Phenotype of Parathyroid-targeted Cdc73 Deletion in Mice Is Strain-dependent.

Hyperparathyroidism jaw-tumor syndrome is an autosomal dominant disorder caused by mutations in the CDC73/HRPT2 tumor suppressor gene, encoding parafibromin, and manifesting benign or malignant parathyroid tumors, ossifying jaw fibromas, uterine tumors, and kidney lesions. Sporadic parathyroid carcinomas also frequently exhibit inactivating CDC73 mutations and loss of parafibromin. To study the role of CDC73 in parathyroid cell proliferation in vivo, we generated mice with a parathyroid-specific deletion of Cdc73. Homozygous knockout mice on a mixed B6/129/CD1 background had decreased serum calcium and PTH and smaller parathyroid glands compared with heterozygous or wild-type littermates, whereas homozygous Cdc73-null mice on other backgrounds exhibited no abnormalities in parathyroid gland function or development. No hypercalcemia or parathyroid hypercellularity was observed in mice of any background examined at any age. Thus, although postnatally acquired complete loss of CDC73 causes parathyroid cell proliferation and hyperparathyroidism, such as seen in human hyperparathyroidism jaw-tumor syndrome, our results suggest that earlier, developmentally imposed complete loss of Cdc73 can cause a primary defect in parathyroid gland structure/function in a strain-dependent manner. This striking disparity in parathyroid phenotype related to genetic background offers a unique opportunity in an in vivo model system to precisely dissect and identify the responsible molecular mechanisms.

Influence of Vitamin D Deficiency on Cyclin D1-Induced Parathyroid Tumorigenesis.

Primary hyperparathyroidism (PHPT) is a common endocrinopathy for which several pathogenic mechanisms, including cyclin D1 overexpression, have been identified. Vitamin D nutritional status may influence parathyroid tumorigenesis, but evidence remains circumstantial. To assess the potential influence of vitamin D insufficiency/deficiency on initiation or progression of parathyroid tumorigenesis, we superimposed vitamin D insufficiency or deficiency on parathyroid tumor-prone parathyroid hormone-cyclin D1 transgenic mice. Mice were placed on diets containing either 2.75 IU/g, 0.25 IU/g, or 0.05 IU/g cholecalciferol, either prior to expected onset of PHPT or after onset of biochemical PHPT. When introduced early, superimposed vitamin D insufficiency/deficiency had no effect on serum calcium or on parathyroid gland growth. However, when introduced after the onset of biochemical PHPT, vitamin D deficiency led to larger parathyroid glands without differences in serum biochemical parameters. Our results suggest that low vitamin D status enhances proliferation of parathyroid cells whose growth is already being tumorigenically driven, in contrast to its apparent lack of direct proliferation-initiating action on normally growing parathyroid cells in this model. These results are consistent with the hypothesis that suboptimal vitamin D status may not increase incidence of de novo parathyroid tumorigenesis but may accelerate growth of a preexisting parathyroid tumor.

Epidemiology, Pathophysiology, and Genetics of Primary Hyperparathyroidism.

In this narrative review, we present data gathered over four decades (1980-2020) on the epidemiology, pathophysiology and genetics of primary hyperparathyroidism (PHPT). PHPT is typically a disease of postmenopausal women, but its prevalence and incidence vary globally and depend on a number of factors, the most important being the availability to measure serum calcium and parathyroid hormone levels for screening. In the Western world, the change in presentation to asymptomatic PHPT is likely to occur, over time also, in Eastern regions. The selection of the population to be screened will, of course, affect the epidemiological data (ie, general practice as opposed to tertiary center). Parathyroid hormone has a pivotal role in regulating calcium homeostasis; small changes in extracellular Ca++ concentrations are detected by parathyroid cells, which express calcium-sensing receptors (CaSRs). Clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of CaSRs is the most important pathophysiologic basis of PHPT. The spectrum of skeletal disease reflects different degrees of dysregulated bone remodeling. Intestinal calcium hyperabsorption together with increased bone resorption lead to increased filtered load of calcium that, in addition to other metabolic factors, predispose to the appearance of calcium-containing kidney stones. A genetic basis of PHPT can be identified in about 10% of all cases. These may occur as a part of multiple endocrine neoplasia syndromes (MEN1-MEN4), or the hyperparathyroidism jaw-tumor syndrome, or it may be caused by nonsyndromic isolated endocrinopathy, such as familial isolated PHPT and neonatal severe hyperparathyroidism. DNA testing may have value in: confirming the clinical diagnosis in a proband; eg, by distinguishing PHPT from familial hypocalciuric hypercalcemia (FHH). Mutation-specific carrier testing can be performed on a proband's relatives and identify where the proband is a mutation carrier, ruling out phenocopies that may confound the diagnosis; and potentially prevention via prenatal/preimplantation diagnosis. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Parathyroid Hormone Regulates Circulating Levels of Sclerostin and FGF23 in a Primary Hyperparathyroidism Model.

Parathyroid hormone (PTH) increases fibroblast growth factor 23 (FGF23), mediated both by protein kinase A (PKA) and Wnt signaling, and decreases expression of sclerostin, a Wnt antagonist derived from osteocytes. Patients with primary hyperparathyroidism (PHPT) have lower serum sclerostin levels than healthy controls, consistent with the idea of SOST downregulation by PTH. Nevertheless, the relationship between FGF23 and sclerostin in PHPT is still unclear. We examined this issue in a mouse model of PHPT. PHPT mice had increased FGF23 and decreased sclerostin expression in calvaria and in their serum concentrations compared with wild-type (WT) mice. In UMR106 osteoblasts, PTH increased Fgf23 expression and decreased Sost expression, as well as forskolin, a PKA agonist, whereas inhibition of PKA reversed the changes in Fgf23 and Sost expression, stimulated by PTH. Sclerostin treatment had no effect on Fgf23 expression, but when it was added together with PTH, it statistically significantly abrogated the increase in Fgf23 expression. By contrast, there was no statistically significant correlation between serum FGF23 and sclerostin, whereas PTH was positively and negatively correlated with serum FGF23 and sclerostin, respectively. These results indicate that the high level of PTH in PHPT mice leads to increased FGF23 and decreased sclerostin expression in serum and calvaria. A decrease of sclerostin may further augment FGF23 in vitro; however, there was no statistically significant association between circulating FGF23 and sclerostin. It is suggested that the pathogenesis of increased FGF23 expression in PHPT mice may be modified by not only sclerostin, but also other regulatory factors modulated by PTH.

GCM2 Variants in Familial and Multiglandular Primary Hyperparathyroidism.

CONTEXT: Multiglandular and familial parathyroid disease constitute important fractions of primary hyperparathyroidism (PHPT). Germline missense variants of GCM2, a regulator of parathyroid development, were observed in familial isolated hyperparathyroidism and sporadic PHPT. However, as these previously reported GCM2 variants occur at relatively high frequencies in the population, understanding their potential clinical utility will require both additional penetrance data and functional evidence relevant to tumorigenicity. OBJECTIVE: Determine the frequency of GCM2 variants of interest among patients with sporadic multigland or familial parathyroid disease and assess their penetrance. DESIGN AND PATIENTS: DNA-encoding PHPT-associated GCM2 germline variants were polymerase chain reaction-amplified and sequenced from 107 patients with either sporadic multigland or suspected/confirmed familial parathyroid tumors. RESULTS: GCM2 variants were observed in 9 of 107 cases (8.4%): Y282D in 4 patients (6.3%) with sporadic multigland disease; Y394S in 2 patients (11.1%) with familial PHPT and 3 (4.8%) with sporadic multigland disease. Compared with the general population, Y282D was enriched 5.9-fold in multigland disease, but its penetrance was very low (0.02%). Y394S was enriched 79-fold in sporadic multigland disease and 93-fold in familial PHPT, but its penetrance was low (1.33% and 1.04%, respectively). CONCLUSIONS: Observed in vitro-activating GCM2 variant alleles are significantly overrepresented in PHPT patients with multiglandular or familial disease compared to the general population, yet penetrance values are very low; that is, most individuals with these variants in the population have a very low risk of developing PHPT. The potential clinical utility of detecting these GCM2 variants requires further investigation, including assessing their possible role as pathogenic/low-penetrance alleles.

Ellipsoid Spectacle Comparison of Plusoptix, Retinomax and 2WIN Autorefractors.

BACKGROUND: Handheld devices can automatically give an estimate of refraction. The established method for refraction comparison using spherical equivalent (M) and J0, J45 vector transformations by Bland-Altman analysis is too complex for non-eye doctors involved with vision screening and remote vision clinics. Therefore, a simpler comparison technique was developed. METHODS: Based on the spectacle limit to resolve grade A 1 logMAR, B 3 logMAR and C 6 logMAR blur, J0, J45, and M are combined into the Alaska Blind Child Discovery (ABCD) composite ellipsoid GRADE system. Pediatric eye patients had confirmatory examination after dry refraction with three portable autorefractors: Plusoptix, 2WIN and Retinomax. The refractions were then compared using both Bland-Altman and ABCD composite. Performance to detect AAPOS amblyopia risk factors was also assessed. RESULTS: A total of 202 children, mean age seven years, 28% high spectacle need and 43% AAPOS 2013 amblyopia risk factors showed high correlation with cycloplegic refraction (intraclass correlation 0.49 to 0.90) for sphere, J0 and J45 spectacle components. Plusoptix had more (10%) inconclusives due to patients out-of-range. The Retinomax was unable to screen some younger children and was less reliable for sphere but gave more precise astigmatism estimates. The proportion of autorefractions expected to give GRADE A/B high-need patients acuity improvement to 20/40 would be 41% for Plusoptix, 39% for 2WIN and 65% for Retinomax. Sensitivity/specificity for amblyopia risk factor detection was 80%/83% for Plusoptix, 72%/88% for 2WIN and 84%/73% for Retinomax. CONCLUSION: The simplified spectacle comparison resembled Bland-Altman and could assist lay vision screeners and non-eye doctors attempting remote spectacle donation worldwide.

Mutations in EPHB4 cause human venous valve aplasia.

Venous valve (VV) failure causes chronic venous insufficiency, but the molecular regulation of valve development is poorly understood. A primary lymphatic anomaly, caused by mutations in the receptor tyrosine kinase EPHB4, was recently described, with these patients also presenting with venous insufficiency. Whether the venous anomalies are the result of an effect on VVs is not known. VV formation requires complex "organization" of valve-forming endothelial cells, including their reorientation perpendicular to the direction of blood flow. Using quantitative ultrasound, we identified substantial VV aplasia and deep venous reflux in patients with mutations in EPHB4. We used a GFP reporter in mice to study expression of its ligand, ephrinB2, and analyzed developmental phenotypes after conditional deletion of floxed Ephb4 and Efnb2 alleles. EphB4 and ephrinB2 expression patterns were dynamically regulated around organizing valve-forming cells. Efnb2 deletion disrupted the normal endothelial expression patterns of the gap junction proteins connexin37 and connexin43 (both required for normal valve development) around reorientating valve-forming cells and produced deficient valve-forming cell elongation, reorientation, polarity, and proliferation. Ephb4 was also required for valve-forming cell organization and subsequent growth of the valve leaflets. These results uncover a potentially novel cause of primary human VV aplasia.

Editor's Choice - A Comparison of Computed Tomography Angiography and Colour Duplex Ultrasound Surveillance Post Infrarenal Endovascular Aortic Aneurysm Repair: Financial Implications and Impact of Different International Surveillance Guidelines.

OBJECTIVE: Use of colour duplex ultrasound (CDUS) and computed tomography angiography (CTA) for infrarenal endovascular aortic aneurysm repair (EVAR) surveillance differs in internationally published guidelines. This study aimed firstly to compare CDUS detection of significant sac abnormalities with CTA. Secondly, a sensitivity analysis was conducted to compare financial estimates of the, predominantly CDUS based, local and Society of Vascular Surgery (SVS) protocols, the risk stratified European Society of Vascular Surgery (ESVS) protocol, and the CTA based National Institute of Health and Care Excellence (NICE) protocol. METHODS: Agreement between CDUS and CTA was assessed for detection of significant sac abnormalities. Surveillance protocols were extrapolated from published guidelines and applied to infrarenal EVAR patients active on local surveillance at a large, single centre. Surveillance intensity was dependent on presence of endoleak and subsequent risk of treatment failure in accordance with surveillance recommendations. Estimates for each surveillance protocol were inclusive of a range of published incidences of endoleak, contrast associated acute kidney injury (AKI), and excess hospital bed days, and estimated for a hypothetical five year surveillance period. RESULTS: The kappa coefficient between CDUS and CTA for detecting sac abnormalities was 0.68. Maximum five year surveillance cost estimates for the 289 active EVAR patients were £272 359 for SVS, £230 708 for ESVS, £643 802 for NICE, and £266 777 for local protocols, or £1 270, £1 076, £3 003, and £1 244 per patient. Differences in endoleak incidence accounted for a 1.1 to 1.4 fold increase in costs. AKI incidence accounted for a 3.3 to 6.2 fold increase in costs. CONCLUSION: A combined CTA and CDUS EVAR surveillance protocol, with CTA reserved for early seal assessment and confirmatory purposes, provides an economical approach without compromising detection of sac abnormalities. AKI, as opposed to direct imaging costs, accounted for the largest differences in surveillance cost estimates.

Parafibromin Abnormalities in Ossifying Fibroma.

Ossifying fibromas are very rare tumors that are sometimes seen as part of the hyperparathyroidism-jaw tumor syndrome (HPT-JT), which is caused by inactivating mutations of the HRPT2/CDC73 tumor suppressor gene. CDC73 mutations have been identified in a subset of sporadic cases but aberrant expression of the encoded protein, parafibromin, has not been demonstrated in ossifying fibroma. We sought to determine if loss of parafibromin regularly contributes to the development of sporadic, nonsyndromic ossifying fibroma. We examined a series of 9 ossifying fibromas, including ossifying, cemento-ossifying, and juvenile active variants, for parafibromin protein expression by immunohistochemistry and for CDC73 sequence abnormalities by Sanger sequencing and/or targeted AmpliSeq panel sequencing. Four ossifying fibromas showed a complete absence of nuclear parafibromin expression; loss of parafibromin expression was coupled with aberrant cytoplasmic parafibromin expression in 1 case. CDC73 mutations were detected in 2 cases with aberrant parafibromin expression. These results provide novel evidence, at the level of protein expression, that loss of the parathyroid CDC73/parafibromin tumor suppressor may play a role in the pathogenesis of a subset of ossifying fibromas.

Trichromatic Enhanced Dynamic Color Screening on the PDI Check Nintendo 3DS Game.

INTRODUCTION: Classification of color deficiency has required substantial time and expense with the static Farnsworth-Munsell and Innova Rabin tests. Therefore, dynamic color tests were developed for the Nintendo 3DS. METHODS: Fifteen color deficient patients and 17 age-matched normals performed Rabin color test in addition to PDI Check dynamic color games resembling Farnsworth-Munsell presentation (version 0.2.8) and 3-color iso-luminance gray (version 0.2.13). RESULTS: Tests of red, green and blue cone-deficient with the v0.2.8 had sensitivity/specificity/PPV of 92%/86%/92% protanopes, 78%/90%/88% deutanopes and 87%/50%/93% tritanopes. Version 0.2.13 had sens/spec/PPV of 78%/83%/78% red-cone, 100%/85%/80% green cone and 67%/78%/33% blue cone. Corresponding IntraClass Correlation (ICC) utilizing v0.2.8 were red-cone 0.22 (-0.02-0.60), green-cone 0.34 (-0.10-0.67) and blue-cone 0.38 (0.12-0.75). ICC for v0.2.13 was higher with protanope 0.62 (-0.07-0.87), deuteranope 0.64 (-0.09-0.88) and tritanope 0.31 (-0.07-0.70). The PDI Check color game took 65 seconds compared to 197 seconds for Innova Rabin. CONCLUSION: The PDI Check color game quickly identifies patients with inherited color deficiencies.

The Role of Comparisons in Judgments of Loneliness.

Loneliness-perceived social isolation-is defined as a discrepancy between existing social relationships and desired quality of relationships. Whereas most research has focused on existing relationships, we consider the standards against which people compare them. Participants who made downward social or temporal comparisons that depicted their contact with others as better (compared to other people's contact or compared to the past) reported less loneliness than participants who made upward comparisons that depicted their contact with others as worse (Study 1-3). Extending these causal results, in a survey of British adults, upward social comparisons predicted current loneliness, even when controlling for loneliness at a previous point in time (Study 4). Finally, content analyses of interviews with American adults who lived alone showed that social and temporal comparisons about contact with others were both prevalent and linked to expressed loneliness (Study 5). These findings contribute to understanding the social cognition of loneliness, extend the effects of comparisons about social connection to the important public health problem of loneliness, and provide a novel tool for acutely manipulating loneliness.

Hormonal regulation of biomineralization.

Biomineralization is the process by which organisms produce mineralized tissues. This crucial process makes possible the rigidity and flexibility that the skeleton needs for ambulation and protection of vital organs, and the hardness that teeth require to tear and grind food. The skeleton also serves as a source of mineral in times of short supply, and the intestines absorb and the kidneys reclaim or excrete minerals as needed. This Review focuses on physiological and pathological aspects of the hormonal regulation of biomineralization. We discuss the roles of calcium and inorganic phosphate, dietary intake of minerals and the delicate balance between activators and inhibitors of mineralization. We also highlight the importance of tight regulation of serum concentrations of calcium and phosphate, and the major regulators of biomineralization: parathyroid hormone (PTH), the vitamin D system, vitamin K, fibroblast growth factor 23 (FGF23) and phosphatase enzymes. Finally, we summarize how developmental stresses in the fetus and neonate, and in the mother during pregnancy and lactation, invoke alternative hormonal regulatory pathways to control mineral delivery, skeletal metabolism and biomineralization.

Molecular analysis of cyclin D1 modulators PRKN and FBX4 as candidate tumor suppressors in sporadic parathyroid adenomas.

OBJECTIVE: Primary hyperparathyroidism is most often caused by a sporadic single-gland parathyroid adenoma (PTA), a tumor type for which cyclin D1 is the only known and experimentally validated oncoprotein. However, the molecular origins of its frequent overexpression have remained mostly elusive. In this study, we explored a potential tumorigenic mechanism that could increase cyclin D1 stability through a defect in molecules responsible for its degradation. METHODS: We examined two tumor suppressor genes known to modulate cyclin D1 ubiquitination, PRKN and FBXO4 (FBX4), for evidence of classic two-hit tumor suppressor inactivation within a cohort of 82 PTA cases. We examined the cohort for intragenic inactivating and splice site mutations by Sanger sequencing and for locus-associated loss of heterozygosity (LOH) by microsatellite analysis. RESULTS: We identified no evidence of bi-allelic tumor suppressor inactivation of PRKN or FBXO4 via inactivating mutation or splice site perturbation, neither in combination with nor independent of LOH. Among the 82 cases, we encountered previously documented benign single nucleotide polymorphisms (SNPs) in 35 tumors at frequencies similar to those reported in the germlines of the general population. Eight cases exhibited intragenic LOH at the PRKN locus, in some cases extending to cover at least an additional 1.7 Mb of chromosome 6q25-26. FBXO4 was not affected by LOH. CONCLUSION: The absence of evidence for specific bi-allelic inactivation in PRKN and FBXO4 in this sizeable cohort suggests that these genes only rarely, if ever, serve as classic driver tumor suppressors responsible for the growth of PTAs.

Satisfiability Attack-Resistant Camouflaged Two-Dimensional Heterostructure Devices.

Reverse engineering (RE) is one of the major security threats to the semiconductor industry due to the involvement of untrustworthy parties in an increasingly globalized chip manufacturing supply chain. RE efforts have already been successful in extracting device level functionalities from an integrated circuit (IC) with very limited resources. Camouflaging is an obfuscation method that can thwart such RE. Existing work on IC camouflaging primarily involves transformable interconnects and/or covert gates where variation in doping and dummy contacts hide the circuit structure or build cells that look alike but have different functionalities. Emerging solutions, such as polymorphic gates based on a giant spin Hall effect and Si nanowire field effect transistors (FETs), are also promising but add significant area overhead and are successfully decamouflaged by the satisfiability solver (SAT)-based RE techniques. Here, we harness the properties of two-dimensional (2D) transition-metal dichalcogenides (TMDs) including MoS2, MoSe2, MoTe2, WS2, and WSe2 and their optically transparent transition-metal oxides (TMOs) to demonstrate area efficient camouflaging solutions that are resilient to SAT attack and automatic test pattern generation attacks. We show that resistors with resistance values differing by 5 orders of magnitude, diodes with variable turn-on voltages and reverse saturation currents, and FETs with adjustable conduction type, threshold voltages, and switching characteristics can be optically camouflaged to look exactly similar by engineering TMO/TMD heterostructures, allowing hardware obfuscation of both digital and analog circuits. Since this 2D heterostructure devices family is intrinsically camouflaged, NAND/NOR/AND/OR gates in the circuit can be obfuscated with significantly less area overhead, allowing 100% logic obfuscation compared to only 5% for complementary metal oxide semiconductor (CMOS)-based camouflaging. Finally, we demonstrate that the largest benchmarking circuit from ISCAS'85, comprised of more than 4000 logic gates when obfuscated with the CMOS-based technique, is successfully decamouflaged by SAT attack in <40 min; whereas, it renders to be invulnerable even in more than 10 h when camouflaged with 2D heterostructure devices, thereby corroborating our hypothesis of high resilience against RE. Our approach of connecting material properties to innovative devices to secure circuits can be considered as a one of a kind demonstration, highlighting the benefits of cross-layer optimization.

Smile (but only deliberately) though your heart is aching: Loneliness is associated with impaired spontaneous smile mimicry.

As social beings, humans harbor an evolved capacity for loneliness - perceived social isolation. Loneliness is associated with atypical affective and social processing, as well as physiological dysregulation. We investigated how loneliness influences spontaneous facial mimicry (SFM), an interpersonal response involved in social connection and emotional contagion. We presented participants with emotional stimuli, such as video clips of actors expressing anger, fear, sadness, or joy, and emotional IAPS images. We measured participants' zygomaticus major ("smiling") muscle and their corrugator supercilii ("frowning") muscle with facial electromyography (fEMG). We also measured self-reported loneliness, depression, and extraversion levels. For socially connected individuals we found intact SFM, as reflected in greater fEMG activity of the zygomaticus and corrugator to positive and negative expressions, respectively. However, individuals reporting higher levels of loneliness lacked SFM for expressions of joy. Loneliness did not impair deliberate mimicry activity to the same expressions, or spontaneous reactions to positive, negative, or neutral IAPS images. Depression and extraversion did not predict any differences in fEMG responses. We suggest that impairments in spontaneous "smiling back" at another - a decreased interpersonal resonance - could contribute to negative social and emotional consequences of loneliness and may facilitate loneliness contagion.

Oculocardiac Reflex During ROP Exams.

PURPOSE: Reducing physiologic stress including bradycardia during staging eye exams for retinopathy of prematurity (ROP) is desirable. We observed heart rate change during routine retinopathy of prematurity eye examinations and compared the response with our ongoing study of oculocardiac reflex (OCR) elicited by uniform EOM tension during strabismus surgery. PATIENTS AND METHODS: Electrocardiograph was prospectively monitored during ROP exams featuring indirect ophthalmoscopy with Alfonso lid speculum and see-through scleral depressor without topical anesthesia. Clinical data were retrieved from ROP-Check software. OCR was defined as maximally changed heart rate (HR) as a percent of baseline. Strabismus surgery patients under general anesthesia served as controls. RESULTS: From 10/2017 to 9/2020, 281 infants had ROP exams, and the median OCR was 55.9% of baseline HR (IQR 41.4% to 72.6%), the kurtosis 0.93 and skewness 1.01 representing a drop from HR 169 ± 16 bpm to 102 ± 39 bpm. In comparison, 1493 adult and pediatric strabismus surgery patients had less OCR median bradycardia 87.8% (IQR 72-98%), kurtosis 1.60 and skewness -1.18. ROP %OCR correlated with birth gestational age (%OCR = 2.5 (GA) - 11, r(279)=0.33, p<0.01) and with birthweight (%OCR = 0.02 (BW) + 38, r(279) =0.35, p<0.01). The duration of bradycardia induced by ROP exam averaged 92 ± 34 seconds (range 34-240 seconds). CONCLUSION: Bradycardia is common during eye exams in the smallest premature infants with greater degree, more rapid onset and longer duration than OCR during strabismus surgery.

The Impact of Re-Operation, Relatives and Race on the Oculocardiac Reflex During Strabismus Surgery.

PURPOSE: The oculocardiac reflex (OCR) is a trigeminovagal bradycardia elicited by tension on an extraocular muscle (EOM). Using three decades of observational data, we investigated whether or not individual strabismus patients are prone to oculocardiac reflex. PATIENTS AND METHODS: All patients undergoing strabismus surgery from 1992 to 2019 had deliberate 10-second, 200-gram square-wave tension on extraocular rectus muscles with anesthetic variables recorded. OCR was defined as the maximally tension-altered heart rate as a percent of stable baseline heart rate. RESULTS: OCR was compared in 2532 original cases with 323 re-operations. The 169 cases that used anticholinergics (99% OCR) were excluded from the analysis. The median OCR, a 15% drop, was found to be 85% (95% CI 39%, 102%,; range 5-151%). Factors that showed a significant effect on the OCR were the type of EOM with lateral rectus least (Kruskal-Wallis X2(3)=8, p<0.05), and adults had less OCR compared to the children (X2(2)=105, p<0.01). Factors that showed an augmenting effect on the OCR were peri-operative opioids (X2(6)=62, p<0.01) and Caucasian race (X2(4)=12, p<0.02). Gender and iris color were not found to have an impact on OCR. Re-operations and first-degree relatives did not differ from age-matched controls, but EOM- and opioid-adjusted re-operations correlated with their initial cases (r=0.37). CONCLUSION: We confirmed the previously published blocking effect of atropine, augmenting impact of opioids, and an inverse relationship of age on OCR. There was a weak proclivity for individuals to be prone to OCR. We found an impact of race with Caucasians having more OCR.

Thickness Trends of Electron and Hole Conduction and Contact Carrier Injection in Surface Charge Transfer Doped 2D Field Effect Transistors.

One of the main limiting factors in the performance of devices based on two-dimensional (2D) materials is Fermi level pinning at the contacts, which creates Schottky barriers (SBs) that increase contact resistance and, for most transition metal dichalcogenides (TMDs), limit hole conduction. A promising method to mitigate these problems is surface charge transfer doping (SCTD), which places fixed charge at the surface of the material and thins the SBs by locally shifting the energy bands. We use a mild O2 plasma to convert the top few layers of a given TMD into a substoichiometric oxide that serves as a p-type SCTD layer. A comprehensive experimental study, backed by TCAD simulations, involving MoS2, MoSe2, MoTe2, WS2, and WSe2 flakes of various thicknesses exposed to different plasma times is used to investigate the underlying mechanisms responsible for SCTD. The surface charge at the top of the channel and the gate-modulated surface potential at the bottom are found to have competing effects on the channel potential, which results in a decrease in the doping-induced threshold shift and an increase in minimum OFF state current with increasing thickness. Additionally, an undoped channel region is shown to mitigate carrier injection issues in sufficiently thin flakes. Notably, the band movements underlying the SCTD effects are independent of the particular semiconductor material, SCTD strategy, and doping polarity. Consequently, our findings provide critical insights for the design of high-performance transistors for a wide range of materials and SCTD mechanisms including TMD devices with strong hole conduction.

CDK4/6 Dependence of Cyclin D1-Driven Parathyroid Neoplasia in Transgenic Mice.

The protein product of the cyclin D1 oncogene functions by activating partner cyclin-dependent kinases (cdk)4 or cdk6 to phosphorylate, thereby inactivating, the retinoblastoma protein pRB. Nonclassical, cdk-independent, functions of cyclin D1 have been described but their role in cyclin D1-driven neoplasia, with attendant implications for recently approved cdk4/6 chemotherapeutic inhibitors, requires further examination. We investigated whether cyclin D1's role in parathyroid tumorigenesis in vivo is effected primarily through kinase-dependent or kinase-independent mechanisms. Using a mouse model of cyclin D1-driven parathyroid tumorigenesis (PTH-D1), we generated new transgenic lines harboring a mutant cyclin D1 (KE) that is unable to activate its partner kinases. While this kinase-dead KE mutant effectively drove mammary tumorigenesis in an analogous model, parathyroid-overexpressed cyclin D1 KE mice did not develop the characteristic biochemical hyperparathyroidism or parathyroid hypercellularity of PTH-D1 mice. These results strongly suggest that in parathyroid cells, cyclin D1 drives tumorigenesis predominantly through cdk-dependent mechanisms, in marked contrast with the cdk-independence of cyclin D1-driven mouse mammary cancer. These findings highlight crucial tissue-specific mechanistic differences in cyclin D1-driven tumorigenesis, suggest that parathyroid/endocrine cells may be more tumorigenically vulnerable to acquired genetic perturbations in cdk-mediated proliferative control than other tissues, and carry important considerations for therapeutic intervention.

PIK3CA Mutational Analysis of Parathyroid Adenomas.

Benign parathyroid adenoma is the most common cause of primary hyperparathyroidism, whereas malignant parathyroid carcinoma is exceedingly rare. Distinguishing parathyroid carcinoma from benign adenoma is often difficult, and may be considerably delayed even after surgical resection until the rigorous diagnostic criteria of local invasion of surrounding tissues and/or distant metastases are fulfilled. Thus, new insights into their respective molecular bases may potentially aid in earlier diagnostic discrimination between the two, as well as informing new directions for treatment. In two recent studies, gain-of-function mutations in PIK3CA, a recognized driver oncogene in many human malignancies, have been newly identified in parathyroid carcinoma. To assess the potential specificity for malignant, as opposed to benign parathyroid disease, of PIK3CA hotspot mutations, we PCR-amplified and Sanger sequenced codons 111, 542/545, and 1047 and the immediate flanking regions in genomic DNA from 391 typical, sporadic parathyroid adenomas. Four parathyroid adenomas (1%) had subclonal, somatic, heterozygous, activating PIK3CA mutations. The rarity of PIK3CA activating mutations in benign parathyroid adenomas suggests that tumorigenic activation of PIK3CA is strongly associated with malignant parathyroid neoplasia. However, it does not appear that such mutations, at least in isolation, can be relied upon for definitive molecular diagnosis of parathyroid carcinoma. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.