Hyperthyroidism.

Thyrotoxicosis causes a variety of symptoms and adverse health outcomes. Hyperthyroidism refers to increased thyroid hormone synthesis and secretion, most commonly from Graves' disease or toxic nodular goitre, whereas thyroiditis (typically autoimmune, viral, or drug induced) causes thyrotoxicosis without hyperthyroidism. The diagnosis is based on suppressed serum concentrations of thyroid-stimulating hormone (TSH), accompanied by free thyroxine and total or free tri-iodothyronine concentrations, which are raised (overt hyperthyroidism) or within range (subclinical hyperthyroidism). The underlying cause is determined by clinical assessment, detection of TSH-receptor antibodies and, if necessary, radionuclide thyroid scintigraphy. Treatment options for hyperthyroidism include antithyroid drugs, radioactive iodine, and thyroidectomy, whereas thyroiditis is managed symptomatically or with glucocorticoid therapy. In Graves' disease, first-line treatment is a 12-18-month course of antithyroid drugs, whereas for goitre, radioactive iodine or surgery are preferred for toxic nodules or goitres. Evidence also supports long-term treatment with antithyroid drugs as an option for patients with Graves' disease and toxic nodular goitre.

Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment. METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB. RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups. CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Dimethyl Fumarate Delays Multiple Sclerosis in Radiologically Isolated Syndrome.

OBJECTIVE: The radiologically isolated syndrome (RIS) represents the earliest detectable pre-clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in preventing first symptom manifestation at this stage in the disease spectrum. METHODS: We conducted a multi-center, randomized, double-blinded, placebo-controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with central nervous system (CNS) demyelination were included. Within 12 MS centers in the United States, participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240 mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow-up period of 96 weeks. An intention-to-treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at ClinicalTrials.gov, NCT02739542 (ARISE). RESULTS: Participants from 12 centers were recruited from March 9, 2016, to October 31, 2019, with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96-week study period was highly reduced in the unadjusted Cox proportional-hazards regression model (hazard ratio [HR] = 0.18, 95% confidence interval [CI] = 0.05-0.63, p = 0.007). More moderate adverse reactions were present in the DMF (34 [32%]) than placebo groups (19 [21%]) but severe events were similar (DMF, 3 [5%]; placebo, 4 [9%]). INTERPRETATION: This is the first randomized clinical trial demonstrating the benefit of a disease-modifying therapy in preventing a first acute clinical event in people with RIS. ANN NEUROL 2023;93:604-614.

Use of thyroid hormones in hypothyroid and euthyroid patients: A survey of members of the Endocrine Society of Australia.

OBJECTIVE: Hypothyroidism is a common endocrine condition usually managed with levothyroxine (LT4). However, controversy remains around the use of liothyronine (LT3). We aimed to investigate the practices of Australian endocrinologists when managing patients with hypothyroidism, their use of LT3 + LT4 combination therapy and use of thyroid hormones in euthyroid patients. DESIGN AND PARTICIPANTS: Members of the Endocrine Society of Australia (ESA) were invited to participate in an online questionnaire. MEASUREMENTS: We analysed questionnaires that had complete demographic data. RESULTS: Eighty-seven questionnaires fulfilled the criteria. LT4 was used as first line treatment for hypothyroidism by all respondents. Only 45% reported that their patients were dispensed the brand of LT4 that they recommend. LT3 (alone or in combination) was prescribed by 44% in their clinical practice. Although 49% of respondents would consider LT3 + LT4 in patients with normal TSH who had ongoing symptoms of hypothyroidism, the inability of LT4 to restore normal physiology was ranked the least likely explanation for persistent symptoms and only 32% would consider it for themselves if they were diagnosed with hypothyroidism. The majority (55%), in accordance with evidence, would not prescribe thyroid hormone to euthyroid individuals but 39% would consider use in euthyroid female infertility with high levels of thyroid antibodies and 11% in euthyroid patients with a simple goitre growing over time. LT4 use in pregnancy was variable among members. CONCLUSIONS: Australian endocrinologists mostly follow international guidelines when prescribing thyroid hormone therapy and many prescribe combination LT3 and LT4 therapy, particularly for patients who remain symptomatic on LT4 monotherapy. Prescribing practices are largely similar to other countries who have completed similar questionnaires.

Genetic Variation of Turnip Yellows Virus in Arable and Vegetable Brassica Crops, Perennial Wild Brassicas, and Aphid Vectors Collected from the Plants.

Turnip yellows virus (TuYV; Polerovirus, Solemoviridae) infects and causes yield losses in a range of economically important crop species, particularly the Brassicaceae. It is persistently transmitted by several aphid species and is difficult to control. Although the incidence and genetic diversity of TuYV has been extensively investigated in recent years, little is known about how the diversity within host plants relates to that in its vectors. Arable oilseed rape (Brassica napus) and vegetable brassica plants (Brassica oleracea), wild cabbage (B. oleracea), and aphids present on these plants were sampled in the field in three regions of the United Kingdom. High levels of TuYV (82 to 97%) were detected in plants in all three regions following enzyme-linked immunosorbent assays. TuYV was detected by reverse transcription polymerase chain reaction in Brevicoryne brassicae aphids collected from plants, and TuYV sequences were obtained. Two TuYV open reading frames, ORF0 and ORF3, were partially sequenced from 15 plants, and from one aphid collected from each plant. Comparative analyses between TuYV sequences from host plants and B. brassicae collected from respective plants revealed differences between some ORF0 sequences, which possibly indicated that at least two of the aphids might not have been carrying the same TuYV isolates as those present in their host plants. Maximum likelihood phylogenetic analyses including published, the new TuYV sequences described above, 101 previously unpublished sequences of TuYV from oilseed rape in the United Kingdom, and 13 also previously unpublished sequences of TuYV from oilseed rape in Europe and China revealed three distinct major clades for ORF0 and one for ORF3, with some distinct subclades. Some clustering was related to geographic origin. Explanations for TuYV sequence differences between plants and the aphids present on respective plants and implications for the epidemiology and control of TuYV are discussed.

Fatal Case of Exercise Collapse Associated with Sickle Cell Trait with Novel Underlying LAMA2 Mutation.

ABSTRACT: Sickle cell trait is typically thought to be an asymptomatic carrier state, but it is rarely associated with exertional rhabdomyolysis in cases termed Exercise Collapse Associated with Sickle Cell Trait (ECAST). In a subset of these cases, underlying disease contributes to the development and/or severity of the ensuing medical complications. We describe the first ever case of ECAST reported in a previously asymptomatic, multiply deployed, highly physically active service member with an underlying heterozygous LAMA2 mutation. Moreover, the mutation identified via whole exome sequencing is a novel, likely pathogenic variant that has yet to be described in the literature.

Shared genetics and causal relationships between migraine and thyroid function traits.

BACKGROUND: Epidemiological studies have reported a comorbid relationship between migraine and thyroid dysfunction. METHODS: We investigated the genetic relationship between migraine and thyroid function traits using genome-wide association study (GWAS) data. RESULTS: We found a significant genetic correlation (rg) with migraine for hypothyroidism (rg = 0.0608), secondary hypothyroidism (rg = 0.195), free thyroxine (fT4) (rg = 0.0772), and hyperthyroidism (rg = -0.1046), but not thyroid stimulating hormone (TSH). Pairwise GWAS analysis revealed two shared loci with TSH and 11 shared loci with fT4. Cross-trait GWAS meta-analysis of migraine identified novel genome-wide significant loci: 17 with hypothyroidism, one with hyperthyroidism, five with secondary hypothyroidism, eight with TSH, and 15 with fT4. Of the genes at these loci, six (RERE, TGFB2, APLF, SLC9B1, SGTB, BTBD16; migraine + hypothyroidism), three (GADD45A, PFDN1, RSPH6A; migraine + TSH), and three (SSBP3, BRD3, TEF; migraine + fT4) were significant in our gene-based analysis (pFisher's combined P-value < 2.04 × 10-6). In addition, causal analyses suggested a negative causal relationship between migraine and hyperthyroidism (p = 8.90 × 10-3) and a positive causal relationship between migraine and secondary hypothyroidism (p = 1.30 × 10-3). CONCLUSION: These findings provide strong evidence for genetic correlation and suggest complex causal relationships between migraine and thyroid traits.

MR Imaging-Based In Vivo Macrophage Imaging to Monitor Immune Response after Radiofrequency Ablation of the Liver.

PURPOSE: To establish molecular magnetic resonance (MR) imaging instruments for in vivo characterization of the immune response to hepatic radiofrequency (RF) ablation using cell-specific immunoprobes. MATERIALS AND METHODS: Seventy-two C57BL/6 wild-type mice underwent standardized hepatic RF ablation (70 °C for 5 minutes) to generate a coagulation area measuring 6-7 mm in diameter. CD68+ macrophage periablational infiltration was characterized with immunohistochemistry 24 hours, 72 hours, 7 days, and 14 days after ablation (n = 24). Twenty-one mice were subjected to a dose-escalation study with either 10, 15, 30, or 60 mg/kg of rhodamine-labeled superparamagnetic iron oxide nanoparticles (SPIONs) or 2.4, 1.2, or 0.6 mg/kg of gadolinium-160 (160Gd)-labeled CD68 antibody for assessment of the optimal in vivo dose of contrast agent. MR imaging experiments included 9 mice, each receiving 10-mg/kg SPIONs to visualize phagocytes using T2∗-weighted imaging in a horizontal-bore 9.4-T MR imaging scanner, 160Gd-CD68 for T1-weighted MR imaging of macrophages, or 0.1-mmol/kg intravenous gadoterate (control group). Radiological-pathological correlation included Prussian blue staining, rhodamine immunofluorescence, imaging mass cytometry, and immunohistochemistry. RESULTS: RF ablation-induced periablational infiltration (206.92 µm ± 12.2) of CD68+ macrophages peaked at 7 days after ablation (P < .01) compared with the untreated lobe. T2∗-weighted MR imaging with SPION contrast demonstrated curvilinear T2∗ signal in the transitional zone (TZ) (186 µm ± 16.9), corresponsing to Iron Prussian blue staining. T1-weighted MR imaging with 160Gd-CD68 antibody showed curvilinear signal in the TZ (164 µm ± 3.6) corresponding to imaging mass cytometry. CONCLUSIONS: Both SPION-enhanced T2∗-weighted and 160Gd-enhanced T1-weighted MR imaging allow for in vivo monitoring of macrophages after RF ablation, demonstrating the feasibility of this model to investigate local immune responses.

Fatal septic shock due to disseminated coccidioidomycosis: a case series and review of the literature.

BACKGROUND: Coccidioidomycosis is a fungal infection endemic to the southwestern United States and regions of Latin America. Disseminated disease occurs in < 1% of cases. Septic shock is even rarer, with high mortality despite therapy. We describe two cases of coccidioidal septic shock. Both patients were older men of Filipino ancestry presenting with respiratory failure and vasopressor-dependent shock. Antifungal drugs were initiated after failure to improve with empiric antibiotics; in both, Coccidioides was isolated from respiratory cultures. Despite aggressive care, both patients ultimately died of their infections. We provide a review of the published literature on this topic. CONCLUSIONS: Most of the 33 reported cases of coccidioidal septic shock occurred in men (88%) of non-white race and ethnicity (78%). The overall mortality rate was 76%. All survivors received amphotericin B as part of their treatment. Coccidioidomycosis-related septic shock is a rare disease with poor outcomes; delays in diagnosis and treatment are common. Improved diagnostic testing for coccidioidomycosis could enhance recognition of this disease in the future. Although data are limited, early treatment with amphotericin B in cases of coccidioidal septic shock may reduce mortality.

Orellanine: From Fungal Origin to a Potential Future Cancer Treatment.

Fungal metabolites represent an underutilized resource in the development of novel anticancer drugs. This review will focus on the promising fungal nephrotoxin orellanine, found in mushrooms including Cortinarius orellanus (Fools webcap). Emphasis will be placed on its historical significance, structural features, and associated toxicomechanics. Chromatographic methods for analysis of the compound and its metabolites, its synthesis, and chemotherapeutic potential are also discussed. Although orellanine's exceptional selectivity for proximal tubular cells is well documented, the mechanics of its toxicity in kidney tissue remains disputed. Here, the most commonly proposed hypotheses are detailed in the context of the molecule's structure, the symptoms seen following ingestion, and its characteristic prolonged latency period. Chromatographic analysis of orellanine and its related substances remains challenging, while biological evaluation of the compound is complicated by uncertainty regarding the role of active metabolites. This has limited efforts to structurally refine the molecule; despite numerous established methods for its synthesis, there is minimal published material on how orellanine's structure might be optimized for therapeutic use. Despite these obstacles, orellanine has generated promising data in preclinical studies of metastatic clear cell renal cell carcinoma, leading to the early 2022 announcement of phase I/II trials in humans.

Ultrahigh-throughput magnetic sorting of large blood volumes for epitope-agnostic isolation of circulating tumor cells.

Circulating tumor cell (CTC)-based liquid biopsies provide unique opportunities for cancer diagnostics, treatment selection, and response monitoring, but even with advanced microfluidic technologies for rare cell detection the very low number of CTCs in standard 10-mL peripheral blood samples limits their clinical utility. Clinical leukapheresis can concentrate mononuclear cells from almost the entire blood volume, but such large numbers and concentrations of cells are incompatible with current rare cell enrichment technologies. Here, we describe an ultrahigh-throughput microfluidic chip, LPCTC-iChip, that rapidly sorts through an entire leukapheresis product of over 6 billion nucleated cells, increasing CTC isolation capacity by two orders of magnitude (86% recovery with 105 enrichment). Using soft iron-filled channels to act as magnetic microlenses, we intensify the field gradient within sorting channels. Increasing magnetic fields applied to inertially focused streams of cells effectively deplete massive numbers of magnetically labeled leukocytes within microfluidic channels. The negative depletion of antibody-tagged leukocytes enables isolation of potentially viable CTCs without bias for expression of specific tumor epitopes, making this platform applicable to all solid tumors. Thus, the initial enrichment by routine leukapheresis of mononuclear cells from very large blood volumes, followed by rapid flow, high-gradient magnetic sorting of untagged CTCs, provides a technology for noninvasive isolation of cancer cells in sufficient numbers for multiple clinical and experimental applications.

A review of sources of resistance to turnip yellows virus (TuYV) in Brassica species.

Turnip yellows virus (TuYV; previously known as beet western yellows virus) causes major diseases of Brassica species worldwide resulting in severe yield-losses in arable and vegetable crops. It has also been shown to reduce the quality of vegetables, particularly cabbage where it causes tip burn. Incidences of 100% have been recorded in commercial crops of winter oilseed rape (Brassica napus) and vegetable crops (particularly Brassica oleracea) in Europe. This review summarises the known sources of resistance to TuYV in B. napus (AACC genome), Brassica rapa (AA genome) and B. oleracea (CC genome). It also proposes names for the quantitative trait loci (QTLs) responsible for the resistances, Turnip Yellows virus Resistance (TuYR), that have been mapped to at least the chromosome level in the different Brassica species. There is currently only one known source of resistance deployed commercially (TuYR1). This resistance is said to have originated in B. rapa and was introgressed into the A genome of oilseed rape via hybridisation with B. oleracea to produce allotetraploid (AACC) plants that were then backcrossed into oilseed rape. It has been utilised in the majority of known TuYV-resistant oilseed rape varieties. This has placed significant selection pressure for resistance-breaking mutations arising in TuYV. Further QTLs for resistance to TuYV (TuYR2-TuYR9) have been mapped in the genomes of B. napus, B. rapa and B. oleracea and are described here. QTLs from the latter two species have been introgressed into allotetraploid plants, providing for the first time, combined resistance from both the A and the C genomes for deployment in oilseed rape. Introgression of these new resistances into commercial oilseed rape and vegetable brassicas can be accelerated using the molecular markers that have been developed. The deployment of these resistances should lessen selection pressure for resistance-breaking isolates of TuYV and thereby prolong the effectiveness of each other and extant resistance.

Exertional-Related Sudden Cardiac Death in a Young, Presumed Healthy, and Medically Screened Population: A Military Case Series.

ABSTRACT: Sudden cardiac death (SCD) is defined as death from cardiac causes with loss of consciousness occurring within 1 hour of a change in cardiovascular status. As subset, SCD associated with physical exertion (SCD/E) can be defined as a cardiac event whose symptoms start during or within 1 hour of physical exertion. The US military represents a unique opportunity for studying SCD/E because of medical screening at recruitment, mandatory physical training, an active surveillance system, and centralized autopsy services. Because of medical screening, recruits are presumed healthy, but significant conditions can go undetected. We present 4 diverse cases of SCD/E in the military setting. Sudden cardiac death associated with physical exertion is often the first indication of a serious occult cardiac pathology. Postmortem genetic testing revealed a causative pathogenic mutation in 1 of 4 cases, enabling genetic testing of family members to prevent similar catastrophic loss of life, underscoring the importance of postmortem evaluation including genetic testing. Further investigations will help direct screening and prevention to capture those at risk for SCD. The cases presented in this series are a sample of the diverse etiologies and contexts surrounding SCD/E in the military setting that have been captured by Armed Forces Medical Examiner System.

Improving the Angular Visibility of Photopolymer-Based Reflection Holograms for Sensing Applications.

Volume reflection hologram-based sensors are designed to visibly change colour in response to a target stressor or analyte. However, reflection holograms fabricated in thick photopolymer films are highly angularly selective, making these sensors challenging to view and interpret by non-experts. Here, the use of speckle holography to improve the visibility of reflection holograms is presented. A novel recording approach combining speckle recording techniques with Denisyuk reflection recording geometry is described. The recorded speckle reflection grating operates as a series of multiplexed reflection gratings with a range of spatial frequencies, capable of reflecting light at a wider range of angles. A comparative study of the angular and wavelength selectivity of speckle and standard reflection gratings was conducted. The FWHM of the angular selectivity curves of the speckle reflection gratings is doubled (4°) in comparison to standard 4500 lines/mm reflection gratings (2°). The wavelength selectivity FWHM is also doubled from 4.2 to 8.6 nm. The comparative ability of the speckle and standard reflection gratings to act as colour-changing compressional pressure sensors in the 0.88-5.31 MPa range is described. Finally, we present a prototype reflection hologram viewer which enables the easy observation of angularly specific reflection holograms by non-experts.

High-resolution pH imaging using ratiometric chemical exchange saturation transfer combined with biosensor imaging of redundant deviation in shifts featuring paramagnetic DOTA-tetraglycinate agents.

Chemical exchange saturation transfer (CEST) and biosensor imaging of redundant deviation in shifts (BIRDS) methods differ respectively by detecting exchangeable and nonexchangeable proton signals by magnetic resonance. Because CEST contrast depends on both temperature and pH, simultaneous CEST and BIRDS imaging can be employed to separate these contributions. Here, we test if high-resolution pH imaging in vivo is possible with ratiometric CEST calibrated for temperature variations measured by BIRDS. Thulium- and europium-based DOTA-tetraglycinate agents, TmDOTA-(gly)4- and EuDOTA-(gly)4- , were used for high-resolution pH mapping in vitro and in vivo, using BIRDS for temperature adjustments needed for a more accurate ratiometric CEST approach. Although neither agent showed pH dependence with BIRDS in vitro in the pH range 6 to 8, each one's temperature sensitivity was enhanced when mixed because of increased redundancy. By contrast, the CEST signal of each agent was affected by the presence of the other agent in vitro. However, pH could be measured more accurately when temperature from BIRDS was detected. These in vitro calibrations with TmDOTA-(gly)4- and EuDOTA-(gly)4- enabled high-resolution pH imaging of glioblastoma in rat brains. It was concluded that temperature mapping with BIRDS can calibrate the ratiometric CEST signal from a cocktail of TmDOTA-(gly)4- and EuDOTA-(gly)4- agents to provide temperature-independent absolute pH imaging in vivo.

Prospective Associations of Sugar-Sweetened Beverage Consumption During Adolescence with Body Composition and Bone Mass at Early Adulthood.

BACKGROUND: Adolescents have a higher consumption of sugar-sweetened beverages (SSBs) than other age groups, but little is known of the impact of SSB intake during adolescence on body composition and bone mass in early adulthood. OBJECTIVES: Associations of SSB intake from 14 to 20 y with fat, lean, and bone mass at 20 y of age were evaluated. METHODS: Study participants were 1137 offspring (562 females) from the Raine Study. Food intake, including SSB consumption in servings/d (1 serving = 250 mL), was estimated using FFQs at 14, 17, and 20 y of age. DXA scanning at 20 y measured whole body fat mass, lean mass, and bone mineral content (BMC). Using latent class growth analysis, 4 SSB intake trajectory classes were identified: consistently low (n = 540, intakes mostly <0.5 serving/d), increasing (n = 65), decreasing (n = 258), and consistently high (n = 274, intakes mostly >1.3 servings/d). RESULTS: Median total SSB intake was 0.8, 0.7, and 0.5 serving/d, and median carbonated SSB intake was 0.3, 0.3, and 0.4 serving/d at 14, 17, and 20 y, respectively. Mean ± SD BMI (in kg/m2) was 23.9 ± 4.2 at 20 y. After adjustment for covariates including sex, demographic, energy intake, and maternal factors, individuals with "consistently high" SSB consumption had significantly higher total body fat mass at 20 y than those with "consistently low" consumption (23.3 ± 0.6 compared with 21.2 ± 0.4 kg, P = 0.004), which remained significant after further adjustment for "Healthy" and "Western" dietary patterns (23.2 ± 0.6 compared with 21.2 ± 0.4 kg, P = 0.011). No significant associations were observed between SSB intake trajectory classes and lean body mass or BMC at 20 y. CONCLUSIONS: In this cohort, consistently higher consumption of SSBs in adolescence and early adulthood are associated with increased fat mass but not with bone mass at 20 y of age.

Comparison of metabolic and immunologic responses to transarterial chemoembolization with different chemoembolic regimens in a rabbit VX2 liver tumor model.

OBJECTIVES: The goal of this study was to investigate the effects of TACE using Lipiodol, Oncozene™ drug-eluting embolics (DEEs), or LUMI™-DEEs alone, or combined with bicarbonate on the metabolic and immunological tumor microenvironment in a rabbit VX2 tumor model. METHODS: VX2 liver tumor-bearing rabbits were assigned to five groups. MRI and extracellular pH (pHe) mapping using Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) were performed before and after intra-arterial therapy with conventional TACE (cTACE), DEE-TACE with Idarubicin-eluting Oncozene™-DEEs, or Doxorubicin-eluting LUMI™-DEEs, each with or without prior bicarbonate infusion, and in untreated rabbits or treated with intra-arterial bicarbonate only. Imaging results were validated with immunohistochemistry (IHC) staining of cell viability (PCNA, TUNEL) and immune response (HLA-DR, CD3). Statistical analysis was performed using Mann-Whitney U test. RESULTS: pHe mapping revealed that combining cTACE with prior bicarbonate infusion significantly increased tumor pHe compared to control (p = 0.0175) and cTACE alone (p = 0.0025). IHC staining revealed peritumoral accumulation of HLA-DR+ antigen-presenting cells and CD3 + T-lymphocytes in controls. cTACE-treated tumors showed reduced immune infiltration, which was restored through combination with bicarbonate. DEE-TACE with Oncozene™-DEEs induced moderate intratumoral and marked peritumoral infiltration, which was slightly reduced with bicarbonate. Addition of bicarbonate prior to LUMI™-beads enhanced peritumoral immune cell infiltration compared to LUMI™-beads alone and resulted in the strongest intratumoral immune cell infiltration across all treated groups. CONCLUSIONS: The choice of chemoembolic regimen for TACE strongly affects post-treatment TME pHe and the ability of immune cells to accumulate and infiltrate the tumor tissue. KEY POINTS: • Combining conventional transarterial chemotherapy with prior bicarbonate infusion increases the pHe towards a more physiological value (p = 0.0025). • Peritumoral infiltration and intratumoral accumulation patterns of antigen-presenting cells and T-lymphocytes after transarterial chemotherapy were dependent on the choice of the chemoembolic regimen. • Combination of intra-arterial treatment with Doxorubicin-eluting LUMI™-beads and bicarbonate infusion resulted in the strongest intratumoral presence of immune cells (positivity index of 0.47 for HLADR+-cells and 0.62 for CD3+-cells).

Establishing a Total Hip T-Score Threshold to Measure Contralateral Hip Bone Mineral Density: Avoiding Missed Diagnosis of Osteoporosis.

Bone mineral density (BMD) of the hip is routinely measured unilaterally, but can differ between left and right. This study aimed to establish total hip T-score thresholds for measuring contralateral hip BMD, to avoid missing the diagnosis of osteoporosis. In 4914 participants (2709 females) in the Busselton Healthy Ageing Study, BMD of both hips and lumbar spine (L1-L4) was measured by dual-energy x-ray absorptiometry (DXA) using a GE Lunar Prodigy Pro densitometer. Least significant change (LSC) was calculated according to International Society for Clinical Densitometry recommendations. For participants whose left-right total hip BMD difference exceeded LSC, the 95th percentile of the difference in T-score was calculated, then added to -2.5 (the cut-off for osteoporosis) to derive T-score thresholds for measuring contralateral hip to avoid a missed diagnosis in 95% of individuals. Participant mean age (±SD) was 57.4 ± 5.8 years; total hip T-score was 0.7 ± 0.1 in males and -0.2 ± 1.1 in females. Left and right total hip BMD were highly correlated (r = 0.943 for males, 0.959 for females), but in 56.2% of males and 50.0% of females, the left-right difference exceeded the LSC of 0.026 g/cm2. In these participants, the 95th percentile of difference in T-score between two hips was 0.872 in males and 0.742 in females. This gave T-score thresholds for measuring contralateral total hip BMD of -1.6 (males) and -1.8 (females). When total hip T-score is between -1.6 and -2.5 (males), or between -1.8 and -2.5 (females), measuring contralateral hip BMD could avoid a missed diagnosis of osteoporosis.

DXA-Derived vs Standard Anthropometric Measures for Predicting Cardiometabolic Risk in Middle-Aged Australian Men and Women.

It is not clear if dual-energy X-ray absorptiometry (DXA) adiposity measures are superior to standard anthropometric measures for predicting cardiometabolic (CM) risk factors in a middle-aged general population. In the Busselton Healthy Ageing Study, we assessed a range of standard anthropometric and DXA-derived adiposity measures to predict metabolic syndrome (MetS) and CM risk factors in 4831 "baby boomers" aged 45-69 yr. Anthropometric and whole body DXA (GE Lunar Prodigy) measures were collected. Cross-sectional relationships of overall adiposity (BMI; DXA fat mass index, body fat %), central adiposity (waist circumference (WC); DXA trunk fat, android fat, abdominal visceral adipose tissue (VAT)) and ratio index (waist-to-hip ratio; DXA trunk/legs fat, android/gynoid ratio, VAT/total fat) with MetS and its components (as both continuous and binary outcomes) were evaluated using linear and logistic regression adjusting for age and lifestyle factors. Youden's Index was used to determine the optimal cut-points for predicting MetS. In linear regression analyses, central adiposity measures showed stronger associations with MetS score and CM risk factors than overall adiposity measures and fat ratio index, and DXA-VAT provided stronger associations than WC. Logistic regression models showed similar findings. For MetS diagnosis present in 35.9% of males and 24.4% of females, the highest odds ratio (95% CI) per SD change was observed for DXA-VAT (males: 5.02 [4.28, 5.88]; females: 3.91 [3.40, 4.49]), which remained significant (all p < 0.001) after further adjustment for BMI (males: 3.27 [2.65, 4.02]; females: 3.37 [2.79, 4.06]) or WC (males: 2.46 [1.95, 3.10]; females: 2.75 [2.21, 3.43]). The optimal DXA-VAT mass cut-point for predicting MetS was 1608 grams in males and 893 grams in females. DXA-VAT was superior to standard anthropometric and other DXA-derived adiposity measures for prediction of cardiometabolic risk factors, and has clinical utility for identifying middle-aged individuals at increased risk of MetS.

Decreased Immunoglobulin G Core Fucosylation, A Player in Antibody-dependent Cell-mediated Cytotoxicity, is Associated with Autoimmune Thyroid Diseases.

Autoimmune thyroid diseases (AITD) are the most common group of autoimmune diseases, associated with lymphocyte infiltration and the production of thyroid autoantibodies, like thyroid peroxidase antibodies (TPOAb), in the thyroid gland. Immunoglobulins and cell-surface receptors are glycoproteins with distinctive glycosylation patterns that play a structural role in maintaining and modulating their functions. We investigated associations of total circulating IgG and peripheral blood mononuclear cells glycosylation with AITD and the influence of genetic background in a case-control study with several independent cohorts and over 3,000 individuals in total. The study revealed an inverse association of IgG core fucosylation with TPOAb and AITD, as well as decreased peripheral blood mononuclear cells antennary α1,2 fucosylation in AITD, but no shared genetic variance between AITD and glycosylation. These data suggest that the decreased level of IgG core fucosylation is a risk factor for AITD that promotes antibody-dependent cell-mediated cytotoxicity previously associated with TPOAb levels.