Comparison of an oral mixed meal plus arginine and intravenous glucose, GLP-1 plus arginine to unmask residual islet function in longstanding type 1 diabetes.

Residual beta cells are present in most patients with longstanding type 1 diabetes but it is unknown whether these beta cells react normally to different stimuli. Moreover a defect in proinsulin conversion and abnormal alpha cell response are also part of the islet dysfunction. A three-phase [euglycemia, hyperglycemia, and hyperglycemia + glucagon-like peptide 1 (GLP-1)] clamp was performed in patients with longstanding type 1 diabetes. Intravenous arginine boluses were administered at the end of each phase. On another day, a mixed meal stimulation test with a subsequent intravenous arginine bolus was performed. C-peptide was detectable in a subgroup of subjects at baseline (2/15) or only after stimulation (3/15). When detectable, C-peptide increased 2.9-fold [95% CI: 1.2-7.1] during the hyperglycemia phase and 14.1-fold [95% CI: 3.1-65.2] during the hyperglycemia + GLP-1 phase, and 22.3-fold [95% CI: 5.6-89.1] during hyperglycemia + GLP-1 + arginine phase when compared with baseline. The same subset of patients with a C-peptide response were identified during the mixed meal stimulation test as during the clamp. There was an inhibition of glucagon secretion (0.72-fold, [95% CI: 0.63-0.84]) during the glucose clamp irrespective of the presence of detectable beta cell function. Proinsulin was only present in a subset of subjects with detectable C-peptide (3/15) and proinsulin mimicked the C-peptide response to the different stimuli when detectable. Residual beta cells in longstanding type 1 diabetes respond adequately to different stimuli and could be of clinical benefit.NEW & NOTEWORTHY If beta cell function is detectable, the beta cells react relatively normal to the different stimuli except for the first phase response to intravenous glucose. An oral mixed meal followed by an intravenous arginine bolus can identify residual beta cell function/mass as well as the more commonly used glucose potentiated arginine-induced insulin secretion during a hyperglycemic clamp.

Risks associated with antidepressants in patients with hypertension during pregnancy: a retrospective cohort study.

PURPOSE: In a cohort of pregnant women using antihypertensive drugs, we compared exposure to antidepressants versus no exposure and the possible association with birth weight, APGAR scores, NICU admission, and maternal admission to an obstetrical intensive care unit (OHC). It was hypothesized that pregnant women with hypertensive disorders using antidepressants are at greater risk of complications. METHODS: A retrospective cohort study in a general teaching hospital in Zwolle, in the Middle-Northern part of The Netherlands. Finally, 58 pregnancies in the exposed group and 273 pregnancies in the reference group met all inclusion and exclusion criteria. We compared the neonate's birthweight between the exposed to antidepressants group and the reference group as the primary outcome. Secondary outcomes were the APGAR score at 1 and 5 min and obstetric high care (OHC) admission of the mother and neonatal intensive care unit (NICU) admission of the child. RESULTS: We found no differences in birth weight in neonates of mothers with hypertensive disorders and whether or not to use antidepressants. Besides a possible higher risk of admission to an OHC in women with hypertension-complicated pregnancies using antidepressants, we found no other maternal or neonatal risks in this population. CONCLUSION: We found no additional maternal or neonatal risks of using antidepressants prescribed to women with hypertension disorders during pregnancy.

Clinical impact of an integrated e-health system for diabetes self-management support and shared decision making (POWER2DM): a randomised controlled trial.

AIMS/HYPOTHESIS: There is a lack of e-health systems that integrate the complex variety of aspects relevant for diabetes self-management. We developed and field-tested an e-health system (POWER2DM) that integrates medical, psychological and behavioural aspects and connected wearables to support patients and healthcare professionals in shared decision making and diabetes self-management. METHODS: Participants with type 1 or type 2 diabetes (aged >18 years) from hospital outpatient diabetes clinics in the Netherlands and Spain were randomised using randomisation software to POWER2DM or usual care for 37 weeks. This RCT assessed the change in HbA1c between the POWER2DM and usual care groups at the end of the study (37 weeks) as a primary outcome measure. Participants and clinicians were not blinded to the intervention. Changes in quality of life (QoL) (WHO-5 Well-Being Index [WHO-5]), diabetes self-management (Diabetes Self-Management Questionnaire - Revised [DSMQ-R]), glycaemic profiles from continuous glucose monitoring devices, awareness of hypoglycaemia (Clarke hypoglycaemia unawareness instrument), incidence of hypoglycaemic episodes and technology acceptance were secondary outcome measures. Additionally, sub-analyses were performed for participants with type 1 and type 2 diabetes separately. RESULTS: A total of 226 participants participated in the trial (108 with type 1 diabetes; 118 with type 2 diabetes). In the POWER2DM group (n=111), HbA1c decreased from 60.6±14.7 mmol/mol (7.7±1.3%) to 56.7±12.1 mmol/mol (7.3±1.1%) (means ± SD, p<0.001), compared with no change in the usual care group (n=115) (baseline: 61.7±13.7 mmol/mol, 7.8±1.3%; end of study: 61.0±12.4 mmol/mol, 7.7±1.1%; p=0.19) (between-group difference 0.24%, p=0.008). In the sub-analyses in the POWER2DM group, HbA1c in participants with type 2 diabetes decreased from 62.3±17.3 mmol/mol (7.9±1.6%) to 54.3±11.1 mmol/mol (7.1±1.0%) (p<0.001) compared with no change in HbA1c in participants with type 1 diabetes (baseline: 58.8±11.2 mmol/mol [7.5±1.0%]; end of study: 59.2±12.7 mmol/mol [7.6±1.2%]; p=0.84). There was an increase in the time during which interstitial glucose levels were between 3.0 and 3.9 mmol/l in the POWER2DM group, but no increase in clinically relevant hypoglycaemia (interstitial glucose level below 3.0 mmol/l). QoL improved in participants with type 1 diabetes in the POWER2DM group compared with the usual care group (baseline: 15.7±3.8; end of study: 16.3±3.5; p=0.047 for between-group difference). Diabetes self-management improved in both participants with type 1 diabetes (from 7.3±1.2 to 7.7±1.2; p=0.002) and those with type 2 diabetes (from 6.5±1.3 to 6.7±1.3; p=0.003) within the POWER2DM group. The POWER2DM integrated e-health support was well accepted in daily life and no important adverse (or unexpected) effects or side effects were observed. CONCLUSIONS/INTERPRETATION: POWER2DM improves HbA1c levels compared with usual care in those with type 2 diabetes, improves QoL in those with type 1 diabetes, improves diabetes self-management in those with type 1 and type 2 diabetes, and is well accepted in daily life. TRIAL REGISTRATION: ClinicalTrials.gov NCT03588104. FUNDING: This study was funded by the European Union's Horizon 2020 Research and Innovation Programme (grant agreement number 689444).

Maternal and neonatal outcomes after benzodiazepine and benzodiazepine agonist exposure during pregnancy in women with mental disorders.

AIMS: To compare the gestational age of neonates in utero exposed to benzodiazepines (BDZs) with nonexposed controls. Secondary objectives were birth weight, presence of congenital malformations, APGAR score and the need for >3 months (prolonged) maternal psychiatric care. METHODS: A retrospective cohort study of women and neonates from 2013 to 2021 with univariate and multivariable analysis to study the associations between BDZ exposure and gestational age compared to nonexposed women with mental health problems. RESULTS: We found that BDZ exposure was not associated with a lower gestational age. We found that women in the exposed group had an increased risk of psychiatric care (adjusted odds ratio 2.58 [95% confidence interval 1.71-3.91], P < .001). CONCLUSION: We found that in utero BDZ exposure was not associated with a significantly lower gestational age of the neonates and was associated with prolonged psychiatric care of their mothers.

Fasting parameters for estimation of stimulated ß cell function in islet transplant recipients with or without basal insulin treatment.

In order to assess ß cell secretory capacity after islet transplantation, standardized mixed meal stimulation tests are often used. But these tests are cumbersome and the effect of exogenous insulin on the test results is unclear. The aim of our study was to determine to what extent fasting glycemic indices can estimate stimulated ß cell function in islet transplant recipients with and without basal insulin. In total 100 mixed meal stimulation tests, including 31 with concurrent basal insulin treatment, were performed in 36 islet transplant recipients. In a multivariate model, fasting C-peptide and fasting glucose together estimated peak C-peptide with R2  = .87 and area under the curve (AUC) C-peptide with a R2  = .93. There was a larger increase of glucose during tests in which exogenous insulin was used (+7.9 vs +5.3 mmol/L, P < .001) and exogenous insulin use was associated with a slightly lower estimated peak C-peptide (relative change: -15%, P = .02). In islet transplant recipients the combination of fasting C-peptide and glucose can be used to accurately estimate stimulated ß cell function after a mixed meal stimulation test, whether exogenous basal insulin is present or not. These data indicate that graft function can be reliably determined during exogenous insulin treatment and that regular islet graft stimulation tests can be minimized.

Effects of postpartum acetylsalicylic acid on metabolic status, health, and production in lactating dairy cattle.

The transition period is one of the most challenging times for dairy cattle. Previous research suggests that treatment of postpartum cows with anti-inflammatory drugs may decrease pain and inflammation, enhancing cow welfare and performance during this challenging period. However, these strategies involve numerous time-consuming interventions, which require extra labor and do not fit modern farm logistics. The objective of this experiment was to assess the effects of acetylsalicylic acid (ASA) every 24 h for 2 d after calving on (1) daily milk yield, daily milk conductivity, and daily rumination during the first 60 days in milk (DIM), and 305-d mature-equivalent milk, milk fat, and milk protein yields, (2) body condition score, ß-hydroxybutyrate (BHB), and haptoglobin, and (3) incidence of clinical diseases during the first 60 DIM. Dairy cows (n = 246) from a dairy farm located in Pennsylvania were enrolled in this experiment. Cows were blocked by parity and assigned randomly to 1 of 2 treatments: (1) ASA (n = 121), in which cows received 2 treatments with ASA (200 mg/kg; 4 boluses), the first within 12 h after parturition and the second 24 h later; or (2) untreated (UNT; n = 125), in which cows remained untreated. Blood samples were collected at 30 ± 6 h, 7 ± 3 d, and 14 ± 3 d after calving to measure BHB and haptoglobin concentrations. Body condition score was assessed at enrollment, 7 ± 3 DIM, 14 ± 3 DIM, and 50 ± 10 DIM. Furthermore, incidences of diseases, daily rumination, daily milk yield, and daily milk conductivity during the first 60 DIM and 305-d mature-equivalent milk, milk fat, and milk protein yields were collected from on-farm computer records. The data were analyzed using mixed multiple linear and logistic regression models as a randomized complete block design. Multiparous cows treated with ASA produced 1.64 kg/d more milk compared with multiparous cows that remained untreated (ASA = 41.66 ± 0.88 kg/d; UNT = 40.02 ± 0.81 kg/d) during the first 60 DIM. There was no difference in daily milk conductivity and rumination between treatments. Cows treated with ASA had lower concentration of BHB (ASA = 1.16 ± 0.64 mmol/L; UNT = 1.23 ± 0.80 mmol/L) during the first 14 ± 3 DIM and had higher body condition score within the first 50 ± 10 DIM compared with cows that remained UNT. There were no differences in circulating concentrations of haptoglobin between treatments. These results support previous findings showing that the use of anti-inflammatory drugs after calving may increase milk production and affect the metabolic status of dairy cows.

Administration of acetylsalicylic acid after parturition in lactating dairy cows under certified organic management: Part I. Milk yield, milk components, activity patterns, fertility, and health.

Parturition is a natural process that gradually progresses from one stage to the next. However, around 5% of dairy cows will experience dystocia, which is considered to be a painful and stressful event. Studies have reported positive effects on cow performance and welfare after treatment with nonsteroidal anti-inflammatory drugs during the first postpartum days. The objectives were to assess the effects of acetylsalicylic acid administration after calving on (1) milk yield and components, (2) daily activity patterns, (3) reproductive performance, and (4) health in lactating dairy cows under certified organic management. Cows from 3 organic herds were enrolled. Within 12 h after parturition, cows were blocked by parity and calving ease and randomly assigned to 2 treatments: (1) aspirin (ASP; n = 278), in which cows received 4 consecutive treatments every 12 h with acetylsalicylic acid (100 mg/kg; 2 boluses) or (2) placebo (PLC, n = 285), in which cows received 4 treatments every 12 h with gelatin capsules (2 capsules) filled with water. Daily milk yield for the first 30 d in milk (DIM) and monthly milk yield, fat, protein, and somatic cell count (SCC) data from the first 5 Dairy Herd Improvement Association tests were collected. Activity patterns were measured using activity data loggers in the first 7 DIM. Clinical disease events (60 DIM) and fertility data were collected from on-farm computer records. Statistical analysis was performed using the MIXED (milk yield, components, and activity), LIFETEST (fertility), and GLIMMIX (health) procedures of SAS (SAS Institute Inc., Cary, NC). Overall, ASP cows produced 1.82 kg/d more milk than PLC cows during the first 30 DIM. Interestingly, cows that experienced dystocia and received ASP produced 4.48 kg/d more milk compared with cows in the PLC group that experienced dystocia. Cows treated with ASP had lower somatic cell count during the first 5 Dairy Herd Improvement Association tests. There were no differences in daily lying time, lying bouts, and lying bout duration between the ASP and PLC groups. However, cows in the ASP group had 587,64 steps/d more compared with PLC cows. In addition, ASP cows tended to require fewer days (ASP = 113.76 ± 4.99 d; PLC = 125.36 ± 4.74 d) and needed fewer services (ASP = 1.86 ± 0.21 services; PLC = 2.19 ± 0.24 services) to become pregnant compared with PLC cows. There were no differences in clinical disease events between treatments. Results from this study suggest that treating cows with ASP after calving may help improve milk yields and udder health, increase activity, and enhance fertility in dairy cattle under certified organic management.

Administration of acetylsalicylic acid after parturition in lactating dairy cows under certified organic management: Part II. Biomarkers of nociception, inflammation, and stress.

The objective was to assess the effect of oral administration of acetylsalicylic acid after calving on the concentrations of substance P (SP), haptoglobin (HP), and cortisol in lactating dairy cows. Holstein dairy cows (n = 152) from 3 organic herds were included. At parturition, cows were blocked by parity [multiparous (MULT) and primiparous (PRIM)] and calving ease [eutocia (EUT) and dystocia (DYS)] and were randomly assigned to 1 of 2 treatment groups: aspirin (ASP; n = 76), in which within 12 h after parturition cows received 4 treatments with acetylsalicylic acid (100 mg/kg; 2 boluses) at 12-h intervals, or placebo (PLC; n = 76), in which within 12 h after parturition cows received 4 consecutive treatments with gelatin capsules (2 capsules) containing water 12 h apart. Blood samples were collected immediately before treatment and at 12, 24, 36, 48, and 168 h (7 DIM) for assessment of circulating concentration of SP, HP, and cortisol. Based on farm records, cows were classified in the following clinical disease categories: no clinical disease event (NO-EVT), a single clinical disease event (SI-EVT), and more than 1 clinical disease event (MU-EVT). The study data were analyzed as a randomized complete block design using mixed multiple linear and logistic regression models. With regard to HP, there was a tendency for an interaction between treatment and parity, where MULT cows treated with ASP had lower concentration of HP compared with MULT cows treated with PLC (ASP = 124.33 ± 6.83 µg/mL; PLC = 143.9 ± 7.24 µg/mL). Analysis by calving ease showed that cows with DYS had higher concentrations of HP (DYS = 159.17 ± 5.97 µg/mL; EUT = 138.72 ± 6.22 µg/mL) and SP (only at 168 h; DYS = 64.99 pg/mL, 95% confidence interval, CI: 2.68-2.81; EUT = 60.33 pg/mL, 95% CI: 2.91-3.06) after calving compared with EUT cows. Regardless of treatment, PRIM cows had higher concentrations of SP (MULT = 55.11 pg/mL, 95% CI: 1.27-1.30; PRIM = 57.62 pg/mL, 95% CI: 1.99-2.06), HP (MULT = 134.14 ± 4.96 µg/mL; PRIM = 163.75 ± 7.76 µg/mL), and cortisol (MULT = 18.65 µg/mL, 95% CI: 1.02-1.05; PRIM = 21.92 µg/mL, 95% CI: 1.67-1.74) compared with MULT cows. In addition, cows that experienced SI-EVT or MU-EVT had higher concentrations of HP (NO-EVT = 134.13 ± 5.95 µg/mL; SI-EVT = 142.68 ± 7.32 µg/mL; MU-EVT = 170.03 ± 9.42 µg/mL) and cortisol (NO-EVT = 17.86 µg/mL, 95% CI: 1.20-1.24; SI-EVT = 21.01 µg/mL, 95% CI: 1.61-1.67; MU-EVT = 22.01 µg/mL, 95% CI: 2.08-2.18) compared with cows with NO-EVT recorded. Results from this study suggest that a short-duration anti-inflammatory therapy after calving reduced HP in MULT cows but may not have effects on SP and cortisol concentrations. Calving ease and parity affected the concentrations of markers of inflammation, nociception, and stress regardless of treatment. Further research is warranted to assess anti-inflammatory strategies aimed at decreasing inflammation and stress in DYS and PRIM cows and therefore improve welfare and performance of these high-priority groups.

Ergonomics in handheld and robot-assisted camera control: a randomized controlled trial.

BACKGROUND: Laparoscopic surgery potentially increases the physical burden to operating theater personnel and can cause physical discomfort. This study aims to evaluate if a robotic camera holder (AutoLap™ system) can improve ergonomics for the surgeon and the camera assistant during laparoscopic procedures. METHODS: A total of thirty cases were included and randomized (15 AutoLap™, 15 control). Five types of surgery were included: right hemicolectomy, fundoplication, sigmoid resection, rectopexy, and low anterior resection. The posture of the surgeon and assistant was photographed during predefined steps of the procedure. MATLAB was used to calculate angles relevant for the RULA score. The RULA score is a validated method to evaluate body posture, force and repetition of the upper extremities. Two investigators assessed the RULA score independently. Three subjective questionnaires (SMEQ, NASA TLX, and LED) were used to assess mental and physical discomfort. RESULTS: No differences in patient characteristics were observed. Sixteen fundoplications, seven right hemicolectomies, five sigmoid resections, one rectopexy, and one low anterior resection were included. The mean RULA score of the surgeon was comparable in both groups, 2.58 (AutoLap™) versus 2.72 (control). The mean RULA score of the assistant was significantly different in both groups, with 2.55 (AutoLap™) versus 3.70 (control) (p = 0.001). The inter-observer variability (ICC) was excellent with 0.93 (surgeon) and 0.97 (assistant). The questionnaires showed a significant difference in physical discomfort for the assistant. The LED and SMEQ score were significantly lower in the robotic group. The NASA TLX demonstrated a significant reduction in scores in all domains when using robotics with the exception of the mental domain. CONCLUSION: Use of the AutoLap™ system shows improvement in ergonomics and posture of the first assistant, and ergonomics of the surgeon are not affected. Furthermore, the subjective work load is significantly reduced by using a robotic camera holder. TRIAL REGISTRATION NUMBER: NCT0339960, https://clinicaltrials.gov/ct2/show/study/NCT03339960?term=autolap&rank=5 .

Short communication: Assessment of biomarkers of inflammation in the vaginal discharge of postpartum dairy cows diagnosed with clinical metritis.

Clinical metritis, characterized by the presence of an enlarged uterus and abnormal red-brownish foul-smelling vaginal discharge (VD), is a prevalent condition that causes important economic losses to dairy operations. The accurate diagnosis and treatment of this disease can help decrease its negative effects on the well-being and performance of dairy cows. The objectives of this study were to assess (1) the concentration of haptoglobin (Hp) and neutrophil-derived haptoglobin-matrix metalloproteinase 9 (Hp-MMP 9) in the VD of postpartum cows; and (2) the correlation between Hp and Hp-MMP 9 concentrations in serum and VD. Fifty-three dairy cows from 4 farms in central Pennsylvania were enrolled in this observational study.. Postpartum cows (7 ± 3 DIM) were screened using a Metricheck device to assess VD score (VDS): 1, clear fluid (n = 4); 2, < 50% white purulent fluid (n = 14); 3, > 50% white purulent fluid (n = 8); 4, red-brownish watery fluid without fetid smell (n = 22); and 5, fetid red-brownish watery fluid (n = 5). Blood and VD samples were collected for assessment of Hp and Hp-MMP 9 concentrations. Cows with a VDS of 4 or 5 (VDS4/5) had higher serum Hp concentrations than cows with a VDS of 1, 2, or 3 (VDS1/3; 93 ± 187 µg/mL vs. 59 ± 106 µg/mL, respectively). Similarly, cows with VDS4/5 had higher VD Hp concentrations than cows with VDS1/3 (73 ± 56 µg/mL vs. 17 ± 16 µg/mL, respectively). We found a significant correlation (0.37) between Hp levels in serum and in VD. We found no difference in serum Hp-MMP 9 between VDS4/5 and VDS1/3 cows. The VD concentrations of Hp-MMP 9 were higher in VDS4/5 cows than in VDS1/3 cows (7,629 ± 9,847 ng/mL vs. 1,567 ± 2,165 ng/mL, respectively). The correlation between Hp-MMP 9 in serum and VD was 0.22; nevertheless, it was not statistically significant. Interestingly, Hp and Hp-MMP 9 concentrations were higher in VD samples than in serum, regardless of VDS. Results from this study suggest that inflammatory biomarkers may be increased in cows with a VDS of 4 or 5. Further research should be aimed at elucidating the processes involved in inflammatory biomarker production and transportation in the uterus, as well as the effect of these biomarkers on endometrial cells.

Associations of pre- and postpartum lying time with metabolic, inflammation, and health status of lactating dairy cows.

The objective was to evaluate the associations of pre- and postpartum lying time (LT) with serum total calcium (Ca), nonesterified fatty acids (NEFA), ß-hydroxybutyrate (BHB), and haptoglobin concentrations, hemogram, and health status of dairy cows. A total of 1,052 Holstein cattle (401 nulliparous heifers and 651 parous cows) from 3 commercial dairy farms were fitted with electronic data loggers (IceQube, IceRobotics, Edinburgh, UK) on a hind leg 14 ± 3 d before parturition (dpp) and removed at 14 ± 3 d in milk (DIM) to assess their LT. Lying time data were summarized and reported daily (min/d or h/d). Serum concentrations of NEFA (at 14 ± 3 and 7 ± 3 dpp), total serum calcium within 48 h after calving, and BHB (at 7 ± 3 and 14 ± 3 DIM) were determined. Serum concentration of haptoglobin was determined and a hemogram was performed on a subsample of 577 cows (237 primiparous and 340 multiparous) at 7 ± 3 DIM. Cases of milk fever, retained placenta, metritis, mastitis, pneumonia, and digestive disorders within 30 DIM were recorded and cows were categorized into 1 of 4 groups: (1) nondiseased (ND, n = 613; cows without ketosis and any other health conditions); (2) cows with only ketosis (KET, n = 152); (3) sick cows experiencing ≥1 health conditions, but without ketosis (SICK, n = 198); or (4) cows with ketosis plus at least one other health condition (KET+, n = 61). Data were analyzed using mixed linear regression models or logistic regression (MIXED or GLIMMIX procedures). Lying time within 14 dpp had a significant positive quadratic association with serum NEFA concentrations at 14 ± 3 and 7 ± 3 dpp but was not significantly associated with serum Ca concentration within 48 h after calving. Lying time during the first 14 DIM after parturition had a significant linear association with the risk of ketosis within 14 DIM. For every 1-h increment in mean LT (from 8 to 15 h/d) within the first 14 DIM after calving, the risk of diagnosis with ketosis within 14 DIM increased by 3.7 percentage points. Regardless of parity, a greater proportion of KET and KET+ groups had increased serum prepartum NEFA concentration (≥400 µEq/L) and increased body condition loss from 14 dpp to 28 DIM compared with SICK and ND cows. A greater proportion of multiparous KET and KET+ cows had hypocalcemia within 48 h after calving compared with ND and SICK cows, but we did not detect a significant association between hypocalcemia and health status on primiparous cows. Multiparous KET+ cows had significantly reduced neutrophils and white blood cell count compared with ND cows, but lymphocytes did not differ. Regardless of parity, KET+ and SICK cows had significantly higher concentrations of serum haptoglobin compared with ND cows. These results suggest that LT along with energy and Ca balance are critical for transition cow health.

Associations of postpartum lying time with culling, milk yield, cyclicity, and reproductive performance of lactating dairy cows.

The objectives were to evaluate the associations of lying time (LT) during the first 14 d in milk (DIM) with milk yield, cyclicity (CYC), culling within 60 DIM (CULL), and reproductive performance of lactating dairy cows. A total of 1,052 Holstein cattle (401 nulliparous heifers and 651 parous cows) from 3 commercial dairy farms had electronic data loggers (IceQube, IceRobotics, Edinburgh, UK) placed on a hind leg 14 ± 3 d before the expected parturition date and removed at 14 ± 3 DIM to assess their LT. Serum concentrations of ß-hydroxybutyrate were determined at 7 ± 3 and 14 ± 3 DIM. Cases of retained placenta, metritis, mastitis, pneumonia, and digestive disorders within 30 DIM were recorded and lactating cows were categorized into 1 of 4 groups: (1) nondiseased (ND, n = 613; cows without ketosis or any other diagnosed health condition); (2) cows with only ketosis (KET, n = 152); (3) sick cows experiencing ≥1 health conditions but without ketosis (SICK, n = 198); or (4) cows with ketosis plus ≥1 health condition (KET+, n = 61). Ultrasound was performed at 28 ± 3 and 42 ± 3 DIM to assess ovarian cyclicity (presence or absence of corpus luteum). Milk yield at first Dairy Herd Improvement Association test was not associated with LT during the first 14 DIM, but it was negatively correlated with the coefficient of variation of LT during the first 14 DIM. Lactating dairy cows experiencing KET+ had the lowest milk yield compared with ND, regardless of parity. Parity, health status, and season were significantly associated with CYC and CULL. Lying time had a significantly linear association with the risk of being culled: for every 1-h increment of LT during 0 to 14 DIM, the risk of culling within 60 DIM increased by 1 percentage point. Lying time had a negative quadratic association with cyclicity at 42 DIM. Multiparous cows with a LT of 9 to 13 h/d had a significantly greater probability of pregnancy up to 300 DIM compared with cows with a LT >13 h/d. Regardless of parity, KET+ cows had significantly higher proportion of culling within 60 DIM and decreased probability of pregnancy up to 300 DIM compared with ND cows. These findings suggest that there is an optimum daily LT range for early postpartum cows housed in freestall barns, different from that reported for mid-lactation cows, with the potential for improved survival, health, and the overall performance (milk yield and reproduction).

EFFICACY OF INSULIN, HEPARIN AND FENOFIBRATE COMBINATION TREATMENT IN SEVERE HYPERTRIGLYCERIDEMIA: DOUBLE CENTER EXPERIENCE.

CONTEXT: Severe hypertriglyceridemia (SH), which calls for a triglyceride (TG) level above 1000 mg/dL, remains an important health issue. While some data exist to offer combination of heparin, insulin and fenofibrate as a reasonable treatment option, safety and benefits of this therapy have not been accurately weighted, largely due to the limited sample size of the relevant studies. AIM: Assess the efficacy and safety of the heparin, insulin and fenofibrate combination in the treatment of patients with SH. PATIENTS - METHODS: Patients aged ≥18 years with TG level above 1000 mg/dL and adequate organ function were included. Triglyceride levels were measured immediately before the treatment and on the 3rd and 6th days of the treatment. Treatment dosage, duration, response and side effects were assessed. Patients with hypertriglyceridemia presenting with acute pancreatitis were treated additionally with lipid apheresis. RESULTS: A total of 42 patients were included. Of these, 85.8% came to medical attention with some kind of secondary hypertriglyceridemia causes. The baseline median TG value of the cases was 2141.0 mg/ dL (1026-12250). There were 6 patients (14.3%) with acute pancreatitis at presentation. In patients without pancreatitis, with administration of insulin infusion, unfractionated heparin infusion and fenofibrate capsule, median TG values decreased to 921 mg/ dL (190-6400) on the 3rd day and to 437 mg/ dL (112-1950) on the 6th day of the treatment (p<0.0001, Friedman test). Potential toxicities related to insulin, heparin and fenofibrate combination treatment including hypoglycemia, hemorrhage, rise in creatine kinase levels, hepato - and nephrotoxicity were not observed. CONCLUSION: In this trial involving patients with SH, our data suggest that insulin, heparin and fenofibrate combination therapy was safe and effective.

Assessment of daily activity patterns and biomarkers of pain, inflammation, and stress in lactating dairy cows diagnosed with clinical metritis.

The objectives of the present case-control study were to assess (1) daily activity patterns (lying time, number of steps, number of lying bouts, and lying bout duration), and (2) circulating concentrations of biomarkers of pain (substance P), inflammation (haptoglobin), and stress (cortisol) in lactating dairy cows diagnosed with clinical metritis. Lactating dairy cows (n = 200) from 2 commercial dairy herds were enrolled in the present study. Cows diagnosed with clinical metritis (n = 100) at 7 ± 3 d in milk were matched according to lactation and days in milk to cows without clinical metritis (NO-CM; n = 100). On study d 1, clinical metritis was diagnosed (using a Metricheck device, Simcro Tech Ltd., Hamilton, New Zealand) by the presence of watery, reddish, or brownish foul-smelling vaginal discharge, and blood samples were collected for assessment of circulating concentration of substance P, haptoglobin, cortisol, total calcium, ß-hydroxybutyrate, and blood cells. In addition, on study d 1 body condition of cows was visually assessed, and activity monitors were placed on the hind leg of a subset of cows (CM, n = 56; CON, n = 56) and were kept until study d 7. Cows showing any other signs of other diseases were not included in the study. Cows with clinical metritis tended to spend more time lying (CM = 628.92 min/d; NO-CM = 591.23 min/d) compared with NO-CM cows. Activity analysis by parity revealed that primiparous cows with clinical metritis spent more time lying compared with primiparous cows without clinical metritis. However, no differences in daily lying time were observed between multiparous cows with and without clinical metritis. Furthermore, cows in the CM group had a higher circulating concentration of substance P (CM = 47.15 pg/mL; NO-CM = 37.73 pg/mL) and haptoglobin (CM = 233.00 µg/mL; NO-CM = 99.98 µg/mL) when compared with NO-CM cows. Cows with clinical metritis had lower body condition score, and a greater proportion of cows in this group had hypocalcemia when compared with cows without clinical metritis. The circulating concentration of leukocytes and erythrocytes were decreased in cows with clinical metritis compared with cows without clinical metritis. Results from this study showed that concentrations of markers of inflammation, stress, pain, and activity were affected in cows diagnosed with clinical metritis; thus, strategies aimed to minimize the negative effects associated with clinical metritis may be required to improve the welfare of dairy cows.

Effect of serum calcium status at calving on survival, health, and performance of postpartum Holstein cows and calves under certified organic management.

The study objective was to assess the effect of hypocalcemia (HYPO; ≤2.0 mmol/L) of the dam at calving on survival, health, and performance of lactating dairy cows and their calves under certified organic management. Prepartum dairy cows (primiparous, n = 445; multiparous, n = 328) from 1 dairy herd were monitored (prepartum pen) for imminent signs of parturition (appearance of amniotic sac outside the vulva) until birth. All calves were subject to the same newborn care, colostrum management, and failure of passive transfer assessment (serum total protein ≤5.5 mg/dL). Serum total calcium of cows was determined in samples taken within 2 h after calving. To define HYPO cows after calving, a cut-point of total serum Ca concentration with optimal sensitivity and specificity to predict metritis or calf diarrhea was established by using the receiver operator characteristic. The effect of HYPO on survival (died or culled within 60 DIM), health status, and pregnancy per artificial insemination (PAI) for first services of lactating cows were analyzed using the GLIMMIX procedure of SAS. Additionally, the effect of HYPO at calving on days in milk (DIM) at first service (DIMFS), milk yield (kg), milk components (percent fat and protein), and somatic cell count were analyzed for the first 3 Dairy Herd Improvement Association (DHIA) tests using the MIXED procedure of SAS (SAS Institute Inc., Cary, NC). The effect of parity (primiparous and multiparous), body condition score at calving, and manure hygiene score at calving were also included in the statistical models. The effect of HYPO at calving on calf survival, serum total protein, and diarrhea within 10 d of age were assessed using GLIMMIX procedure of SAS. The overall prevalence of HYPO was 14.6% (2.7% for primiparous and 30.8% for multiparous cows). Cows experiencing HYPO at calving had greater proportion of metritis (25.1 vs. 14.7%) and culling within 60 DIM (15.9 vs. 6.8%) compared with non-HYPO cows, respectively. For the first 3 DHIA tests, milk yield and components did not differ between HYPO and non-HYPO cows. The DIMFS as well as proportion of cows with dystocia, births of twins, mastitis, and PAI at first service were not different between HYPO and non-HYPO cows. The proportion of stillbirth, weaned calves, and serum total protein did not differ between calves born from HYPO or non-HYPO cows. However, calves born from HYPO cows had greater incidence of diarrhea (49%) than calves born (33.3%) from non-HYPO cows. Findings from the present study showed that HYPO at calving had significant health implications for both dams and calves under certified organic management.

Spatiotemporal closure of fractional laser-ablated channels imaged by optical coherence tomography and reflectance confocal microscopy.

BACKGROUND AND OBJECTIVE: Optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) offer high-resolution optical imaging of the skin, which may provide benefit in the context of laser-assisted drug delivery. We aimed to characterize postoperative healing of ablative fractional laser (AFXL)-induced channels and dynamics in their spatiotemporal closure using in vivo OCT and RCM techniques. STUDY DESIGN/MATERIALS AND METHODS: The inner forearm of healthy subjects (n = 6) was exposed to 10,600 nm fractional CO2 laser using 5 and 25% densities, 120 µm beam diameter, 5, 15, and 25 mJ/microbeam. Treatment sites were scanned with OCT to evaluate closure of AFXL-channels and RCM to evaluate subsequent re-epithelialization. RESULTS: OCT and RCM identified laser channels in epidermis and upper dermis as black, ablated tissue defects surrounded by characteristic hyper-and hyporeflective zones. OCT imaged individual laser channels of the entire laser grid, and RCM imaged epidermal cellular and structural changes around a single laser channel to the depth of the dermoepidermal junction (DEJ) and upper papillary dermis. OCT images visualized a heterogeneous material in the lower part of open laser channels, indicating tissue fluid. By OCT the median percentage of open channels was evaluated at several time points within the first 24 hours and laser channels were found to gradually close, depending on the used energy level. Thus, at 5 mJ/microbeam, 87% (range 73-100%) of channels were open one hour after laser exposure, which declined to 27% (range 20-100%) and 20% (range 7-93%) at 12 and 24 hours after laser exposure, respectively. At 25 mJ/microbeam, 100% (range 100-100%) of channels were open 1 hour after laser exposure while 53% (range 33-100%) and 40% (range 0-100%) remained open at 12 and 24 hours after exposure. Median depth and width of open channels decreased over time depending of applied energy. RCM verified initial re-epithelialization from day 2 for all energy levels used. Morphology of ablation defects by OCT and RCM corresponded to histological assessments. CONCLUSIONS: OCT and RCM enabled imaging of AFXL-channels and their spatiotemporal closure. Laser channels remained open up to 24 hours post laser, which may be important for the time perspective to deliver topical substances through AFXL channels.

Assessment of an application for touchscreen devices to record calving-related events in dairy herds and monitor personnel performance.

The objectives of the present study were to assess (1) the effectiveness of a calving training workshop and an application (app) for touchscreen devices to capture calving-related events, and (2) personnel compliance with calving protocols (time from birth to feeding of first colostrum and time that cows spent in labor). Calving personnel (n=23) from 5 large dairy farms (range: 800-10,000 cows) participated in the study. Participants received training through an on-farm workshop regarding calving management practices and functioning of the app before recording calving-related events. Pre- and posttest evaluations were administered to each participant to measure their knowledge gain and satisfaction with the workshop. Calving personnel recorded calving-related events (n=323) using the app for 7 d following training. Furthermore, the records collected with the app were used to assess missing and incorrect data and calving personnel compliance with calving management protocols (recording time that cows spent in labor and timing of feeding first colostrum to calves). Calving personnel reported that the information provided during the training was relevant (agree=14.3% and strongly agree=85.7%) and of great immediate use (agree=33.3% and strongly agree=66.7%). The presented materials and hands-on demonstrations substantially increased the knowledge level of the attendees (by 23.7 percentage points from pre- to posttest scores). The follow-up assessment with participants revealed that the app was easy to use (91.3%) and that they would continue to use it (100%). Frequency of incorrect (r=0.77) or missing (r=0.76) data was positively correlated with calving:personnel ratio. Furthermore, calving personnel compliance with calving protocols was significantly different within and between herds. These results substantiated the great variation in compliance with calving management protocols within and between dairy farms. Furthermore, the app may serve as a tool to monitor personnel compliance with first feeding of colostrum to calves and their awareness and recognition of amount of time that each cow spent in labor. This would allow decision-makers to adjust, reassign tasks, or plan the management according to actual calving rate to improve the overall quality of data (frequency of incorrect and missing data) and calf welfare (survival and performance).

Prediction of parturition in Holstein dairy cattle using electronic data loggers.

The objective of the present study was to assess the effect of parturition on behavioral activity [steps, standing time, lying time, lying bouts (LB), and duration of LB] 4 d before calving using electronic data loggers. Animals (n=132) from 3 herds were housed in similar freestall barns using a prepartum pen 21 d before the expected calving date and were moved into a contiguous individual maternity pen for parturition. Electronic data loggers were placed on a hind leg of prepartum heifers (heifers, n=33) and cows (cows, n=99) at 7±3 d before the expected calving date and removed at 14±3 d in milk. Calving ease (scale 1-4), parity, calving date and time, and stillbirth (born dead or died within 24h) were recorded. The number of steps (no./d), standing time (min/d), lying time (min/d), number of LB (no./d), and duration of LB (min/b) were recorded. Data were analyzed using MIXED procedures of SAS, adjusting for the herd effect. Only cows experiencing unassisted births (calving ease=1) were included in the study. An activity index was developed to predict calving time. Heifers and cows with unassisted births had significantly higher number of steps and longer standing time, decreased lying time, and more LB of shorter duration 24h before calving compared with d -4, -3, and -2. Additionally, the number of LB increased as both heifers and cows approached labor starting on d -2 and peaked at the day of calving. The time since the activity index increased over 50% to parturition did not differ between heifers and cows, and the activity index revealed the shift in activity on average 6h 14min (range from 2h to 14h 15min) before calf birth. This study provided evidence that heifers and cows approaching parturition showed a similar, but distinct, behavioral pattern that can be observed on average 6h before calf birth. The potential benefits of electronic data loggers as predictors of parturition along with proactive management practices should improve the overall survival and welfare of both the dam and calf.

Exploring vaginal discharge scoring to assess clinical metritis severity: Comparison between intrauterine dextrose and systemic antibiotics treatments.

The objectives of this study were to assess: 1) differences in the metabolic status, systemic inflammation, daily milk yield, and daily rumination time between Holstein dairy cows with different vaginal discharge scores (VDS) in the first 7±3 DIM, and 2) effects of intrauterine dextrose infusion on metabolic status, systemic inflammation, daily milk yield and daily rumination time in dairy cows with VDS4 and VDS5. Cows (n=641) from a farm located in central Pennsylvania were screened at 7±3 DIM (study d 0) to assess vaginal discharge scores. Vaginal discharge was scored using a five-point scale (i.e., 1- clear fluid, 2- <50% white purulent fluid, 3- >50% white purulent fluid, 4- red-brownish fluid without fetid smell, and 5- fetid red-brownish watery fluid). Cows with VDS4 and VDS5 were blocked by parity and randomly assigned to one of two treatment groups: 1) CONV (VDS4 n=15; VDS5 n= 23): two injections of ceftiofur (per label; 6.6 mg/Kg) 72 h apart; and 2) DEX (VDS4 n=15; VDS5 n=22): three intrauterine infusions of a 50% dextrose solution (1 L/cow) every 24 h. Cows that presented a VDS 1, 2, and 3 were categorized as normal vaginal discharge animals (NOMVDS; n=35) and were randomly selected and matched by parity to CONV and DEX cows. Daily milk yield and rumination time for the first 150 DIM were collected from on-farm computer records. Blood samples were collected to assess haptoglobin (HP) and ß-hydroxybutyrate (BHB) concentrations at study d 0, d 7, and d 14 relative to enrollment. Subclinical ketosis was defined as having a BHB concentration >1.2 mmol/dL at any of the sampling points. The data were analyzed using the MIXED and GLIMMIX procedures of SAS as a randomized complete block design. When comparing cows with different VDS (i.e., NOMVDS, VDS4, VDS5) separately, cows with VDS5 had the highest concentration of HP at enrollment compared to cows with VDS4 and NOMVDS; however, cows with VDS4 had higher concentrations of HP compared to cows with NOMVDS. Cows with VDS4 or VDS5 had a higher incidence of subclinical ketosis compared to cows with NOMVDS (p=0.005; VDS4= 62.08±9.16%; VDS5=74.44±6.74%; NOMVDS=34.36±8.53%). Similarly, daily milk yield (p<.0001; VDS4=30.17±1.32 kg/d; VDS5=27.40±1.27 kg/d; NOMVDS=35.14±1.35 kg/d) and daily rumination time (p=0.001; VDS4=490.77±19.44 min; VDS5=465±16.67 min; NOMVDS=558.29±18.80 min) was lower for cows with VDS4 and VDS5 compared to cows with NOMVDS at 7±3 days in milk. When analyzing HP concentration between treatment groups in cows with VDS4 (p=0.70), VDS5 (p=0.25), or VDS4 and VDS5 combined (p=0.31), there was no difference in HP concentration by study d 14 between treatment groups. Interestingly, when only cows with VDS4 were considered for treatment, both treatments, DEX and CONV, increased the daily milk yield to the levels of NOMVDS cows by 14 days in milk. On the other hand, when only cows with VDS5 were considered for treatment, cows treated with DEX produced, on average, 4.48 kg/d less milk in the first 150 days in milk compared to cows treated with CONV or cows that had NOMVDS. Similarly, when cows with either VDS4 or VDS5 were considered for treatment, DEX treatment also impaired milk yield. These results suggest that cows with either VDS 4 or 5 have an altered inflammatory status, and decreased milk yield and rumination compared to cows with NOMVDS. Furthermore, DEX treatment may have similar effects on daily milk yield and metabolic status compared to CONV in cows with VDS4, while DEX is not recommended for cows with VDS5.

Antenatal cardiotocography in primary midwife-led care: a budget impact analysis.

OBJECTIVES: In many countries, the healthcare sector is dealing with important challenges such as increased demand for healthcare services, capacity problems in hospitals and rising healthcare costs. Therefore, one of the aims of the Dutch government is to move care from in-hospital to out-of-hospital care settings. An example of an innovation where care is moved from a more specialised setting to a less specialised setting is the performance of an antenatal cardiotocography (aCTG) in primary midwife-led care. The aim of this study was to assess the budget impact of implementing aCTG for healthy pregnant women in midwife-led care compared with usual obstetrician-led care in the Netherlands. METHODS: A budget impact analysis was conducted to estimate the actual costs and reimbursement of aCTG performed in midwife-led care and obstetrician-led care (ie, base-case analysis) from the Dutch healthcare perspective. Epidemiological and healthcare utilisation data describing both care pathways were obtained from a prospective cohort, survey and national databases. Different implementation rates of aCTG in midwife-led care were explored. A probabilistic sensitivity analysis was conducted to estimate the uncertainty surrounding the budget impact estimates. RESULTS: Shifting aCTG from obstetrician-led care to midwife-led-care would increase actual costs with €311 763 (97.5% CI €188 574 to €426 072) and €1 247 052 (97.5% CI €754 296 to €1 704 290) for implementation rates of 25% and 100%, respectively, while it would decrease reimbursement with -€7 538 335 (97.5% CI -€10 302 306 to -€4 559 661) and -€30 153 342 (97.5% CI -€41 209 225 to -€18 238 645) for implementation rates of 25% and 100%, respectively. The sensitivity analysis results were consistent with those of the main analysis. CONCLUSIONS: From the Dutch healthcare perspective, we estimated that implementing aCTG in midwife-led care may increase the associated actual costs. At the same time, it might lower the healthcare reimbursement.