and greater PC2 value (0.86 vs 0.00, respectively; P = .002). Conclusion: The concentrations of select synovial fluid cytokines assessed at the time of knee arthroscopy can be used to explain more than half of the variance in intermediate-term functional outcomes.
Drug Resistance Mutations during Structured Treatment Interruptions
Authors: Yerly Sabine , Fagard Catherine , Günthard Huldrych F , Hirschel Bernard , Perrin Luc ,   the Swiss HIV Cohort Study (SHCS)
Published: April 2022

Background We assessed whether treatment interruptions induce selection of mutations associated with drug resistance in the Swiss–Spanish Intermittent Treatment Trial (SSITT). Patients had been on HAART without previous failure and had undetectable viraemia for at least 6 months. Their HAART was interrupted for 2 weeks and restarted for 8 weeks. After four of these cycles, treatment was definitively interrupted at week 40. Methods Genotypic resistance testing was performed in 87/97 Swiss patients: in those failing treatment before week 40, at the time of first viral rebound >500 copies/ml off treatment and preceding failure to reach RNA <50 copies/ml after 8 weeks of re-treatment; for patients without virological failure, on the first sample with HIV-1 RNA >1000 copies/ml after week 40. Results Mutations associated with drug resistance were detected in 9/25 (36%) patients with virological failure during the first 40 weeks and in 6/59 (10%) patients after week 40. Overall, drug resistance mutations were detected in 17% of patients, all but two with the 184V/I mutation. Among the 74 patients receiving lamivudine, the M184V/I mutation was detected in 13/74 (17.6%) patients. A wild-type codon at position 184 was detected in previous samples in all b'ut two. The relative risk for virological failure was 2.55-fold higher in patients with the M184V/I mutation than in patients without detectable mutation ( P=0.007). Conclusions The M184V/I mutation is frequently selected during repeated treatment interruptions.
Intracellular Accumulation of Nelfinavir and Its Relationship to P-Glycoprotein Expression and Function in HIV-Infected Patients
Authors: Hennessy Martina , Clarke Susan , Spiers J Paul , Kelleher Dermot , Mulcahy Fiona , Hoggard Patrick , Back David , Barry Michael 
Published: April 2022

Objective To compare plasma and intracellular nelfinavir pharmacokinetics, and determine their relationship to P-glycoprotein (P-gp) expression and function in lymphocytes of HIV-infected patients. Methods A pharmacokinetic study of 12 patients receiving nelfinavir plus dual nucleoside analogue therapy. Blood samples were taken at intervals to 12 h. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation, and nelfinavir extracted from cells in the presence of 60% methanol and evaporated to dryness. Both plasma and intracellular nelfinavir samples were assayed by high performance liquid chromatography linked to mass spectrometry. P-gp expression and function were measured by flow cytometric analysis. Data were analysed by non-compartmental analysis using WinNonLin pharmacokinetic software. Results The mean intracellular nelfinavir AUC0–12 (mean ±SE) was about ninefold higher than that of plasma (264 200 ±63420 vs 29250 ±6629 ng/ml/h; P<0.001, and intracellular Cmin and C0 values for nelfinavir were five- to sixfold higher than that of plasma (Cmin: 5712 ±2156 vs 1062 ±357 ng/ml; C0: 15860 ±3662 vs 2553 ±539 ng/ml; P<0.0005). The intracellular nelfinavir Cmax was 15-fold higher than plasma (59420 ±13940 vs 3986 ±822 ng/ml; P<0.0005). There were no differences between plasma and intracellular values for Tmax, elimination half-life or mean residence time. In patients chronically treated with nelfinavir mean P-gp expression was 8.85 ±1.3 MFI, there was no correlation between Pgp expression and either intracellular AUC0–12 (r=–0.35; P=0.29) or intracellular C0 values. There was a correlation between intracellular nelfinavir concentrations and P-gp function at baseline (r=0.59; P<0.05). Basal P-gp-mediated rhodamine efflux was 61.0 ±4.2%. In the presence of ritonavir, cellular rhodamine efflux decreased to 25.6 ±5.5% ( P=0.001), representing an additional reversible efflux potential of 56.1 ±9.78%. There was a strong correlation between plasma and intracellular AUC0–12 for nelfinavir (r=0.75; P=0.011). Conclusions Nelfinavir undergoes significant intracellular accumulation within the PBMCs of HIV-infected patients, which may be in part related to its moderate ability to inhibit P-gp-mediated drug efflux. The addition of ritonavir further reduced P-gp function. Intracellular accumulation of nelfinavir correlated with P-gp function but not P-gp expression, suggesting pump activity is substrate concentration-dependant. There was a significant correlation between plasma and intracellular nelfinavir concentrations, suggesting one is a good surrogate marker of the other.
Discordant Conclusions from HIV Clinical Trials — An Evaluation of Efficacy Endpoints
Authors: Hill Andrew , DeMasi Ralph 
Published: April 2022

The three main components of long-term efficacy for a combination of antiretrovirals are: (i) the strength of the antiviral effect, (ii) toxicity profile and (iii) patient acceptability of the regimen. Intent-to-treat (ITT) analysis, where discontinuations and switches are considered failures [ITT, switch equals failure (ITT/S=F)], is a regulatory standard for analysing the efficacy of anti-retrovirals. A review of all clinical trials published in FDA product labels was conducted, including all clinical trials of boosted protease inhibitor- or nucleoside reverse transcriptase inhibitor-based highly active antiretroviral therapy in treatment-naive patients, and all clinical trials of antiretrovirals in treatment-experienced patients. Clinical trials where the results are presented in the standard ITT/S=F method were included. For randomized clinical trials in treatment-naive patients, the majority of treatment discontinuations have been either for toxicity (32%) or patient refusal of treatment (41%), with only 27% of failure endpoints for virological reasons among recent clinical trials in naive patients. Therefore, there is the potential for the results from ITT/S=F analysis to be driven by non-virological endpoints – a new treatment can be classified as ‘more efficacious’ than control owing to fewer discontinuations due to adverse events or patient preference. In order to understand the intrinsic potency of the anti-retroviral regimen under study, ITT analysis needs to be supplemented by standardized as-treated analyses, excluding withdrawals for toxicity or other reasons. To evaluate the efficacy of a treatment strategy or sequential treatment regimens, the ‘ITT, switch included’ (ITT/SI) method: where changes from the initial randomized treatment are not classified as treatment failure – can be used. However, interpretation of clinical trials using ITT/SI analysis is difficult and depends on the frequency of treatment switching in the different arms of a trial. Conclusions on efficacy from clinical trials can depend on the primary analysis used; most commonly, treatments could be significantly different by ITT/S=F analysis, but then interpreted as equivalent using the ITT/SI or as-treated methods.
In Vivo Effects of Highly Active Antiretroviral Therapies Containing the Protease Inhibitor Nelfinavir on Mitochondrially Driven Apoptosis
Authors: Miró Òscar , Villarroya Joan , Garrabou Glòria , López Sònia , de la Concepción Marisa Rodríguez , Pedrol Enric , Martínez Esteban , Giralt Marta , Gatell Josep M , Cardellach Francesc , Casademont Jordi , Villarroya Francesc 
Published: April 2022

Background In vitro studies have reported controversial effects of protease inhibitors (PIs) on mitochondrially driven apoptosis. Additionally, since PIs in the clinical setting are almost always given in combination with nucleoside analogues, which may have negative effects on mitochondrial DNA (mtDNA), the impact of PI-containing highly active antiretroviral therapy (HAART) on apoptosis and mtDNA content is unclear. Patients and methods A cross-sectional study was performed including 20 HIV-negative (HIV-) patients, 16 HIV-positive, antiretroviral-naive (HIV+) patients and 17 HIV-positive patients receiving the PI nelfinavir (NFV) plus zidovudine and lamivudine (AZT+3TC) or didanosine and stavudine (ddI+d4T) - collectively known as HIV+PI - as first-line antiretroviral treatment for at least 12 months. Peripheral blood mononuclear cells (PBMCs) were isolated. BCL2 expression (anti-apoptotic) and the levels of the cleaved, active form of caspase-9 (pro-apoptotic) were determined by western blot. An index of mitochondrially driven apoptotic activation was estimated calculating the ratio caspase-9:BCL2. Mitochondrial DNA content was measured by real-time PCR. Results BCL2 expression was lower in HIV+ than in HIV-patients ( P<0.01), whereas levels of caspase-9 were higher ( P=0.001). The caspase-9:BCL2 ratio was significantly increased in HIV+ compared with HIV- individuals ( P<0.001). Mitochondrial DNA content was also decreased in HIV+ compared with HIV- patients ( P<0.001). The HIV+PI group exhibited a trend to normalization for BCL2 expression and caspase-9 compared with the HIV+ group, whereas the caspase-9:BCL2 ratio significantly improved (decreased, P<0.05 compared with HIV+ group). The mtDNA content in the HIV+PI group was similar to that of the HIV+ group, although the results of mtDNA content differed depending on whether NFV was combined with AZT+3TC (preserved) or with ddI+d4T (depleted). Conversely, no differences were found in apoptotic markers between the two subgroups of HIV+PI. Conclusions NFV-based PI-containing HAART regimens may exert some beneficial effects counteracting the increased mitochondrially driven apoptosis present in HIV-infected people.
A Multiphase Model of the Dynamics of HBV Infection in Hbeag-Negative Patients during Pegylated Interferon-α2A, Lamivudine and Combination Therapy
Authors: Colombatto Piero , Civitano Luigi , Bizzarri Ranieri , Oliveri Filippo , Choudhury Somesh , Gieschke Ronald , Bonino Ferruccio , Brunetto Maurizia R ,   Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group, Farci P , Germanidis G , Kittis G , Cadeo G , Pastore G , Hadziyannis S 
Published: April 2022

Using a multiphase bio-mathematical model, we studied the dynamics of hepatitis B virus (HBV) infection in 72 HBeAg-negative patients who received 48 weeks of either lamivudine (3TC; 25 patients); pegylated interferon-α2a (peg-IFN-α2a) 180 mg weekly plus 3TC (23 patients), or peg-IFN-α2a 180 mg weekly plus placebo (24 patients). During the first month of therapy most of the 3TC -/+ peg-IFN-α2a treated patients showed a multiphase decay of viral load: during the first two phases, where we hypothesized a direct inhibition of virus production, the mean viral production per infected cell was reduced by 2.22 log10 and 2.36 log10, respectively. At variance, peg-IFN-α2a treated patients had a biphasic profile: the first phase HBV DNA decline was slower than that observed in 3TC patients (mean HBV DNA t1/2=1.6 ±1.1 days and 9.5 ±3.0 h, respectively) and the direct antiviral effect reduced virus production by 1.14 log10 From day 14 onwards (third or second phase according to multi- or biphasic patterns), HBV DNA declined mainly because of the infected hepatocyte clearance that slowed down in approximately 50% of the patients from day 35, possibly because of a negative feedback on the immune system activity. Computing the number of infected cells at the end of therapy we found that peg-IFN-α2a and 3TC monotherapy determined a similar reduction of infected hepatocytes (mean: -3.3 log10), whereas there was a greater reduction in combination therapy patients (-5.0 versus -3.3 log10, P=0.039). In conclusion, peg-IFN-α2a, in spite of having direct antiviral activity lower than that of 3TC, achieved a comparable reduction of infected hepatocytes, possibly because of a higher infected cell clearance rate.
Lamivudine and Indinavir/Ritonavir Maintenance Therapy in Highly Pretreated HIV-Infected Patients (Vista Anrs 109)
Authors:   for the ANRS 109 VISTA Study Group, Launay Odile , Duval Xavier , Dalban Cécile , Descamps Diane , Peytavin Gilles , Certain Agnès , Mouajjah Saïd , Ralaimazava Pascal , Verdon Renaud , Costagliola Dominique , Clavel François 
Published: April 2022

Objective In patients with extensive HIV resistance, one option is to delay salvage therapy until new drugs become available. We hypothesized that this delay period could be based on a simplified treatment, which would reduce drug toxicity, stabilize resistance, and prevent resurgence of wild-type virus. Methods A prospective 24-week treatment simplification study in HIV-1-infected patients having failed several lines of antiretroviral therapy, with CD4+ T-cell counts ≥100 cells/ml, plasma HIV RNA (viral load [VL]) ≥4 log10 copies/ml and a resistance genotype predicting less than two active drugs. Treatment associated ritonavir-boosted low-dose indinavir (200 mg twice daily) and lamivudine (150 mg twice daily). The primary endpoint was a decrease in CD4+ T-cell counts ≥25% or increase in VL ≥0.7 log copies/ml relative to baseline. Results; Twenty-six patients were included. Baseline median VL was 4.5 log10 copies/ml and median CD4+ T-cell count was 290 cells/ml. During the study, 10/26 patients (38%, 95% confidence interval=20.2–59.4) reached the primary endpoint. No patient had an AIDS-defining event. At week 24, the median change in plasma VL was +0.2 log10 copies/ml (interquartile range (IQR): 0–0.5; P=0.003). The median change in CD4+ T-cell counts was -49 cells/ml (IQR: -14 to -93, P<0.001), with a median decline slope of 10 cells/ml/month, which was not different from that measured under full highly active antiretroviral therapy during the 6 months preceding inclusion. There were no significant changes in HIV-1 protease and reverse transcriptase genotypes during the study. Conclusions In patients with advanced resistance, treatment simplification prevented resurgence of wild-type HIV, reduced drug burden, but failed to stabilize progression of the immune deficiency.
HIV-1 Transmission Cluster with M41L ‘Singleton’ Mutation and Decreased Transmission of Resistance in Newly Diagnosed Swedish Homosexual Men
Authors: Lindström Anna , Ohlis Anna , Huigen Marleen , Nijhuis Monique , Berglund Torsten , Bratt Göran , Sandström Eric , Albert Jan 
Published: April 2022

Objective To investigate the prevalence of HIV-1 with major drug resistance-associated mutations among 261 men who have sex with men (MSM) who were newly diagnosed as HIV-1-infected at Venhälsan, Stockholm, between 1992–2002. Methods Major resistance-associated mutations were identified using an in-house method on stored plasma samples collected within 6 months of diagnosis. Additional samples were investigated from selected patients. Phylogenetic tree analyses were used to study evolutionary relationships between the viruses. Epidemiological data were retrieved from the partner notification investigations and the medical records. Results Informed consent as well as results from the resistance test were available for 201 out of 261 patients (77%) diagnosed during 1992–2002. Viruses from 28 of these 201 patients (14%) displayed major resistance-associated mutations; 27 of these viruses displayed only zidovudine/stavudine resistance-associated mutations. None of the patients displayed resistance mutations to protease inhibitors. The prevalence of resistance-associated mutations decreased over time; 20% in 1992–1996 versus 9% in 1997–2002 ( P=0.04). A transmission cluster involving six patients with a singleton M41L mutation was identified. These viruses were phenotypically sensitive to zidovudine and stavudine. The M41L mutation, as well as most other resistance mutations, was stable for many years after transmission and may have been fixated by other putative compensatory mutations. Conclusions In this Swedish population of MSM with newly diagnosed HIV-1 infection, the prevalence of resistance-associated mutations decreased over time. Reversion of resistance-associated mutations following transmission was slow and incomplete. A large transmission cluster with an interesting M41L singleton mutation was also observed.