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RATIONALE Whereas non-invasive ventilation (NIV) may prevent reintubation in patients at high-risk of extubation failure in intensive care units (ICUs), this oxygenation strategy has not been specifically assessed in obese patients. OBJECTIVES We hypothesized that NIV may decrease the risk of reintubation in obese patients compared with high-flow nasal oxygen (HFNO). METHODS Post-hoc analysis of a multicenter, randomized, controlled trial (not pre-specified) comparing NIV alternating with HFNO versus HFNO alone after extubation, with the aim of assessing NIV effects according to patient body-mass index (BMI). MEASUREMENTS AND MAIN RESULTS Among 623 patients at high-risk of extubation failure, 206 (33%) were obese (BMI≥30 kg/m2), 204 (33%) were overweight (25≤BMI

BACKGROUND: The use of noninvasive ventilation (NIV) is debated in de novo respiratory failure. Prolonged sessions, using a dedicated NIV ventilator, with high PEEP levels could be associated with better outcomes than shorter sessions using an ICU ventilator, with low PEEP levels. We performed a systematic review of randomized controlled trials to test whether the incidence of intubation was influenced by the NIV protocol in subjects admitted to the ICU for de novo respiratory failure. METHODS: We selected randomized trials on NIV indexed in medical literature databases from their inception to April 2018. Pediatric studies, those performed outside of the ICU, trials with subjects on NIV for a reason other than de novo respiratory failure, and studies in which NIV protocol was not specified were excluded. Two authors independently extracted intubation rates and the NIV protocol (prolonged or short sessions, type of ventilator, and PEEP levels). RESULTS: Fourteen studies, which included 750 subjects treated with NIV for de novo respiratory failure in ICU, were analyzed. Overall intubation rate was 38%, 95% CI 31–45% and was not influenced by prolonged NIV sessions or the type of ventilator. The 154 subjects treated with PEEP greater than the median overall PEEP (6 cm H2O) had a PEEP level of 8 ± 2 cm H2O and a pressure support level of 7 ± 2 cm H2O. Their intubation rate was lower than the 293 subjects treated with lower PEEP levels (25%, 95% CI 15–37% vs 43%, 95% CI 33–54%, respectively, P = .03). Inclusion criteria were heterogeneous, and critical information on NIV application were frequently lacking. CONCLUSIONS: Except for high PEEP levels that might be associated with lower intubation rates, the protocol for carrying out NIV does not seem to influence intubation rate in patients with de novo respiratory failure.

The World Health Organization recommends dolutegravir with two nucleoside reverse-transcriptase inhibitors (NRTIs) for second-line treatment of human immunodeficiency virus type 1 (HIV-1) infection. Evidence is limited for the efficacy of this regimen when NRTIs are predicted to lack activity because of drug resistance, as well as for the recommended switch of an NRTI from tenofovir to zidovudine.In a two-by-two factorial, open-label, noninferiority trial, we randomly assigned patients for whom first-line therapy was failing (HIV-1 viral load, ≥1000 copies per milliliter) to receive dolutegravir or ritonavir-boosted darunavir and to receive tenofovir or zidovudine; all patients received lamivudine. The primary outcome was a week 48 viral load of less than 400 copies per milliliter, assessed with the Food and Drug Administration snapshot algorithm (noninferiority margin for the between-group difference in the percentage of patients with the primary outcome, 12 percentage points).We enrolled 464 patients at seven sub-Saharan African sites. A week 48 viral load of less than 400 copies per milliliter was observed in 90.2% of the patients in the dolutegravir group (212 of 235) and in 91.7% of those in the darunavir group (210 of 229) (difference, -1.5 percentage points; 95% confidence interval [CI], -6.7 to 3.7; P = 0.58; indicating noninferiority of dolutegravir, without superiority) and in 92.3% of the patients in the tenofovir group (215 of 233) and in 89.6% of those in the zidovudine group (207 of 231) (difference, 2.7 percentage points; 95% CI, -2.6 to 7.9; P = 0.32; indicating noninferiority of tenofovir, without superiority). In the subgroup of patients with no NRTIs that were predicted to have activity, a viral load of less than 400 copies per milliliter was observed in more than 90% of the patients in the dolutegravir group and the darunavir group. The incidence of adverse events did not differ substantially between the groups in either factorial comparison.Dolutegravir in combination with NRTIs was effective in treating patients with HIV-1 infection, including those with extensive NRTI resistance in whom no NRTIs were predicted to have activity. Tenofovir was noninferior to zidovudine as second-line therapy. (Funded by Janssen; NADIA ClinicalTrials.gov number, NCT03988452.).

Background Spontaneous breathing trial (SBT) using a T-piece remains the most frequently performed trial before extubation in ICUs. Research Question We aimed at determining whether initial SBT using pressure-support ventilation (PSV) could increase successful extubation rates among patients at high risk of extubation failure. Study Design and Methods Post hoc analysis of a multicenter trial focusing on reintubation in patients at high-risk of extubation failure. The initial SBT was performed using PSV or T-piece according to the physician/center decision. The primary outcome was the proportion of patients successfully extubated 72 hours after initial SBT, that is, extubated after initial SBT and not reintubated within the following 72 hours. Results Among the 641 patients included in the original study, initial SBT was performed using PSV (7.0 cm H2O in median without positive end-expiratory pressure) in 243 patients (38%) and using a T-piece in 398 patients (62%). The proportion of patients successfully extubated 72 hours after initial SBT was 67% (162/243) using PSV and 56% (223/398) using T-piece (absolute difference 10.6%; 95% CI, 2.8 to 28.1; P = .0076). The proportion of patients extubated after initial SBT was 77% (186/283) using PSV and 63% (249/398) using T-piece (P = .0002), whereas reintubation rates within the following 72 hours did not significantly differ (13% vs 10%, respectively; P = .4259). Performing an initial SBT using PSV was independently associated with successful extubation (adjusted OR, 1.60; 95% CI, 1.30 to 2.18; P = .0061). Interpretation In patients at high risk of extubation failure in the ICU, performing an initial SBT using PSV may hasten extubation without an increased risk of reintubation.

Background HIV is transmitted primarily through sexual intercourse, and the objective of this study was therefore to assess whether there is occult viral replication and resistance in genital secretions in patients on protease inhibitor (PI)-based second-line therapy. Methods HIV-infected adults taking ritonavir-boosted lopinavir with either two nucleoside reverse transcriptase inhibitors (NRTIs), raltegravir or as monotherapy for 96 weeks, were enrolled at seven clinical sites in Uganda. Viral load (VL) was measured in cervico-vaginal secretions or semen and in a corresponding plasma sample. Genotypic resistance was assessed in genital secretion samples and plasma samples. Results were compared between compartments and with the plasma resistance profile at first-line failure. Results Of the 111 participants enrolled (91 female, 20 male), 16 (14%) and 30 (27%) had VL >1,000 and >40 copies/ml, respectively, in plasma; 3 (3%) and 23 (21%) had VL >1,000 copies/ml and >40 copies/ml, respectively, in genital secretions. There was 74% agreement between plasma and genital secretion VL classification above/below 40 copies/ml threshold (kappa-statistic =0.29; P=0.001). RT mutations (both NRTI and non-nucleoside reverse transcriptase inhibitor) were detected in genital secretions in four patients (similar profile to corresponding plasma sample at first-line failure) and PI mutations were detected in two (one polymorphism with no impact on resistance; one with high-level PI resistance). Conclusions High level (>1,000 copies/ml) viral replication and development of new RT or PI resistance in the genital compartment were rare. The risks of transmission arising from resistance evolution in the genital compartment are likely to be low on PI-based second-line therapy.

Background Phylogenetic mapping of HIV-1 lineages circulating across defined geographical locations is promising for better understanding HIV transmission networks to design optimal prevention interventions. Methods We obtained near full-length HIV-1 genome sequences from people living with HIV (PLWH), including participants on antiretroviral treatment in the Botswana Combination Prevention Project, conducted in 30 Botswana communities in 2013–2018. Phylogenetic relationships among viral sequences were estimated by maximum likelihood. Results We obtained 6078 near full-length HIV-1C genome sequences from 6075 PLWH. We identified 984 phylogenetically distinct HIV-1 lineages (molecular HIV clusters) circulating in Botswana by mid-2018, with 2–27 members per cluster. Of these, dyads accounted for 62%, approximately 32% (n = 316) were found in single communities, and 68% (n = 668) were spread across multiple communities. Men in clusters were approximately 3 years older than women (median age 42 years, vs 39 years; P Conclusions A large number of circulating phylogenetically distinct HIV-1C lineages (molecular HIV clusters) suggests highly diversified HIV transmission networks across Botswana communities by 2018.

To assess the benefit-to-risk balance of bronchoalveolar lavage (BAL) in intensive care unit (ICU) patients. In 16 ICUs, we prospectively collected adverse events during or within 24 h after BAL and assessed the BAL input for decision making in consecutive adult patients. The occurrence of a clinical adverse event at least of grade 3, i.e., sufficiently severe to need therapeutic action(s), including modification(s) in respiratory support, defined poor BAL tolerance. The BAL input for decision making was declared satisfactory if it allowed to interrupt or initiate one or several treatments. We included 483 BAL in 483 patients [age 63 years (interquartile range (IQR) 53–72); female gender: 162 (33.5%); simplified acute physiology score II: 48 (IQR 37-61); immunosuppression 244 (50.5%)]. BAL was begun in non-intubated patients in 105 (21.7%) cases. Sixty-seven (13.9%) patients reached the grade 3 of adverse event or higher. Logistic regression showed that a BAL performed by a non-experienced physician (non-pulmonologist, or intensivist with less than 10 years in the specialty or less than 50 BAL performed) was the main predictor of poor BAL tolerance in non-intubated patients [OR: 3.57 (95% confidence interval 1.04–12.35); P = 0.04]. A satisfactory BAL input for decision making was observed in 227 (47.0%) cases and was not predictable using logistic regression. Adverse events related to BAL in ICU patients are not infrequent nor necessarily benign. Our findings call for an extreme caution, when envisaging a BAL in ICU patients and for a mandatory accompaniment of the less experienced physicians.

International audience; Background: International and global organisations advocate targeting interventions to areas of high HIV prevalence (ie, hotspots). To better understand the potential benefits of geo-targeted control, we assessed the extent to which HIV hotspots along Lake Victoria sustain transmission in neighbouring populations in south-central Uganda.Methods: We did a population-based survey in Rakai, Uganda, using data from the Rakai Community Cohort Study. The study surveyed all individuals aged 15-49 years in four high-prevalence Lake Victoria fishing communities and 36 neighbouring inland communities. Viral RNA was deep sequenced from participants infected with HIV who were antiretroviral therapy-naive during the observation period. Phylogenetic analysis was used to infer partial HIV transmission networks, including direction of transmission. Reconstructed networks were interpreted through data for current residence and migration history. HIV transmission flows within and between high-prevalence and low-prevalence areas were quantified adjusting for incomplete sampling of the population.Findings: Between Aug 10, 2011, and Jan 30, 2015, data were collected for the Rakai Community Cohort Study. 25 882 individuals participated, including an estimated 75·7% of the lakeside population and 16·2% of the inland population in the Rakai region of Uganda. 5142 participants were HIV-positive (2703 [13·7%] in inland and 2439 [40·1%] in fishing communities). 3878 (75·4%) people who were HIV-positive did not report antiretroviral therapy use, of whom 2652 (68·4%) had virus deep-sequenced at sufficient quality for phylogenetic analysis. 446 transmission networks were reconstructed, including 293 linked pairs with inferred direction of transmission. Adjusting for incomplete sampling, an estimated 5·7% (95% credibility interval 4·4-7·3) of transmissions occurred within lakeside areas, 89·2% (86·0-91·8) within inland areas, 1·3% (0·6-2·6) from lakeside to inland areas, and 3·7% (2·3-5·8) from inland to lakeside areas.Interpretation: Cross-community HIV transmissions between Lake Victoria hotspots and surrounding inland populations are infrequent and when they occur, virus more commonly flows into rather than out of hotspots. This result suggests that targeted interventions to these hotspots will not alone control the epidemic in inland populations, where most transmissions occur. Thus, geographical targeting of high prevalence areas might not be effective for broader epidemic control depending on underlying epidemic dynamics.Funding: The Bill & Melinda Gates Foundation, the National Institute of Allergy and Infectious Diseases, the National Institute of Mental Health, the National Institute of Child Health and Development, the Division of Intramural Research of the National Institute for Allergy and Infectious Diseases, the World Bank, the Doris Duke Charitable Foundation, the Johns Hopkins University Center for AIDS Research, and the President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention.

OBJECTIVE: To assess neurocognitive function at the first-line antiretroviral therapy failure and change on the second-line therapy. DESIGN: Randomized controlled trial was conducted in 5 sub-Saharan African countries. METHODS: Patients failing the first-line therapy according to WHO criteria after >12 months on non-nucleoside reverse transcriptase inhibitors-based regimens were randomized to the second-line therapy (open-label) with lopinavir/ritonavir (400 mg/100 mg twice daily) plus either 2-3 clinician-selected nucleoside reverse transcriptase inhibitors, raltegravir, or as monotherapy after 12-week induction with raltegravir. Neurocognitive function was tested at baseline, weeks 48 and 96 using color trails tests 1 and 2, and the Grooved Pegboard test. Test results were converted to an average of the 3 individual test z-scores. RESULTS: A total of 1036 patients (90% of those >18 years enrolled at 13 evaluable sites) had valid baseline tests (58% women, median: 38 years, viral load: 65,000 copies per milliliter, CD4 count: 73 cells per cubic millimeter). Mean (SD) baseline z-score was -2.96 (1.74); lower baseline z-scores were independently associated with older age, lower body weight, higher viral load, lower hemoglobin, less education, fewer weekly working hours, previous central nervous system disease, and taking fluconazole (P < 0.05 in multivariable model). Z-score was increased by mean (SE) of +1.23 (0.04) after 96 weeks on the second-line therapy (P < 0.001; n = 915 evaluable), with no evidence of difference between the treatment arms (P = 0.35). CONCLUSIONS: Patients in sub-Saharan Africa failing the first-line therapy had low neurocognitive function test scores, but performance improved on the second-line therapy. Regimens with more central nervous system-penetrating drugs did not enhance neurocognitive recovery indicating this need not be a primary consideration in choosing a second-line regimen.

BACKGROUND: Limited viral load (VL) testing in HIV-infected individuals on treatment in low-income countries often results in late detection of treatment failure. The impact of remaining on failing second-line, protease inhibitor (PI) containing regimens is unclear. METHODS: We retrospectively tested VL from 2,164 stored plasma samples from 386 patients randomised to receive PI-monotherapy (ritonavir-boosted lopinavir, after initial PI+raltegravir induction) in the EARNEST trial. Protease genotypic resistance testing was performed in samples with VL>1000 copies/ml. We assessed evolution of drug resistance mutations from virological failure (confirmed VL>1000 copies/ml) until discontinuation of PI-monotherapy and examined associations using Poisson and linear mixed-effects models. RESULTS: 118 patients had a median 68(IQR 48-88) weeks on PI-monotherapy post-failure. At failure, 21/107(20%) had intermediate/high resistance to lopinavir. 40-48 weeks post-failure, 49/72(68%) and 36/71(51%) had intermediate/high-level resistance to lopinavir and atazanavir. Most remained susceptible to darunavir (12/72[17%] intermediate, no high resistance). Common PI mutations were M46I, I54V, and V82A. On average, 1.7(95% CI 1.5,2.0) PI mutations developed per year; this increased after the first mutation developed, but decreased with subsequent mutations (p

Phylogenetic analysis of pathogens is an increasingly powerful way to reduce the spread of epidemics, including HIV. As a result, phylogenetic approaches are becoming embedded in public health and research programmes, as well as outbreak responses, presenting unique ethical, legal, and social issues that are not adequately addressed by existing bioethics literature. We formed a multidisciplinary working group to explore the ethical issues arising from the design of, conduct in, and use of results from HIV phylogenetic studies, and to propose recommendations to minimise the associated risks to both individuals and groups. We identified eight key ethical domains, within which we highlighted factors that make HIV phylogenetic research unique. In this Review, we endeavoured to provide a framework to assist researchers, public health practitioners, and funding institutions to ensure that HIV phylogenetic studies are designed, done, and disseminated in an ethical manner. Our conclusions also have broader relevance for pathogen phylogenetics. ispartof: LANCET HIV vol:5 issue:11 pages:E656-E666 ispartof: location:Netherlands status: published

Background Variability exists between ICUs in the limitations of therapy. Moreover practices may evolve over time. This single-center observational study aimed to compare withholding or withdrawing practices between 2012 and 2016. Methods For each period and patient concerned by limitations, withholding “do-not start”, withholding “do-not-increase” and withdrawal measures were recorded. Results At a four-year interval, the rate of patients undergoing withholding or withdrawal rose from 10 to 23% and 4 to 7%, respectively. The proportion of patients dying in the ICU with previous limitations increased (53 to 89%), as did patients discharged alive despite withholding instructions (12 to 36%). The overall mortality (28%) was stable over time as the rate of failed resuscitation attempt declined (47 to 11%). In 2016 vs 2012, limitations started earlier following admission: 1 vs 7 days for withholding” do-not-start”, 4 vs 8 for withholding “do-not-increase”, 4 vs 7 for withdrawal. Notwithstanding the outcome and limitations applied, the median length of ICU stay of patients involved dropped from 13 days in 2012 to 8 days in 2016. Conclusion A timely inclination to forego hopeless treatments resulted in a lower rate of failed resuscitations before death without change in global mortality.

Interstitial deletions of chromosome 12p are rare, and the phenotype spectrum is therefore still unknown. The thirteen patients reported so far suffer from developmental delay, optic nerve hypoplasia, micropenis, hypoplastic hair and skin, oligodontia, brachydactyly, and arterial hypertension. We report a de novo 12p12.2–p11.22 deletion of 9.2 Mb detected by array CGH analysis in a boy with global developmental delay, muscular hypotonia, postnatal microcephaly, facial dysmorphism including small ears, epicanthus, broad nasal bridge and hypoplastic nostrils. In addition, the patient had optic nerve atrophy, inverted nipples, micropenis, and a hemangioma. The deleted region encompasses more than 40 reference genes. We compare phenotype and deletion extent of our index patient to that of previous reports and thereby contribute to the understanding of interstitial 12p deletion phenotypes. Knowledge of the pattern of this deletion phenotype will help clinicians to diagnose this abnormality in their patients and to counsel the parents accordingly. Further descriptions may be able to contribute to the clarification.

Supplemental Digital Content is Available in the Text., Objective: To determine drug resistance mutation (DRM) patterns in a large cohort of patients failing nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy regimens in programs without routine viral load (VL) monitoring and to examine intersubtype differences in DRMs. Design: Sequences from 787 adults/adolescents who failed an NNRTI-based first-line regimen in 13 clinics in Uganda, Kenya, Zimbabwe, and Malawi were analyzed. Multivariable logistic regression was used to determine the association between specific DRMs and Stanford intermediate-/high-level resistance and factors including REGA subtype, first-line antiretroviral therapy drugs, CD4, and VL at failure. Results: The median first-line treatment duration was 4 years (interquartile range 30–43 months); 42% of participants had VL ≥100,000 copies/mL and 63% participants had CD4

Diffuse cutaneous mastocytosis is a less common but potentially life-threatening variant of childhood mastocytosis. Here we report 2 children with diffuse cutaneous mastocytosis in whom an activating somatic KIT mutation was detected. Treatment with imatinib, a KIT inhibitor, resulted in resolution of the lesions and were well tolerated by the patients.

BACKGROUND: The efficacy and toxic effects of nucleoside reverse-transcriptase inhibitors (NRTIs) are uncertain when these agents are used with a protease inhibitor in second-line therapy for human immunodeficiency virus (HIV) infection in resource-limited settings. Removing the NRTIs or replacing them with raltegravir may provide a benefit. METHODS: In this open-label trial in sub-Saharan Africa, we randomly assigned 1277 adults and adolescents with HIV infection and first-line treatment failure to receive a ritonavir-boosted protease inhibitor (lopinavir-ritonavir) plus clinician-selected NRTIs (NRTI group, 426 patients), a protease inhibitor plus raltegravir in a superiority comparison (raltegravir group, 433 patients), or protease-inhibitor monotherapy after 12 weeks of induction therapy with raltegravir in a noninferiority comparison (monotherapy group, 418 patients). The primary composite end point, good HIV disease control, was defined as survival with no new World Health Organization stage 4 events, a CD4+ count of more than 250 cells per cubic millimeter, and a viral load of less than 10,000 copies per milliliter or 10,000 copies or more with no protease resistance mutations at week 96 and was analyzed with the use of imputation of data (≤4%). RESULTS: Good HIV disease control was achieved in 60% of the patients (mean, 255 patients) in the NRTI group, 64% of the patients (mean, 277) in the raltegravir group (P=0.21 for the comparison with the NRTI group; superiority of raltegravir not shown), and 55% of the patients (mean, 232) in the monotherapy group (noninferiority of monotherapy not shown, based on a 10-percentage-point margin). There was no significant difference in rates of grade 3 or 4 adverse events among the three groups (P=0.82). The viral load was less than 400 copies per milliliter in 86% of patients in the NRTI group, 86% in the raltegravir group (P=0.97), and 61% in the monotherapy group (P

Nuclear domain 10 (ND10s), or promyelocytic leukemia protein (PML) nuclear bodies, are spherical nuclear structures that require PML proteins for their formation. Many viruses target these structures during infection. The E4 Orf3 protein of adenovirus 5 (Ad5) rearranges ND10s, causing PML to colocalize with Orf3 in nuclear tracks or fibers. There are six different PML isoforms (I to VI) present at ND10s, all sharing a common N terminus but with structural differences at their C termini. In this study, PML II was the only one of these six isoforms that was found to interact directly and specifically with Ad5 E4 Orf3 in vitro and in vivo; these results define a new Orf3 activity. Three of a series of 18 mutant Orf3 proteins were unable to interact with PML II; these were also unable to cause ND10 rearrangement. Moreover, in PML-null cells that contained neoformed ND10s comprising a single PML isoform, only ND10s formed of PML II were rearranged by Orf3. These data show that the interaction between Orf3 and PML II is necessary for ND10 rearrangement to occur. Finally, Orf3 was shown to self-associate in vitro. This activity was absent in mutant Orf3 proteins that were unable to form tracks and to bind PML II. Thus, Orf3 oligomerization may mediate the formation of nuclear tracks in vivo and may also be important for PML II binding.

Objective To establish a hospital-based nocturnal hemodialysis (NHD) program for children and adolescents. Study design Sixteen patients (age, 0.5 to 17 years) were prospectively included. Uremia-associated measures as well as amount and dosage of medication were enumerated. Quality of life also was evaluated. Results were compared with data of the same patients on conventional hemodialysis and with matched control subjects (conventional HD). Results NHD was well tolerated. Median Kt/V values increased. Predialytic mean arterial pressure, urea, phosphate, and parathyroid hormone levels decreased. There was an increase in protein catabolic rate. Dietary and fluid restrictions could be lifted. Amount and dosage of phosphate and potassium binders and antihypertensive medication could be reduced. Quality of life improved and days of absence from school decreased in all patients. Conclusions In addition to a better control of uremia-associated measures, NHD allows free dietary and fluid intake and improves patient well-being. Given the continuing shortage of donor organs for kidney transplantation and the high morbidity and mortality on conventional HD, intensified dialysis regimens are a much-needed therapeutic option.