COVID-19 hospitalization is associated with pulmonary/diffusion abnormalities but not post-acute sequelae of COVID-19 severity.

Coronavirus disease-19 (COVID-19) has resulted in much acute morbidity and mortality worldwide. There is now a growing recognition of the post-acute sequela of COVID-19, termed long COVID. However, the risk factors contributing to this condition remain unclear. Here, we address the growing controversy in the literature of whether hospitalization is a risk factor for long COVID. We found that hospitalization is associated with worse pulmonary restriction and reduction in diffusion capacity at 3 months post-infection. However, the impact on mental health, functional and quality of life is equally severe in those who have and have not been hospitalized during the acute infection. These findings suggest that hospitalization is a risk factor for pulmonary complications of long COVID but not the overall severity of long COVID.

Inhaled nitric oxide improves ventilatory efficiency and exercise capacity in patients with mild COPD: A randomized-control cross-over trial.

KEY POINTS: Patients with mild chronic obstructive pulmonary disease (COPD) have an elevated ventilatory equivalent to CO2 production ( V̇E / V̇CO2 ) during exercise, secondary to increased dead space ventilation. The reason for the increased dead space is unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. Despite emerging evidence that mild COPD is associated with pulmonary microvascular dysfunction, limited research has focused on experimentally modulating the pulmonary microvasculature during exercise in mild COPD. The present study sought to examine the effect of inhaled nitric oxide (iNO), a selective pulmonary vasodilator, on V̇E / V̇CO2 , dyspnoea and exercise capacity in patients with mild COPD. Experimental iNO increased peak oxygen uptake in mild COPD, secondary to reduced V̇E / V̇CO2 and dyspnoea. This is the first study to demonstrate that experimental manipulation of the pulmonary circulation alone, can positively impact dyspnoea and exercise capacity in mild COPD. ABSTRACT: Patients with mild chronic obstructive pulmonary disease (COPD) have an exaggerated ventilatory response to exercise, contributing to dyspnoea and exercise intolerance. Previous research in mild COPD has demonstrated an elevated ventilatory equivalent to CO2 production ( V̇E / V̇CO2 ) during exercise, secondary to increased dead space ventilation. The reason for the increased dead space is unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. The present study tested the hypothesis that inhaled nitric oxide (iNO), a selective pulmonary vasodilator, would lower V̇E / V̇CO2 and dyspnoea, and improve exercise capacity in patients with mild COPD. In this multigroup randomized-control cross-over study, 15 patients with mild COPD (FEV1  =  89 ± 11% predicted) and 15 healthy controls completed symptom-limited cardiopulmonary exercise tests while breathing normoxic gas or 40 ppm iNO. Compared with placebo, iNO significantly increased peak oxygen uptake (1.80 ± 0.14 vs. 1.53 ± 0.10 L·min-1 , P < 0.001) in COPD, whereas no effect was observed in controls. At an equivalent work rate of 60 W, iNO reduced V̇E / V̇CO2 by 3.8 ± 4.2 units (P = 0.002) and dyspnoea by 1.1 ± 1.2 Borg units (P < 0.001) in COPD, whereas no effect was observed in controls. Operating lung volumes and oxygen saturation were unaffected by iNO in both groups. iNO increased peak oxygen uptake in COPD, secondary to reduced V̇E / V̇CO2 and dyspnoea. These data suggest that mild COPD patients demonstrate pulmonary microvascular dysfunction that contributes to increased V̇E / V̇CO2 , dyspnoea and exercise intolerance. This is the first study to demonstrate that experimental manipulation of the pulmonary circulation alone, can positively impact dyspnoea and exercise capacity in mild COPD.

Exertional intolerance and dyspnea with preserved lung function: an emerging long COVID phenotype?

The COVID-19 pandemic has resulted in significant acute morbidity and mortality worldwide. There is now a growing recognition of the longer-term sequelae of this infection, termed "long COVID". However, little is known about this condition. Here, we describe a distinct phenotype seen in a subset of patients with long COVID who have reduced exercise tolerance as measured by the 6 min walk test. They are associated with significant exertional dyspnea, reduced health-related quality of life and poor functional status. However, surprisingly, they do not appear to have any major pulmonary function abnormalities or increased burden of neurologic, musculoskeletal or fatigue symptoms.

Blunted sympathetic neurovascular transduction is associated to the severity of obstructive sleep apnea.

PURPOSE: Obstructive sleep apnea (OSA) is a common disorder (~ 4%) that augments sympathetic nerve activity (SNA) and elevates blood pressure. The relationship between sympathetic vasomotor outflow and vascular responsiveness, termed sympathetic neurovascular transduction (sNVT), has been sparsely characterized in patients with OSA. Therefore, we sought to quantify spontaneous sympathetic bursts and related changes in diastolic pressure. METHODS: Twelve participants with variable severities of OSA were recruited. We collected muscle sympathetic nerve activity (MSNA) (microneurography) and beat-by-beat diastolic pressure (finger photoplethysmography) during normoxia (FiO2 = 0.21) and hyperoxia (FiO2 = 1.0) to decrease MSNA burst frequency. MSNA burst sequences (i.e. singlets, doublets, triplets and quadruplets) were identified and coupled to changes in diastolic pressure over 15 cardiac cycles as an index of sNVT. sNVT slope for each individual was calculated from the slope of the relationship between peak responses in outcome plotted against normalized burst amplitude. RESULTS: sNVT slope was unchanged during hyperoxia compared to normoxia (normoxia 0.0024 ± 0.0011 Δ mmHg total activity [a.u.]-1 vs. hyperoxia 0.0029 ± 0.00098 Δ mmHg total activity [a.u.]-1; p = 0.14). sNVT slope was inversely associated with burst frequency during hyperoxia (r = -0.58; p = 0.04), but not normoxia (r = -0.11; p = 0.71). sNVT slope was inversely associated with the apnea-hypopnea index (AHI) (r = -0.62; p = 0.030), but not after age was considered. CONCLUSIONS: We have demonstrated that the prevailing MSNA frequency is unmatched to the level of sNVT, and this can be altered by acute hyperoxia.

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-experienced, virologically suppressed patients with HIV-1: subgroup analyses of the phase 3 EMERALD study.

BACKGROUND: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is a once-daily, single-tablet regimen for treatment of HIV-1 infection. The efficacy/safety of switching to D/C/F/TAF versus continuing boosted protease inhibitor (bPI) + emtricitabine/tenofovir disoproxil fumarate (control) were demonstrated in a phase 3, randomized study (EMERALD) of treatment-experienced, virologically suppressed adults through week 48. The objective of this analysis was to evaluate EMERALD outcomes across subgroups of patients based on demographic characteristics, prior treatment experience, and baseline antiretroviral regimen. METHODS: EMERALD patients were virologically suppressed (viral load [VL] < 50 copies/mL for ≥ 2 months at screening). Prior non-darunavir virologic failure (VF) was allowed. Primary endpoint was proportion of patients with virologic rebound (confirmed VL ≥ 50 copies/mL) cumulative through week 48. Virologic response was VL < 50 copies/mL (FDA snapshot). Safety was assessed by adverse events, renal proteinuria markers, and bone mineral density. Outcomes were examined for prespecified subgroups by age (≤/> 50 years), gender, race (black/non-black), prior number of antiretrovirals used (4/5/6/7/> 7), prior VF (0/≥ 1), baseline bPI (darunavir/atazanavir or lopinavir), and baseline boosting agent (ritonavir/cobicistat). RESULTS: Among 1141 patients in the D/C/F/TAF (n = 763) and control (n = 378) arms, virologic rebound rates (2.5% and 2.1%, respectively) were similar, and this was consistent across all subgroups. Virologic response rates ranged from 91 to 97% (D/C/F/TAF) and 89 to 99% (control) across all subgroups, with differences between treatment arms of 0 and 6%. Adverse event rates were low in both arms and across subgroups. Improvements in renal and bone parameters were observed with D/C/F/TAF across demographic subgroups. CONCLUSIONS: For treatment-experienced, virologically suppressed patients, switching to D/C/F/TAF was highly effective and safe, regardless of demographic characteristics, prior treatment experience, or pre-switch bPI. Trial registration ClinicalTrials.gov Identifier: NCT02269917. Registered 21 October 2014. https://clinicaltrials.gov/ct2/show/NCT02269917.

The carotid chemoreceptor contributes to the elevated arterial stiffness and vasoconstrictor outflow in chronic obstructive pulmonary disease.

KEY POINTS: The reason(s) for the increased central arterial stiffness in chronic obstructive pulmonary disease (COPD) are not well understood. In this study, we inhibited the carotid chemoreceptor with both low-dose dopamine and hyperoxia, and observed a decrease in central arterial stiffness and muscle sympathetic nervous activity in COPD patients, while no change was observed in age- and risk-matched controls. Carotid chemoreceptor inhibition increased vascular conductance, secondary to reduced arterial blood pressure in COPD patients. Findings from the current study suggest that elevated carotid chemoreceptor activity may contribute to the increased arterial stiffness typically observed in COPD patients. ABSTRACT: Chronic obstructive pulmonary disease (COPD) patients have increased central arterial stiffness and muscle sympathetic nervous activity (MSNA), both of which contribute to cardiovascular (CV) dysfunction and increased CV risk. Previous work suggests that COPD patients have elevated carotid chemoreceptor (CC) activity/sensitivity, which may contribute to the elevated MSNA and arterial stiffness. Accordingly, the effect of CC inhibition on central arterial stiffness, MSNA and CV function at rest in COPD patients was examined in a randomized placebo-controlled study. Thirteen mild-moderate COPD patients (forced expired volume in 1 s (FEV1 ) predicted ± SD: 83 ± 18%) and 13 age- and risk-matched controls completed resting CV function measurements with either i.v. saline or i.v. dopamine (2 µg kg-1  min-1 ) while breathing normoxic or hyperoxic air (100% O2 ). On a separate day, a subset of COPD patients and controls completed MSNA measurements while breathing normoxic or hyperoxic air. Arterial stiffness was determined by pulse-wave velocity (PWV) and MSNA was measured by microneurography. Brachial blood flow was determined using Doppler ultrasound, cardiac output was estimated by impedance cardiography, and vascular conductance was calculated as flow/mean arterial pressure (MAP). CC inhibition with dopamine decreased central and peripheral PWV, and MAP (P < 0.05) while increasing vascular conductance in COPD. No change in CV function was observed with dopamine in controls. CC inhibition with hyperoxia decreased peripheral PWV and MSNA (P < 0.05) in COPD, while no change was observed in controls. CC inhibition decreased PWV and MSNA, and improved vascular conductance in COPD, suggesting that tonic CC activity is elevated at rest and contributes to the elevated arterial stiffness in COPD.

Disparities in HIV knowledge and attitudes toward biomedical interventions among the non-medical HIV workforce in the United States.

Non-medical, community-based workers play a critical role in supporting people living with (or at risk of acquiring) HIV along the care continuum. The biomedical nature of promising advances in HIV prevention, such as pre-exposure prophylaxis and treatment-as-prevention, requires frontline workers to be knowledgeable about HIV science and treatment. This study was developed to: measure knowledge of HIV science and treatment within the HIV non-medical workforce, evaluate workers' familiarity with and attitudes toward recent biomedical interventions, and identify factors that may affect HIV knowledge and attitudes. A 62-question, web-based survey was completed in English or Spanish between 2012 and 2014 by 3663 US-based employees, contractors, and volunteers working in AIDS service organizations, state/local health departments, and other community-based organizations in a non-medical capacity. Survey items captured the following: respondent demographics, HIV science and treatment knowledge, and familiarity with and attitudes toward biomedical interventions. An average of 61% of HIV knowledge questions were answered correctly. Higher knowledge scores were associated with higher education levels, work at organizations that serve people living with HIV/AIDS or who are at a high risk of acquiring HIV, and longer tenure in the field. Lower knowledge scores were associated with non-Hispanic Black or Black race/ethnicity and taking the survey in Spanish. Similarly, subgroup analyses showed that respondents who were non-Hispanic Black or Hispanic (versus non-Hispanic white), as well as those located in the South (versus other regions) scored significantly lower. These subpopulations were also less familiar with and had less positive attitudes toward newer biomedical prevention interventions. Respondents who took the survey in Spanish (versus English) had lower knowledge scores and higher familiarity with, but generally less positive attitudes toward, biomedical interventions. In summary, low knowledge scores suggest the need for additional capacity-building efforts and training for non-medical HIV workers, particularly those who provide services in the communities most affected by HIV.

An experimental assessment of the influence of exercise versus social implementation intentions on physical activity during and following pulmonary rehabilitation.

Techniques to increase physical activity among pulmonary rehabilitation patients outside of the rehabilitation context are warranted. Implementation intentions are a strategy used to initiate goal-directed behaviour, and have been found to be useful in other populations. This study compared the long-term effects of exercise and social implementation intentions interventions on objectively measured physical activity in 40 pulmonary rehabilitation patients randomly assigned to condition. Repeated measures ANOVAs found that those in the exercise implementation intentions group took more steps (p = .007) at the end of pulmonary rehabilitation than those in the social implementation intentions group. Improvements attained by the exercise group during the intervention were not maintained 6-months following rehabilitation. Implementation intentions targeting physical activity appear to have positive short term effects on physical activity, although the long term effects are less consistent. This may be due in part to methods used to assess physical activity behaviour.

HIV testing practices among black primary care physicians in the United States.

BACKGROUND: The Centers for Disease Control and Prevention recommends routine HIV testing in all healthcare settings, but it is unclear how consistently physicians adopt the recommendation. Making the most of each interaction between black physicians and their patients is extremely important to address the HIV health disparities that disproportionately afflict the black community. The goal of this survey-based study was to evaluate the perceptions and practices of black, primary care physicians regarding HIV testing. METHODS: A physician survey was administered at the 2010 National Medical Association Annual Convention, via online physician panels, and by email. Physician eligibility criteria: black race; practicing at least 1 year in the US; practice comprised of at least 60% adults and 20% black patients. Contingency tables and ordinary least squares regression were used for comparisons and statistical analyses. A Chi-square test compared percentages of physicians who gave a particular response and a t-test compared the means of values provided by physicians. RESULTS: Physicians over-estimated HIV prevalence and believed that HIV is a crisis in the black community, yet reported that only 34% of patients were HIV tested in the past year. Physicians reported that 67% of those patients tested did so due to a physician recommendation. Physicians who were younger, female, obstetricians/gynecologists, and had a higher proportion of black, low-socioeconomic status, and Medicaid patients reported higher testing rates. Most testing was risk-based rather than routine, and three of the five most commonly reported barriers to testing were related to disease stigma and perceived value judgments. Physicians reported that in-office patient informational materials, increased media attention, additional education and training on HIV testing, government mandates requiring routine testing, and accurate pre-packed tests would most help them test more frequently for HIV. CONCLUSIONS: In this sample of black, primary care physicians, HIV testing practices differed according to physician characteristics and practice demographics, and overall reported testing rates were low. More physician education and training around testing guidelines is needed to enable more routine testing, treatment, and long-term management of patients with HIV.

Reliability and validity of the post COVID-19 condition stigma questionnaire: A prospective cohort study.

Background: Many of the 10-20% percent of COVID-19 survivors who develop Post COVID-19 Condition (PCC, or Long COVID) describe experiences suggestive of stigmatization, a known social determinant of health. Our objective was to develop an instrument, the Post COVID-19 Condition Stigma Questionnaire (PCCSQ), with which to quantify and characterise PCC-related stigma. Methods: We conducted a prospective cohort study to assess the reliability and validity of the PCCSQ. Patients referred to our Post COVID-19 Clinic in the Canadian City of Edmonton, Alberta between May 29, 2021 and May 24, 2022 who met inclusion criteria (attending an academic post COVID-19 clinic; age ≥18 years; persistent symptoms and impairment at ≥ 12 weeks since PCR positive acute COVID-19 infection; English-speaking; internet access; consenting) were invited to complete online questionnaires, including the PCCSQ. Analyses were conducted to estimate the instrument's reliability, construct validity, and association with relevant instruments and defined health outcomes. Findings: Of the 198 patients invited, 145 (73%) met inclusion criteria and completed usable questionnaires. Total Stigma Score (TSS) on the PCCSQ ranged from 40 to 174/200. The mean (SD) was 103.9 (31.3). Cronbach's alpha was 0.97. Test-retest reliability was 0.92. Factor analysis supported a 6-factor latent construct. Subtest reliabilities were >0.75. Individuals reporting increased TSS occurred across all demographic groups. Increased risk categories included women, white ethnicity, and limited educational opportunities. TSS was positively correlated with symptoms, depression, anxiety, loneliness, reduced self-esteem, thoughts of self-harm, post-COVID functional status, frailty, EQ5D5L score, and number of ED visits. It was negatively correlated with perceived social support, 6-min walk distance, and EQ5D5L global rating. Stigma scores were significantly increased among participants reporting employment status as disabled. Interpretation: Our findings suggested that the PCCSQ is a valid, reliable tool with which to estimate PCC-related stigma. It allows for the identification of patients reporting increased stigma and offers insights into their experiences. Funding: The Edmonton Post COVID-19 Clinic is supported by the University of Alberta and Alberta Health Services. No additional sources of funding were involved in the execution of this research study.

Pulmonary rehabilitation in chronic obstructive pulmonary disease: predictors of program completion and success.

Although participation in pulmonary rehabilitation (PR) improves the health outcomes in patients with Chronic Obstructive Pulmonary Disease (COPD), there are insufficient resources to provide PR to all patients with COPD. Thus, predicting which patients are at risk for drop-out and non-response to rehabilitation is necessary in order to optimize limited resources. This study examined which patient characteristics are predictive of PR drop-out and non-response. 814 patients with COPD took part in standard out-patient PR for 8 weeks. Demographic and standard clinical data were collected before the rehabilitation program had started. Data was analyzed retrospectively to determine if baseline patient characteristics could predict drop-out and non-response to rehabilitation. Drop-out was defined as participation in less than 50% of the rehabilitation sessions. Non-response was defined as improvement less than 4% on the St. George's Respiratory Questionnaire (SGRQ). A discriminant function analysis identified age, smoking history, and health status as predictors of patient drop-out, p < .0001, with younger, current smokers and patients with lower health status being at risk for drop-out. No variables measured significantly predicted who those at risk would be for non-response to rehabilitation, p > .05. Pulmonary function data did not predict drop-out or non-response to PR. These findings indicate that perceived impairment (i.e., health status) is more likely to influence completion of rehabilitation than actual pulmonary impairment and that demographic and standard clinical data do not adequately predict patient drop-out and non-response to rehabilitation.

Progressive Dyspnea With Recurrent Pneumothoraces.

CASE PRESENTATION: A 34-year-old previously healthy man of Korean descent (height, 174 cm; weight, 47.4 kg) demonstrated dyspnea with cough and chest tightness. The patient had no relevant occupational exposures and no history of illicit drug or tobacco use. His medical history was notable for chronic sinus tachycardia of undetermined cause, hypertension, gout, glaucoma of the right eye, and a remote history of an intracranial malignancy 24 years prior treated with unspecified chemotherapy, craniotomy, and ventriculoperitoneal shunt placement. His active medications included diltiazem, candesartan, and colchicine as needed.

Ultrasensitive detection of HIV-1 p24 antigen using nanofunctionalized surfaces in a capacitive immunosensor.

The HIV-1 capsid protein, p24 antigen, is of considerable diagnostic interest because following HIV exposure it is detectable several days earlier than host-generated HIV antibodies (which are the target of almost all current tests used in the field) and can be used to design very sensitive assays without the need for PCR. Here, we present an ultrasensitive capacitive immunosensor that is capable of detecting subattogram per milliliter concentrations of p24 antigen, which to our knowledge is the lowest level of detection ever reported. Dilution studies using p24-spiked human plasma samples indicate that the immunosensor is robust against the interfering effects of a complex biological matrix. Moreover, the capacitive immunosensor assay is rapid (<20 min), label-free, and generates data in real-time, with a portable format in development. Additional optimization of the capture agents and/or surface chemistries may further improve performance, highlighting the potential of this platform to serve as a diagnostic tool for early detection of HIV in field settings.

Multiplexed, rapid detection of H5N1 using a PCR-free nanoparticle-based genomic microarray assay.

BACKGROUND: For more than a decade there has been increasing interest in the use of nanotechnology and microarray platforms for diagnostic applications. In this report, we describe a rapid and simple gold nanoparticle (NP)-based genomic microarray assay for specific identification of avian influenza virus H5N1 and its discrimination from other major influenza A virus strains (H1N1, H3N2). RESULTS: Capture and intermediate oligonucleotides were designed based on the consensus sequences of the matrix (M) gene of H1N1, H3N2 and H5N1 viruses, and sequences specific for the hemaglutinin (HA) and neuraminidase (NA) genes of the H5N1 virus. Viral RNA was detected within 2.5 hours using capture-target-intermediate oligonucleotide hybridization and gold NP-mediated silver staining in the absence of RNA fragmentation, target amplification, and enzymatic reactions. The lower limit of detection (LOD) of the assay was less than 100 fM for purified PCR fragments and 103 TCID50 units for H5N1 viral RNA. CONCLUSIONS: The NP-based microarray assay was able to detect and distinguish H5N1 sequences from those of major influenza A viruses (H1N1, H3N2). The new method described here may be useful for simultaneous detection and subtyping of major influenza A viruses.

Pooled resistance analyses of darunavir once-daily regimens and formulations across 10 clinical studies of treatment-naïve and treatment-experienced patients with human immunodeficiency virus-1 infection.

BACKGROUND: The efficacy and high barrier to resistance of darunavir have been demonstrated across diverse populations with HIV-1 infection. OBJECTIVE: To evaluate post-baseline resistance among patients in studies of once-daily (QD) darunavir-based regimens and formulations. METHODS: The analysis included treatment-naïve and virologically failing or suppressed patients from 10 phase 2/3 studies (48-192 weeks in duration) of boosted darunavir 800 mg QD-based regimens. Three were phase 3 studies of the QD darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg single-tablet regimen. Post-baseline resistance was evaluated upon protocol-defined virologic failure (PDVF). Resistance-associated mutations (RAMs) were identified using International Antiviral Society-USA mutation lists. Phenotypic analyses varied across studies. RESULTS: Overall, 250 of 3635 patients in the analysis met PDVF criteria; 205 had post-baseline genotypes/phenotypes. In total, four (0.1%) patients developed (or had identified) ≥1 darunavir and/or primary protease inhibitor (PI) RAM; only one (<0.1%) patient (with prior lopinavir virologic failure) lost darunavir phenotypic susceptibility. Among 3317 patients using nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs; mostly emtricitabine and tenofovir), 13 (0.4%) had ≥1 N(t)RTI RAM (10 with M184I/V). Among patients receiving D/C/F/TAF (n = 1949), none had post-baseline darunavir, primary PI, or tenofovir RAMs; only two (0.1%) patients developed an emtricitabine RAM, M184V/I. CONCLUSIONS: Across a large, diverse population using darunavir 800 mg QD-based regimens and formulations, resistance development remains rare. After clinical trials that span >10 years, loss of phenotypic susceptibility to darunavir was only observed once in a PI-experienced patient and has never been observed in treatment-naïve patients, treatment-experienced PI-naïve patients, or treatment-experienced virologically suppressed patients.

Week 48 Resistance Analyses of the Once-Daily, Single-Tablet Regimen Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) in Adults Living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials.

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatment-experienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) ≥400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL <50 copies/mL) in EMERALD. Through week 48 across both studies, no darunavir, primary PI, or tenofovir resistance-associated mutations (RAMs) were observed in HIV-1 viruses of 1,125 participants receiving D/C/F/TAF or 629 receiving boosted darunavir plus emtricitabine/tenofovir-disoproxil-fumarate. In AMBER, the nucleos(t)ide analog reverse transcriptase inhibitor (N(t)RTI) RAM M184I/V was identified in HIV-1 of one participant during D/C/F/TAF treatment. M184V was detected pretreatment as a minority variant (9%). In EMERALD, in participants with prior VF and genoarchive data (N = 140; 98 D/C/F/TAF and 42 control), 4% had viruses with darunavir RAMs, 38% with emtricitabine RAMs, mainly at position 184 (41% not fully susceptible to emtricitabine), 4% with tenofovir RAMs, and 21% ≥ 3 thymidine analog-associated mutations (24% not fully susceptible to tenofovir) detected at screening. All achieved VL <50 copies/mL at week 48 or prior discontinuation. D/C/F/TAF has a high genetic barrier to resistance; no darunavir, primary PI, or tenofovir RAMs were observed through 48 weeks in AMBER and EMERALD. Only one postbaseline M184I/V RAM was observed in HIV-1 of an AMBER participant. In EMERALD, baseline archived RAMs to darunavir, emtricitabine, and tenofovir in participants with prior VF did not preclude virologic response.

From imide to lactam metallo-pyridocarbazoles: distinct scaffolds for the design of selective protein kinase inhibitors.

Organometallic pyridocarbazole scaffolds are investigated as protein kinase inhibitors. Whereas our previous designs employed solely a maleimide pharmacophore for achieving the two crucial canonical hydrogen bonds to the hinge region of the ATP binding site, we have now extended our investigations to include the related lactam metallo-pyridocarbazoles. The synthetic access of the two regioisomeric lactam pyridocarbazoles is described, and the distinct biological properties of the two lactam scaffolds are revealed by employing a ruthenium half sandwich complex as a model system, resulting in organometallic lead structures for the inhibition of the protein kinases TrkA and CLK2. These new lactam metallo-pyridocarbazoles expand our existing molecular toolbox and assist toward the generation of metal complex scaffolds as lead structures for the design of selective inhibitors for numerous kinases of the human kinome.

The effect of pulmonary rehabilitation on carotid chemoreceptor activity and sensitivity in chronic obstructive pulmonary disease.

Recent work demonstrates that carotid chemoreceptor (CC) activity/sensitivity is elevated in patients with chronic obstructive pulmonary disease (COPD) compared with healthy controls, and this elevated chemoreception appears to contribute to increased cardiovascular risk. Exercise training has been shown to normalize CC activity/sensitivity in other populations, and therefore, the purpose of this study was to determine whether pulmonary rehabilitation (PR) can reduce CC activity/sensitivity in COPD. Forty-five COPD patients [mean FEV1 (forced expiratory volume in 1 s) = 56.6% predicted] completed PR, while 15 COPD patients (mean FEV1 = 74.6% predicted) served as non-PR controls. CC activity was determined by the reduction in ventilation while breathing transient hyperoxia ([Formula: see text] = 1.0); CC sensitivity was evaluated by the increase in ventilation relative to the drop in arterial saturation while breathing hypoxia. Dyspnea, six-minute walk and autonomic function data were also obtained. PR improved 6-minute walk distance (P < 0.001) and dyspnea (P = 0.04); however, there was no effect on CC activity (P = 0.60), sensitivity (P = 0.69), or autonomic function (P > 0.05 for all). Subgroup analyses indicated that PR reduced CC activity in those with elevated baseline CC activity, independent of changes in autonomic function. No change in dyspnea (P = 0.24), CC activity (P = 0.19), sensitivity (P = 0.80), or autonomic function (P > 0.05 for all) was observed in the control group. Despite improvements in exercise tolerance and dyspnea, PR appears to be generally ineffective at reducing CC sensitivity in stable COPD patients; while PR reduced CC activity in those with elevated basal CC activity, the physiological significance of this is unclear. Further investigations aimed at improving CC function in COPD are needed.NEW & NOTEWORTHY While work in other chronic diseases has shown that exercise training may help normalize carotid chemoreceptor (CC) activity/sensitivity, the current study found that exercise training through pulmonary rehabilitation did not consistently reduce CC activity/sensitivity in patients with chronic obstructive pulmonary disease (COPD). These results suggest that other interventions are needed to normalize CC activity/sensitivity in COPD.

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naïve patients with HIV-1: subgroup analyses of the phase 3 AMBER study.

Background: The once-daily, single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is approved for the treatment of HIV-1 infection. The 48-week efficacy and safety of D/C/F/TAF versus darunavir/cobicistat + emtricitabine/tenofovir disoproxil fumarate (control) in treatment-naïve adults were demonstrated in the phase 3 AMBER study. Objective: To describe AMBER outcomes across patient subgroups based on demographic and clinical characteristics at baseline. Methods: AMBER patients had viral load (VL) ≥1000 copies/mL, CD4+ cell count >50 cells/µL, and genotypic susceptibility to darunavir, emtricitabine, and tenofovir. Primary endpoint was the proportion of patients with virologic response (VL <50 copies/mL; FDA snapshot). Safety was assessed by adverse events, estimated glomerular filtration rate (cystatin C; eGFRcystC), and bone mineral density. Outcomes were assessed by age (≤/>50 years), gender, race (black/non-black), baseline VL (≤/>100,000 copies/mL), baseline CD4+ cell count (50 years and women, relative to their comparator groups, regardless of treatment arm (notably, sample sizes were small for patients >50 years and women). Improvements in eGFRcystC and stable bone mineral density were observed with D/C/F/TAF overall, and results were generally consistent across subgroups. Conclusions: For treatment-naïve patients in AMBER, initiating therapy with the D/C/F/TAF single-tablet regimen was an effective and well-tolerated option, regardless of demographic or clinical characteristics.

The effect of carotid chemoreceptor inhibition on exercise tolerance in chronic obstructive pulmonary disease: A randomized-controlled crossover trial.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have an exaggerated ventilatory response to exercise, contributing to exertional dyspnea and exercise intolerance. We recently demonstrated enhanced activity and sensitivity of the carotid chemoreceptor (CC) in COPD which may alter ventilatory and cardiovascular regulation and negatively affect exercise tolerance. We sought to determine whether CC inhibition improves ventilatory and cardiovascular regulation, dyspnea and exercise tolerance in COPD. METHODS: Twelve mild-moderate COPD patients (FEV1 83 ±â€¯15 %predicted) and twelve age- and sex-matched healthy controls completed two time-to-symptom limitation (TLIM) constant load exercise tests at 75% peak power output with either intravenous saline or low-dose dopamine (2 µg·kg-1·min-1, order randomized) to inhibit the CC. Ventilatory responses were evaluated using expired gas data and dyspnea was evaluated using a modified Borg scale. Inspiratory capacity maneuvers were performed to determine operating lung volumes. Cardiac output was estimated using impedance cardiography and vascular conductance was calculated as cardiac output/mean arterial pressure (MAP). RESULTS: At a standardized exercise time of 4-min and at TLIM; ventilation, operating volumes and dyspnea were unaffected by dopamine in COPD patients and controls. In COPD, dopamine decreased MAP and increased vascular conductance at all time points. In controls, dopamine increased vascular conductance at TLIM, while MAP was unaffected. CONCLUSION: There was no change in time to exhaustion in either group with dopamine. These data suggest that the CC plays a role in cardiovascular regulation during exercise in COPD; however, ventilation, dyspnea and exercise tolerance were unaffected by CC inhibition in COPD patients.