Structure-driven development of a biomimetic rare earth artificial metalloprotein.

The 2011 discovery of the first rare earth-dependent enzyme in methylotrophic Methylobacterium extorquens AM1 prompted intensive research toward understanding the unique chemistry at play in these systems. This enzyme, an alcohol dehydrogenase (ADH), features a La3+ ion closely associated with redox-active coenzyme pyrroloquinoline quinone (PQQ) and is structurally homologous to the Ca2+-dependent ADH from the same organism. AM1 also produces a periplasmic PQQ-binding protein, PqqT, which we have now structurally characterized to 1.46-Å resolution by X-ray diffraction. This crystal structure reveals a Lys residue hydrogen-bonded to PQQ at the site analogously occupied by a Lewis acidic cation in ADH. Accordingly, we prepared K142A- and K142D-PqqT variants to assess the relevance of this site toward metal binding. Isothermal titration calorimetry experiments and titrations monitored by UV-Vis absorption and emission spectroscopies support that K142D-PqqT binds tightly (Kd = 0.6 ± 0.2 µM) to La3+ in the presence of bound PQQ and produces spectral signatures consistent with those of ADH enzymes. These spectral signatures are not observed for WT- or K142A-variants or upon addition of Ca2+ to PQQ ⸦ K142D-PqqT. Addition of benzyl alcohol to La3+-bound PQQ ⸦ K142D-PqqT (but not Ca2+-bound PQQ ⸦ K142D-PqqT, or La3+-bound PQQ ⸦ WT-PqqT) produces spectroscopic changes associated with PQQ reduction, and chemical trapping experiments reveal the production of benzaldehyde, supporting ADH activity. By creating a metal binding site that mimics native ADH enzymes, we present a rare earth-dependent artificial metalloenzyme primed for future mechanistic, biocatalytic, and biosensing applications.

Human flap endonuclease structures, DNA double-base flipping, and a unified understanding of the FEN1 superfamily.

Flap endonuclease (FEN1), essential for DNA replication and repair, removes RNA and DNA 5' flaps. FEN1 5' nuclease superfamily members acting in nucleotide excision repair (XPG), mismatch repair (EXO1), and homologous recombination (GEN1) paradoxically incise structurally distinct bubbles, ends, or Holliday junctions, respectively. Here, structural and functional analyses of human FEN1:DNA complexes show structure-specific, sequence-independent recognition for nicked dsDNA bent 100° with unpaired 3' and 5' flaps. Above the active site, a helical cap over a gateway formed by two helices enforces ssDNA threading and specificity for free 5' ends. Crystallographic analyses of product and substrate complexes reveal that dsDNA binding and bending, the ssDNA gateway, and double-base unpairing flanking the scissile phosphate control precise flap incision by the two-metal-ion active site. Superfamily conserved motifs bind and open dsDNA; direct the target region into the helical gateway, permitting only nonbase-paired oligonucleotides active site access; and support a unified understanding of superfamily substrate specificity.

An adaptive teosinte mexicana introgression modulates phosphatidylcholine levels and is associated with maize flowering time.

Native Americans domesticated maize (Zea mays ssp. mays) from lowland teosinte parviglumis (Zea mays ssp. parviglumis) in the warm Mexican southwest and brought it to the highlands of Mexico and South America where it was exposed to lower temperatures that imposed strong selection on flowering time. Phospholipids are important metabolites in plant responses to low-temperature and phosphorus availability and have been suggested to influence flowering time. Here, we combined linkage mapping with genome scans to identify High PhosphatidylCholine 1 (HPC1), a gene that encodes a phospholipase A1 enzyme, as a major driver of phospholipid variation in highland maize. Common garden experiments demonstrated strong genotype-by-environment interactions associated with variation at HPC1, with the highland HPC1 allele leading to higher fitness in highlands, possibly by hastening flowering. The highland maize HPC1 variant resulted in impaired function of the encoded protein due to a polymorphism in a highly conserved sequence. A meta-analysis across HPC1 orthologs indicated a strong association between the identity of the amino acid at this position and optimal growth in prokaryotes. Mutagenesis of HPC1 via genome editing validated its role in regulating phospholipid metabolism. Finally, we showed that the highland HPC1 allele entered cultivated maize by introgression from the wild highland teosinte Zea mays ssp. mexicana and has been maintained in maize breeding lines from the Northern United States, Canada, and Europe. Thus, HPC1 introgressed from teosinte mexicana underlies a large metabolic QTL that modulates phosphatidylcholine levels and has an adaptive effect at least in part via induction of early flowering time.

Rift Valley Fever virus M and L genome segment detection: a comparison of field-deployable reverse transcription insulated isothermal PCR (RT-iiPCR) and laboratory-based multiplex reverse transcription real-time PCR.

Rift Valley Fever phlebovirus (RVFV) is a mosquito-borne zoonotic pathogen that causes major agricultural and public health problems in Africa and the Arabian Peninsula. It is considered a potential agro-bioterrorism agent for which limited countermeasures are available. To address diagnostic needs, here we describe a rapid and sensitive molecular method immediately employable at sites of suspected outbreaks in animals that commonly precede outbreaks in humans. The strategy involves the concurrent detection of two of the three RVFV genome segments (large and medium) using reverse transcription insulated isothermal PCR (RT-iiPCR) performed on a portable, touch screen nucleic acid analyzer, POCKIT. The analytical sensitivity for both the RT-iiPCR and a laboratory-based L and M multiplex reverse transcription real-time PCR assay was estimated at approximately 0.1-3 copies/reaction using synthetic RNA or viral RNA. The diagnostic sensitivity and specificity of detection of RVFV on the POCKIT, determined using sera from sheep and cattle (n = 181) experimentally infected with two strains of RVFV (SA01 and Ken06), were 93.8% and 100% (kappa = 0.93), respectively. Testing of ruminant field sera (n = 193) in two locations in Africa demonstrated 100% diagnostic sensitivity and specificity. We conclude that the POCKIT dual-gene RVFV detection strategy can provide reliable, sensitive, and specific point-of-need viral RNA detection. Moreover, the field detection of RVFV in vectors or susceptible animal species can aid in the surveillance and epidemiological studies to better understand and control RVFV outbreaks. IMPORTANCE: The content of this manuscript is of interest to the diverse readership of the Journal of Clinical Microbiology, including research scientists, diagnosticians, healthcare professionals, and policymakers. Rift Valley Fever virus (RVFV) is a zoonotic mosquito-borne pathogen that causes major agricultural and public health problems. Current and most sensitive diagnostic approaches that are molecular-based are performed in highly specialized molecular diagnostic laboratories. To address diagnostic needs, we developed a novel, rapid, and sensitive molecular method using a portable PCR machine, POCKIT, capable of immediate deployment at sites of suspected outbreaks. Here, we demonstrate that field-deployable RVFV detection can provide reliable, sensitive, and specific point-of-need viral RNA detection that could be used for diagnostic investigations and epidemiological studies, and can be performed in the field.

Colchicine exerts anti-atherosclerotic and -plaque-stabilizing effects targeting foam cell formation.

Colchicine is a broad-acting anti-inflammatory agent that has attracted interest for repurposing in atherosclerotic cardiovascular disease. Here, we studied its ability at a human equivalent dose of 0.5 mg/day to modify plaque formation and composition in murine atherosclerosis and investigated its actions on macrophage responses to atherogenic stimuli in vitro. In atherosclerosis induced by high-cholesterol diet, Apoe-/- mice treated with colchicine had 50% reduction in aortic oil Red O+ plaque area compared to saline control (p = .001) and lower oil Red O+ staining of aortic sinus lesions (p = .03). In vitro, addition of 10 nM colchicine inhibited foam cell formation from murine and human macrophages after treatment with oxidized LDL (ox-LDL). Mechanistically, colchicine downregulated glycosylation and surface expression of the ox-LDL uptake receptor, CD36, and reduced CD36+ staining in aortic sinus plaques. It also decreased macrophage uptake of cholesterol crystals, resulting in lower intracellular lysosomal activity, inhibition of the NLRP3 inflammasome, and reduced secretion of IL-1ß and IL-18. Colchicine's anti-atherosclerotic actions were accentuated in a mouse model of unstable plaque induced by carotid artery tandem stenosis surgery, where it decreased lesion size by 48% (p = .01), reduced lipid (p = .006) and necrotic core area (p = .007), increased collagen content and cap-to-necrotic core ratio (p = .05), and attenuated plaque neutrophil extracellular traps (p < .001). At low dose, colchicine's effects were not accompanied by the evidence of microtubule depolymerization. Together, these results show that colchicine exerts anti-atherosclerotic and plaque-stabilizing effects at low dose by inhibiting foam cell formation and cholesterol crystal-induced inflammation. This provides a new framework to support its repurposing for atherosclerotic cardiovascular disease.

Long Terminal Repeats: From Parasitic Elements to Building Blocks of the Transcriptional Regulatory Repertoire.

The life cycle of endogenous retroviruses (ERVs), also called long terminal repeat (LTR) retrotransposons, begins with transcription by RNA polymerase II followed by reverse transcription and re-integration into the host genome. While most ERVs are relics of ancient integration events, "young" proviruses competent for retrotransposition-found in many mammals, but not humans-represent an ongoing threat to host fitness. As a consequence, several restriction pathways have evolved to suppress their activity at both transcriptional and post-transcriptional stages of the viral life cycle. Nevertheless, accumulating evidence has revealed that LTR sequences derived from distantly related ERVs have been exapted as regulatory sequences for many host genes in a wide range of cell types throughout mammalian evolution. Here, we focus on emerging themes from recent studies cataloging the diversity of ERV LTRs acting as important transcriptional regulatory elements in mammals and explore the molecular features that likely account for LTR exaptation in developmental and tissue-specific gene regulation.

The mosquito protein AEG12 displays both cytolytic and antiviral properties via a common lipid transfer mechanism.

The mosquito protein AEG12 is up-regulated in response to blood meals and flavivirus infection though its function remained elusive. Here, we determine the three-dimensional structure of AEG12 and describe the binding specificity of acyl-chain ligands within its large central hydrophobic cavity. We show that AEG12 displays hemolytic and cytolytic activity by selectively delivering unsaturated fatty acid cargoes into phosphatidylcholine-rich lipid bilayers. This property of AEG12 also enables it to inhibit replication of enveloped viruses such as Dengue and Zika viruses at low micromolar concentrations. Weaker inhibition was observed against more distantly related coronaviruses and lentivirus, while no inhibition was observed against the nonenveloped virus adeno-associated virus. Together, our results uncover the mechanistic understanding of AEG12 function and provide the necessary implications for its use as a broad-spectrum therapeutic against cellular and viral targets.

Association of Low-Dose Colchicine With Incidence of Knee and Hip Replacements : Exploratory Analyses From a Randomized, Controlled, Double-Blind Trial.

BACKGROUND: Osteoarthritis is a major contributor to pain and disability worldwide. Given that inflammation plays an important role in the development of osteoarthritis, anti-inflammatory drugs may slow disease progression. OBJECTIVE: To examine whether colchicine, 0.5 mg daily, reduces incident total knee replacements (TKRs) and total hip replacements (THRs). DESIGN: Exploratory analysis of the LoDoCo2 (Low-Dose Colchicine 2) randomized, controlled, double-blind trial. (Australian New Zealand Clinical Trials Registry: ACTRN12614000093684). SETTING: 43 centers in Australia and the Netherlands. PATIENTS: 5522 patients with chronic coronary artery disease. INTERVENTION: Colchicine, 0.5 mg, or placebo once daily. MEASUREMENTS: The primary outcome was time to first TKR or THR since randomization. All analyses were performed on an intention-to-treat basis. RESULTS: A total of 2762 patients received colchicine and 2760 received placebo during a median follow-up of 28.6 months. During the trial, TKR or THR was performed in 68 patients (2.5%) in the colchicine group and 97 (3.5%) in the placebo group (incidence rate, 0.90 vs. 1.30 per 100 person-years; incidence rate difference, -0.40 [95% CI, -0.74 to -0.06] per 100 person-years; hazard ratio, 0.69 [CI, 0.51 to 0.95]). In sensitivity analyses, similar results were obtained when patients with gout at baseline were excluded and when joint replacements that occurred in the first 3 and 6 months of follow-up were omitted. LIMITATION: LoDoCo2 was not designed to investigate the effect of colchicine in osteoarthritis of the knee or hip and did not collect information specifically on osteoarthritis. CONCLUSION: In this exploratory analysis of the LoDoCo2 trial, use of colchicine, 0.5 mg daily, was associated with a lower incidence of TKR and THR. Further investigation of colchicine therapy to slow disease progression in osteoarthritis is warranted. PRIMARY FUNDING SOURCE: None.

Seroprevalence and associated risk factors for Neospora caninum infection in dairy cattle in South Africa.

Bovine neosporosis is a widespread parasitic disease associated with significant economic losses. Its effects on the reproductive performance of cows have resulted in losses that run into the hundreds of millions of US dollars in dairy industries in various countries (Reichel et al., Int J Parasitol 43:133-142, 2013). Due to outdated and scant information on the occurrence of Neospora caninum infection in South Africa, the study aimed to determine the seroprevalence and risk factors associated with infection in dairy cattle in South Africa. A total of 1401 blood samples were randomly collected from cattle on 48 dairy farms in seven of the nine provinces in South Africa. A close-ended questionnaire was used in a cross-sectional study to obtain farm-level and animal-level data. Serological testing was done using a commercial IDvet Screen® Neospora caninum Indirect ELISA. An overall seroprevalence, adjusted for test sensitivity and specificity, of 2.3% (95% CI, 1.3-4.1) was detected and 48% (23/48) of sampled farms had at least one animal testing positive. The highest seroprevalence of N. caninum was in the KwaZulu-Natal province with 7.5% (95% CI, 3.8-14.3), and the lowest in Western Cape with 0.1% (95% CI, 0-1.2). The highest within-farm seroprevalence of 25% was detected on a farm in the North West Province. In a multivariable logistic regression model, the odds of N. caninum seropositivity were higher in Holstein-Friesian cattle when compared to other breeds. Good hygiene was identified as a protective factor. Cattle left out on pasture had increased odds of testing positive for N. caninum compared to those that were penned. The odds of testing seropositive for N. caninum was higher on farms that practised segregation of cattle into different age groups. The purchase of replacement animals was a significant risk factor, as open herds had increased odds of N. caninum seropositivity. Cattle on farms that did not have a specific calving location were more likely to be seropositive. This is the first such study in South Africa and shows that N. caninum is widely distributed in the country at a low seroprevalence, but it may be a cause of concern on certain farms.

Monitoring for Breast Cancer Recurrence Following Goldilocks Breast Reconstruction.

BACKGROUND: The Goldilocks breast reconstruction utilizes redundant mastectomy skin flaps to fashion a breast mound; however, there is concern that imbrication of these skin flaps may predispose to fat necrosis and make detection of local breast cancer recurrence more difficult. Goldilocks patients follow a traditional postmastectomy screening pathway that includes clinical examination for locoregional recurrence, but it is unclear if this is sufficient. We evaluate our Goldilocks reconstruction case series to determine rates of diagnostic imaging, biopsy, and locoregional and distant recurrence. METHODS: Sixty-six patients (94 breasts) undergoing Goldilocks breast reconstruction were retrospectively reviewed. Any diagnostic postoperative imaging/biopsies performed and that confirmed local or distant breast cancer recurrence were noted. RESULTS: Average time of follow-up was 45 months. Most patients in this cohort had stage 0 (27.3%) or stage I (40.9%) breast cancer. There were a total of 11 (11.7%) concerning breast masses identified. Seven (7.4%) masses were biopsied, of which 5 were benign and 2 were invasive cancer recurrence. Four masses (4.3%) underwent diagnostic imaging only, all with benign findings. Five patients in this series were found to have either distant disease or a second primary cancer in the nonoperative contralateral breast. CONCLUSIONS: Rates of local recurrence following Goldilocks are not higher than expected after other types of postmastectomy reconstruction. Clinical monitoring successfully detected local recurrence in all affected patients in this series. More definite guidelines around the routine screening of Goldilocks mastectomy patients may aid in early detection of local breast cancer recurrence.

Scalp Reconstruction With Free Tissue Transfer as a Palliative Surgical Intervention in a High-Risk Population.

Microvascular reconstruction of the scalp is frequently indicated in patients with locally advanced tumors, among other etiologies, in a relatively high-risk, older patient population that often has multiple medical comorbidities. A retrospective analysis was performed on patients undergoing microvascular scalp reconstruction at Emory University Hospital and Grady Memorial Hospital between 2011 and 2021. Patient demographics, wound characteristics, operative details, and complications were recorded. Statistical analysis using univariate and multivariate models was performed. Forty-two patients underwent 45 microvascular scalp reconstructive procedures during the study period. The median age was 63 years. Wounds were predominantly oncologic (n=38, 84.4%) and frequently involved deeper structures [calvarium (n=38, 84.4%), dura (n=17, 37.8%)]. At a median follow-up of 350 days, 33 patients (73.3%) had healed flaps, 9 (20.0%) had wound healing issues but ultimately successful reconstruction, and 3 (6.7%) experienced flap failure. Most patients (n=33, 80.9%) were discharged home or to a rehabilitation facility, while the remaining 8 patients (19.1%) were discharged to hospice or died. The 30-day mortality was 4 patients (8.9%) and the 6-month mortality was 8 patients (20.5%). There was a statistically significant difference in 30-day mortality (P=0.0001) on univariate analysis and 6-month mortality (P=0.003) on both univariate and multivariate analysis for patients >70 years. While age >70 years is a risk factor for mortality in patients undergoing microvascular scalp reconstruction, mortality was commonly related to underlying disease processes rather than complication of surgery. Microvascular reconstruction for scalp defects has a high success rate and can be offered as a palliative procedure for patients with locally advanced cancers, advanced age, and multiple comorbidities.

Excision of a Protein-Derived Amine for p-Aminobenzoate Assembly by the Self-Sacrificial Heterobimetallic Protein CADD.

Chlamydia protein associating with death domains (CADD), the founding member of a recently discovered class of nonheme dimetal enzymes termed hemeoxygenase-like dimetaloxidases (HDOs), plays an indispensable role in pathogen survival. CADD orchestrates the biosynthesis of p-aminobenzoic acid (pABA) for integration into folate via the self-sacrificial excision of a protein-derived tyrosine (Tyr27) and several additional processing steps, the nature and timing of which have yet to be fully clarified. Nuclear magnetic resonance (NMR) and proteomics approaches reveal the source and probable timing of amine installation by a neighboring lysine (Lys152). Turnover studies using limiting O2 have identified a para-aminobenzaldehyde (pABCHO) metabolic intermediate that is formed on the path to pABA formation. The use of pABCHO and other probe substrates shows that the heterobimetallic Fe/Mn form of the enzyme is capable of oxygen insertion to generate the pABA-carboxylate.

Islet autoimmunity in human type 1 diabetes: initiation and progression from the perspective of the beta cell.

Type 1 diabetes results from the poorly understood process of islet autoimmunity, which ultimately leads to the loss of functional pancreatic beta cells. Mounting evidence supports the notion that the activation and evolution of islet autoimmunity in genetically susceptible people is contingent upon early life exposures affecting the islets, especially beta cells. Here, we review some of the recent advances and studies that highlight the roles of these changes as well as antigen presentation and stress response pathways in beta cells in the onset and propagation of the autoimmune process in type 1 diabetes. Future progress in this area holds promise for advancing islet- and beta cell-directed therapies that could be implemented in the early stages of the disease and could be combined with immunotherapies.

Text Messages to Improve Medication Adherence and Secondary Prevention After Acute Coronary Syndrome: The TEXTMEDS Randomized Clinical Trial.

BACKGROUND: TEXTMEDS (Text Messages to Improve Medication Adherence and Secondary Prevention After Acute Coronary Syndrome) examined the effects of text message-delivered cardiac education and support on medication adherence after an acute coronary syndrome. METHODS: TEXTMEDS was a single-blind, multicenter, randomized controlled trial of patients after acute coronary syndrome. The control group received usual care (secondary prevention as determined by the treating clinician); the intervention group also received multiple motivational and supportive weekly text messages on medications and healthy lifestyle with the opportunity for 2-way communication (text or telephone). The primary end point of self-reported medication adherence was the percentage of patients who were adherent, defined as >80% adherence to each of up to 5 indicated cardioprotective medications, at both 6 and 12 months. RESULTS: A total of 1424 patients (mean age, 58 years [SD, 11]; 79% male) were randomized from 18 Australian public teaching hospitals. There was no significant difference in the primary end point of self-reported medication adherence between the intervention and control groups (relative risk, 0.93 [95% CI, 0.84-1.03]; P=0.15). There was no difference between intervention and control groups at 12 months in adherence to individual medications (aspirin, 96% vs 96%; ß-blocker, 84% vs 84%; angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, 77% vs 80%; statin, 95% vs 95%; second antiplatelet, 84% vs 84% [all P>0.05]), systolic blood pressure (130 vs 129 mm Hg; P=0.26), low-density lipoprotein cholesterol (2.0 vs 1.9 mmol/L; P=0.34), smoking (P=0.59), or exercising regularly (71% vs 68%; P=0.52). There were small differences in lifestyle risk factors in favor of intervention on body mass index <25 kg/m2 (21% vs 18%; P=0.01), eating ≥5 servings per day of vegetables (9% vs 5%; P=0.03), and eating ≥2 servings per day of fruit (44% vs 39%; P=0.01). CONCLUSIONS: A text message-based program had no effect on medical adherence but small effects on lifestyle risk factors. REGISTRATION: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364448; Unique identifier: ANZCTR ACTRN12613000793718.

Colchicine in Patients with Chronic Coronary Disease.

BACKGROUND: Evidence from a recent trial has shown that the antiinflammatory effects of colchicine reduce the risk of cardiovascular events in patients with recent myocardial infarction, but evidence of such a risk reduction in patients with chronic coronary disease is limited. METHODS: In a randomized, controlled, double-blind trial, we assigned patients with chronic coronary disease to receive 0.5 mg of colchicine once daily or matching placebo. The primary end point was a composite of cardiovascular death, spontaneous (nonprocedural) myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization. The key secondary end point was a composite of cardiovascular death, spontaneous myocardial infarction, or ischemic stroke. RESULTS: A total of 5522 patients underwent randomization; 2762 were assigned to the colchicine group and 2760 to the placebo group. The median duration of follow-up was 28.6 months. A primary end-point event occurred in 187 patients (6.8%) in the colchicine group and in 264 patients (9.6%) in the placebo group (incidence, 2.5 vs. 3.6 events per 100 person-years; hazard ratio, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P<0.001). A key secondary end-point event occurred in 115 patients (4.2%) in the colchicine group and in 157 patients (5.7%) in the placebo group (incidence, 1.5 vs. 2.1 events per 100 person-years; hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.007). The incidence rates of spontaneous myocardial infarction or ischemia-driven coronary revascularization (composite end point), cardiovascular death or spontaneous myocardial infarction (composite end point), ischemia-driven coronary revascularization, and spontaneous myocardial infarction were also significantly lower with colchicine than with placebo. The incidence of death from noncardiovascular causes was higher in the colchicine group than in the placebo group (incidence, 0.7 vs. 0.5 events per 100 person-years; hazard ratio, 1.51; 95% CI, 0.99 to 2.31). CONCLUSIONS: In a randomized trial involving patients with chronic coronary disease, the risk of cardiovascular events was significantly lower among those who received 0.5 mg of colchicine once daily than among those who received placebo. (Funded by the National Health Medical Research Council of Australia and others; LoDoCo2 Australian New Zealand Clinical Trials Registry number, ACTRN12614000093684.).

Mechanistic model for human brain metabolism and its connection to the neurovascular coupling.

The neurovascular and neurometabolic couplings (NVC and NMC) connect cerebral activity, blood flow, and metabolism. This interconnection is used in for instance functional imaging, which analyses the blood-oxygen-dependent (BOLD) signal. The mechanisms underlying the NVC are complex, which warrants a model-based analysis of data. We have previously developed a mechanistically detailed model for the NVC, and others have proposed detailed models for cerebral metabolism. However, existing metabolic models are still not fully utilizing available magnetic resonance spectroscopy (MRS) data and are not connected to detailed models for NVC. Therefore, we herein present a new model that integrates mechanistic modelling of both MRS and BOLD data. The metabolic model covers central metabolism, using a minimal set of interactions, and can describe time-series data for glucose, lactate, aspartate, and glutamate, measured after visual stimuli. Statistical tests confirm that the model can describe both estimation data and predict independent validation data, not used for model training. The interconnected NVC model can simultaneously describe BOLD data and can be used to predict expected metabolic responses in experiments where metabolism has not been measured. This model is a step towards a useful and mechanistically detailed model for cerebral blood flow and metabolism, with potential applications in both basic research and clinical applications.

Socio-ecologic Correlates of HIV/AIDS-Related Sexual Risk Behavior of African American Emerging Adults.

There is growing evidence showing that patterns of individual sexual risk behaviors are insufficient in explaining the disproportionate HIV/AIDS burden borne by African Americans. Instead, dynamic features of social, economic, political, and geographic contexts play a more determining role. However, not enough studies have examined the impact of multi-level factors including neighborhood-level influences on HIV/AIDS sexual risk among African American emerging adults using a socio-ecologic perspective. Anchored on the socio-ecologic framework, this study examines the collective role of relevant socio-ecologic determinants of sexual risk-taking among African American emerging adults. Results from both bivariate and multivariate analyses revealed that individual and neighborhood-level variables were significantly associated with sexual risk in our study population partially confirming the hypothesis of the study. Male gender, educational attainment, and neighborhood social disorder were the strongest predictors of sexual risk. Our findings contribute to the vast literature on sexual risk behavior patterns of young adults, and increasing evidence demonstrating the role of contextual factors as stronger predictors of sexual risk and HIV infection among at-risk youth. Our findings, however, underscore the need for further research on the pathways of HIV socio-behavioral vulnerability in this demographic group.

Measures of carotid atherosclerosis and fall-related hospitalization risk: The Perth Longitudinal Study of Ageing Women.

BACKGROUND AND AIMS: We and others have identified links between cardiovascular conditions and poor musculoskeletal health. However, the relationship between measures of carotid atherosclerosis such as focal carotid plaque and common carotid intima media thickness (CCA-IMT) and falls remains understudied. This study examined the association between measures of carotid atherosclerosis and fall-related hospitalization over 11.5 years in community dwelling older women. METHODS AND RESULTS: 1116 older women recruited in 1998 to a five-year randomized controlled trial to examine the effect of calcium supplementation in preventing fracture and who had undertaken B-mode ultrasound in 2001 (three years after the baseline clinical visit) were included in this study. The participants were followed for over 11.5 years as Perth Longitudinal Study of Ageing Women (PLSAW). Over the follow up period, 428 (38.4%) women experienced a fall-related hospitalization. Older women with carotid plaque had 44% a higher relative hazard for fall-related hospitalization (HR 1.44; 95%CI, 1.18 to 1.76) compared to those without carotid plaque. The association persisted after adjustment for established falls risk factors such as measures of muscle strength and physical function.Each SD increase in the mean and maximum CCA-IMT was also associated with a higher risk of fall-related hospitalizations (HR 1.10; 95%CI, 1.00 to 1.21 and HR 1.11; 95%CI, 1.01 to 1.22, respectively). CONCLUSIONS: Measures of carotid atherosclerosis are associated with a higher risk of fall-related hospitalization independent of established falls risk factors. These findings suggest the importance of vascular health when considering falls risk.

Q fever and toxoplasmosis in South African livestock and wildlife: a retrospective study on seropositivity, sporadic abortion, and stillbirth cases in livestock caused by Coxiella burnetii.

BACKGROUND: Q fever and toxoplasmosis are economically important zoonoses as they cause considerable losses in livestock (cattle, sheep and goats) and wildlife (antelopes, giraffes, lions, and cheetahs) through reproductive disorders such as abortions and stillbirths. Q fever and toxoplasmosis testing in South Africa is conducted by the Agricultural Research Council-Onderstepoort Veterinary Research (ARC-OVR). However, both zoonoses are understudied and not monitored in South Africa as they are not considered controlled or notifiable diseases in the Animal Disease Act 35 of 1984. A retrospective study was conducted on Q fever (2007-2009) and toxoplasmosis (2007-2017) using diagnostic laboratory data at the ARC-OVR. Also, we report on sporadic abortion and stillbirth cases in livestock from diagnostic tissue samples submitted for Coxiella burnetii polymerase chain reaction (PCR) detection at the ARC-OVR. RESULTS: During 2007 to 2009, 766 animal samples were tested for C. burnetii antibodies and seropositivity was 0.9% (95%CI: 0.3-1.7) with sheep (1.9%; 95%CI: 0.6-4.4) having the highest seropositivity followed by cattle (0.7%; 95%CI: 0.09-2.6), while all goats (0.0%; 95%CI: 0.0-4.2) and wildlife (0.0%; 95%CI: 0.0-2.5) tested were negative. From 2007 to 2017, 567 sera were tested for T. gondii antibodies; overall seropositivity was 12.2% (95%CI: 9.6-15). Wildlife had highest seropositivity to T. gondii antibodies (13.9%; 95%CI: 9.0-19.7) followed by goats (12.9%; 95%CI: 9.2-17.4) and sheep (12.3%; 95%CI: 5.1-23.8) while seropositivity in cattle was 2.4% (95%CI: 0.06-12.9). Of 11 animals tested by C. burnetii PCR detection (2021-2022), 10 (91.0%) were positive. The amplicon sequences showed similarity to Coxiella burnetii strain 54T1 transposase gene partial coding sequence. CONCLUSIONS: We have confirmed the occurrence of the causative agents of Q fever and toxoplasmosis in livestock and wildlife in South Africa, with data limitations. These zoonoses remain of importance with limited information about them in South Africa. This study provides baseline information for future studies on Q fever and toxoplasmosis in South African livestock and wildlife, as well other African countries. Due to limited data collection experienced in this study, it is recommended that improvements in data collection samples tested should include associated factors such as sex, age, and breed of the animals.

Implant-Based Breast Reconstruction in the Elderly: Complications and Patient-Reported Outcomes in Women Older Than 70 Years.

BACKGROUND: Advanced age is considered by many to be a relative contraindication to breast reconstruction. However, despite increased medical comorbidities and a perception that elderly patients are less concerned with body image, more women older than 70 years are choosing to undergo breast reconstruction. There is a paucity of data to guide reconstructive decision-making and counseling in this population. OBJECTIVES: The aim of this study was to evaluate patient satisfaction, complication rates, and long-term outcomes in women older than 70 years undergoing implant-based breast reconstruction. METHODS: A total of 400 patients were identified at the authors' institution and divided into 2 groups: ≥70 and <70 years old. Medical comorbidities, surgical outcomes, and patient-reported outcomes as defined by the BREAST-Q were compared using the χ2 tests for categorical variables and t tests for continuous variables. RESULTS: The cohort of patients older than 70 years was made up of 25 women, with a mean age of 73 years, and the cohort of patients younger than 70 years was made up of 375 women, with a mean age of 50 years. There was no significant difference in body mass index (P = 0.373), smoking status (P = 0.360), or history of prior ipsilateral radiation (P = 0.508) between the 2 cohorts; however, the elderly cohort was significantly more likely to have diabetes (P = 0.026). Although elderly patients were less likely to undergo bilateral mastectomy (P < 0.001), there was no significant difference in the type of mastectomy, pathological diagnosis, or method of reconstruction. There was no significant difference in complication rates when looking at minor infection (P = 0.553) or major infection (P = 0.553). The 2 groups were equally likely to undergo secondary procedures (P = 0.192). Overall satisfaction rates were high in all BREAST-Q categories in the elderly group and not significantly different when compared with the group of patients younger than 70 years. Matched-pair analysis showed a significant difference with the group of patients older than 70 years having higher levels physical well-being (P < 0.001). CONCLUSIONS: Immediate breast reconstruction can be performed safely and with similar high satisfaction rates in the elderly population as their younger counterparts. Age alone should not be used as a reason for excluding women from these life-changing operations.