Temporary increase in circulating replication-competent latent HIV-infected resting CD4+ T cells after switch to an integrase inhibitor based antiretroviral regimen.

BACKGROUND: The principal barrier to an HIV cure is the presence of the latent viral reservoir (LVR), which has been understudied in African populations. From 2018 to 2019, Uganda instituted a nationwide rollout of ART consisting of Dolutegravir (DTG) with two NRTI, which replaced the previous regimen of one NNRTI and the same two NRTI. METHODS: Changes in the inducible replication-competent LVR (RC-LVR) of ART-suppressed Ugandans with HIV (n = 88) from 2015 to 2020 were examined using the quantitative viral outgrowth assay. Outgrowth viruses were examined for viral evolution. Changes in the RC-LVR were analyzed using three versions of a Bayesian model that estimated the decay rate over time as a single, linear rate (model A), or allowing for a change at time of DTG initiation (model B&C). FINDINGS: Model A estimated the slope of RC-LVR change as a non-significant positive increase, which was due to a temporary spike in the RC-LVR that occurred 0-12 months post-DTG initiation (p < 0.005). This was confirmed with models B and C; for instance, model B estimated a significant decay pre-DTG initiation with a half-life of 6.9 years, and an ∼1.7-fold increase in the size of the RC-LVR post-DTG initiation. There was no evidence of viral failure or consistent evolution in the cohort. INTERPRETATION: These data suggest that the change from NNRTI- to DTG-based ART is associated with a significant temporary increase in the circulating RC-LVR. FUNDING: Supported by the NIH (grant 1-UM1AI164565); Gilead HIV Cure Grants Program (90072171); Canadian Institutes of Health Research (PJT-155990); and Ontario Genomics-Canadian Statistical Sciences Institute.

Prevalence of sexually transmitted infections among transgender women living with and without HIV in the eastern and southern United States.

BACKGROUND: Data on the epidemiology of sexually transmitted infections (STIs) among transgender women (TGW) with and without HIV are limited. METHODS: We analyzed baseline data collected from a cohort of adult TGW across 6 eastern and southern US cities between March 2018-August 2020 (n = 1,018). Participants completed oral HIV screening, provided self-collected rectal and urogenital specimens for chlamydia and gonorrhea testing, and provided sera specimens for syphilis testing. We assessed associations with ≥1 prevalent bacterial STI using modified Poisson regression. RESULTS: Bacterial STI prevalence was high and differed by HIV status: 32% among TGW with HIV and 11% among those without HIV (demographic-adjusted prevalence ratio = 1.91 [95%CI = 1.39-2.62]). Among TGW without HIV, bacterial STI prevalence differed by geographic region, race and ethnicity, and gender identity, and was positively associated with reporting >1 sexual partner, hazardous alcohol use, homelessness, having safety concerns regarding transit to healthcare, and no prior receipt of gender-affirming health services. Among TGW with HIV, older age was inversely associated with bacterial STI. CONCLUSIONS: TGW had a high prevalence of bacterial STIs. The prevalence and correlates of bacterial STI differed by HIV status, highlighting the unique needs and risks of TGW with and without HIV. Tailored interventions may reduce sexual health-related inequities.

Temporary increase in circulating replication-competent latent HIV-infected resting CD4+ T cells after switch to an integrase inhibitor based antiretroviral regimen.

The principal barrier to an HIV cure is the presence of a latent viral reservoir (LVR) made up primarily of latently infected resting CD4+ (rCD4) T-cells. Studies in the United States have shown that the LVR decays slowly (half-life=3.8 years), but this rate in African populations has been understudied. This study examined longitudinal changes in the inducible replication competent LVR (RC-LVR) of ART-suppressed Ugandans living with HIV (n=88) from 2015-2020 using the quantitative viral outgrowth assay, which measures infectious units per million (IUPM) rCD4 T-cells. In addition, outgrowth viruses were examined with site-directed next-generation sequencing to assess for possible ongoing viral evolution. During the study period (2018-19), Uganda instituted a nationwide rollout of first-line ART consisting of Dolutegravir (DTG) with two NRTI, which replaced the previous regimen that consisted of one NNRTI and the same two NRTI. Changes in the RC-LVR were analyzed using two versions of a novel Bayesian model that estimated the decay rate over time on ART as a single, linear rate (model A) or allowing for an inflection at time of DTG initiation (model B). Model A estimated the population-level slope of RC-LVR change as a non-significant positive increase. This positive slope was due to a temporary increase in the RC-LVR that occurred 0-12 months post-DTG initiation (p<0.0001). This was confirmed with model B, which estimated a significant decay pre-DTG initiation with a half-life of 7.7 years, but a significant positive slope post-DTG initiation leading to a transient estimated doubling-time of 8.1 years. There was no evidence of viral failure in the cohort, or consistent evolution in the outgrowth sequences associated with DTG initiation. These data suggest that either the initiation of DTG, or cessation of NNRTI use, is associated with a significant temporary increase in the circulating RC-LVR.

Evaluation of early de-escalation of empiric antimicrobial therapy in acute leukemia patients with febrile neutropenia at a large academic medical center.

INTRODUCTION: Recent trials have shown early de-escalation of empiric antimicrobial therapy (EAT) in febrile neutropenia has led to less adverse effects with no difference in patient mortality. In 2019, our institution adjusted internal guidelines to de-escalate EAT after 7 days of intravenous anti-pseudomonal therapy in patients with signs of clinical recovery from febrile neutropenia and no evidence of infection. METHODS: This was a retrospective, single-center, observational, cohort study. Eligible patients were adults with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) who received induction chemotherapy and developed febrile neutropenia without documented infection. Patients were separated based on EAT duration: ≤ 9 days and > 9 days. Empiric antimicrobial therapy was defined as the initiation of an anti-pseudomonal beta-lactam. The primary outcome was the difference in number of EAT-free days. Secondary outcomes included fever recurrence, ICU admissions, fever duration, infections post de-escalation, and Clostridioides difficile infection (CDI). RESULTS: Forty-four encounters met inclusion. The EAT ≤ 9 days group had 7 more EAT-free days compared to the EAT > 9 days group (p < 0.001). No between-group differences were identified in terms of fever after EAT discontinuation (p = 0.335), ICU admission (p = 0.498), or CDI (p = 0.498). The EAT > 9 days group experienced longer initial fever (p < 0.001) and received addition of resistant Gram-positive coverage (p = 0.014). More patients receiving EAT > 9 days had a diagnosis of AML (p = 0.001). CONCLUSIONS: Shorter EAT duration did not lead to worse outcomes in patients with AML or ALL who received induction chemotherapy and developed febrile neutropenia without a documented infection source.

Development and Application of Endothelial Cells Derived From Pluripotent Stem Cells in Microphysiological Systems Models.

The vascular endothelium is present in all organs and blood vessels, facilitates the exchange of nutrients and waste throughout different organ systems in the body, and sets the tone for healthy vessel function. Mechanosensitive in nature, the endothelium responds to the magnitude and temporal waveform of shear stress in the vessels. Endothelial dysfunction can lead to atherosclerosis and other diseases. Modeling endothelial function and dysfunction in organ systems in vitro, such as the blood-brain barrier and tissue-engineered blood vessels, requires sourcing endothelial cells (ECs) for these biomedical engineering applications. It can be difficult to source primary, easily renewable ECs that possess the function or dysfunction in question. In contrast, human pluripotent stem cells (hPSCs) can be sourced from donors of interest and renewed almost indefinitely. In this review, we highlight how knowledge of vascular EC development in vivo is used to differentiate induced pluripotent stem cells (iPSC) into ECs. We then describe how iPSC-derived ECs are being used currently in in vitro models of organ function and disease and in vivo applications.

The Canadian plastic surgery workforce survey: interpretation and implications.

BACKGROUND: Few studies have monitored physician supply in Canada, and no studies have specifically examined the Canadian plastic surgery workforce. METHODS: In this study, data were gathered by three methods. A survey was distributed to all members of the Canadian Society of Plastic Surgeons in October of 2004. Opinions on the availability of plastic surgery services were solicited. A second survey that focused on demographics and workload was distributed in December of 2004. Finally, the locations of all Canadian trainees graduating between 1995 and 2005 were reviewed. RESULTS: The response rate to the first survey was 42 percent. Seventy-eight percent of respondents felt that there was a shortage of plastic surgeons in their community. The response rate to the second survey was 40 percent. Twenty-eight percent of respondents were within 5 years of retirement and 3.2 percent stated that they planned to emigrate by 2010. The mean waiting time for an elective consultation was 32 +/- 33 weeks. Review of all 179 plastic surgery graduates over the past 10 years revealed that 23 percent now practice outside of Canada. CONCLUSIONS: When these results are projected to the total workforce, they indicate that there will be a future shortage of plastic surgeons in Canada. To prevent a further deficit, there is a need to increase the number of plastic surgery trainees in Canada, to offer incentives for graduates to stay in Canada, and to possibly recruit more foreign-trained plastic surgeons to practice within Canada.

Temporary arteriovenous loop between the saphenous vein and the first plantar metatarsal artery in toe-to-hand transfers.

We describe a technique for creating a temporary arteriovenous loop by anastomosing the saphenous vein to the first plantar metatarsal artery to facilitate harvesting and subsequent anastomosis of a great or second toe transfer. This technique has been used in 9 patients: 6 pediatric toe-to-hand transfers for congenital hand differences and 3 adult toe transfers for a thumb amputation. All 9 toe transfers survived. The advantages of this technique are that it allows precise determination of the exact length of the loop to reach the recipient artery, it facilitates palmar positioning of the arterial pedicle, and, if necessary, the saphenous vein can be anastomosed directly to the lateral digital artery of a great toe transfer or the medial digital artery of a second toe transfer rather than the first plantar metatarsal artery itself, thereby minimizing more proximal dissection of the first plantar metatarsal artery, which is more difficult and time consuming.

Healing of a scaphoid nonunion using human bone morphogenetic protein.

A chronic nonunion of a proximal pole fracture of the scaphoid was treated by curettage of the nonunion, single K-wire fixation, and implantation of 50 mg of human bone morphogenetic protein followed by 12 weeks of cast immobilization without any conventional corticocancellous bone grafting or rigid screw fixation. Radiographs showed signs of bony healing by 12 weeks and a magnetic resonance imaging scan 6 years after surgery showed no signs of avascular necrosis. The potential future applications of human bone morphogenetic protein in hand surgery are discussed.

Iatrogenic arteriovenous fistula after revascularization of the hand.

This is the first report of an iatrogenic arteriovenous fistula complicating revascularization of an incomplete amputation of the hand, due to inadvertent anastomosis of the proximal radial artery to the distal cephalic vein. This resulted in a severely painful, massively swollen hand, which was initially diagnosed as an infection or poor venous outflow and eventually required a below-elbow amputation. This complication of replantation or revascularization should be preventable by carefully matching the thickness of the vessel wall and the diameter of the lumen, to avoid anastomosing a proximal artery to a distal vein.