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Individuals with type 2 diabetes (T2DM) are at high risk for nonalcoholic fatty liver disease (NAFLD), and evidence suggests that poor glycemic control is linked to heightened risk of progressive NAFLD. We conducted an observational study based on data from a telehealth trial conducted in 2018-2020. Our objectives were to (1) characterize patterns of NAFLD testing/care in a cohort of individuals with poorly controlled T2DM; and (2) explore how laboratory based measures of NAFLD (eg, liver enzymes, fibrosis-4 [FIB-4]) vary by glycemic control. We included individuals with poorly controlled T2DM (n = 228), defined as hemoglobin A1c (HbA1c) ≥ 8.5% despite clinic-based care. Two groups of interest were (1) T2DM without known NAFLD; and (2) T2DM with known NAFLD. Demographics, medical history, medication use, glycemic control (HbA1c), and NAFLD testing/care patterns were obtained by chart review. Among those without known NAFLD (n = 213), most were male (78.4%) and self-identified as Black race (68.5%). Mean HbA1c was 9.8%. Most had liver enzymes (85.4%) and platelets (84.5%) ordered in the outpatient department over a 2-year period that would allow for FIB-4 calculation, yet only 2 individuals had FIB-4 documented in clinical notes. Approximately one-third had abnormal liver enzymes at least once over a 2-year period, yet only 7% had undergone liver ultrasound and 4.7% had referral to hepatology. Among those with known NAFLD (n = 15), mean HbA1c was 9.5%. Only 4 individuals had undergone transient elastography, half of whom had advanced fibrosis. NAFLD is underrecognized in poorly controlled T2DM, even though this is a high-risk group for NAFLD and its complications.

Nonalcoholic fatty liver disease (NAFLD) and its complications disproportionately impact individuals with T2DM. NAFLD prevalence is thought to be 60-70% in T2DM. In response to this, guidelines now recommend additional liver testing and risk stratification of NAFLD in patients with T2DM who have elevated liver enzymes or steatosis seen on ultrasound. In this secondary analysis of data from a randomized trial of a telehealth intervention, we investigated NAFLD testing and care patterns in a cohort of Veterans with poor T2DM control across two VA sites (n=244) over a 2-year period (2018-2020). Mean HbA1c and BMI were 9.8% (SD 1.5%) and 35.0 kg/m2 (SD 6.3), respectively. Only 6.6% (n=16) had a documented diagnosis of NAFLD. Excluding those with known NAFLD or other liver diseases (i.e., hepatitis B/C [n=14], alcohol overuse [n=6]), the majority of patients had documented liver enzyme (87%, n=184) and platelet (89%, n=187) testing. Based on established lab criteria for NAFLD diagnosis (i.e., at least two ALT ≥ 40 IU/mL in men, ≥ 31 IU/mL in women, ≥ 6 months apart), 17% (n=36) had undiagnosed NAFLD. Despite available lab data, no patients had a lab-based risk stratification score (such as the fibrosis-4 index or NAFLD fibrosis score) documented in clinical notes or electronic problem lists. Only 7% of patients had undergone liver ultrasound (n=15) and 2.4% Fibroscan (n=5), which are the usual first-line imaging modalities for diagnosis and risk stratification of NAFLD, respectively. Of patients with persistently elevated liver enzymes (n=36), only 14% (n=5) were referred to Hepatology. In summary, this study highlights the underrecognition of NAFLD in T2DM, even in patients with poor glycemic control and obesity who are exceedingly high risk of NAFLD complications. Since Endocrinologists commonly see patients with high metabolic risk, this study also highlights an important role for Endocrinologists in the proactive detection and risk stratification of NAFLD in T2DM. Disclosure A. Alexopoulos: None. R. Duffy: None. E. A. Kobe: None. C. A. Moylan: None. A. S. Jeffreys: None. C. Coffman: None. D. Soliman: None. J. German: None. M. Crowley: None.

1. Introduced carnivores are often cryptic, making it difficult to quantify their presence in ecosystems, and assess how this varies in relation to management interventions. Survey design should thus seek to improve detectability and maximize statistical power to ensure sound inference regarding carnivore population trends. Roads may facilitate carnivore movements, possibly leading to high detectability. Therefore, targeting roads may improve inferences about carnivore populations. 2. We assessed our ability to monitor feral cats Felis catus and red foxes Vulpes vulpes on‐ and off‐road, with explicit consideration of the location of monitoring sites on our ability to detect population changes. We also assessed whether there was evidence of spatial or temporal interaction between these species that might influence their road‐use. 3. Surveys were conducted in a conservation reserve in south‐eastern Australia between 2016 and 2018. At each of 30 sites, we deployed two motion‐sensor cameras, one on‐road, and the other off‐road. Using occupancy models, we estimated cat and fox occupancy and detectability, and conducted a power analysis to assess our ability to detect declines in occupancy under three monitoring regimes (efforts targeted equally on‐ and off‐road, efforts targeted entirely off‐road and efforts targeted entirely on‐road). 4. On average, on‐road detectability was seven times higher for cats and three times higher for foxes. Targeting survey effort on‐road yielded the greatest power for detecting declines in both species, but our ability to detect smaller declines decreased with decreasing initial occupancy probability. No level of decline was detectable for cats when survey efforts were targeted off‐road, while only large declines (>50%) were detectable for foxes (assuming high initial occupancy probabilities). We found little evidence of spatial or temporal segregation, suggesting limited avoidance or suppression between the two species within this landscape. 5. Our results suggest that targeting monitoring on roads may be an effective approach for detecting declines in introduced carnivore populations, particularly following management intervention (e.g. lethal control), and in the face of resource limitations. We provide a framework that can help assist land managers to make informed decisions, which balance monitoring efforts and resource constraints with sufficient statistical power to assess management objectives.

Objective To determine the effect of Normosol™-R as compared to normal saline on the outcomes of acute kidney injury and the need for renal replacement therapy in the resuscitation phase of sepsis. Design Our study is a retrospective before-and-after cohort study. Setting The study occurred at a 700-bed tertiary academic level 1-trauma center. Patients A total of 1218 patients were enrolled through emergency department admissions. The normal saline (before) cohort was defined as the dates between 1 March and 30 September 2014 and the Normosol™-R (after) cohort was assessed from 1 March to 30 September 2015. Interventions None. Measurements and main results Intravenous fluid volumes received during the first 24 h, 72 h, and total hospital stays were compared. Sodium, chloride, potassium, and bicarbonate levels at 72 h were also compared. The medical coded diagnosis of acute kidney failure, need for renal replacement therapy, hospital LOS, ICU admission, ICU LOS, in-hospital mortality, and need for mechanical ventilation were all compared. There was no significant difference in intravenous fluid volumes between groups. Regression modelling controlling for baseline characteristics and 24-h fluid intake volume found no differences between groups for the primary outcomes of acute kidney injury ( P = 0.99) and renal replacement therapy ( P = 0.88). Patients in the Normosol™-R cohort were found to have a lower rate of hyperchloremia at 72 h post-admission (28% vs. 13%, P Conclusions This study was unable to detect any difference in outcomes between sepsis patients who received intravenous fluid resuscitation with either a balanced crystalloid (Normosol™-R) or normal saline, except for a decreased rate of hyperchloremia.

In the RV144 gp120 HIV vaccine trial, decreased transmission risk was correlated with Abs that reacted with a linear epitope at a lysine residue at position 169 (K169) in the HIV-1 envelope (Env) V2 region. The K169 V2 response was restricted to Abs bearing Vλ rearrangements that expressed aspartic acid/glutamic acid in CDR L2. The AE.A244 gp120 in AIDSVAX B/E also bound to the unmutated ancestor of a V2-glycan broadly neutralizing Ab, but this Ab type was not induced in the RV144 trial. In this study, we sought to determine whether immunodominance of the V2 linear epitope could be overcome in the absence of human Vλ rearrangements. We immunized IgH- and Igκ-humanized mice with the AE.A244 gp120 Env. In these mice, the V2 Ab response was focused on a linear epitope that did not include K169. V2 Abs were isolated that used the same human VH gene segment as an RV144 V2 Ab but paired with a mouse λ L chain. Structural characterization of one of these V2 Abs revealed how the linear V2 epitope could be engaged, despite the lack of aspartic acid/glutamic acid encoded in the mouse repertoire. Thus, despite the absence of the human Vλ locus in these humanized mice, the dominance of Vλ pairing with human VH for HIV-1 Env V2 recognition resulted in human VH pairing with mouse λ L chains instead of allowing otherwise subdominant V2-glycan broadly neutralizing Abs to develop.

Aim Extreme climatic events and large wildfires are predicted to increase as the world's climate warms. Understanding how they shape species’ distributions will be critical for conserving biodiversity. We used a 7-year dataset of mammals collected during and after south-east Australia's Millennium Drought to assess the roles of fire history, climatic extremes and their interactions in shaping mammal distributions. Location Grampians National Park, south-eastern Australia. Methods We surveyed mammals at 36 sites along a ~50-year post-fire chronosequence in each of the 7 years. We modelled ten mammal species in relation to fire history, productivity and recent rainfall. Next, we examined the consistency of species’ fire response curves across each of three climatic phases relating to the Millennium Drought. Finally, we identified the optimal distribution of fire ages for small and medium-sized mammal conservation in each of the three climatic phases. Results The majority of species were influenced by fire history, and all native species were negatively associated with recently burned vegetation. Seven of ten species responded positively to the end of the Millennium Drought, but six of these declined quickly thereafter. Species’ responses to fire history differed depending on the climatic conditions. However, the optimal distribution of fire-age classes consistently emphasized the importance of older age classes, regardless of climatic phase. This distribution is in stark contrast to the current distribution of fire ages across the study region. Main conclusions Mammals in the study region face an uncertain future. The negative impact of drought, the short-lived nature of post-drought recovery and, now, the possibility of a new drought beginning forewarn of further declines. The stark contrast between the optimal and current fire-age distributions means that reducing the incidence of further fires is critical to enhance the capacity of native mammal communities to weather an increasingly turbulent climate.

Maternal vaccination to induce anti-HIV immune factors in breast milk is a potential intervention to prevent postnatal HIV-1 mother-to-child transmission (MTCT). We previously demonstrated that immunization of lactating rhesus monkeys with a modified vaccinia Ankara (MVA) prime/intramuscular (i.m.) protein boost regimen induced functional IgG responses in milk, while MVA prime/intranasal (i.n.) boost induced robust milk Env-specific IgA responses. Yet, recent studies have suggested that prevention of postnatal MTCT may require both Env-specific IgA and functional IgG responses in milk. Thus, to investigate whether both responses could be elicited by a combined systemic/mucosal immunization strategy, animals previously immunized with the MVA prime/i.n. boost regimen received an i.n./i.m. combined C.1086 gp120 boost. Remarkably, high-magnitude Env-specific IgA responses were observed in milk, surpassing those in plasma. Furthermore, 29% of vaccine-elicited Env-specific B cells isolated from breast milk were IgA isotype, in stark contrast to the overwhelming predominance of IgG isotype Env-specific B cells in breast milk of chronically HIV-infected women. A clonal relationship was identified between Env-specific blood and breast milk B cells, suggesting trafficking of that cell population between the two compartments. Furthermore, IgA and IgG monoclonal antibodies isolated from Env-specific breast milk B cells demonstrated diverse Env epitope specificities and multiple effector functions, including tier 1 neutralization, antibody-dependent cellular cytotoxicity (ADCC), infected cell binding, and inhibition of viral attachment to epithelial cells. Thus, maternal i.n./i.m. combined immunization is a novel strategy to enhance protective Env-specific IgA in milk, which is subsequently transferred to the infant via breastfeeding. IMPORTANCE Efforts to increase the availability of antiretroviral therapy to pregnant and breastfeeding women in resource-limited areas have proven remarkably successful at reducing HIV vertical transmission rates. However, more than 200,000 children are infected annually due to failures in therapy implementation, monitoring, and adherence, nearly half by postnatal HIV exposure via maternal breast milk. Intriguingly, in the absence of antiretroviral therapy, only 10% of breastfed infants born to HIV-infected mothers acquire the virus, suggesting the existence of naturally protective immune factors in milk. Enhancement of these protective immune factors through maternal vaccination will be a critical strategy to reduce the global pediatric AIDS epidemic. We have previously demonstrated that a high magnitude of HIV Env-specific IgA in milk correlates with reduced risk of infant HIV acquisition. In this study, we describe a novel HIV vaccine regimen that induces potent IgA responses in milk and therefore could potentially protect against breast milk HIV MTCT.

To evaluate antibody specificities induced by simian immunodeficiency virus (SIV) versus human immunodeficiency virus type 1 (HIV-1) envelope antigens in nonhuman primate (NHP), we profiled binding antibody responses to linear epitopes in NHP studies with HIV-1 or SIV immunogens. We found that, overall, HIV-1 Env IgG responses were dominated by V3, with the notable exception of the responses to the vaccine strain A244 Env that were dominated by V2, whereas the anti-SIVmac239 Env responses were dominated by V2 regardless of the vaccine regimen.

HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses., Author Summary Antibodies specifically recognize antigenic sites on pathogens and can mediate multiple antiviral functions through engagement of effector cells via their Fc region. Current HIV-1 vaccine candidates induce polyclonal antibody responses with multiple antiviral functions, but do not induce broadly neutralizing antibodies. An improved understanding of whether certain types of non-neutralizing HIV-1 specific antibodies can individually protect against HIV-1 infection may facilitate vaccine development. Here, we test whether non-neutralizing antibodies with multiple antiviral functions mediated through FcR engagement and recognition of virus particles or virus-infected cells can limit infection, despite lacking classical virus neutralization activity. In a passive antibody infusion-rhesus macaque challenge model, we tested the ability of non-neutralizing monoclonal antibodies to limit virus acquisition. We demonstrate that two different types of non-neutralizing antibodies, one that recognizes both virus particles and infected cells (7B2) and another that recognizes only infected cells (A32) were capable of decreasing the number of transmitted founder viruses. Further, we provide the structure of 7B2 in complex with the gp41 cyclical loop motif, a motif critical for entry. These findings provide insights into the role that antibodies with antiviral properties, including virion capture and FcR mediated effector function, may play in protecting against HIV-1 acquisition.

The absence of fish remains in archaeological sites in Moreton Bay, southeast Queensland, Australia, may be a function of recovery techniques, rather than a reflection of resource paucity and late onset of occupation, as has been posited in archaeological literature. An excavation on Peel Island in Moreton Bay was devised, in part, to test this proposition, and a 1-mm mesh screen was used to enhance recovery. But sorting this fine fraction took 20 h. In this article we outline experiments to find a more efficient and effective technique for sieving and sorting fine fraction archaeological deposits, using methods borrowed from soil science. We show how sorting time can be reduced to 2 h 30 min per 100 g sample and argue that the vast increase in knowledge about the site occurring as a result of using the very fine mesh sieve warrants the continued application of these laboratory methods.