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Enhanced infection and transmission of the 2022-2024 Oropouche virus strain in the North American biting midge Culicoides sonorensis
No full textOropouche virus (OROV) is a vector-borne zoonotic virus that causes febrile illness in humans. Biting midges of the Culicoides genus are the primary vectors during human outbreaks. The 2022-2024 OROV outbreak has seen an increase in incidence, geographic expansion, and the emergence of previously undocumented symptoms. To better understand the basis of increased disease incidence, infection of the outbreak virus (OROV240023) was compared to a historical virus strain (rOROVBeAn19991) in Culicoides sonorensis, a midge species that has demonstrated historical competence. Higher levels of infection, dissemination, and transmission potential were observed in C. sonorensis infected with the outbreak strain compared to the historical strain, although infectious titers did not differ between the two viruses. OROV240023 was also detected in saliva at earlier time points than rOROVBeAn19991, indicating a shorter extrinsic incubation period of < 5 days compared to 7-14 days for rOROVBeAn19991. Taken together, our results demonstrate increased transmission potential of the outbreak strain in C. sonorensis midges, raising concern about the risk of spread within the United States following potential introduction. However, further studies are needed to evaluate the current strain in Culicoides species occurring within its outbreak range, including Culicoides paraensis, the confirmed South American vector of OROV
Climate Resilience Building in the Emergency Response Network
No full textWeather models show Indiana has experienced a 45% increase in the risk of heavy flooding during the past 60 years. Government agencies cannot respond to the increase in weather disasters affecting Indiana and every region of the United States alone. U.S. public policy assumes that nonprofit charities that care for the day-to-day needs of economically vulnerable people, through food banks, shelters, community health clinics, and other organizations that provide each community’s social safety net will also meet these needs post disaster. However, policymakers have not considered those organizations’ own level of disaster preparedness to assure service continuity.
A statewide Indiana survey of leaders of social safety network organizations, carried out by Paul H. O'Neill School of Public and Environmental Affairs professor Beth Gazley and doctoral student Rachel Cash, provides rich descriptive place-based data about the realities of nonprofit service providers’ disaster planning relating to climate change. This data provides some comparisons relevant to other inland states.
This brief offers Indiana nonprofit service providers, community networks, and policymakers a neutral and objective analysis of what kinds of organizations respond to local disasters in Indiana and to what extent they engage in risk reduction to adapt to climate change. It also looks at attitudes and behaviors to understand how thinking about climate change may predict an organization’s success in disaster planning. The brief underscores the need to consider nonprofits in the formulation of policy not only in the response and recovery following a disaster but also reducing risk and increasing preparedness in advance
CAA Accumulation in the Tg2576 APPSw Mouse Model Is Associated With Inflammation and Vascular Remodeling
No full textCerebral amyloid angiopathy (CAA) is an extremely common pathology of Alzheimer’s disease (AD) included under vascular contributions to cognitive impairment and dementia (VCID). CAA has been reported in 78-98% of AD cases and has clinical significance when considering amyloid related imaging abnormalities (ARIA) that arise when using amyloid targeting immunotherapies. Despite its prevalence, studies addressing CAA mechanisms have been scarce and there are clear gaps in our understanding of how CAA progresses. This study uses Tg2576 mice, who develop CAA over time, to establish a time course of CAA progression at 8-, 14-, and 20-months of age. We identify changes in transcriptomic signatures of glial cells using NanoString nCounter and targeted protein changes using Nanostring Digital Spatial Profiling. Meso Scale Discovery and immunohistochemistry are used to establish disease progression. In this study, we saw many changes primarily associated with inflammatory response, with some changes being transient (Tnf, Lsr; VEGF) and others remaining chronically altered (Osmr, Ccl3; CTSD). Overarchingly, many of these changes relate to the perpetuation of inflammation or recruiting additional immune support, which we see in across our timepoints. Further, we identified differences in abundance of proteins (CD45, GFAP, CD31) based on presence of CAA positive vessels within a brain region. We also identified sex-specific differences in CAA burden, as well as how glial reactivity and vessel density change during disease progression. This data represents a comprehensive analysis of CAA progression and differential responses to parenchymal and vascular amyloid that could inform future basic and clinical studies
Longitudinal plasma proteomics: relation to incident Alzheimer's disease dementia and biomarkers
No full textIntroduction: We investigated whether longitudinal changes in plasma proteins were associated with baseline cognitive stages related to Alzheimer's disease (AD), their progression, and AD biomarkers.
Methods: We analyzed longitudinal proteomics (SomaScan 7K) data (N = 347) from the Indiana AD Research Center using linear mixed-effects models for associations with baseline cognitive stages, AD dementia (ADD) conversion, and AD imaging/plasma biomarkers, followed by machine learning analysis to evaluate predictive performance for incident ADD.
Results: Our analysis identified two proteins (ACES and IGFALS) associated with baseline diagnosis stages and six proteins (ACES, C7, ZCD1, IL-17C, CC055, and SO5A1) associated with incident ADD. Longitudinal changes of the identified proteins were also associated with AD imaging/plasma biomarkers. The inclusion of longitudinal protein changes yielded an AUC of 84.8% for predicting incident ADD.
Conclusion: Our findings showed molecular signatures for AD progression and the potential of dynamic changes in plasma proteins as biomarkers for predicting incident ADD.
Highlights: Changes in plasma ACES and IGFALS linked to baseline AD cognitive stages Changes in ACES, C7, ZCD1, IL-17C, CC055, and SO5A1 associated with incident ADD Changes in those proteins correlated with baseline AD imaging and plasma biomarkers Proteomics model achieved 84.8% AUC-ROC in predicting incident ADD
Medicine quality assessment in Nepal using semi randomised sampling and evaluation of a small scale dissolution test and portable Raman spectrometers
No full textSubstandard and falsified medicines threaten global health and require reliable data and screening technologies to combat their spread. This study examined the quality of 241 samples containing azithromycin, cefixime, esomeprazole and losartan collected from licenced private vendors in the Saptari (121 samples; convenience sampling) and Kathmandu (120 samples; randomised sampling) districts of Nepal. Nearly 10% (24 samples; 95% CI 6.5-14.5) of samples failed pharmacopoeial quality analysis and were classified as 'substandard' or 'probably substandard'. No falsified medicines were identified. Small-scale dissolution acceptance criteria were applied to all 20 three-unit combinations of 213 samples tested in the first stage of the United States Pharmacopoeia dissolution test. Approximately 1% of these results were false positives when compared with the final United States Pharmacopoeia dissolution test results, suggesting the test's usefulness in encouraging dissolution testing in resource-limited contexts. In the narrow sense of presence/absence, two portable Raman spectrometers reliably detected azithromycin, cefixime and losartan in most samples based on effective methods for detecting falsified medicines; however, none of the substandard samples were identified. The findings suggest that falsified medicines are less prevalent in Nepal and the surrounding region than suggested by regional concerns about Nepal and global concerns about low- and middle-income countries. Nevertheless, the Nepalese government should continue to ensure the quality of all distributed medicines
MON-361 Time to Thyroid Function Normalization in Graves' Disease Patients Initiating Methimazole Therapy
No full textObjective: Graves’ disease is an autoimmune thyroid gland disorder and the most common cause of hyperthyroidism in developed countries. Methimazole is an effective therapy in treating this condition. Initial dosing strategies and titration approaches vary widely among clinicians—some favor starting with a loading dose followed by a rapid taper. In contrast, others prefer initiating therapy with a lower dose and tapering gradually over time. In this study, we aimed to evaluate the time for thyroid function tests to normalize following the initiation of methimazole therapy with a loading dose in patients with Graves' disease. Methods: A retrospective cohort analysis included 78 patients with Graves' disease who were treated with methimazole at an academic outpatient endocrinology practice in the United States. All patients began methimazole therapy with a loading dose tailored to the severity of their hyperthyroidism at diagnosis, ranging from 10 to 60 mg daily, followed by a taper to either daily or weekly methimazole dosing. Methimazole doses were initially titrated every few weeks and then every few months, based on laboratory results. Collected data included baseline thyroid function tests (TFT) and the time to normalization of TSH, free T4 (FT4), and total T3 (TT3). Normal TFT ranges were TSH 0.4-4.2 mCu/mL, FT4 0.6-1.5 ng/dL, and TT3 89-179 ng/dL. Descriptive and inferential statistical tests were utilized. Data with a normal distribution were presented as mean ± standard deviation (SD). Non-normally distributed data were reported as the median [25th-75th percentiles], as determined by the Shapiro-Wilk test. Results: Most patients (70 out of 78) had undetectable TSH levels at diagnosis. The median initial FT4 was 2.6 ng/dL [1.7-3.9], and the median initial TT3 was 260.5 ng/dL [180.5-352.5]. The median times to normalization were 66.5 days for FT4 and 60.5 days for TT3. The median time to detectable TSH levels was 109 days, while the median time to TSH normalization was 176 days. Conclusion: Our findings indicate that TSH values take nearly six months to normalize with a loading dose, whereas FT4 and TT3 concentrations normalize much faster within a couple of months. In the future, it would be valuable to compare these outcomes to those of patients treated with lower initial methimazole doses
Adipocyte‐specific ablation of plakoglobin in mice does not affect adiposity but results in sexual‐dimorphic effects on weight gain
No full textThe main transcriptional coactivator of the WNT pathway, β-catenin, is a well-established regulator of adipogenesis and fat expansion, but our knowledge of how other members of the catenin family participate in adipogenesis remains incomplete. Previous studies have elucidated a role for the β-catenin homolog, plakoglobin, in the regulation of adipogenesis in vitro, as its depletion impaired lipid accumulation. Moreover, plakoglobin overexpression in murine cardiomyocytes has been reported to enhance adipogenesis within the heart, further implicating its role as a key regulator of differentiation. In the present study, we investigated the adipocyte-specific contributions of plakoglobin to adipogenesis and metabolism. Although deletion of plakoglobin in mature adipocytes had sex-specific effects on body weight gain, whereby only chow-fed knockout females weighed more than controls, no differences in adiposity or adipocyte size were observed. Moreover, no differences in glucose tolerance or insulin sensitivity were noted. Challenging mice with a high-fat diet revealed diet-induced metabolic disturbances only in male mice, but had no impact on adiposity or body weight. Together, our data demonstrate that plakoglobin in mature adipocytes is not required for adipogenesis or the expansion of adipose tissue mass
Modeling human retinal ganglion cell axonal outgrowth, development, and pathology using pluripotent stem cell-based microfluidic platforms
No full textRetinal ganglion cells (RGCs) are highly compartmentalized cells, with long axons serving as the sole connection between the eye and the brain. RGC degeneration in injury and/or disease also occurs in a compartmentalized manner, with distinct injury responses in axonal and somatodendritic compartments. Thus, the goal of this study was to establish a novel microfluidic-based platform for the analysis of RGC compartmentalization in health and disease states. Human pluripotent stem cell (hPSC)-derived RGCs were seeded into microfluidics, enabling the recruitment and isolation of axons apart from the somatodendritic compartment. Initial studies explored axonal outgrowth and compartmentalization of axons and dendrites. We then compared the differential response of RGCs differentiated from hPSCs carrying the OPTN(E50K) glaucoma mutation with isogenic control RGCs in their respective axonal and somatodendritic compartments, followed by analysis of axonal transport. Further, we explored the axonal transcriptome via RNA-seq, focusing on disease-related axonal differences. Finally, we established models to uniquely orient astrocytes along the axonal compartment combined with modulation of astrocyte reactivity as a pathological feature of neurodegeneration. Overall, RGC culture within microfluidic chips allowed enhanced cell growth and maturation, including long-distance axonal projections and proper compartmentalization, while patient-specific RGCs exhibited axonal outgrowth deficits as well as decreased rate of axonal transport. Finally, the induction of astrocyte reactivity uniquely along the proximal region of RGC axons led to the onset of neurodegenerative phenotypes in RGCs. These results represent the first study to effectively recapitulate the highly compartmentalized properties of hPSC-derived RGCs in healthy and disease states, providing a more physiologically relevant in vitro model for neuronal development and degeneration
Lateral Femoral Cutaneous Neurectomy With Nerve End Implantation for Meralgia Paresthetica: A Technique Guide
No full textMeralgia paresthetica is an uncommon but painful neuropathy causing anterolateral thigh pain. Compression or injury of the lateral femoral cutaneous nerve (LFCN) leads to pain and/or numbness in its distribution throughout the thigh. Historically, surgical decompression of the LFCN just below the inguinal ligament was most commonly utilized for first-line surgical management, but recently, fully transecting the LFCN is becoming increasingly popular as more favorable outcomes are reported. This Technical Note describes our surgical approach to neurectomy and nerve end implantation for the treatment of meralgia paresthetica
Switching from active vitamin D and phosphate supplementation to burosumab significantly corrects lower limb malalignment in pediatric X-linked hypophosphatemia
No full textX-linked hypophosphatemia (XLH) is a rare disorder of renal phosphate wasting and dysregulated active vitamin D metabolism, ultimately presenting as rickets and osteomalacia, among other manifestations. Lower extremity deformity (genu valgum and/or varum) is frequent in this pediatric population. Despite prompt active vitamin D and phosphate supplementation (active D/Pi), many patients require corrective surgery for lower limb malformation. Burosumab has demonstrated improvements in lower limb malalignment in children with XLH in several studies. We expand on those reports by assessing mechanical femoral tibial angle (mFTA) change in patients enrolled in the XLH Disease Monitoring Program (DMP), (NCT03651505) to determine the impact of initiating burosumab treatment after a history of active D/Pi. Included patients had either switched from active D/Pi to burosumab treatment at the discretion of their treating physician or as part of a burosumab clinical trial, or remained on active D/Pi through Year 3 of the DMP. Year 3 radiographs were compared with baseline to assess mFTA change and gauge improvement. Additional multivariate factor analysis examined 24 attributes to determine which had the greatest association with mFTA change. Change in mFTA was assessed for each limb independently. A greater proportion of limbs of patients switching from active D/Pi to burosumab had improved mFTA compared with those remaining on active D/Pi (p < .023). Odds ratios comparing limbs that improved to those that did not showed that switching to burosumab yields a significantly greater chance of improvement than continuing active D/Pi (OR [95% CI]: 4.38 [1.09-17.50]; p = .0469). Factor analysis identified younger age at burosumab initiation (p = .001) and lower baseline height Z-score (p = .006) as being significantly associated with greater change in mFTA Z-score. This study shows that switching to burosumab significantly improves lower limb malalignment in children with XLH over benefits conferred by active D/Pi, with early burosumab initiation providing the greatest benefit