Adaptation strategies of the Icelandic horse with induced forelimb lameness at walk, trot and tölt.

BACKGROUND AND OBJECTIVE: Lameness assessment in the gaited Icelandic horse is complex. We aimed to describe their kinematic and temporal adaptation strategies in response to forelimb lameness at walk, trot and tölt. STUDY DESIGN: In vivo experiment. METHODS: Ten clinically non-lame Icelandic horses were measured before and after reversible forelimb lameness induction. Upper body and limb kinematics were measured using 11 inertial measurement units mounted on the poll, withers, pelvis (tubera sacrale) and all four limbs and hoofs (Equimoves®, 500 Hz). Horses were measured on a straight line at walk and trot in-hand and at walk, trot and tölt while ridden. Linear mixed models were used to compare baseline and lame conditions (random factor = 'horse'), and results are presented as the difference in estimated marginal means or percentage of change. RESULTS: Lameness induction significantly (p < 0.05) increased head vertical movement asymmetry at walk (HDmin/HDmaxHAND: 18.8/5.7 mm, HDmin/HDmaxRIDDEN: 9.8/0.3 mm) and trot (HDmin/HDmaxHAND: 18.1/7.8 mm, HDmin/HDmaxRIDDEN: 24.0/9.3 mm). At the tölt, however, HDmin did not change significantly (1.1 mm), but HDmax increased by 11.2 mm (p < 0.05). Furthermore, pelvis vertical movement asymmetry (PDmax) increased by 4.9 mm, sound side dissociation decreased (-8.3%), and sound diagonal dissociation increased (6.5%). Other temporal stride variables were also affected, such as increased stance duration of both forelimbs at walk, tölt and in-hand trot. MAIN LIMITATIONS: Only one degree of lameness (mild) was induced with an acute lameness model. CONCLUSIONS: Classical forelimb lameness metrics, such as vertical head and withers movement asymmetry, were less valuable at tölt compared to walk and trot, except for HDmax. Therefore, it is advised to primarily use the walk and trot to detect and quantify forelimb lameness in the Icelandic horse.

Improving diagnostic precision in primary ovarian insufficiency using comprehensive genetic and autoantibody testing.

STUDY QUESTION: Is it possible to find the cause of primary ovarian insufficiency (POI) in more women by extensive screening? SUMMARY ANSWER: Adding next generation sequencing techniques including a POI-associated gene panel, extended whole exome sequencing data, as well as specific autoantibody assays to the recommended diagnostic investigations increased the determination of a potential etiological diagnosis of POI from 11% to 41%. WHAT IS KNOWN ALREADY: POI affects ∼1% of women. Clinical presentations and pathogenic mechanisms are heterogeneous and include genetic, autoimmune, and environmental factors, but the underlying etiology remains unknown in the majority of cases. STUDY DESIGN, SIZE, DURATION: Prospective cross-sectional study of 100 women with newly diagnosed POI of unknown cause consecutively referred to Haukeland University Hospital, Bergen, Norway, January 2019 to December 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: In addition to standard recommended diagnostic investigations including screening for chromosomal anomalies and premutations in the fragile X mental retardation 1 gene (FMR1) we used whole exome sequencing, including targeted analysis of 103 ovarian-related genes, and assays of autoantibodies against steroid cell antigens. MAIN RESULTS AND THE ROLE OF CHANCE: We identified chromosomal aberrations in 8%, FMR1 premutations in 3%, genetic variants related to POI in 16%, and autoimmune POI in 3%. Furthermore in 11% we identified POI associated genetic Variants of unknown signifcance (VUS). A homozygous pathogenic variant in the ZSWIM7 gene (NM_001042697.2) was found in two women, corroborating this as a novel cause of monogenic POI. No associations between phenotypes and genotypes were found. LIMITATIONS, REASONS FOR CAUTION: Use of candidate genetic and autoimmune markers limit the possibility to discover new markers. To further investigate the genetic variants, family studies would have been useful. We found a relatively high proportion of genetic variants in women from Africa and lack of genetic diversity in the genomic databases can impact diagnostic accuracy. WIDER IMPLICATIONS OF THE FINDINGS: Since no specific clinical or biochemical markers predicted the underlying cause of POI discussion of which tests should be part of diagnostic screening in clinical practice remains open. New technology has altered the availability and effectiveness of genetic testing, and cost-effectiveness analyses are required to aid sustainable diagnostics. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by grants and fellowships from Stiftelsen Kristian Gerhard Jebsen, the Novonordisk Foundation, the Norwegian Research Council, University of Bergen, and the Regional Health Authorities of Western Norway. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: NCT04082169.

Osteochondrosis in the central and third tarsal bones of young horses.

Recently, the central and third tarsal bones of 23 equine fetuses and foals were examined using micro-computed tomography. Radiological changes, including incomplete ossification and focal ossification defects interpreted as osteochondrosis, were detected in 16 of 23 cases. The geometry of the osteochondrosis defects suggested they were the result of vascular failure, but this requires histological confirmation. The study aim was to examine central and third tarsal bones from the 16 cases and to describe the tissues present, cartilage canals, and lesions, including suspected osteochondrosis lesions. Cases included 9 males and 7 females from 0 to 150 days of age, comprising 11 Icelandic horses, 2 standardbred horses, 2 warmblood riding horses, and 1 coldblooded trotting horse. Until 4 days of age, all aspects of the bones were covered by growth cartilage, but from 105 days, the dorsal and plantar aspects were covered by fibrous tissue undergoing intramembranous ossification. Cartilage canal vessels gradually decreased but were present in most cases up to 122 days and were absent in the next available case at 150 days. Radiological osteochondrosis defects were confirmed in histological sections from 3 cases and consisted of necrotic vessels surrounded by ischemic chondronecrosis (articular osteochondrosis) and areas of retained, morphologically viable hypertrophic chondrocytes (physeal osteochondrosis). The central and third tarsal bones formed by both endochondral and intramembranous ossification. The blood supply to the growth cartilage of the central and third tarsal bones regressed between 122 and 150 days of age. Radiological osteochondrosis defects represented vascular failure, with chondrocyte necrosis and retention, or a combination of articular and physeal osteochondrosis.

User Engagement, Acceptability, and Clinical Markers in a Digital Health Program for Nonalcoholic Fatty Liver Disease: Prospective, Single-Arm Feasibility Study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the world. Common comorbidities are central obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome. Cardiovascular disease is the most common cause of death among people with NAFLD, and lifestyle changes can improve health outcomes. OBJECTIVE: This study aims to explore the acceptability of a digital health program in terms of engagement, retention, and user satisfaction in addition to exploring changes in clinical outcomes, such as weight, cardiometabolic risk factors, and health-related quality of life. METHODS: We conducted a prospective, open-label, single-arm, 12-week study including 38 individuals with either a BMI >30, metabolic syndrome, or type 2 diabetes mellitus and NAFLD screened by FibroScan. An NAFLD-specific digital health program focused on disease education, lowering carbohydrates in the diet, food logging, increasing activity level, reducing stress, and healthy lifestyle coaching was offered to participants. The coach provided weekly feedback on food logs and other in-app activities and opportunities for participants to ask questions. The coaching was active throughout the 12-week intervention period. The primary outcome was feasibility and acceptability of the 12-week program, assessed through patient engagement, retention, and satisfaction with the program. Secondary outcomes included changes in weight, liver fat, body composition, and other cardiometabolic clinical parameters at baseline and 12 weeks. RESULTS: In total, 38 individuals were included in the study (median age 59.5, IQR 46.3-68.8 years; n=23, 61% female). Overall, 34 (89%) participants completed the program and 29 (76%) were active during the 12-week program period. The median satisfaction score was 6.3 (IQR 5.8-6.7) of 7. Mean weight loss was 3.5 (SD 3.7) kg (P<.001) or 3.2% (SD 3.4%), with a 2.2 (SD 2.7) kg reduction in fat mass (P<.001). Relative liver fat reduction was 19.4% (SD 23.9%). Systolic blood pressure was reduced by 6.0 (SD 13.5) mmHg (P=.009). The median reduction was 0.14 (IQR 0-0.47) mmol/L for triglyceride levels (P=.003), 3.2 (IQR 0.0-5.4) µU/ml for serum insulin (s-insulin) levels (P=.003), and 0.5 (IQR -0.7 to 3.8) mmol/mol for hemoglobin A1c (HbA1c) levels (P=.03). Participants who were highly engaged (ie, who used the app at least 5 days per week) had greater weight loss and liver fat reduction. CONCLUSIONS: The 12-week-long digital health program was feasible for individuals with NAFLD, receiving high user engagement, retention, and satisfaction. Improved liver-specific and cardiometabolic health was observed, and more engaged participants showed greater improvements. This digital health program could provide a new tool to improve health outcomes in people with NAFLD. TRIAL REGISTRATION: Clinicaltrials.gov NCT05426382; https://clinicaltrials.gov/study/NCT05426382.

Dental health of patients with X-linked hypophosphatemia: A controlled study.

Objective: The present study compared the dental health of patients with X-linked hypophosphatemia (XLH) with healthy age- and gender-matched controls to increase our knowledge of the impact of XLH on oral health. Materials and methods: Twenty-two adult patients with XLH in the Stockholm region of Sweden were referred to the Department of Orofacial Medicine at Karolinska Institutet for an extended clinical and radiological examination. Pre-existing radiologic examinations of 44 healthy age- and gender-matched controls were retrieved from the Department of Oral Radiology, at Karolinska Institutet. Results: The 22 patients with XLH (15 females, median age 38 years, range 20-71; 7 males, median age 49 years, range 24-67) had a significantly higher number of root-filled teeth compared to healthy controls (p = .001). In the XLH group, females had significantly better oral health than males, especially concerning endodontic and cariological status (p's = .01 and .02, respectively). Periodontal status differed non-significantly between the XLH and control groups. Conclusion: Patients with XLH had a significantly lower oral health status compared to a healthy population especially concerning endodontic conditions. Male patients with XLH had a higher risk of poor oral health compared to female patients with XLH.

Timing of Vertical Head, Withers and Pelvis Movements Relative to the Footfalls in Different Equine Gaits and Breeds.

Knowledge of vertical motion patterns of the axial body segments is a prerequisite for the development of algorithms used in automated detection of lameness. To date, the focus has been on the trot. This study investigates the temporal synchronization between vertical motion of the axial body segments with limb kinematic events in walk and trot across three popular types of sport horses (19 Warmbloods, 23 Iberians, 26 Icelandics) that are known to have different stride kinematics, and it presents novel data describing vertical motion of the axial body segments in tölting and pacing Icelandic horses. Inertial measurement unit sensors recorded limb kinematics, vertical motion of the axial body at all symmetrical gaits that the horse could perform (walk, trot, tölt, pace). Limb kinematics, vertical range of motion and lowest/highest positions of the head, withers and pelvis were calculated. For all gaits except walk and pace, lowest/highest positions of the pelvis and withers were found to be closely related temporally to midstance and start of suspension of the hind/fore quarter, respectively. There were differences in pelvic/withers range of motion between all breeds where the Icelandic horses showed the smallest motion, which may explain why lameness evaluation in this breed is challenging.

Epidemiology and Financial Burden of Adult Chronic Hypoparathyroidism.

Chronic hypoparathyroidism is characterized by low serum calcium, increased serum phosphorus, and inappropriately low or decreased serum parathyroid hormone. This rare disorder is associated with a variety of complications. The prevalence, incidence, mortality, financial burden, and epidemiology of complications of this disorder are not well understood. This narrative review summarizes current information on the epidemiology and complications of chronic hypoparathyroidism. The reported prevalence of chronic hypoparathyroidism ranges from 6.4-37/100,000, and the incidence is reported to be 0.8-2.3/100,000/year. Mortality is not increased in studies from Denmark or South Korea but was increased in studies from Scotland and Sweden. The financial burden of this disorder is substantial because of increased health care resource utilization in two studies but not well quantitated. Recognized complications include hypercalciuria, nephrocalcinosis, kidney stones, and chronic kidney disease; low bone turnover and possibly upper extremity fractures; cardiac and vascular calcifications; basal ganglia calcifications, cataracts, infections, neuropsychiatric complications, and difficulties with pregnancy. This review concludes that chronic hypoparathyroidism is a rare disorder associated with significant morbidity that may not increase overall mortality but is associated with a substantial financial burden. © 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).

Male osteoporosis-what are the causes, diagnostic challenges, and management.

Osteoporosis is underrecognized and undertreated in men, even though up to 25% of fractures in patients over the age of 50 years occur in men. Men develop osteoporosis with normal aging and accumulation of comorbidities that cause bone loss. Secondary causes of bone loss may be found in up to 60% of men with osteoporosis. Mortality in men who experience major fragility fracture is greater than in women. Diagnosis of osteoporosis in men is similar to women, based on low-trauma or fragility fractures, and/or bone mineral density dual-energy X-ray absorptiometry (DXA) T-scores at or below -2.5. Because most clinical trials with osteoporosis drugs in men were based on bone density endpoints, not fracture reduction, the antifracture efficacy of approved treatments in men is not as well documented as that in women. Men at a high risk of fracture should be offered treatment to reduce future fractures.

Kidney Complications and Hospitalization in Patients With Chronic Hypoparathyroidism: A Cohort Study in Sweden.

CONTEXT: Kidney complications may be considerably higher in patients with chronic hypoparathyroidism (hypoPT) treated with activated vitamin D and calcium supplementation. OBJECTIVE: We aimed to investigate the risk of chronic kidney disease (CKD), urolithiasis, and hospitalization in patients with chronic hypoPT. METHODS: In this population-based cohort study in Sweden, national registries (Swedish National Patient Register, Swedish Prescribed Drug Register, and Total Population Register, 1997-2018) were used to identify patients with chronic hypoPT and controls matched by sex, age, and county of residence. We determined time to CKD and urolithiasis diagnosis, and incidence rates of hospitalization. RESULTS: A total of 1562 patients with chronic hypoPT without preexisting CKD and 15 620 controls were included. The risk of developing CKD was higher in patients with chronic hypoPT compared with controls (hazard ratio [HR] 4.45; 95% CI, 3.66-5.41). In people without prior urolithiasis (n = 1810 chronic hypoPT and n = 18 100 controls), the risk of developing urolithiasis was higher in patients with chronic hypoPT (HR 3.55; 95% CI, 2.84-4.44) compared with controls. Patients with chronic hypoPT had higher incidence rates for all-cause hospitalization (49.59; 95% CI, 48.50-50.70, per 100 person-years vs 28.43; 95% CI, 28.15-28.71, respectively) and for CKD (3.46; 95% CI, 3.18-3.76, per 100 person-years vs 0.72; 95% CI, 0.68-0.77, respectively), compared with controls. Men with hypoPT appear to have a higher risk of CKD than women. CONCLUSION: Patients with chronic hypoPT had an increased risk of CKD, urolithiasis, and hospitalization compared with controls.

Premature menopause and autoimmune primary ovarian insufficiency in two international multi-center cohorts.

Objective: To investigate markers of premature menopause (<40 years) and specifically the prevalence of autoimmune primary ovarian insufficiency (POI) in European women. Design: Postmenopausal women were categorized according to age at menopause and self-reported reason for menopause in a cross-sectional analysis of 6870 women. Methods: Variables associated with the timing of menopause and hormone measurements of 17ß-estradiol and follicle-stimulating hormone were explored using multivariable logistic regression analysis. Specific immunoprecipitating assays of steroidogenic autoantibodies against 21-hydroxylase (21-OH), side-chain cleavage enzyme (anti-SCC) and 17alpha-hydroxylase (17 OH), as well as NACHT leucine-rich-repeat protein 5 were used to identify women with likely autoimmune POI. Results: Premature menopause was identified in 2.8% of women, and these women had higher frequencies of nulliparity (37.4% vs 19.7%), obesity (28.7% vs 21.4%), osteoporosis (17.1% vs 11.6%), hormone replacement therapy (59.1% vs 36.9%) and never smokers (60.1% vs 50.9%) (P < 0.05), compared to women with menopause ≥40 years. Iatrogenic causes were found in 91 (47%) and non-ovarian causes in 27 (14%) women, while 77 (39%) women were classified as POI of unknown cause, resulting in a 1.1% prevalence of idiopathic POI. After adjustments nulliparity was the only variable significantly associated with POI (odds ratio 2.46; 95% CI 1.63-3.42). Based on the presence of autoantibodies against 21 OH and SCC, 4.5% of POI cases were of likely autoimmune origin. Conclusion: Idiopathic POI affects 1.1% of all women and almost half of the women with premature menopause. Autoimmunity explains 4.5% of these cases judged by positive steroidogenic autoantibodies.

European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders.

This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders (PARAT) in 2019, were discussed during two virtual workshops in 2021, and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosing to familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represent areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT, need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborns children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed for a broader clinical audience, and were developed with focus on endocrinologists in training.

Radiological, vascular osteochondrosis occurs in the distal tarsus, and may cause osteoarthritis.

BACKGROUND: Osteochondrosis occurs due to failure of the blood supply to growth cartilage. Osteochondrosis lesions have been identified in small tarsal bones and suggested to cause distal tarsal osteoarthritis; however, it has not been determined whether distal tarsal osteochondrosis lesions were the result of vascular failure. OBJECTIVES: To perform post-mortem arterial perfusion and micro-computed tomography (CT) of the central (CTB) and third tarsal bones (TIII) of fetuses and foals up to 5 months old, to describe tarsal development and any lesions detected. STUDY DESIGN: Descriptive, nonconsecutive case series. METHODS: Twenty-three animals that died or were euthanased from 228 days of gestation to 5 months old were collected, comprising two fetuses and nine foals of miscellaneous breeds and 12 Icelandic Horse foals, a breed with high prevalence of distal tarsal osteoarthritis. One hindlimb from each foal was perfused arterially with barium, and the CTB and TIII were examined with micro-CT. RESULTS: Perfusion yielded partial information from 41% of the animals. The CTB and TIII were supplied by nutrient arteries and perichondrial vessels with vertical, transverse and circumferential configurations. Fourteen of the 23 (61%) animals had focal defects in the ossification front, that is, radiological osteochondrosis. The majority of lesions matched the configuration and development of vertical vessels. Additionally, full-thickness, cylindrical defects matched transverse vessels, and the long axes of some dorsal lesions matched circumferential vessels. MAIN LIMITATIONS: Lack of histological validation. CONCLUSIONS: Post-mortem perfusion was poor for examination of the blood supply to the growth cartilage of the CTB and TIII. Radiological osteochondrosis lesions were compatible with vascular failure because they were focal, and because lesion geometry matched vessel configuration. The relationship between osteochondrosis and distal tarsal osteoarthritis warrants further investigation.

The PARADIGHM (physicians advancing disease knowledge in hypoparathyroidism) registry for patients with chronic hypoparathyroidism: study protocol and interim baseline patient characteristics.

BACKGROUND: The PARADIGHM registry of adult and pediatric patients with chronic hypoparathyroidism evaluates the long-term safety and effectiveness of treatment with recombinant human parathyroid hormone, rhPTH(1-84), and describes the clinical disease course under conditions of routine clinical practice. In this first report, we detail the registry protocol and describe the baseline characteristics of two adult patient cohorts from an interim database analysis. One cohort after study entry were prescribed rhPTH(1-84), and the other cohort received conventional therapy of calcium and active vitamin D. METHODS: An observational study of patients with chronic hypoparathyroidism in North America and Europe, collecting data for ≥10 years per patient. Main outcome measures were baseline patient demographics, clinical characteristics, medications, and disease outcome variables of symptoms, biochemical parameters, and health assessments. Baseline is the enrollment assessment for all variables except biochemical measurements in patients treated with rhPTH(1-84); those measurements were the most recent value before the first rhPTH(1-84) dose. Exclusion criteria applied to the analysis of specified outcomes included pediatric patients, patients who initiated rhPTH(1-84) prior to enrollment, and those who received rhPTH(1-34). Clinically implausible biochemical outlier data were excluded. RESULTS: As of 30 June 2019, data of 737 patients were analyzed from 64 centers; 587 (80%) were women, mean ± SD age 49.1±16.45 years. At enrollment, symptoms reported for patients later prescribed rhPTH(1-84) (n=60) and those who received conventional therapy (n=571), respectively, included fatigue (51.7%, 40.1%), paresthesia (51.7%, 29.6%), muscle twitching (48.3%, 21.9%), and muscle cramping (41.7%, 33.8%). Mean serum total calcium, serum phosphate, creatinine, and estimated glomerular filtration rate were similar between cohorts. Health-related quality of life (HRQoL) 36-item Short Form Health Survey questionnaire scores for those later prescribed rhPTH(1-84) were generally lower than those for patients in the conventional therapy cohort. CONCLUSIONS: At enrollment, based on symptoms and HRQoL, a greater percentage of patients subsequently prescribed rhPTH(1-84) appeared to have an increased burden of disease than those who received conventional therapy despite having normal biochemistry measurements. PARADIGHM will provide valuable real-world insights on the clinical course of hypoparathyroidism in patients treated with rhPTH(1-84) or conventional therapy in routine clinical practice. TRIAL REGISTRATION: EUPAS16927, NCT01922440.

Women With Chronic Hypoparathyroidism Have Low Risk of Adverse Pregnancy Outcomes.

CONTEXT: There are scarce data on the management of chronic hypoparathyroidism (hypoPT) in pregnant women. OBJECTIVE: The aim of this study was to evaluate pregnancy outcome and total number of births in maternal chronic hypoPT. METHODS: The Swedish National Patient Register, The Swedish Prescribed Drug Register, Swedish Medical Birth Register, and the Total Population Register were used to identify 97 women with chronic hypoPT and 1030 age-matched controls who delivered 139 and 1577 singleton infants, respectively, following diagnosis between 1997 and 2017. RESULTS: Women in the chronic hypoPT group had more frequent diabetes (DM) and chronic kidney disease (CKD) compared with the control group (P = 0.043 and P < 0.001, respectively). After adjusting for DM, CKD, maternal age at delivery, and calendar year of delivery, chronic hypoPT cases were associated with increased risk of induction of labor (OR, 1.82; 95% CI, 1.13-2.94) and birth of infants with lower birth weight (ß-coefficient -188 g; 95% CI, -312.2 to -63.8) compared with controls. No difference was found in infant length, small for gestational age, or head circumference after adjustments. Mean gestational age at delivery after controlling for DM, CKD, and pre-eclampsia was not significantly younger (P = 0.119). There was no difference in congenital malformations or perinatal death and no difference in the total number of infants born between groups (P = 0.518). CONCLUSION: The majority of women with chronic hypoPT had normal pregnancy outcomes, and the overall risks appear low. Maternal chronic hypoPT is, however, associated with higher risk of induction of labor and slightly lower infant birth weight.

Productivity and the acquisition of gender.

Children's differing learning trajectories cross-linguistically have been at the forefront of gender acquisition research, often with conflicting results and conclusions. As a result, the source of children's different learning behaviors in gender acquisition has been unclear. I argue that children's gender acquisition is driven by the search for productive patterns. First, I provide corpus studies where the predictions of a learning model (Yang, 2016) are formulated. Second, I report the results of an elicited production task on Icelandic-speaking children (N = 26, ages 2;6-6;3 years) and adults (N = 18) that puts these predictions to test. The results suggest that Icelandic-speaking children and adults draw a categorical distinction between productive and unproductive suffixes in Icelandic gender assignment. I discuss the implications of these findings for morphological learning beyond gender acquisition.

Potential Transcriptional Biomarkers to Guide Glucocorticoid Replacement in Autoimmune Addison's Disease.

BACKGROUND: No reliable biomarkers exist to guide glucocorticoid (GC) replacement treatment in autoimmune Addison's disease (AAD), leading to overtreatment with alarming and persistent side effects or undertreatment, which could be fatal. OBJECTIVE: To explore changes in gene expression following different GC replacement doses as a means of identifying candidate transcriptional biomarkers to guide GC replacement in AAD. METHODS: Step 1: Global microarray expression analysis on RNA from whole blood before and after intravenous infusion of 100 mg hydrocortisone (HC) in 10 patients with AAD. In 3 of the most highly upregulated genes, we performed real-time PCR (rt-PCR) to compare gene expression levels before and 3, 4, and 6 hours after the HC infusion. Step 2: Rt-PCR to compare expression levels of 93 GC-regulated genes in normal versus very low morning cortisol levels in 27 patients with AAD. RESULTS: Step 1: Two hours after infusion of 100 mg HC, there was a marked increase in FKBP5, MMP9, and DSIPI expression levels. MMP9 and DSIPI expression levels correlated with serum cortisol. Step 2: Expression levels of CEBPB, DDIT4, FKBP5, DSIPI, and VDR were increased and levels of ADARB1, ARIDB5, and POU2F1 decreased in normal versus very low morning cortisol. Normal serum cortisol levels positively correlated with DSIPI, DDIT4, and FKBP5 expression. CONCLUSIONS: We introduce gene expression as a novel approach to guide GC replacement in AAD. We suggest that gene expression of DSIPI, DDIT4, and FKBP5 are particularly promising candidate biomarkers of GC replacement, followed by MMP9, CEBPB, VDR, ADARB1, ARID5B, and POU2F1.

Cul o 2 specific IgG3/5 antibodies predicted Culicoides hypersensitivity in a group imported Icelandic horses.

BACKGROUND: Culicoides hypersensitivity (CH) is induced in horses by salivary allergens of Culicoides midges. In Iceland, the causal Culicoides species for CH are not present. Previous epidemiological data indicated that Icelandic horses are more susceptible to CH when they are exported from Iceland and first exposed to Culicoides at adult age. Horses born in countries where Culicoides is endemic, develop the disease less frequently. Here, we established a longitudinal allergy model to identify predictive and diagnostic serological biomarkers of CH. RESULTS: Sixteen adult Icelandic horses from Iceland were imported to the Northeastern United States (US) during the winter and were kept in the same environment with natural Culicoides exposure for the next two years. None of the horses showed clinical allergy during the first summer of Culicoides exposure. In the second summer, 9/16 horses (56%) developed CH. Allergen specific IgE and IgG isotype responses in serum samples were analysed using nine potential Culicoides allergens in a fluorescent bead-based multiplex assay. During the first summer of Culicoides exposure, while all horses were still clinically healthy, Cul o 2 specific IgG3/5 antibodies were higher in horses that developed the allergic disease in the second summer compared to those that did not become allergic (p = 0.043). The difference in Cul o 2 specific IgG3/5 antibodies between the two groups continued to be detectable through fall (p = 0.035) and winter of the first year. During the second summer, clinical signs first appeared and Cul o 3 specific IgG3/5 isotypes were elevated in allergic horses (p = 0.041). Cul o 2 specific IgG5 (p = 0.035), and Cul o 3 specific IgG3/5 (p = 0.043) were increased in late fall of year two when clinical signs started to improve again. CONCLUSIONS: Our results identified IgG5 and IgG3/5 antibodies against Cul o 2 and Cul o 3, respectively, as markers for CH during and shortly after the allergy season in the Northeastern US. In addition, Cul o 2 specific IgG3/5 antibodies may be valuable as a predictive biomarker of CH in horses that have been exposed to Culicoides but did not yet develop clinical signs.

Concordance Between ICD-10 Codes and Clinical Diagnosis of Hypoparathyroidism in Sweden.

INTRODUCTION: Chronic hypoparathyroidism is a rare disorder. The disease is characterized by low serum calcium, high serum phosphate, and deficient production of parathyroid hormone. The most common etiology is unintentional damage and intentional removal to the parathyroid glands during anterior neck surgery. Other causes include genetic disorders and autoimmune diseases. Knowledge about the epidemiology of chronic hypoparathyroidism is sparse and the prevalence in Sweden is unknown. It is of importance to know the validity of the registers used to study the epidemiology of hypoparathyroidism in Sweden. The purpose of this study was to validate the International Classification of Diseases - 10th revision (ICD-10) diagnosis of hypoparathyroidism in the Swedish National Patient Register. METHODS: We included patients with the ICD-10 diagnosis of hypoparathyroidism that were found in the Swedish National Patient Register during 2004 to 2016. Through the unique national registration number assigned to all Swedish inhabitants, we could link this information to the Swedish Prescribed Drug Register. We included patients with an ICD-10 diagnosis for hypoparathyroidism and on concurrent conventional treatment for the disease. The validation of the diagnosis was assessed through review of medical records of 120 patients. RESULTS: A total of 958 patients, 70% women (n=671) and 30% men (n=287) met the inclusion criteria. In total, 120 randomly chosen medical records were reviewed and 109 cases were confirmed. This corresponds to an overall positive predictive value of 91%. CONCLUSION: The validity of the ICD-10 diagnosis of hypoparathyroidism in the Swedish National Patient Register is high and the register is a reliable source for further research. There is a risk of miscoding when assigning an ICD-code to the medical records. We urge clinicians to be aware of this risk, especially the risk of mix-ups with the more common diagnosis of hyperparathyroidism.