Immune Checkpoint Inhibitors-Associated Diabetes and Ketoacidosis Were Found in FDA Adverse Event Reporting System: A Real-World Evidence Database Study.

OBJECTIVE: To investigate the risk of developing diabetes and ketoacidosis in clinical patients with immune checkpoint inhibitors (ICIs). METHODS: We looked in the FDA Adverse Event Reporting System for reports of ICIs-associated diabetes mellitus (DM) and ketoacidosis between January 2004 and March 2022. We explored the signals using fourfold table-based proportional imbalance algorithms. Patient characteristics, country distribution, and outcomes of adverse reactions were described. Kruskal-Wallis test was used to compare the time of onset and prognosis of adverse reactions. RESULTS: A total of 2110 reports of ICIs-related DM were included in the study. The largest number of reports was from Japan (752, 35.64%), followed by the United States and France (624, 29.57%; 183, 8.67%). Seven drugs detected signals of DM and ketoacidosis according to 4 proportional imbalance algorithms: nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab. Diabetes and ketoacidosis generally occurred early in the course of ICIs treatment, the median time to event onset was 144.5 (interquartile range 27-199) days. ICIs-related diabetes and ketoacidosis events resulted in 934 major medical events (44.3%), 524 hospitalizations (24.8%), 60 life-threatening events (2.8%), 42 deaths (2.0%), and 39 disability events (1.8%). CONCLUSION: The study reveals the risk and characteristics of diabetes and ketoacidosis associated with ICIs, which may provide evidence for postmarketing evaluation. Careful consideration should be given to the possibility of an increased risk of diabetes and ketoacidosis after using ICIs, and careful monitoring for diabetes and ketoacidosis is recommended.

Farm-level risk factors associated with increased milk ß-hydroxybutyrate and hyperketolactia prevalence on farms with automated milking systems.

The objectives of this study were to determine the farm-level hyperketolactia (HKL) prevalence, as diagnosed from the milk BHB concentration, on dairy farms milking with an automated milking system (AMS) and to describe the farm-level housing, management, and nutritional risk factors associated with increased farm-average milk BHB and the within-herd HKL prevalence in the first 45 DIM. Canadian AMS farms (n = 162; eastern Canada, n = 8; Quebec, n = 24; Ontario, n = 75; western Canada n = 55) were visited once between April and September 2019 to record housing and herd management practices. The first test milk data for each cow under 45 DIM were collected, along with the final test of the previous lactations for all multiparous cows, from April 1, 2019, to September 30, 2020. The first test milk BHB was then used to classify each individual cow as having or not having HKL (milk BHB ≥0.15 mmol/L) at the time of testing. Milk fat and protein content, milk BHB, and HKL prevalence were summarized by farm and lactation group (all, primiparous, and multiparous). During this same time period, formulated diets for dry and lactating cows, including ingredients and nutrient composition, and AMS milking data were collected. Data from the AMS were used to determine milking behaviors and milk production of each herd during the first 45 DIM. Multivariable regression models were used to associate herd-level housing, feeding management practices, and formulated nutrient composition with first test milk BHB concentrations and within-herd HKL levels separately for primiparous and multiparous cows. The within-herd HKL prevalence for all cows was 21.8%, with primiparous cows having a lower mean prevalence (12.2 ± 9.2%) than multiparous cows (26.6 ± 11.3%). Milk BHB concentration (0.095 ± 0.018 mmol/L) and HKL prevalence for primiparous cows were positively associated with formulated prepartum DMI and forage content of the dry cow diet; however, they were negatively associated with formulated postpartum DMI, the major ingredient in the concentrate supplemented through the AMS, and the partially mixed ration to AMS concentrate ratio. Multiparous cows' milk BHB concentration (0.12 ± 0.023 mmol/L) and HKL prevalence were positively associated with the length of the previous lactation, milk BHB at dry-off, prepartum diet nonfiber carbohydrate content, and the major forage fed on farm, while tending to be negatively associated with feed bunk space during lactation. This study is the first to determine the farm-level risk factors associated with herd-level prevalence of HKL in AMS dairy herds. The results may help to optimize management and guide diet formulation and thus promote the reduction of HKL prevalence.

Incidence of sodium-glucose cotransporter-2 inhibitor-associated perioperative ketoacidosis in surgical patients: a prospective cohort study.

PURPOSE: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are commonly prescribed anti-diabetic medications with various beneficial effects; however, they have also been associated with ketoacidosis. The aim of this study was to determine the incidence of SGLT2i-associated perioperative ketoacidosis (SAPKA) in surgical patients. METHODS: We conducted a multicenter, prospective cohort study across 16 centers in Japan, enrolling surgical patients with diabetes who were prescribed SGLT2is between January 2021 and August 2022. Patients were monitored until the third postoperative day to screen for SAPKA, defined as urine ketone positivity with a blood pH of < 7.30 and HCO3 level ≤ 18.0 mEq/L, excluding cases of respiratory acidosis. RESULTS: In total, 759 of the 762 evaluated patients were included in the final analysis. Among these, three patients (0.40%) had urine ketones with a blood pH of < 7.30; however, blood gas analysis revealed respiratory acidosis in all three, and none of them was considered to have SAPKA. The estimated incidence of SGLT2i-associated postoperative ketoacidosis was 0% (95% confidence interval, 0%-0.4%). CONCLUSIONS: The observed incidence of SAPKA in our general surgical population was lower than expected. However, given that the study was observational in nature, interpretation of study results warrants careful considerations for biases.

Reproductive performance of lactating dairy cows with elevated milk ß-hydroxybutyrate levels during first 6 weeks of lactation.

Although there is evidence that ketosis negatively affects fertility, the effect of late and early ketosis on the reproductive performance of lactating cows has not been systematically investigated. The aim of this study was to evaluate the association between time and amplitude of elevated milk BHB (EMB) occurring within 42 d in milk (DIM) and subsequent reproductive performance of lactating Holstein cows. The dairy herd information data of 30,413 cows with 2 test-day milk BHB recordings during early lactation periods 1 and 2 (5-14 and 15-42 DIM, respectively) assessed as negative (<0.15 mmol/L), suspect (0.15-0.19 mmol/L), or positive (≥0.2 mmol/L) for EMB were used in this study. Based on the time and amplitude of milk BHB, cows were grouped into 7 groups: (1) healthy cows negative in both periods 1 and 2 were classified as NEG; (2) suspect in period 1 and negative in period 2: EARLY_SUSP; (3) suspect in period 1 and suspect/positive in period 2: EARLY_SUSP_Pro; (4) positive in period 1 and negative in period 2: EARLY_POS; (5) positive in period 1 and suspect/positive in period 2: EARLY_POS_Pro; (6) negative in period 1 and suspect in period 2: LATE_SUSP; and (7) negative in period 1 and positive in period 2: LATE_POS. The overall prevalence of EMB within 42 DIM was 27.4%, with the highest prevalence being EARLY_SUSP (10.49%). Cows in EARLY_POS and EARLY_POS_Pro, but not other EMB categories, had a longer interval from calving to first service compared with NEG cows. For the reproductive parameters, first service to conception interval, days open and calving interval, cows in all EMB groups except EARLY_SUSP had longer intervals compared with NEG cows. These data indicate that there is a negative association between EMB within 42 d and reproductive performance after the voluntary waiting period. The intriguing findings of this study are the unaltered reproductive performance of EARLY_SUSP cows, and the negative association between late EMB and reproductive performance. Hence, monitoring and prevention of ketosis during the first 6 wk of lactation is necessary to optimize reproductive performance of lactating dairy cows.

Estimates of dairy herd health indicators of mastitis, ketosis, inter-calving interval, and fresh cow replacement in the Piedmont region, Italy.

Test-day milk analysis has largely been used to study health and performance parameters in dairy cows. In this study, we estimated four health indicators of dairy cows using test-day data. Our purpose was to estimate (1) mastitis incidence rate, prevalence, and the probability of recovery; (2) the incidence proportion of ketosis; (3) the duration of inter-calving interval; and (4) the risk of a fresh cow being replaced, in a large cohort of dairy herds in the Piedmont region (Italy). We retrospectively analysed test day records of 261,121 lactating cows and 1315 herds during five years (2015-2020). Mastitis was defined by somatic cell count and ketosis by fat-to-protein ratio. Calving dates were used to calculate ICI and to estimate the removal of a fresh cow from the herd. Mixed-effect generalized linear models were used to adjust for unmeasured herd-level risk factors. The risk of mastitis increased by 120% with parity (Odds ratio [OR] = 2.20, confidence interval [CI]: 2.17 - 2.23), by 7% by months in milking (OR = 1.07, CI: 1.07 - 1.07), and even more if the cow was already affected during the same lactation (OR = 8.74, CI: 8.67 - 8.82). Lactose concentration on the previous test day was the best positive prognostic factor for mastitis recovery (OR = 1.12, CI: 1.08 - 1.17). Ketosis risk was the highest between 3rd and 4th lactations and itself increased the risk of having ICI longer than 440 days (OR = 1.12, CI: 1.02 - 1.22), and fresh-cow removal (OR = 1.75, CI: 1.58 - 1.93). Also, the removal of fresh cows was more likely when mastitis (OR = 1.31, CI: 1.19 - 1.45) or long ICI (OR = 1.34, CI: 1.22 - 1.48) occurred. For each health indicator, herd-level risk factors had an important role (18-56% of within-herd covariance). Our results indicate that milk analysis could be also useful for predicting mastitis, its cure rate, and ketosis. Cow-level risk factors are not enough to explain the risk of these issues. By studying a large population over a long period, this study provides an updated estimate of dairy cow health indicators in Piedmont (north-western Italy), useful for benchmarking dairy herds.

Characteristics of Holstein cows predisposed to ketosis during the post-partum transition period.

BACKGROUND: Ketosis is a common metabolic disorder during the post-partum transition period of dairy cattle. How the method of reproduction, parturition time, and calf birth weight affect the occurrence of ketosis on dairy herds remains elusive. OBJECTIVES: This study investigated factors associated with the severity of ketosis. METHODS: We divided 186 Holstein cows into three classifications based on the highest ß-hydroxybutyrate (BHBA) concentration during the post-partum transition period, namely non-ketosis (<1.2 mmol/L, n = 94), subclinical ketosis (1.2-2.9 mmol/L, n = 58), and clinical ketosis (≥3.0 mmol/L, n = 34). We evaluated characteristics of cows associated with the severity of ketosis. RESULTS: Ketosis was not associated with the method of reproduction, parturition time, pregnancy wastage, premature delivery, retained placenta, and type of calf. Cows calving in spring and especially summer were at higher risk of severe ketosis (p < 0.01). Cows with increased body condition score (BCS) at parturition, age, lactation number, and calving interval were more likely to develop severe ketosis (p < 0.05). Cows with clinical ketosis produced most milk (29.9 ± 1.0 kg) from days four to six, whereas cows without ketosis produced the least (21.3 ± 0.8 kg) (p < 0.001). Heavier calf birth weight resulted in high risk of severe ketosis (p < 0.01), due to increased milk yield during the early lactation. CONCLUSIONS: The severity of ketosis is associated with the calving season, BCS at parturition, age, lactation number, calving interval, milk yield in the early lactation period, and calf birth weight. Nonetheless, it was not associated with the method of reproduction, parturition time, pregnancy wastage, premature delivery, retained placenta, and type of calf. This study is the first to investigate the associations between ketosis and calf birth weight. Our findings could help predict cows at risk of ketosis and take precautions.

Associations of parity with health disorders and blood metabolite concentrations in Holstein cows in different production systems.

Data were obtained from studies in Australia, Canada, and the United States using individual cow data from 28,230 Holstein cows to evaluate associations between parity and disease. Our goal was to develop understanding of disease risks for cows of differing parity. We hypothesized that there would be increased risks of disease and changes in metabolite concentrations with increased parity. Parity ≥5 represented 2,533 cows or 9.0%, parity 4 was 9.8% (2,778), parity 3 as 19.0% (5,355), parity 2 as 28.1% (7,925), and parity 1 was 34.1% (9,639) of the sample. Of these cows, 15.5% were in Australia, 14.7% in Canada, and 69.8% in the United States. Lactational incidence (LI) risk of clinical hypocalcemia increased with parity from 0.1% for parity 1 to 13% for parity ≥5 cows. The marked increase suggests profound differences in metabolism with increased parity. The LI of clinical mastitis was 17.4%. The odds of mastitis increased with parity to 2.5 times greater in parity ≥5 than in parity 1. The LI of lameness increased with parity; specifically, the odds of lameness was 5.6 times greater for parity ≥5 than parity 1. Dystocia incidence was 8.7% and greatest for parity 1 cows. The LI of retained placenta was 7.4% and increased with parity, with the odds for parity ≥5 2.3 times greater than for parity 1. The LI of metritis was 10% and of endometritis 14%, with the greatest odds in parity 1. The LI of clinical ketosis was 3.3% with a marked increase in odds with parity. The prevalence of subclinical ketosis was 26.8% with only cows in parity 1 having lower odds than other parities. Parity ≥5 cows had greater odds (odds ratio = 1.7) of respiratory disease than parity 1 cows, which were lesser than other parities. Metabolite concentrations were evaluated in 5,154 Holstein cows in the precalving, calving, and immediate postcalving data sets. Metabolic measures near peak lactation provided 1,906 observations. Concentrations of ß-hydroxybutyrate (BHB) and nonesterified fatty acids increased with parity on d 1 to 3 of lactation and at peak lactation. On d 1 to 3 after calving differences in glucose, nonesterified fatty acids, and BHB indicated a greater reliance on mobilized lipid to export energy to peripheral tissues as BHB for greater parity cows. Differences in concentrations among parity groups were marked at times, for example >0.20 mM in Ca for parity 1 and 2 to parity ≥5 and >0.33 mM for all older parities compared with parity 1 for P on the day of calving. The marked increase suggests profound differences in metabolism with increased parity are probably influenced, in part, by increased production. We found marked differences in concentrations of metabolites with parity that are consistent with reduced reproduction, health, and body condition for higher parity cows. These unfavorable differences in metabolism in Ca, P, glucose, and cholesterol concentrations for higher parity cows also complement the often-substantial differences in disease risk with parity and suggest a need to carefully consider the parity structure in study design. Managers and advisors will need to consider methods to reduce risk of health disorders tailored to cows of different ages.

New diagnoses of type 1 diabetes mellitus in children during the COVID-19 pandemic Regional multicenter study in Spain.

INTRODUCTION: The aim of this study is to determine whether during the year 2020, coinciding with the COVID-19 pandemic, there has been an increase in the incidence of diabetes mellitus in children compared to the previous 2 years. It is also to find out if lockdowns and the difficulty providing face-to-face care in the health system have led to children showing more severe symptoms at the time of diagnosis. MATERIAL AND METHODS: Retrospective observational multicenter study of the province of Tarragona where data is collected from new diagnoses of type 1 diabetes mellitus in patients under the age of 15 during the year 2020 and compared with years 2018 and 2019. RESULTS: The number of new diagnoses of type 1 diabetes during 2020 was 37 cases compared to 2019 and 2018 which was 23 and 29 respectively. The median age at onset was 9 years, 54% males. There was an increase in new diagnoses in the range of 10 to14-year-olds, with a decrease in the range of 0-4 year-olds. In 2020, the incidence in the group of patients with families from the Maghreb area rose from 52.2 cases per 100,000 population/year (c/105 p-y) in 2019 to 135.8 in 2020. Compared to the previous year, 2020 showed a significant decrease of ketoacidosis at the onset. None of the patients was diagnosed with COVID-19 during admission. CONCLUSION: During the year 2020 concurring with the COVID-19 pandemic, there was an increase in the number of new diagnoses of type 1 diabetes mellitus in pediatrics. Contrary to expectations, the presentation did not worsen by decreasing the proportions of ketoacidosis at onset. This data would suggest that, although attendance in the different health facilities dropped drastically during the year 2020 at the expense of virtual consultations, health systems and families were able to detect the symptoms of the disease early.

A systematic review of the cost of ketosis in dairy cattle.

A systematic review was conducted to assess the cost of ketosis in dairy cattle, and to elucidate how ketosis cost is estimated in each of the studies. Scientific papers addressing the economic impact of ketosis in dairy cows were identified through a search in 4 databases (Medline, ISI Web of Science, CAB Abstracts, and Agricola). The literature search was conducted with no restrictions on the date of study publication, publication type, or language. The methodological quality of the studies was assessed regarding study design, data collection, and analysis and interpretation of the study results. Of 531 identified records, 10 were selected, of which 9 were published from 2015 onward. Of the 10 studies reviewed, 9 report cost of a case of ketosis, and the estimates vary widely, with values ranging from €19 to €812. Two studies report ketosis cost at a farm level (€3.6-€29/cow per year). Among the studies, we observed great variation not only in the estimation models and inputs used (costs and losses associated with the disease) but also in the definition of ketosis and its prevalence or incidence figures. Moreover, the cost of ketosis was estimated for dairy farms in the United States, Canada, the Netherlands, Denmark, France, Germany, Spain, Sweden, Norway, and India. Consequently, there was great heterogeneity regarding herd characteristics, milk production, milk prices, culled cows' value, feed prices, and costs of veterinary services. Ketosis cost estimates vary as a consequence of all these aspects. Therefore, although most of the studies were well-designed and used high-quality data, the systematic approach review does not allow combination of the cost estimates of into a single figure. In conclusion, our review highlights an overall considerable economic impact of ketosis in dairy cattle. Economic prevention and mitigation strategies should be taken according to herd- and country-specific conditions. Ketosis cost figures reported in economic studies should always be considered carefully and interpreted with appropriate consideration of the inputs of the estimation, country context, and herd parameters.

Global prevalence of subclinical ketosis in dairy cows: A systematic review and meta-analysis.

The objectives of this study were to estimate the global prevalence of SCK in dairy cows, to identify optimum thresholds for BHB determining, to explore heterogeneity for some particular characteristics (continents, diagnosis techniques, cut-off, sample type, parity, breed, and housing), and to determine the SCK prevalence trend. SCK prevalence levels in dairy cows from various countries were calculated using bibliographic databases up until May 17, 2021 to screen titles and abstracts for possible eligibility. Thirty-eight studies from six continents were then included using a random-effects model to calculate the pooled SCK prevalence. Subgroup meta-analyses were performed to assess the heterogeneity of the prevalence for the above characteristics. Meta-regression and cumulative meta-analysis were used to assess the SCK prevalence trends. The results showed that the global prevalence of SCK in dairy cows was 22.7% [95% CI 21.2-24.3%]. No significant differences in SCK prevalence were observed among continents, diagnostic techniques, cut-off values-≥1.0, ≥1.2 and ≥1.4 mmol/L, sample types-milk and blood, and parities. However, the prevalence in Holsteins (19.8%) was significantly lower than other mixed breeds (23.7%). The SCK prevalence was significantly higher in indoor barns (27.8%) than in pasture and unspecified housing. In meta-regression, the SCK prevalence was not associated with study years or days in milk. The cumulative evidence suggested that the prevalence of SCK in dairy cows was associated with a wide range of risk factors. This study illustrates that the global prevalence of SCK in dairy cows is quite high; therefore, there is an urgent need to globally reduce the SCK prevalence in dairy farms.

Clinical study of autoantibodies in type 1 diabetes mellitus children with ketoacidosis or microalbuminuria.

AIMS: The study aimed to investigate the value of autoantibodies in predicting the risk of ketoacidosis or microalbuminuria in children with type 1 diabetes mellitus. METHODS: Clinical data and laboratory indicators of 80 patients with type 1 diabetes admitted to the Department of Endocrinology in Tianjin Children's Hospital, from June 2017 to March 2019, were retrospectively analyzed. The patients were divided into two groups: diabetes without ketoacidosis group (n = 20) and diabetes with ketoacidosis group (n = 60). The differences in general data, laboratory test indexes, and autoantibodies between the two groups were analyzed. Finally, ROC curves and multivariate logistic regression analysis were used to explore the value of autoantibodies in patients with ketoacidosis or microalbuminuria. RESULTS: A total of 80 children with type 1 diabetes were assessed, including 35 boys and 45 girls, ranging in age from 10 months to 15 years. The concentration of GADA, IA2A, and ZnT8A was not statistically different between the two groups, but the positive rate of ZnT8A was statistically significant (p = 0.038) and had a diagnostic value for the occurrence of ketoacidosis (p = 0.025). ZnT8A-positive patients had a higher titer of IA2A and a more frequent prevalence of GADA and IA2A than ZnT8A-negative patients (p < 0.01). In multivariate logistic regression analyses, the presence of positive ZnT8A was associated with a higher risk of microalbuminuria independent of age, sex, and BMI (OR = 4.184 [95% CI 1.034~16.934], p = 0.045). CONCLUSIONS: The positive ZnT8A had diagnostic value for ketoacidosis in children with type 1 diabetes and had the highest specificity among the three kinds of autoantibodies. Moreover, ZnT8A positivity was related to a higher titer of IA2A and more frequent occurrence of multiple diabetes-related autoantibodies. Besides, the presence of positive ZnT8A was an independent risk factor of microalbuminuria in children with type 1 diabetes. Therefore, we can infer that positive ZnT8A may be related to ketoacidosis and microalbuminuria, accelerating the progression of T1DM.

Starvation Ketosis in the Pediatric Emergency Department: A Prospective Estimate of Prevalence.

OBJECTIVES: Starvation ketosis may occur in children during intercurrent illnesses due to metabolic adaptation to fasting, resulting in significant ketonemia and sometimes ketoacidosis. Also known as accelerated starvation, common symptoms are vomiting, lethargy, and seizures. Previous studies found the prevalence of ketotic hypoglycemia to be 4 per 100,000 presentations to the emergency department (ED). We hypothesized that the prevalence had been underestimated due to the retrospective nature and restricted definitions of previous studies. Our aim was to determine if a prospective study would confirm a higher prevalence of starvation ketosis in pediatric patients presenting to the ED. METHODS: A prospective observational study of consecutive patients was performed in an urban pediatric ED utilizing point-of-care testing of capillary blood glucose and ketones in symptomatic children. RESULTS: This study found the prevalence of clinically significant ketosis (defined as beta-hydroxybutyrate 2.5 mmol/L or more) to be approximately 1800 per 100,000 ED presentations, with more than 170 per 100,000 also being hypoglycemic. Affected patients were 3 months to 9 years of age. Fifty-five percent of the presentations were boys, and 56% were under the 50th centile for weight. CONCLUSIONS: This prospective observational study using a targeted testing regimen found the prevalence of both starvation ketosis and hypoglycemia to be much greater than previous studies which used retrospective analyses. A simple capillary test for ketones should be considered in unwell children younger than 10 years who present with vomiting or lethargy, as this may identify the need for specific therapy to resolve ketosis.

Incidence of urinary ketosis and the effect of carbohydrate drink supplementation during fasting for elective caesarean section: Audit.

Elective lower segment caesarean section patients are routinely instructed to fast from food for 6h before surgery, with clear fluids up until 2h before surgery. We conducted an audit examining the true fasting times of mothers undergoing an elective caesarean section and the incidence of urinary ketones before and after introducing a preop carbohydrate drink (Nutricia preOp 400ml) to be administered to all patients at 6am on the day of surgery. We audited 50 patients prior to introducing the preop carbohydrate drink and 54 patients after the introduction of a carbohydrate drink. We found the mean fasting time from last caloric intake was reduced from 13h 35min to 5h 5min after the introduction of a preoperative carbohydrate drink. We found that the incidence of urinary ketones was 40.4% prior to the introduction of a preoperative carbohydrate drink and 38.3% after the introduction of a preop drink (p = 1). If fasting times were limited to under 4h, the incidence of urinary ketones is 10%. Our audit demonstrates that reducing preoperative fasting times is possible and preventing metabolic derangements may be possible, requiring an approach targeted at keeping fasting times to a minimum.

Relationship Between Time in Range, Glycemic Variability, HbA1c, and Complications in Adults With Type 1 Diabetes Mellitus.

PURPOSE: Real-time continuous glucose monitoring (RT-CGM) provides information on glycemic variability (GV), time in range (TIR), and guidance to avoid hypoglycemia, thereby complimenting HbA1c for diabetes management. We investigated whether GV and TIR were independently associated with chronic and acute diabetes complications. METHODS: Between September 2014 and January 2017, 515 subjects with type 1 diabetes using sensor-augmented pump therapy were followed for 24 months. The link between baseline HbA1c and CGM-derived glucometrics (TIR [70-180 mg/dL], coefficient of variation [CV], and SD) obtained from the first 2 weeks of RT-CGM use and the presence of complications was investigated. Complications were defined as: composite microvascular complications (presence of neuropathy, retinopathy, or nephropathy), macrovascular complications, and hospitalization for hypoglycemia and/or ketoacidosis. RESULTS: Individuals with microvascular complications were older (P < 0.001), had a longer diabetes duration (P < 0.001), a higher HbA1c (7.8 ± 0.9 vs 7.5 ± 0.9%, P < 0.001), and spent less time in range (60.4 ± 12.2 vs 63.9 ± 13.8%, P = 0.022) compared with those without microvascular complication. Diabetes duration (odds ratio [OR] = 1.12 [1.09-1.15], P < 0.001) and TIR (OR = 0.97 [0.95-0.99], P = 0.005) were independent risk factors for composite microvascular complications, whereas SD and CV were not. Age (OR = 1.08 [1.03-1.14], P = 0.003) and HbA1c (OR = 1.80 [1.02-3.14], P = 0.044) were risk factors for macrovascular complications. TIR (OR = 0.97 [0.95-0.99], P = 0.021) was the only independent risk factor for hospitalizations for hypoglycemia or ketoacidosis. CONCLUSIONS: Lower TIR was associated with the presence of composite microvascular complications and with hospitalization for hypoglycemia or ketoacidosis. TIR, SD, and CV were not associated with macrovascular complications.

Development and Validation of a Prevalence Model for Latent Autoimmune Diabetes in Adults (LADA) Among Patients First Diagnosed with Type 2 Diabetes Mellitus (T2DM).

BACKGROUND We designed this study to develop and validate a prevalence model for latent autoimmune diabetes in adults (LADA) among people initially diagnosed with type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS The study recruited 930 patients aged ≥18 years who were diagnosed with T2DM within the past year. Demographic information, medical history, and clinical biochemistry records were collected. Logistic regression was used to develop a regression model to distinguish LADA from T2DM. Predictors of LADA were identified in a subgroup of patients (n=632) by univariate logistic regression analysis. From this we developed a prediction model using multivariate logistic regression analysis and tested its sensitivity and specificity among the remaining patients (n=298). RESULTS Among 930 recruited patients, 880 had T2DM (96.4%) and 50 had LADA (5.4%). Compared to T2DM patients, LADA patients had fewer surviving b cells and reduced insulin production. We identified age, ketosis, history of tobacco smoking, 1-hour plasma glucose (1hPG-AUC), and 2-hour C-peptide (2hCP-AUC) as the main predictive factors for LADA (P<0.05). Based on this, we developed a multivariable logistic regression model: Y=-8.249-0.035(X1)+1.755(X2)+1.008(X3)+0.321(X4)-0.126(X5), where Y is diabetes status (0=T2DM, 1=LADA), X1 is age, X2 is ketosis (1=no, 2=yes), X3 is history of tobacco smoking (1=no, 2=yes), X4 is 1hPG-AUC, and X5 is 2hCP-AUC. The model has high sensitivity (78.57%) and selectivity (67.96%). CONCLUSIONS This model can be applied to people newly diagnosed with T2DM. When Y ≥0.0472, total autoantibody screening is recommended to assess LADA.

Prepartum behavior changes in dry Holstein cows at risk of postpartum diseases.

The objective of this study was to identify changes in prepartum behavior associated with the incidence of postpartum diseases in dairy cows. Multiparous Holstein cows (n = 489) were monitored with accelerometers for 3 wk prepartum. Accelerometers measured steps, time at the feed bunk, frequency of meals, lying bouts, and lying time. Postpartum health was monitored from 0 to 30 d in milk and cases of metritis, mastitis, retained placenta, displaced abomasum (DA), ketosis, and hypocalcemia were recorded. A multivariate linear mixed model was used to assess differences in behavior between diseased and not diagnosed diseased cows. A multivariate logistic regression was used to predict the occurrence of diseases. Predictors were selected using a manual backward stepwise selection process of variables until all remaining predictors had a P < 0.10. Models were submitted to a leave-one-out cross-validation process, and sensitivity, specificity, false discovery rate, and false omission rate were calculated. On average, over the 3-wk prepartum period, cows not diagnosed diseased (n = 345) took 1,613 ± 38 steps, spent 181 ± 7.1 min at the feed bunk, had 8.3 ± 0.17 meals, had 9.8 ± 0.32 lying bouts, and spent 742 ± 11.3 min lying per day. Behavior of diseased cows (n = 144) did not differ from those not diagnosed diseased. However, differences for specific diseases were observed, being significant in the week prepartum. When considering changes in behavior for only the week before calving, cows with metritis had more lying bouts (+21%), cows with DA had fewer meals (-24%) and tended to take fewer steps (-18%), and cows with ketosis had fewer meals (-22%) and spent less time at the feed bunk (-40%). Prediction models with the best outcomes were found for DA and ketosis using data of the prepartum week only. The model for DA included time at the feed bunk. Cross-validation resulted in a 80% sensitivity, 58.1% specificity, 59.2% accuracy, 91.2% false discovery rate, and 1.7% false omission rate. The model for ketosis included time at the feed bunk and number of meals. Cross-validation resulted in 64.3% sensitivity, 59.3% specificity, 59.5% accuracy, 93.0% false discovery rate, and 2.8% false omission rate. Prepartum behavior of cows affected with metritis, DA, and ketosis was different from that of cows not diagnosed with diseases. Prediction equations were able to classify cows at high or low risk of ketosis and DA and can be used in taking management decisions, but the high false discovery rates requires further refinement.

Expert opinion as priors for random effects in Bayesian prediction models: Subclinical ketosis in dairy cows as an example.

Random effects regression models are routinely used for clustered data in etiological and intervention research. However, in prediction models, the random effects are either neglected or conventionally substituted with zero for new clusters after model development. In this study, we applied a Bayesian prediction modelling method to the subclinical ketosis data previously collected by Van der Drift et al. (2012). Using a dataset of 118 randomly selected Dutch dairy farms participating in a regular milk recording system, the authors proposed a prediction model with milk measures as well as available test-day information as predictors for the diagnosis of subclinical ketosis in dairy cows. While their original model included random effects to correct for the clustering, the random effect term was removed for their final prediction model. With the Bayesian prediction modelling approach, we first used non-informative priors for the random effects for model development as well as for prediction. This approach was evaluated by comparing it to the original frequentist model. In addition, herd level expert opinion was elicited from a bovine health specialist using three different scales of precision and incorporated in the prediction as informative priors for the random effects, resulting in three more Bayesian prediction models. Results showed that the Bayesian approach could naturally take the clustering structure of clusters into account by keeping the random effects in the prediction model. Expert opinion could be explicitly combined with individual level data for prediction. However in this dataset, when elicited expert opinion was incorporated, little improvement was seen at the individual level as well as at the herd level. When the prediction models were applied to the 118 herds, at the individual cow level, with the original frequentist approach we obtained a sensitivity of 82.4% and a specificity of 83.8% at the optimal cutoff, while with the three Bayesian models with elicited expert opinion, we obtained sensitivities ranged from 78.7% to 84.6% and specificities ranged from 75.0% to 83.6%. At the herd level, 30 out of 118 within herd prevalences were correctly predicted by the original frequentist approach, and 31 to 44 herds were correctly predicted by the three Bayesian models with elicited expert opinion. Further investigation in expert opinion and distributional assumption for the random effects was carried out and discussed.

The relationship of excessive energy deficit with milk somatic cell score and clinical mastitis.

Periparturient cows go through a period of immune suppression often marked by immune cell dysfunction. Further exacerbation of this dysfunction through early-lactation excessive energy deficit (EED) has been associated with increased susceptibility to infectious conditions such as mastitis. Our objective was to explore the association of milk somatic cell score (SCS) and clinical mastitis (CM) diagnosis in cows identified with EED, diagnosed using each of the following: blood and milk ß-hydroxybutyrate (BHB), milk predicted blood nonesterified fatty acid (mpbNEFA) concentrations, or milk de novo fatty acid (FA) relative percentages (rel %). We analyzed data collected from 396 multiparous Holstein cows from 2 New York farms in a prospective cohort study. Coccygeal vessel blood samples and composite milk samples were collected twice weekly from 3 to 18 days in milk (DIM) for a total of 4 time points per cow (T1, T2, T3, T4). Blood was analyzed using a hand-held meter, and milk was analyzed using Fourier-transform mid-infrared spectrometry for milk BHB and mpbNEFA concentrations, milk de novo FA rel %, and somatic cell count. Excessive energy deficit was diagnosed as blood BHB ≥ 1.2 mmol/L, milk BHB ≥ 0.14 mmol/L, mpbNEFA ≥ 0.55 mmol/L, or de novo FA ≤ 22.7 rel %, depending on the model. Clinical mastitis cultures were collected from 4 to 60 DIM by on-farm personnel. Incidence of hyperketonemia as determined by blood BHB was 13.4%, and incidence of CM was 23.9%. Separate repeated-measures ANOVA models were developed for each EED diagnostic analyte for parity groups 2, 3, and ≥4 to assess differences in SCS; t-test analyses were similarly used to assess the association of each diagnostic analyte with CM at each time point. For all diagnostic analytes, apart from milk BHB, cows diagnosed with EED tended to have lower SCS than their non-EED counterparts. This was especially apparent at T1 for all parity groups, and at T2, T3, and T4 for blood BHB and mpbNEFA. For EED diagnosis via mpbNEFA, mean SCS were lower in parity ≥4, with a difference in mean SCS between EED and non-EED animals of 0.7 SCS units, equating to a somatic cell count in EED animals approaching half that of non-EED (EED = 67,000 cells/mL, non-EED = 107,000 cell/mL). No important relationships were observed between CM diagnosis and blood BHB, milk BHB, or mpbNEFA. For de novo FA rel %, reductions in this analyte were noted before CM diagnosis at all time points. Although the relationship between EED and CM is still unclear, our findings suggest that cows in EED, diagnosed using blood BHB or mpbNEFA during the first 18 DIM, have a tendency toward lower SCS compared with their non-EED counterparts.

Frequency and severity of ketoacidosis at diagnosis among childhood type 1 diabetes in Khartoum state, Sudan.

BACKGROUND: Diabetic ketoacidosis (DKA) is a potentially life threatening acute complication of Type I diabetes mellitus (T1DM). This study aimed to determine the frequency and clinical characteristics of pediatric DKA at diagnosis of new-onset T1DM in Khartoum during 2000-2017 period. METHODS: The study was retrospective and involved review of medical files of children (<15 years) with T1DM in the city hospitals and diabetes centers. RESULTS: The overall frequency of DKA among T1DM children at onset of disease diagnosis was 17.6% (173/982). The episodes of DKA increased from 26% in first 6- year period (2000-2005) to 46.3% in the last 6-year period (2011-2012; p<0.001). No significant difference in the frequency of DKA was observed according to gender (p=0.9) and age (p=0.24). Compared to other age groups, the severity of DKA (pH<7.1) was higher in pre-school children (p<0.01). Approximately, 5% of patients were complicated with cerebral edema with a mortality rate of 1.7%. CONCLUSION: The DKA frequency at diagnosis of childhood T1DM in Khartoum was lower than previous reports. In addition, the severity of DKA was high among pre-school age children with a relatively high mortality rate when compared to the global rate.