ABSTRACT
BACKGROUND: Nailfold Videocapillaroscopy (NVC) is a valuable tool in the differential diagnosis of Raynaud's phenomenon (RP), present in certain Rheumatic diseases (RD). Knowing that many people have cardiovascular risk factors (CVRF), the main objective was to demonstrate that CVRF and carotid plaques produce NVC alterations. METHODS: Cross-sectional unicentric study carried out from 2020 to 2023. Four groups were formed: subjects with RD and RP, participants with RD without RP, subjects with RP without RD and finally participants without RP or RD (study group). Each subject exhibiting CVRF presented only a single risk factor. The variables collected were: sociodemographic, CVRF (diabetes, tobacco, alcohol (ALC), obesity (OBE), dyslipidemia and arterial hypertension (AH)), diseases, RP, treatments, tortuosities and NVC alterations (ramified capillaries, enlarged capillaries, giant capillaries, haemorrhages and density loss) and carotid ultrasound (CU). RESULTS: 402 subjects were included (76 % women, mean age 51 ± 16 years), 67 % had CVRF, 50 % RP and 38 % RD. Tortuosities were present in 100 % of CVRF participants. A statistically significant association was found between the presence of CVRF and all the NVC alterations: ramified capillaries (OR = 95.6), enlarged capillaries (OR = 59.2), giant capillaries (OR = 8.32), haemorrhages (OR = 17.6) and density loss (OR = 14.4). In particular, an association was found between giant capillaries with AH (p = 0,008) and OBE (p ã0,001), and haemorrhages and density loss with ALC and OBE (p < 0,001). On the other hand, 40 subjects presented CU plaques (9.9 %), associated with enlarged capillaries (OR = 8.08), haemorrhages (OR = 4.04) and ramified capillaries (OR = 3.01). The pathological intima-media thickness was also associated with haemorrhages (OR = 3.14). CONCLUSIONS: There is a clear association between CVRF and ultrasound atherosclerotic findings in carotid with NVC alterations. These findings are of special interest for a correct NVC interpretation and to avoid false positives in the diagnosis of primary and secondary RP.
Subject(s)
Capillaries , Heart Disease Risk Factors , Microscopic Angioscopy , Nails , Predictive Value of Tests , Raynaud Disease , Humans , Female , Cross-Sectional Studies , Male , Middle Aged , Adult , Aged , Capillaries/diagnostic imaging , Capillaries/pathology , Capillaries/physiopathology , Nails/blood supply , Raynaud Disease/diagnostic imaging , Raynaud Disease/diagnosis , Raynaud Disease/epidemiology , Raynaud Disease/physiopathology , Risk Assessment , Plaque, Atherosclerotic , Carotid Artery Diseases/diagnostic imaging , Carotid Artery Diseases/epidemiologyABSTRACT
Forty-seven free-ranging sea turtles (46- Chelonia mydas, 1- Eretmochelys imbricata) were examined via novel use of an endoscopy combined with a rectal enema to obtain large fecal sample volumes. The cloaca was insufflated using an endoscope, after which the bladder and rectum separated, allowing access to the colon. Environmental conditions and location influenced the performance of the procedure initially, but after several attempts the procedure was successfully initiated. In all cases, fecal samples were obtained, and the animals were released to their respective locations. Fecal sample collection using this approach enhances the ability to obtain diagnostic information and perform other scientific analyses of sea turtles.
Subject(s)
Turtles , Animals , Animals, Zoo , Endoscopy , EnemaABSTRACT
BACKGROUND: Prophylactic vaccination has proven to be the most effective strategy to fight the COVID-19 pandemic. METHODS: This was a prospective observational cohort study involving 30 predominantly antibody deficiency disorders (ADD)-afflicted adult patients on immunoglobulin replacement therapy vaccinated with three doses of the mRNA-1273 COVID-19 vaccine, and 10 healthy controls. Anti-RBD IgG antibodies were determined in plasma samples collected just before the first dose of mRNA-based COVID-19 vaccine and on weeks 4, 8, 24, and 28 following the first vaccination. Patients were categorized based on the levels of anti-RBD antibodies determined on w8 as non-, low-, and responders. Chi-square and Kruskal-Wallis tests were used to see if any variables correlated with humoral response levels. Any adverse effects of the mRNA-based vaccine were also noted. RESULTS: The COVID-19 vaccine was safe and well-tolerated. The humoral response elicited at w8 after vaccination depended on the type of ADD, the type of immunoglobulin deficiency, the presence of granulomatous lymphocytic interstitial lung disease, recent use of immunosuppressive drugs, and the switched memory B cells counts. The third vaccine dose boosted humoral response in previous responders to second dose but seldom in non-responders. CONCLUSIONS: The humoral response of patients with predominant ADD depends mostly on the type of immunodeficiency and on the frequency of B and T cell populations.
ABSTRACT
Mass vaccination campaigns reduced COVID-19 incidence and severity. Here, we evaluated the immune responses developed in SARS-CoV-2-uninfected patients with predominantly antibody-deficiencies (PAD) after three mRNA-1273 vaccine doses. PAD patients were classified based on their immunodeficiency: unclassified primary antibody-deficiency (unPAD, n = 9), common variable immunodeficiency (CVID, n = 12), combined immunodeficiency (CID, n = 1), and thymoma with immunodeficiency (TID, n = 1). unPAD patients and healthy controls (HCs, n = 10) developed similar vaccine-induced humoral responses after two doses. However, CVID patients showed reduced binding and neutralizing titers compared to HCs. Of interest, these PAD groups showed lower levels of Spike-specific IFN-γ-producing cells. CVID individuals also presented diminished CD8+T cells. CID and TID patients developed cellular but not humoral responses. Although the third vaccine dose boosted humoral responses in most PAD patients, it had limited effect on expanding cellular immunity. Vaccine-induced immune responses in PAD individuals are heterogeneous, and should be immunomonitored to define a personalized therapeutic strategies.
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BACKGROUND: We analyzed humoral and cellular immune responses induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines in people with human immunodeficiency virus (HIV; PWH) who had CD4+ T-cell counts <200/µL (HIV<200 group). METHODS: This prospective cohort study included 58 PWH in the HIV<200 group, 36 with CD4+ T-cell counts >500/µL (HIV>500 group), and 33 HIV-1-negative controls (control group). Antibodies against the SARS-CoV-2 spike protein (anti-S immunoglobulin [Ig] G) and the receptor-binding domain (anti-RBD IgG) were quantified before and 4â weeks after the first and the second doses of BNT162b2 or mRNA-1273 (at week 8). Viral neutralization activity and T-cell responses were also determined. RESULTS: At week 8, anti-S/anti-RBD IgG responses increased in all groups (P < .001). Median (interquartile range) anti-S and anti-RBD IgG levels at week 8 were 153.6 (26.4-654.9) and 171.9 (61.8-425.8) binding antibody units (BAU)/mL, respectively, in the HIV<200 group, compared with 245.6 (145-824) and 555.8 (166.4-1751) BAU/mL in the HIV>500 group and 274.7 (193.7-680.4) and 281.6 (181-831.8) BAU/mL in controls (P < .05). Neutralizing capacity and specific T-cell immune responses were absent or reduced in 33% of those in the HIV<200 group, compared with 3.7% in the HIV>500 group (P < .01). CONCLUSIONS: One-third of PWH with CD4+ T-cell counts <200/µL show low anti-S/anti-RBD IgG levels, reduced in vitro neutralization activity against SARS-CoV-2, and no vaccine-induced T cells after receiving coronavirus disease 2019 mRNA vaccines.
Subject(s)
COVID-19 Vaccines , COVID-19 , HIV Seropositivity , Immune Reconstitution , Humans , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Immunoglobulin G , Prospective Studies , SARS-CoV-2 , Vaccination , Immunity, Humoral , Immunity, Cellular , T-LymphocytesABSTRACT
OBJECTIVE: To assess the central nervous system (CNS) impact of a kick&kill HIV cure strategy using therapeutic vaccine MVA.HIVconsv and the histone deacetylase inhibitor (HDACi) romidepsin (RMD) as latency-reversing agent. DESIGN: Neurological observational substudy of the BCN02 trial (NCT02616874), a proof-of-concept, open-label, single-arm, phase I clinical trial testing the safety and immunogenicity of the MVA.HIVconsv vaccine and RMD in early-treated HIV-1-infected individuals. A monitored antiretroviral pause (MAP) was performed, with cART resumption after 2 pVL more than 2000âcopies/ml. Reinitiated participants were followed for 24âweeks. METHODS: Substudy participation was offered to all BCN02 participants (Nâ=â15). Evaluations covered cognitive, functional, and brain imaging outcomes, performed before RMD administration (pre-RMD), after three RMD infusions (post-RMD), and at the end of the study (EoS). A group of early-treated HIV-1-infected individuals with matched clinical characteristics was additionally recruited (nâ=â10). Primary endpoint was change in a global cognitive score (NPZ-6). RESULTS: Eleven participants from BCN02 trial were enrolled. No significant changes were observed in cognitive, functional, or brain imaging outcomes from pre-RMD to post-RMD. No relevant alterations were detected from pre-RMD to EoS either. Scores at EoS were similar in participants off cART for 32âweeks (nâ=â3) and those who resumed therapy for 24âweeks (nâ=â7). Controls showed comparable punctuations in NPZ-6 across all timepoints. CONCLUSION: No detrimental effects on cognitive status, functional outcomes, or brain imaging parameters were observed after using the HDACi RMD as latency-reversing agent with the MVA.HIVconsv vaccine in early-treated HIV-1-infected individuals. CNS safety was also confirmed after completion of the MAP.
Subject(s)
Depsipeptides , HIV Infections , HIV Seropositivity , HIV-1 , Anti-Retroviral Agents/therapeutic use , Central Nervous System , Depsipeptides/adverse effects , HIV Seropositivity/drug therapy , Histone Deacetylase Inhibitors/adverse effects , HumansABSTRACT
OBJECTIVE: To objectively evaluate acoustic sensitivity of the implanted microphone, and maximum stable gain of a totally implantable active middle ear implant. DESIGN: Prospective, single centre evaluation. STUDY SAMPLE: Fourteen adult patients. RESULTS: Microphone sensitivity is approx. 10 dB lower than an externally worn conventional hearing aid, at frequencies up to 4000 Hz, and substantially lower at higher frequencies. The masking level due to microphone noise, which determines the softest test tones that can be detected, is estimated at <20 to <30 dB HL up to 1000 Hz, and <40 dB HL at higher frequencies. Maximum stable effective gain is the maximum amplification achievable without causing feedback whistling. In sensorineural hearing loss (SNHL) cases, it is 30-40 dB at frequencies up to 2000 Hz, allowing to compensate for even the maximum recommended hearing loss (60-70 dB HL). In both SNHL and mixed hearing loss (MHL) cases, maximum stable effective gain is lower (+20 to -30 dB) around 3000-6000 Hz. CONCLUSIONS: Microphone sensitivity is high enough to achieve aided thresholds of 20-40 dB HL. A strong correlation between actuator coupling efficiency and maximum stable effective gain implies that any effort to improve actuator efficiency should also increase the available gain.
Subject(s)
Deafness , Hearing Aids , Hearing Loss, Sensorineural , Hearing Loss , Ossicular Prosthesis , Adult , Humans , Prospective Studies , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/rehabilitation , Hearing Loss/rehabilitationABSTRACT
OBJECTIVES: Potential interactions between CYP3A4 inhibitors and γ-hydroxybutyric acid (GHB) have been suggested as a possible explanation for cases of GHB overdose in recent years among people living with HIV engaged in chemsex. Our objective was to assess the effect of cobicistat on the pharmacokinetics of GHB. METHODS: Fifteen healthy adults were enrolled in this randomized, double-blind, placebo-controlled, two-arm, crossover clinical trial. Participants underwent two 5 day treatment periods with at least a 1 week washout period between them. In each treatment period, participants received cobicistat (150 mg q24h orally) or matched placebo. On day 5 of each treatment period, participants were given a single oral dose of GHB (25 mg/kg). Plasma concentrations of GHB, subjective effects, blood pressure, heart rate and oxygen saturation were monitored for 5 h after dosing. GHB pharmacokinetic and pharmacodynamic parameters were calculated for each participant during each study period by non-compartmental analysis and were compared using linear mixed-effects models. The study was registered at https://www.clinicaltrialsregister.eu (Eudra-CT number 2019-002122-71) and at https://clinicaltrials.gov (NCT04322214). RESULTS: Ten participants completed the two study periods. No drug-related adverse events that necessitated subject withdrawal or medical intervention occurred during the study. Compared with placebo, none of the primary pharmacokinetic parameters of GHB was substantially changed by the administration of GHB with cobicistat. Similarly, no differences regarding subjective or physiological effects were observed when GHB was administered alone or with cobicistat. CONCLUSIONS: Neither pharmacokinetic nor pharmacodynamic drug-drug interactions between cobicistat and GHB were identified in this study.
Subject(s)
Pharmaceutical Preparations , Sodium Oxybate , Adult , Cobicistat , Drug Interactions , Humans , Hydroxybutyrates , Sodium Oxybate/pharmacokineticsABSTRACT
Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide and it is associated with an increased risk of osteoporosis and fragility fractures. Our aim is to analyze the effect of T2DM on bone quality. This is a case-control study. The studied population consisted of 140 patients: 54 subjects with hip fracture (OP) without T2DM, 36 patients with hip fracture and T2DM (OP-T2DM), 28 patients with osteoarthritis (OA) without T2DM, and 22 patients with OA and T2DM (OA-T2DM). Bone markers, bone mineral density, FRAX score, microstructural, and bone material strength from femoral heads were assessed. The group with hip fracture presented lower BMD values than OA (p < 0.05). The OP, OP-T2DM, and OA-T2DM groups showed a decrease in bone volume fraction (BV/TV), in trabecular number (Tb.N), and in trabecular thickness (Tb.Th), while an increase was presented in the structural model index (SMI) and trabecular bone pattern factor (Tb.Pf), The groups OP, OP-T2DM, and OA-T2DM also presented lower values than those in group OA regarding the biomechanical parameters in the form of Young's modulus or elastic modulus, toughness, ultimate stress, ultimate load, extrinsic stiffness, and work to failure (p < 0.05). Our results show the negative effect of type 2 diabetes mellitus on trabecular bone structure and mechanical properties.
ABSTRACT
OBJECTIVES: To develop a population pharmacokinetic model for romidepsin given as an HIV latency reversing agent (LRA) and to explore the relationship between romidepsin exposure and its in vivo effects on viral gene expression and antiviral immunity. METHODS: A population pharmacokinetic analysis was performed in 15 HIV-1-infected patients who received three weekly infusions of romidepsin (5 mg/m2) within the BCN02 clinical trial. A full pharmacokinetic profile was obtained for each participant at the first dose, and additional samples thereafter. A population pharmacokinetic model was developed. Bayesian estimates of the individual pharmacokinetic parameters of romidepsin were used to simulate individual time-concentration curves on each occasion. The relationship between romidepsin AUC0-∞ and its in vivo effects was assessed. RESULTS: Romidepsin pharmacokinetics were best described by a three-compartment model with linear kinetics. Body weight influenced romidepsin disposition. A significant relationship was observed between romidepsin AUC0-∞ and increases in expression of exhaustion markers by CD4+ and CD8+ T cells and apoptosis markers in CD4+, but not with histone acetylation levels or HIV-1 cell-associated RNA in CD4+ T cells. For each increase of 100 ng·h/mL in romidepsin AUC0-∞, CD4+ counts decreased by a mean (95% CI) of 74 (42-94) cells/mm3 after dosing. CONCLUSIONS: A population model describing the pharmacokinetics of romidepsin as an HIV LRA was developed. Higher exposure to romidepsin resulted in higher expression of apoptosis markers and declines in CD4+ count but did not increase viral reactivation levels. These observations have important implications for the optimization of effective kick-and-kill strategies for an HIV-1 cure.
Subject(s)
HIV Infections , HIV-1 , Bayes Theorem , CD4-Positive T-Lymphocytes , Depsipeptides , HIV Infections/drug therapy , Humans , Virus LatencyABSTRACT
OBJECTIVE: Evaluation of the audiological patient performance with an upgrade of the firmware from the fixed feedback canceller (FFC) to the adaptive feedback canceller (AFC) on an active middle ear implant. STUDY DESIGN: Retrospective observational nonrandomized group study. SETTING: Private hospital. PATIENTS/INTERVENTIONS: From March 2018 to September 2019, 15 patients implanted with an active middle ear implant, with 6 or more months of experience with a FFC system, were upgraded to an AFC algorithm. MAIN OUTCOME MEASURES: Functional gain, speech perception in silence and in noise, and sound localization capacities were examined. Feedback reduction was also analyzed. RESULTS: Thirteen patients were analyzed. Pure tone audiometric evaluation with FFC (mean value of 48.02âdB) compared with AFC at 1 (mean value of 49.12âdB) and 6 months (mean value of 42.75âdB) revealed no statistically significant differences (pâ=â0.889 and pâ=â0.358 respectively).In speech discrimination in silence, clinically relevant improvements were observed with AFC at 1 and 6 months, with a mean value of 41.5 and 38.3âdB, respectively (pâ=â0.03 and pâ=â0.021 correspondingly). In speech discrimination in noisy environments, we observed an improvement of the different conditions tested. No differences were found in localization capacities between FFC and AFC at the two different moments of evaluation. CONCLUSIONS: AFC is more effective than FFC in cancelling feedback and improving sound quality, allowing for better speech understanding in silence and in noise.
Subject(s)
Cochlear Implants , Ossicular Prosthesis , Sound Localization , Speech Perception , Feedback , Humans , Retrospective StudiesABSTRACT
Kick&kill strategies combining drugs aiming to reactivate the viral reservoir with therapeutic vaccines to induce effective cytotoxic immune responses hold potential to achieve a functional cure for HIV-1 infection. Here, we report on an open-label, single-arm, phase I clinical trial, enrolling 15 early-treated HIV-1-infected individuals, testing the combination of the histone deacetylase inhibitor romidepsin as a latency-reversing agent and the MVA.HIVconsv vaccine. Romidepsin treatment resulted in increased histone acetylation, cell-associated HIV-1 RNA, and T-cell activation, which were associated with a marginally significant reduction of the viral reservoir. Vaccinations boosted robust and broad HIVconsv-specific T cells, which were strongly refocused toward conserved regions of the HIV-1 proteome. During a monitored ART interruption phase using plasma viral load over 2,000 copies/ml as a criterium for ART resumption, 23% of individuals showed sustained suppression of viremia up to 32 weeks without evidence for reseeding the viral reservoir. Results from this pilot study show that the combined kick&kill intervention was safe and suggest a role for this strategy in achieving an immune-driven durable viremic control.
Subject(s)
AIDS Vaccines/immunology , Antiviral Agents/therapeutic use , Depsipeptides/therapeutic use , HIV Infections/immunology , HIV-1/physiology , Histone Deacetylase Inhibitors/therapeutic use , Adult , Disease Reservoirs , Drug Therapy, Combination , Female , HIV Infections/drug therapy , Humans , Male , Middle Aged , Pilot Projects , Viral Load , Viremia , Virus LatencyABSTRACT
BACKGROUND: Approximately 4% of European patients are diagnosed with locally advanced breast cancer (LABC), a clinical condition commonly associated with poorer prognosis. Systemic therapy is the recommended initial treatment and when inoperability criteria prevails, radiotherapy (RT) should be used for tumour downstaging. This study intends to evaluate the impact of neoadjuvant radiotherapy (NART) in the treatment of inoperable LABC. METHODS: A retrospective study of female patients, submitted to the NART between January 2014 and December 2018 at our institution. The evaluation of pathological response (pR) was made based on Pinder criteria. Primary endpoint: pR. Secondary endpoints: overall survival (OS) and progression-free survival (PFS). OS and PFS were calculated using the Kaplan-Meier method. Differences between groups were compared using Student's t-test, ANOVA (Analysis of variance) and χ2 test. The statistical analyses were performed using Stata (V.13). RESULTS: A total of 76 patients were included, 18% with breast complete response. The 5 years OS was 54% and PFS was 61%. Subgroup analysis showed that pR >90% is correlated with a better OS (p=0.004). Basal-like intrinsic subtype is correlated with worse OS and PFS (p<0.05). No relation was found between response and age, intrinsic subtype, treatment performed and clinical T stage. CONCLUSION: Our study confirms that NART is an effective downsizing treatment in inoperable LABC, allowing for a surgical resection regardless of the systemic treatment performed. Response to NART is independent of the intrinsic subtype and pR >90% is correlated with a better OS. Prospective studies to explore predictive response biomarkers are necessary in order to improve patient selection and optimisation of the treatment.
Subject(s)
Breast Neoplasms/radiotherapy , Neoadjuvant Therapy/methods , Adult , Aged , Aged, 80 and over , Female , Humans , Middle Aged , Retrospective StudiesABSTRACT
No disponible
Subject(s)
Humans , Male , Middle Aged , Aortic Diseases/etiology , Esophageal Fistula/etiology , Esophageal Diseases/etiology , Esophageal Diseases/complications , Angiography , Autopsy , StentsABSTRACT
BACKGROUND: Ambrisentan is a selective endothelin receptor antagonist used for the treatment of pulmonary arterial hypertension (PAH). Little is known about ambrisentan removal by hemodialysis in patients with end-stage renal disease (ESRD). CASE PRESENTATION: A 53-year-old woman with HIV/hepatitis C virus (HCV) co-infection, PAH and ESRD on regular hemodialyis was admitted in our hospital due to refractory heart failure while on treatment with bosentan (125 mg twice daily) and tadalafil (20 mg once daily) for PAH and antiretroviral treatment (cART) including darunavir/cobicistat (800/150 mg once daily). Excessive exposure to bosentan due to drug interactions between bosentan and darunavir/cobicistat was suspected. Bosentan was replaced by ambrisentan, with progressive improvement in her clinical condition. Pre- and postdialyzer cocentrations of ambrisentan in plasma were determined and hemodialysis extraction ratio for ambrisentan was 2%. CONCLUSIONS: Our results suggest that hemodialysis results in minimal ambrisentan removal, and therefore no specific ambrisentan dosage adjustment seems to be required in ESRD patients undergoing hemodialysis.
Subject(s)
Antihypertensive Agents/blood , Antihypertensive Agents/therapeutic use , Hypertension, Pulmonary/drug therapy , Kidney Failure, Chronic/therapy , Phenylpropionates/blood , Phenylpropionates/therapeutic use , Pyridazines/blood , Pyridazines/therapeutic use , Antihypertensive Agents/analysis , Female , HIV Infections/complications , Hemodialysis Solutions/chemistry , Hepatitis C, Chronic/complications , Humans , Hypertension, Pulmonary/complications , Kidney Failure, Chronic/complications , Middle Aged , Phenylpropionates/analysis , Pyridazines/analysis , Renal DialysisSubject(s)
Aortic Aneurysm, Thoracic/complications , Aortic Diseases/complications , Deglutition Disorders/etiology , Esophageal Fistula/complications , Vascular Fistula/complications , Aortic Aneurysm, Thoracic/diagnostic imaging , Aortic Aneurysm, Thoracic/surgery , Blood Vessel Prosthesis , Blood Vessel Prosthesis Implantation , Computed Tomography Angiography , Fatal Outcome , Humans , Male , Middle Aged , Postoperative Complications/etiology , Shock, Hemorrhagic/etiology , Ulcer/complications , Vomiting/etiologyABSTRACT
PURPOSE: The aim of this study was to assess the first outcomes of a fully implantable active middle ear device. METHODS: Retrospective observational nonrandomized group study. SETTINGS: Private hospital. Fifteen patients underwent device implantation between December 2014 and June 2017. The pre-operative and post-operative air conduction (AC) and bone conduction (BC) thresholds were evaluated. The functional gain, speech perception in silence and in noise, and localization abilities were also analyzed. RESULTS: Sixteen active middle ear implantations were performed. Post-operatively, the mean pure tone thresholds were 50.5 dB ( ± 12.64) for BC and 64.9 dB ( ± 15.36) for AC. No differences were found between the post-operative and pre-operative audiometric thresholds before activating the system (p > 0.05). Post-operatively, the mean thresholds in the free field after the device was activated were 46.8 dB, 45.75 dB, 42.6 dB, and 43.38 dB at 1, 3, 6, and 12 months, respectively. The global results of speech understanding in silence were 50.7 dB, 47.18 dB, 42 dB, and 42 dB for 1, 3, 6, and 12 months, respectively. Patients with mixed hearing loss had better results than those with sensorineural hearing loss. Speech discrimination in noise and localization was improved. CONCLUSIONS: Despite the small number of patients, our results confirmed that this fully implantable active middle ear device is a viable treatment for patients with moderate-to-severe sensorineural hearing loss who cannot or do not want to use traditional hearing aids for clinical or cosmetic reasons.
Subject(s)
Cochlear Implants , Ear, Middle/surgery , Hearing Loss, Sensorineural/surgery , Adult , Aged , Audiometry, Pure-Tone , Audiometry, Speech , Auditory Threshold , Female , Humans , Male , Middle Aged , Retrospective Studies , Young AdultABSTRACT
Objectives: To determine the effect of etravirine on the pharmacokinetics of darunavir/cobicistat and vice versa. Safety and tolerability of this combination were also evaluated. Methods: Open-label, fixed-sequence trial in two cohorts of HIV-infected patients on therapy with darunavir/cobicistat 800/150 mg once daily (DRV cohort; n = 15) or etravirine 400 mg once daily (ETR cohort; n = 15). Etravirine or darunavir/cobicistat were added on days 1-14 and 1-7 in participants in the DRV or ETR cohort, respectively. Full pharmacokinetic profiles were obtained on days 0 and 14 in the DRV cohort, and on days 0 and 7 in the ETR cohort. Darunavir, cobicistat and etravirine pharmacokinetic parameters [AUC0-24, Cmax and trough concentrations in plasma (C24)] were calculated for each individual by non-compartmental analysis and were compared using linear mixed-effects models. Adverse events and HIV-1 RNA in plasma were monitored. Results: Etravirine co-administration decreased cobicistat AUC0-24, Cmax and C24 by 30%, 14% and 66%, respectively. Although darunavir AUC0-24 and Cmax were unchanged by etravirine, darunavir C24 was 56% lower for darunavir/cobicistat co-administered with etravirine relative to darunavir/cobicistat alone. Etravirine pharmacokinetics were unchanged by darunavir/cobicistat. Treatments were well tolerated, and HIV-1 RNA remained undetectable in all participants. Conclusions: Although etravirine pharmacokinetics was unchanged by darunavir/cobicistat, there was a significant decrease in cobicistat exposure and in darunavir C24 when darunavir/cobicistat was co-administered with etravirine. Boosting darunavir with ritonavir instead of with cobicistat may be preferred if darunavir is to be combined with etravirine in clinical practice.
Subject(s)
Anti-HIV Agents/pharmacokinetics , Cobicistat/pharmacokinetics , Darunavir/pharmacokinetics , HIV Infections/drug therapy , HIV Protease Inhibitors/pharmacokinetics , Pyridazines/pharmacokinetics , Adult , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/blood , Cobicistat/administration & dosage , Cobicistat/blood , Cohort Studies , Darunavir/administration & dosage , Darunavir/blood , Drug Therapy, Combination , Female , HIV/drug effects , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/blood , Humans , Male , Middle Aged , Nitriles , Pyridazines/administration & dosage , Pyridazines/blood , Pyrimidines , RNA, Viral/blood , Young AdultABSTRACT
The complex processes involved with animal migration have long been a subject of biological interest, and broad-scale movement patterns of many marine turtle populations still remain unresolved. While it is widely accepted that once marine turtles reach sexual maturity they home to natal areas for nesting or reproduction, the role of philopatry to natal areas during other life stages has received less scrutiny, despite widespread evidence across the taxa. Here we report on genetic research that indicates that juvenile hawksbill turtles (Eretmochelys imbricata) in the eastern Pacific Ocean use foraging grounds in the region of their natal beaches, a pattern we term natal foraging philopatry. Our findings confirm that traditional views of natal homing solely for reproduction are incomplete and that many marine turtle species exhibit philopatry to natal areas to forage. Our results have important implications for life-history research and conservation of marine turtles and may extend to other wide-ranging marine vertebrates that demonstrate natal philopatry.
ABSTRACT
OBJECTIVE: To assess the efficacy and safety of transdermal rivastigmine for the treatment of HIV-associated cognitive impairment. METHODS: We recruited HIV-infected patients with cognitive impairment on stable antiretroviral therapy in a randomized controlled pilot trial with a 48-week follow-up. An additional assessment was held at 12 weeks. Participants received transdermal rivastigmine (9.5 mg daily), lithium (400 mg twice daily, titrated progressively), or remained in a control group (no new medication). The primary efficacy endpoint was change in a global cognitive score (NPZ-7). Secondary endpoints included change in specific cognitive measures, domains, and functional parameters. Safety covered the frequency of adverse events and changes in laboratory results. RESULTS: Seventy-six subjects were screened, and 29 were finally enrolled. Better cognitive outcomes were observed in all groups, although there were no significant differences between the arms (mean NPZ-7 change [SD]): rivastigmine, 0.35 (0.14); lithium, 0.25 (0.40); control, 0.20 (0.44) (p = 0.78). The rivastigmine group showed the highest positive trend (mean NPZ-7 [SD], baseline vs week 48): rivastigmine, -0.47 (0.22) vs -0.11 (0.29), p = 0.06; lithium, -0.50 (0.40) vs -0.26 (0.21), p = 0.22; control, -0.52 (0.34) vs -0.32 (0.52), p = 0.44. The cognitive domains with the highest positive trends were information processing speed at week 12 and executive function at week 48 (rivastigmine vs control): information processing speed, 0.35 (0.64) vs -0.13 (0.25), p = 0.17, d = 0.96; and executive functioning, 0.73 (0.33) vs 0.03 (0.74), p = 0.09, d = 1.18. No relevant changes were observed regarding functional outcomes. A total of 12 (41%) individuals dropped out of the study: 2 (20%) were due to medication-related effects in the rivastigmine group and 4 (36%) in the lithium group. No severe adverse events were reported. CONCLUSIONS: The results from this small randomized trial indicate that transdermal rivastigmine did not provide significant cognitive benefits in people with HAND on stable antiretroviral therapy, even though positive trends were found in specific cognitive domains. Relevant tolerability issues were not observed.