Photogrammetric system and method used in the characterization of a structure

A photogrammetric system uses an array of spaced-apart targets coupled to a structure. Each target exhibits fluorescence when exposed to a broad beam of illumination. A photogrammetric imaging system located remotely with respect to the structure detects and processes the fluorescence (but not the illumination wavelength) to measure the shape of a structure

Fosamprenavir or atazanavir once daily boosted with ritonavir 100 mg, plus tenofovir/emtricitabine, for the initial treatment of HIV infection: 48-week results of ALERT

<p>Abstract</p> <p>Background</p> <p>Once-daily (QD) ritonavir 100 mg-boosted fosamprenavir 1400 mg (FPV/r100) or atazanavir 300 mg (ATV/r100), plus tenofovir/emtricitabine (TDF/FTC) 300 mg/200 mg, have not been compared as initial antiretroviral treatment. To address this data gap, we conducted an open-label, multicenter 48-week study (ALERT) in 106 antiretroviral-naïve, HIV-infected patients (median HIV-1 RNA 4.9 log₁₀copies/mL; CD4+ count 191 cells/mm³) randomly assigned to the FPV/r100 or ATV/r100 regimens.</p> <p>Results</p> <p>At baseline, the FPV/r100 or ATV/r100 arms were well-matched for HIV-1 RNA (median, 4.9 log₁₀copies/mL [both]), CD4+ count (mean, 176 vs 205 cells/mm³). At week 48, intent-to-treat: missing/discontinuation = failure analysis showed similar responses to FPV/r100 and ATV/r100 (HIV-1 RNA < 50 copies/mL: 75% (40/53) vs 83% (44/53), p = 0.34 [Cochran-Mantel-Haenszel test]); mean CD4+ count change-from-baseline: +170 vs +183 cells/mm³, p = 0.398 [Wilcoxon rank sum test]). Fasting total/LDL/HDL-cholesterol changes-from-baseline were also similar, although week 48 median fasting triglycerides were higher with FPV/r100 (150 vs 131 mg/dL). FPV/r100-treated patients experienced fewer treatment-related grade 2–4 adverse events (15% vs 57%), with differences driven by ATV-related hyperbilirubinemia. Three patients discontinued TDF/FTC because their GFR decreased to <50 mL/min.</p> <p>Conclusion</p> <p>The all-QD regimens of FPV/r100 and ATV/r100, plus TDF/FTC, provided similar virologic, CD4+ response, and fasting total/LDL/HDL-cholesterol changes through 48 weeks. Fewer FPV/r100-treated patients experienced treatment-related grade 2–4 adverse events.</p

Twice-daily amprenavir 1200 mg versus amprenavir 600 mg/ritonavir 100 mg, in combination with at least 2 other antiretroviral drugs, in HIV-1-infected patients

BACKGROUND: Low-dose ritonavir (RTV) boosts plasma amprenavir (APV) exposure. Little has been published on the efficacy, tolerability, and safety of APV 600 mg/RTV 100 mg (APV600/RTV) twice daily (BID) compared to APV 1200 mg BID (APV1200). METHODS: ESS40011 was a 24-week, multicenter, open-label, clinical trial in which antiretroviral therapy-naïve and -experienced HIV-1-infected adults were randomized 3:1 to receive either APV600/RTV BID or APV1200 BID, in combination with ≥ 2 non-protease inhibitor antiretroviral drugs. Non-inferiority of the APV600/RTV regimen to the APV1200 regimen was established if the 95% lower confidence limit for the difference in proportion of patients achieving HIV-1 RNA <200 copies/mL at week 24 with APV 600/RTV minus APV1200 was ≥-0.12. Late in the conduct of the trial, patients not yet completing 24 weeks of therapy were given the option of continuing treatment for an additional 24-week period. RESULTS: 211 patients were randomized, 158 to APV600/RTV and 53 to APV1200. At week 24, APV600/RTV was similar to or better than APV1200 (HIV-1 RNA <200 copies/mL in 62% [73/118] vs 53% [20/38] of patients; intent-to-treat: observed analysis). In the APV600/RTV arm, significantly more patients achieved HIV-1 RNA <50 copies/mL (48% [57/118] vs 29% [11/38] with APV1200, P = 0.04), and greater mean reduction from baseline in HIV-1 RNA was observed (-2.21 vs -1.59 log(10 )copies/mL, P = 0.028). The two treatment arms were similar with respect to mean overall change from baseline in CD4+ count, frequency of drug-related grade 1–4 adverse events, and frequency of discontinuing treatment due to adverse events (most commonly nausea, diarrhea, vomiting or fatigue; 7% vs 8%), although a lower proportion of patients in the APV600/RTV arm experienced drug-related oral/perioral paresthesia (2% vs 8%). Eleven (73%) of 15 patients who had HIV-1 RNA <200 copies/mL at week 24 and chose to continue study treatment maintained this level of virologic suppression at follow-up 24 weeks later. CONCLUSIONS: APV600 RTV BID was similar to or better than APV1200 BID in virologic response. Virologic results in a small number of patients who continued treatment for 24 weeks post-study suggest that virologic suppression with APV600 RTV BID is durable

Natural History of Very Early Onset Inflammatory Bowel Disease in North America: A Retrospective Cohort Study

Background: The incidence of very early onset inflammatory bowel disease (VEOIBD) is increasing, yet the phenotype and natural history of VEOIBD are not well described. Methods: We performed a retrospective cohort study of patients diagnosed with VEOIBD (6 years of age and younger) between 2008 and 2013 at 25 North American centers. Eligible patients at each center were randomly selected for chart review. We abstracted data at diagnosis and at 1, 3, and 5 years after diagnosis. We compared the clinical features and outcomes with VEOIBD diagnosed younger than 3 years of age with children diagnosed with VEOIBD at age 3 to 6 years. Results: The study population included 269 children (105 [39%] Crohn\u27s disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). The median age of diagnosis was 4.2 years (interquartile range 2.9-5.2). Most (94%) Crohn\u27s disease patients had inflammatory disease behavior (B1). Isolated colitis (L2) was the most common disease location (70% of children diagnosed younger than 3 years vs 43% of children diagnosed 3 years and older; P = 0.10). By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children. The risk of any bowel surgery in Crohn\u27s disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis. Most ulcerative colitis patients had pancolitis (57% of children diagnosed younger than 3 years vs 45% of children diagnosed 3 years and older; P = 0.18). The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis. Conclusions: Very early onset inflammatory bowel disease has a distinct phenotype with predominantly colonic involvement and infrequent stricturing/penetrating disease. The cumulative risk of bowel surgery in children with VEOIBD was approximately 14%-15% by 5 years. These data can be used to provide anticipatory guidance in this emerging patient population

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Impact of Low Abundance HIV Variants on Response to Ritonavir-Boosted Atazanavir or Fosamprenavir Given Once Daily with Tenofovir/Emtricitabine in Antiretroviral-Naive HIV-Infected Patients

Population genotyping (PG) can underestimate resistance if resistance-containing low abundance variants go undetected. PG and clonal analysis (CA) results were compared in virologic failures (VFs) from a 48-week clinical trial that evaluated once-daily fosamprenavir/ritonavir (FPV/r) 1400 mg/100 mg or atazanavir/ritonavir (ATV/r) 300 mg/100 mg, each combined with tenofovir/emtricitabine, in antiretroviral-naive patients. VF was defined as confirmed HIV-1 RNA ≥400 copies/ml at ≥24 weeks or viral rebound >400 copies/ml any time following viral suppression. All patients had baseline PG. One hundred and six patients enrolled (53/arm). Baseline resistance mutations were more prevalent in patients receiving FPV/r (10/53) than ATV/r (3/53). Seven patients (7%) were VFs-four on FPV/r and three on ATV/r. In the four FPV/r-treated VFs, baseline HIV TAMs combinations and/or PI mutations were detected in one by PG at VF (RT: L210W + T215C; PR: M46I + L76V) and three others by CA alone (RT: L210W + T215Y; RT: M41L; RT: K65R + K70R; PR: I47V); all four had study drug-associated mutations (CA detecting more HIV-1 resistance mutations than PG). In the three ATV/r VFs, no baseline drug-associated mutations were detected by PG; for one patient CA detected RT: K65R; PR: I84V. Phylogenetic analysis revealed tight clustering for FPV/r-treated VFs with highly related clones, whereas HIV-1 from ATV/r-treated VFs had no outgrowth from baseline of low abundance resistance-containing variants. In conclusion, low-abundance HIV resistance-containing variants were detected in baseline samples from patients with VF. The archived viruses that reemerged under selection pressure and acquired additional mutations were found primarily in patients in the FPV/r arm. Despite this and a baseline resistance imbalance between the two arms, FPV/r and ATV/r provided similar virologic suppression through 48 weeks; however, these findings highlight the necessity for the development of quick and inexpensive methods for detection of minority species to better guide therapy selection

Atazanavir Plus Ritonavir or Efavirenz as Part of a 3-Drug Regimen for Initial Treatment of HIV-1: A Randomized Trial

BACKGROUND: Limited data compare once-daily options for initial therapy for HIV-1. OBJECTIVE: To compare time to virologic failure; first grade-3 or -4 sign, symptom, or laboratory abnormality (safety); and change or discontinuation of regimen (tolerability) for atazanavir plus ritonavir with efavirenz-containing initial therapy for HIV-1. DESIGN: A randomized equivalence trial accrued from September 2005 to November 2007, with median follow-up of 138 weeks. Regimens were assigned by using a central computer, stratified by screening HIV-1 RNA level less than 100 000 copies/mL or 100 000 copies/mL or greater; blinding was known only to the site pharmacist. (ClinicalTrials.gov registration number: NCT00118898) SETTING: 59 AIDS Clinical Trials Group sites in the United States and Puerto Rico. PATIENTS: Antiretroviral-naive patients. INTERVENTION: Open-label atazanavir plus ritonavir or efavirenz, each given with with placebo-controlled abacavir–lamivudine or tenofovir disoproxil fumarate (DF)–emtricitabine. MEASUREMENTS: Primary outcomes were time to virologic failure, safety, and tolerability events. Secondary end points included proportion of patients with HIV-1 RNA level less than 50 copies/mL, emergence of drug resistance, changes in CD4 cell counts, calculated creatinine clearance, and lipid levels. RESULTS: 463 eligible patients were randomly assigned to receive atazanavir plus ritonavir and 465 were assigned to receive efavirenz, both with abacavir–lamivudine; 322 (70%) and 324 (70%), respectively, completed follow-up. The respective numbers of participants in each group who received tenofovir DF–emtricitabine were 465 and 464; 342 (74%) and 343 (74%) completed follow-up. Primary efficacy was similar in the group that received atazanavir plus ritonavir and and the group that received efavirenz and did not differ according to whether abacavir–lamivudine or tenofovir DF–emtricitabine was also given. Hazard ratios for time to virologic failure were 1.13 (95% CI, 0.82 to 1.56) and 1.01 (CI, 0.70 to 1.46), respectively, although CIs did not meet prespecified criteria for equivalence. The time to safety (P = 0.048) and tolerability (P < 0.001) events was longer in persons given atazanavir plus ritonavir than in those given efavirenz with abacavir–lamivudine but not with tenofovir DF–emtricitabine. LIMITATIONS: Neither HLA-B*5701 nor resistance testing was the standard of care when A5202 enrolled patients. The third drugs, atazanavir plus ritonavir and efavirenz, were open-label; the nucleoside reverse transcriptase inhibitors were prematurely unblinded in the high viral load stratum; and 32% of patients modified or discontinued treatment with their third drug. CONCLUSION: Atazanavir plus ritonavir and efavirenz have similar antiviral activity when used with abacavir–lamivudine or tenofovir DF–emtricitabine. PRIMARY FUNDING SOURCE: National Institutes of Health