Genetics of inborn errors of immunity: Diagnostic strategies and new approaches to CNV detection.

BACKGROUND: Genetic diagnosis of inborn errors of immunity (IEI) is complex due to the large number of genes involved and their molecular features. Missense variants have been reported as the most common cause of IEI. However, the frequency of copy number variants (CNVs) may be underestimated since their detection requires specific quantitative techniques. At this point, the use of Next Generation Sequencing (NGS) is acquiring relevance. METHODS: In this article, we present our experience in the genetic diagnosis of IEI based on three diagnostic algorithms that allowed the detection of single nucleotide variants (SNVs) and CNVs. Following this approximation, 703 index cases were evaluated between 2014 and 2021. Sanger sequencing, MLPA, CGH array, breakpoint spanning PCR or a customized NGS-based multigene-targeted panel were performed. RESULTS: A genetic diagnosis was reached in 142 of the 703 index cases (20%), 19 of them presented deletions as causal variants. Deletions were also detected in 5 affected relatives and 16 healthy carriers during the family studies. Additionally, we compile, characterize and present all the CNVs detected by our diagnostic algorithms, representing the largest cohort of deletions related to IEI to date. Furthermore, three bioinformatic tools (LACONv, XHMM, VarSeq™) based on NGS data were evaluated. VarSeq™ was the most sensitive and specific bioinformatic tool; detecting 21/23 (91%) deletions located in captured regions. CONCLUSION: Based on our results, we propose a strategy to guide the molecular diagnosis that can be followed by expert and non-expert centres in the field of IEI.

Stress decreases spermatozoa quality and induces molecular alterations in zebrafish progeny.

BACKGROUND: Chronic stress can produce a severe negative impact on health not only in the exposed individuals but also in their offspring. Indeed, chronic stress may be contributing to the current worldwide scenario of increasing infertility and decreasing gamete quality in human populations. Here, we evaluate the effect of chronic stress on behavior and male reproductive parameters in zebrafish. Our goal is to provide information on the impact that chronic stress has at molecular, histological, and physiological level in a vertebrate model species. RESULTS: We evaluated the effects of a 21-day chronic stress protocol covering around three full waves of spermatogenesis in Danio rerio adult males. The induction of chronic stress produced anxiety-like behavior in stressed males as assessed by a novel tank test. At a molecular level, the induction of chronic stress consistently resulted in the overexpression of two genes related to endoplasmic reticulum (ER) stress in the brain. Gene set enrichment analysis (GSEA) of testes suggested a dysregulation of the nonsense-mediated decay (NMD) pathway, which was also confirmed on qPCR analysis. Histological analysis of the testicle did not show significant differences in terms of the relative proportions of each germ-cell type; however, the quality of sperm from stressed males was compromised in terms of motility. RNA-seq analysis in stress-derived larval progenies revealed molecular alterations, including those predicted to affect translation initiation, DNA repair, cell cycle control, and response to stress. CONCLUSIONS: Induction of chronic stress during a few cycles of spermatogenesis in the vertebrate zebrafish model affects behavior, gonadal gene expression, final gamete quality, and progeny. The NMD surveillance pathway (a key cellular mechanism that regulates the stability of both normal and mutant transcripts) is severely affected in the testes by chronic stress and therefore the control and regulation of RNAs during spermatogenesis may be affected altering the molecular status in the progeny.

The modulation of platelet function by growth hormone in growth hormone deficient Hypopituitary patients.

BACKGROUND: Growth hormone deficiency (GHD) has been implicated in increased cardiovascular and cerebrovascular disease risk seen in hypopituitarism, however the mechanism remains speculative. We hypothesise that platelet abnormalities may play a contributory role. Herein we examined platelet behaviour in GHD hypopituitary patients, pre- and post-growth hormone (GH) replacement. METHODS: This study utilizes a physiological flow-based assay to quantify platelet function in whole blood from patient cohorts under arterial shear. Thirteen GH Naïve hypopituitary adults with GHD and thirteen healthy matched controls were studied. Patients were assessed before and after GH treatment. All other pituitary replacements were optimised before the study. In addition to a full endocrine profile, whole blood was labelled and perfused over immobilised von Willibrand factor (vWF). Seven parameters of dynamic platelet-vWF interactions were recorded using digital image microscopy and analysed by customised platelet tracking software. RESULTS: We found a significantly altered profile of platelet-vWF interactions in GHD individuals compared to healthy controls. Specifically, we observed a marked increase in platelets shown to form associations such as tethering, rolling and adherence to immobilized vWF, which were reduced post GH treatment. Speed and distance platelets travelled across vWF was similar between controls and pre-therapy GHD patients, however, this was considerably increased post treatment. This may indicate reduced platelet signaling resulting in less stable adhesion of platelets post GH treatment. CONCLUSIONS: Taken together observed differences in platelet behaviour may contribute to an increased risk of thrombosis in GHD which can in part be reversed by GH therapy.

Easy approach to detect cell immunity to COVID vaccines in common variable immunodeficiency patients.

BACKGROUND: Patients with primary antibody deficiencies, such as Common Variable Immunodeficiency (CVID), have some problems to assess immune response after coronavirus disease (COVID) vaccination. Cutaneous delayed-type hypersensitivity (DTH) has the potential to be used as a useful, simple, and cheaper tool to assess T-cell (T lymphocyte) function. METHODS: Seventeen patients with CVID, a rare disease, received two doses of the mRNA-based Pfizer-BioNTech COVID-19 vaccine. Humoral Immune Response (HIR) was determined by measuring specific immunoglobulin G (IgG) antibodies, and Cellular Immune Response (CIR) was evaluated using an ex vivo interferon-gamma release assay (IGRA) and in vivo by DTH skin test. RESULTS: Two weeks after the second dose of the vaccine, 12 out of 17 CVID patients have high optical density (OD) ratios of specific anti-spike protein (S) IgG whereas five patients were negative or low. Ex vivo CIR was considered positive in 14 out of 17 S1-stimulated patients. Unspecific stimulation was positive in all 17 patients showing no T-cell defect. A positive DTH skin test was observed in 16 CVID patients. The only patient with negative DTH also had negative ex vivo CIR. CONCLUSIONS: The use of DTH to evaluate CIR was validated with an optimal correlation with the ex vivo CIR. The CIR after vaccination in patients with antibody deficiencies seems to have high precision and more sensitivity to antibodies-based methods in CVID. CLINICAL IMPLICATIONS: There is a remarkable correlation between cutaneous DTH and ex vivo IGRA after COVID vaccination. A COVID-specific skin DTH test could be implemented in large populations. CAPSULE SUMMARY: Cutaneous delayed-type hypersensitivity has the potential to be used as a useful, simple, and cheaper tool to assess T-cell functioning.

Changes in Serum Creatinine Levels Can Help Distinguish Hypovolemic from Euvolemic Hyponatremia.

Background and Objectives: Differentiating between hypovolemic (HH) and euvolemic hyponatremia (EH) is crucial for correct diagnosis and therapy, but can be a challenge. We aim to ascertain whether changes in serum creatinine (SC) can be helpful in distinguishing HH from EH. Materials and Methods: Retrospective analysis of patients followed in a monographic hyponatremia outpatient clinic of a tertiary hospital during 1 January 2014−30 November 2019. SC changes during HH and EH from eunatremia were studied. The diagnostic accuracy of the SC change from eunatremia to hyponatremia (∆SC) was analyzed. Results: A total of 122 hyponatremic patients, median age 79 years (70−85), 46.7% women. In total, 70/122 patients had EH, 52/122 HH. During hyponatremia, median SC levels increased in the HH group: +0.18 mg/dL [0.09−0.39, p < 0.001], but decreased in the EH group: −0.07 mg/dL (−0.15−0.02, p < 0.001), as compared to SC in eunatremia. HH subjects presented a higher rate of a positive ∆SC than EH (90.4% vs. 25.7%, p < 0.001). EH subjects presented a higher rate of a negative/null ∆SC than HH (74.3% vs. 9.6%, p < 0.001). ROC curve analysis found an AUC of 0.908 (95%CI: 0.853 to 0.962, p < 0.001) for ∆SC%. A ∆SC% ≥ 10% had an OR of 29.0 (95%CI: 10.3 to 81.7, p < 0.001) for HH. A ∆SC% ≤ 3% had an OR of 68.3 (95%CI: 13.0 to 262.2, p < 0.001) for EH. Conclusions: The assessment of SC changes from eunatremia to hyponatremia can be useful in distinguishing between HH and EH.

Active management of hyponatraemia and mortality in older hospitalised patients compared with younger patients: results of a prospective cohort study.

INTRODUCTION: Hyponatraemia is associated with increased morbidity and mortality; the aetiology and outcomes of hyponatraemia in older patients have not been defined in prospective studies. METHODS: A single-centre 9-month prospective observational study in which clinical outcomes in hospitalised patients ≥ 65 years (older patients with hyponatraemia (OP-HN)) and those <65 years (young patients with hyponatraemia (YP-HN)) with hyponatraemia were analysed, and compared with eunatraemic controls (older patients with normonatraemia (OP-NN) and young patients with normonatraemia (YP-NN)). RESULTS: In total, 1,321 episodes of hyponatraemia in 1,086 patients were included; 437 YP-HN, median age 54 years (IQR 44,60) and 884 OP-HN, median age 77 years (IQR 71,82). A total of 1,120 consecutive eunatraemic control patients were simultaneously recruited; 690 OP-NN, median age 77 years (IQR 71,83) and 430 YP-NN, median age 52 years (IQR 41,58). Euvolaemic hyponatraemia was the commonest cause of hyponatraemia in both age groups (48% in YP-HN and 46% in OP-HN). Sixty-two percent of OP-HN received hyponatraemia-directed treatment within the initial 48 h, compared with 55% of YP-HN, P = 0.01. Despite the greater treatment rates in OP-HN, younger patients were 24% more likely to be discharged with normal plasma sodium concentration (pNa) compared with older patients, relative risk (RR) 1.24 (95% confidence interval (CI) 1.12-1.37), P < 0.001.Using OP-NN as the reference group, the RR of in-hospital death in OP-HN was 2.15 (95% CI 1.3-3.56), P = 0.002. Using YP-NN as the reference group, the RR of in-hospital death in YP-HN was 4.34 (95% CI 1.98-9.56), P < 0.001. CONCLUSION: Despite greater rates of HN-targeted treatment, the risk of in-hospital death is increased in older hyponatraemic patients compared with older eunatraemic controls. The impact of hyponatraemia on mortality is even greater in younger patients.

Hyponatraemia in patients with community-acquired pneumonia; prevalence and aetiology, and natural history of SIAD.

OBJECTIVE: Hyponatraemia is common in community-acquired pneumonia (CAP) and is associated with increased mortality. The mechanism of hyponatraemia in CAP is not completely understood and treatment is therefore ill-defined. We aimed to define the causation of hyponatraemia in CAP. DESIGN: Prospective, single-centre, observational study of all patients with CAP and hyponatraemia (≤ 130 mmol/L) during a 9-month period. PATIENTS: The prevalence of each subtype of hyponatraemia, and the associated mortality, was determined in 143 admissions with CAP (Study 1). A sub-cohort of patients with SIAD (n = 10) was prospectively followed, to document the natural history of SIAD associated with CAP (Study 2). MEASUREMENTS: In Study 2, blood and urine were collected on day 1, 3, 5 and 7 following admission for measurement of plasma vasopressin, sodium, osmolality and urine osmolality. RESULTS: In study 1, 143/1723(8.3%) of CAP patients had hyponatraemia (≤130 mmol/L). About 66 had SIAD (46%), 60(42%) had hypovolaemic hyponatraemia (HON), 13(9%) had hypervolaemic hyponatraemia (HEN) and 4(3%) patients had hyponatraemia due to glucocorticoid hormone deficiency. Mortality was higher in the HEN than in the HON, SIAD or normonatraemic groups (P < 0.01). In Study 2, plasma sodium concentration normalized in 8/10 (80%) by day 7. Two patients with persistent hyponatraemia were discovered to have underlying bronchiectasis. CONCLUSIONS: Hyponatraemia in CAP is most commonly secondary to SIAD or hypovolaemia. HEN is less common, but has worse prognosis. Prospective observation demonstrates that in SIAD, plasma AVP and sodium concentrations normalize with antimicrobials; failure of reversal of suggests underlying lung disease, such as bronchiectasis.

A Mediterranean Diet with an Enhanced Consumption of Extra Virgin Olive Oil and Pistachios Improves Pregnancy Outcomes in Women Without Gestational Diabetes Mellitus: A Sub-Analysis of the St. Carlos Gestational Diabetes Mellitus Prevention Study.

AIMS: The aim of the study was to evaluate the effect of a Mediterranean diet (MedDiet), enhanced with extra virgin olive oil (EVOO) and nuts, on a composite of adverse maternofoetal outcomes of women with normoglycemia during pregnancy. METHODS: This was a sub-analysis of the St Carlos gestational diabetes mellitus Prevention Study. Only normoglycemic women were analysed (697). They were randomized (at 8-12th gestational weeks) to: standard-care control group (337), where fat consumption was limited to 30% of total caloric intake; or intervention group (360), where a MedDiet, enhanced with EVOO and pistachios (40-42% fats of total caloric intake) was recommended. The primary outcome was a composite of maternofoetal outcomes (CMFOs): at least having 1 event of emergency C-section, perineal trauma, pregnancy-induced hypertension and preeclampsia, prematurity, large-for-gestational-age and small-for gestational-age. RESULTS: Crude relative risk showed that the intervention was associated with a significant reduction in the risk of CMFOs (0.48 [0.37-0.63]; p = 0.0001), with a number-needed-to-treat = 5. Risk of urinary tract infections, emergency C-sections, perineal trauma, large-for-gestational-age and small-for gestational age new-borns were also significantly reduced. CONCLUSION: A MedDiet, enhanced with EVOO and nuts, was associated with a risk reduction of CMFOs in over 50% in normoglycemic pregnant women. Therefore, it might be a potentially adequate diet for pregnant women. TRIAL REGISTRATION: Identifier ISRCTN84389045. The study was registered on September 27, 2013. Last edited on September 26, 2018.

Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland.

The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304* ; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275-5,000) years. tMRCA-based simulations predicted 432 (90-5,175) current carriers, including 86 affected (18-1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease.

Mortality rates are lower in SIAD, than in hypervolaemic or hypovolaemic hyponatraemia: Results of a prospective observational study.

OBJECTIVE: Hyponatraemia is associated with increased mortality, but the mortality associated specifically with SIAD is not known. We hypothesized that mortality in SIAD was elevated, but that it was less than in hypervolaemic (HEN) or hypovolaemic (HON) hyponatraemia. DESIGN: Mortality rates are presented as risk ratios (RR),with 95% confidence intervals (CI), and compared to normonatraemic controls (NN). METHODS: Prospective, single centre, noninterventional study of all patients with hyponatraemia (≤130 mmol/L) admitted to hospital. RESULTS: A total of 1323 admissions with hyponatraemia were prospectively evaluated and 1136 contemporaneous NN controls. 431(32.6%) hyponatraemic patients had HON, 573(43.3%) had SIAD and 275(20.8%) patients had HEN. In patient mortality was higher in hyponatraemia than NN (9.1% vs 3.3%, P<.0001). The RRs for in-hospital mortality compared to NN were: SIAD, 1.76 (95% CI 1.08-2.8, P=.02), HON 2.77 (95% CI 1.8-4.3, P<.0001) and HEN, 4.9 (95% CI 3.2-7.4, P<.0001). The mortality rate was higher in HEN (RR 2.85; 95% CI 1.86-4.37, P<.0001) and in HON, (RR 1.6; 95% CI 1.04-2.52; P=.03), when compared to SIAD. The Charlson Comorbidity Index was lower in SIAD than in eunatraemic patients (P<.0001). 9/121(7.4%) patients died with plasma sodium <125 mmol/L and 4(3.3%) with plasma sodium <120 mmol/L. However, 69/121(57%) patients died with a plasma sodium above 133 mmol/L. CONCLUSIONS: We confirmed higher all-cause mortality in hyponatraemia than in NN. Mortality was higher in SIAD than in normonatraemia and was not explained on the basis of co-morbidities. Mortality was higher in HON and HEN than in SIAD. Mortality rates reported for all-cause hyponatraemia in the medical literature are not applicable to SIAD.

Adipsic diabetes insipidus in adult patients.

INTRODUCTION: Adipsic diabetes insipidus (ADI) is a very rare disorder, characterized by hypotonic polyuria due to arginine vasopressin (AVP) deficiency and failure to generate the sensation of thirst in response to hypernatraemia. As the sensation of thirst is the key homeostatic mechanism that prevents hypernatraemic dehydration in patients with untreated diabetes insipidus (DI), adipsia leads to failure to respond to aquaresis with appropriate fluid intake. This predisposes to the development of significant hypernatraemia, which is the typical biochemical manifestation of adipsic DI. METHODS: A literature search was performed to review the background, etiology, management and associated complications of this rare condition. RESULTS: ADI has been reported to occur in association with clipping of an anterior communicating artery aneurysm following subarachnoid haemorrhage, major hypothalamic surgery, traumatic brain injury and toluene exposure among other conditions. Management is very difficult and patients are prone to marked changes in plasma sodium concentration, in particular to the development of severe hypernatraemia. Associated hypothalamic disorders, such as severe obesity, sleep apnoea and thermoregulatory disorders are often observed in patients with ADI. CONCLUSION: The management of ADI is challenging and is associated with significant morbidity and mortality. Prognosis is variable; hypothalamic complications lead to early death in some patients, but recent reports highlight the possibility of recovery of thirst.

Prevalence of Hyponatremia and Its Associated Morbimortality in Hospitalized Patients Receiving Parenteral Nutrition.

BACKGROUND: The objective of the study was to determine the prevalence of hyponatremia (HN) and its associated morbimortality in hospitalized patients receiving parenteral nutrition (PN). METHODS: A retrospective study including 222 patients receiving total PN (parenteral nutrition group [PNG]) over a 7-month period in a tertiary hospital and 176 matched to 179 control subjects without PN (control subjects group [CSG]). Demographic data, Charlson Comorbidity Index (CCI), date of HN detection-(serum sodium or SNa <135 mmol/L)-intrahospital mortality, and hospital length-of-stay (LOS) were registered. In the PNG, body mass index (BMI) and SNa before, during, and after PN were recorded. RESULTS: HN was more prevalent in the PNG: 52.8 vs. 35.8% (p = 0.001), and independent of age, gender, or CCI (OR 1.8 [95% CI 1.1-2.8], p = 0.006). In patients on PN, sustained HN (75% of all intraindividual SNa <135 mmol/L) was associated with a higher mortality rate independent of age, gender, CCI, or BMI (OR 7.38 [95% CI 1.07-50.8], p = 0.042). The absence of HN in PN patients was associated with a shorter hospital LOS (<30 days) and was independent of other comorbidities (OR 3.89 [95% CI 2.11-7.18], p = 0.001). CONCLUSIONS: HN is more prevalent in patients on PN. Sustained HN is associated with a higher intrahospital mortality rate. Absence of HN is associated with a shorter hospital LOS.

The contribution of undiagnosed adrenal insufficiency to euvolaemic hyponatraemia: results of a large prospective single-centre study.

OBJECTIVE: The syndrome of inappropriate antidiuresis (SIAD) is the commonest cause of hyponatraemia. Data on SIAD are mainly derived from retrospective studies, often with poor ascertainment of the minimum criteria for the correct diagnosis. Reliable data on the incidence of adrenal failure in SIAD are therefore unavailable. The aim of the study was to describe the aetiology of SIAD and in particular to define the prevalence of undiagnosed adrenal insufficiency. DESIGN: Prospective, single centre, noninterventional, observational study of patients admitted to Beaumont Hospital with euvolaemic hyponatraemia (plasma sodium ≤ 130 mmol/l) between January 1st and October 1st 2015. PATIENTS: A total of 1323 admissions with hyponatraemia were prospectively evaluated; 576 had euvolaemic hyponatraemia, with 573 (43·4%) initially classified as SIAD. MAIN OUTCOME MEASURES: (i) Aetiology of SIAD, defined by diagnostic criteria; (ii) Incidence of adrenal insufficiency. RESULTS: Central nervous system diseases were the commonest cause of SIAD (n = 148, 26%) followed by pulmonary diseases (n = 111, 19%), malignancy (n = 105, 18%) and drugs (n = 47, 8%). A total of 22 patients (3·8%), initially diagnosed as SIAD, were reclassified as secondary adrenal insufficiency on the basis of cortisol measurements and clinical presentation; 9/22 cases had undiagnosed hypopituitarism; 13/22 patients had secondary adrenal insufficiency due to exogenous steroid administration. CONCLUSIONS: In a large, prospective and well-defined cohort of euvolaemic hyponatraemia, undiagnosed secondary adrenal insufficiency co-occurred in 3·8% of cases initially diagnosed as SIAD. Undiagnosed pituitary disease was responsible for 1·5% of cases presenting as euvolaemic hyponatraemia.

Symptoms of gonadal dysfunction are more predictive of hypopituitarism than nonspecific symptoms in screening for pituitary dysfunction following moderate or severe traumatic brain injury.

OBJECTIVE: The economic and logistic burden of screening for hypopituitarism following moderate/severe traumatic brain injury (TBI) is considerable. A key recommendation in published guidelines is to prioritize for screening those patients with symptoms suggestive of pituitary dysfunction. The purpose of this study was to evaluate the utility of targeted screening for hypopituitarism in long-term survivors after moderate/severe TBI using referrals on the basis of symptoms. DESIGN: In group 1 (G1), consecutive, unselected patients were screened from the Irish National Neurosurgery Centre, whereas in group 2 (G2) patients were targeted based on the presence of symptoms suggestive of pituitary dysfunction. PATIENTS: A total of 137 patients (113 male) were systematically screened (G1) and compared to 112 patients (77 male) referred for pituitary evaluation on the basis of suggestive symptoms (G2). MAIN OUTCOME MEASURES: The rate of GH, ACTH, gonadotrophin (GT), TSH and ADH deficiency was compared among groups. RESULTS: Patients referred with menstrual dysfunction had more GH (50% vs 11%, P = 0·001), ACTH (60% vs 14%, P < 0·0001), GT (90% vs 16%, P < 0·0001) deficiency and any pituitary hormone deficit (80% vs 33%, P = 0·003) than G1. Men with symptoms of hypogonadism had more GH (33% vs 11%, P = 0·003), GT (58% vs 16%, P < 0·0001) and TSH (16% vs 1%, P = 0·03) deficiency than G1. Patients with nonspecific symptoms were no more likely to have hypopituitarism than those consecutively screened. CONCLUSIONS: Symptoms of hypogonadism are sufficiently predictive of hypopituitarism to justify screening for hypopituitarism after moderate/severe TBI. Nonspecific symptoms of hypopituitarism are no more predictive than unselected screening.

The relevance of hyponatraemia to perioperative care of surgical patients.

BACKGROUND: Hyponatraemia is the most common electrolyte disturbance in hospitalized patients. There is an increasing awareness of the impact of hyponatraemia on the perioperative management of surgical patients. METHODS: We performed a literature review. We have included relevant data from different surgical disciplines for analysis. In this review we discuss the differential diagnosis of hyponatraemia, and explain the specific relevance of hyponatraemia to pre-, peri- and post-operative care. RESULTS: Hyponatraemia is common during the preoperative period and is associated with an increase in subsequent peri-operative complications, such as wound infection, pneumonia, higher mortality rate and higher direct and indirect costs. Furthermore, data shows poorer surgical outcomes when plasma sodium concentration drops. Careful preoperative evaluation of the hyponatraemic patient enables assessment of surgical risk and individualization of the management of hyponatraemia. CONCLUSIONS: We outline a practical guide to the assessment of the cause of hyponatraemia, which dictates the correct management of hyponatraemia and the correct selection of perioperative fluids. Finally, for the therapeutic role of the new vasopressin antagonist drugs in the treatment of surgical hyponatraemia is discussed in two illustrative surgical clinical cases.

Real-World Evidence of Off-Label Use of Commercially Automated Insulin Delivery Systems Compared to Multiple Daily Insulin Injections in Pregnancies Complicated by Type 1 Diabetes.

Aims: To compare glycemic control and maternal-fetal outcomes of women with type 1 diabetes (T1D) using hybrid closed loop (HCL) versus multiple daily insulin injections (MDI) plus continuous glucose monitoring. Methods: Multicenter prospective cohort study of pregnant women with T1D in Spain. We evaluated HbA1c and time spent within (TIR), below (TBR), and above (TAR) the pregnancy-specific glucose range of 3.5-7.8 mmol/L. Adjusted models were performed for adverse pregnancy outcomes, including baseline maternal characteristics and center. Results: One hundred twelve women were included (HCL n = 59). Women in the HCL group had a longer duration of diabetes and higher rates of prepregnancy care. There was no between-group difference in HbA1c in any trimester. However, in the second trimester, MDI users had a greater decrease in HbA1c (-6.12 ± 9.06 vs. -2.16 ± 7.42 mmol/mol, P = 0.031). No difference in TIR (3.5-7.8 mmol/L) and TAR was observed between HCL and MDI users, but with a higher total insulin dose in the second trimester [+0.13 IU/kg·day)]. HCL therapy was associated with increased maternal weight gain during pregnancy (ßadjusted = 3.20 kg, 95% confidence interval [CI] 0.90-5.50). Regarding neonatal outcomes, newborns of HCL users were more likely to have higher birthweight (ßadjusted = 279.0 g, 95% CI 39.5-518.5) and macrosomia (ORadjusted = 3.18, 95% CI 1.05-9.67) compared to MDI users. These associations disappeared when maternal weight gain or third trimester HbA1c was included in the models. Conclusions: In a real-world setting, HCL users gained more weight during pregnancy and had larger newborns than MDI users, while achieving similar glycemic control in terms of HbA1c and TIR.

Early Mediterranean-Based Nutritional Intervention Reduces the Rate of Gestational Diabetes in Overweight and Obese Pregnant Women: A Post-Hoc Analysis of the San Carlos Gestational Prevention Study.

Obesity is a risk factor for the development of gestational diabetes mellitus (GDM). However, the most optimal type of nutritional intervention to prevent GDM in high-risk women is not clearly defined. This study investigates if nutritional treatment based on the Mediterranean diet (MedDiet) before the 12th gestational week (GW) in women at high risk due to a body mass index (BMI) ≥ 25 kg/m2 reduces the rate of GDM and metabolic syndrome (MetS) at 3 years postpartum. We performed a post-hoc analysis of the San Carlos Gestational Prevention Study. A total of 735 women with BMI ≥ 25 kg/m2 were evaluated between 2015 and 2018, with 246 in the standard diet control group (CG) and 489 in the MedDiet intervention group (IG). The rate of GDM was significantly lower in IG compared to CG (25.1% vs. 31.7%), relative risk (95% confidence interval), and 0.89 (0.78-0.99); p = 0.037. Postnatal follow-up was completed by 141 women in CG (57%) and 312 women in IG (64%). At 3 years postpartum, we observed a reduction in the rates of impaired fasting glucose (IFG) (0.51 (0.28-0.92); p = 0.019), obesity (0.51 (0.28-0.92); p = 0.041), waist circumference (WC) ≥ 89.5 cm (0.54 (0.31-0.94); p = 0.022), and MetS (0.56 (0.33-0.94); p = 0.003). MedDiet reduces the rate of GDM and postpartum MetS in women with BMI) ≥ 25 kg/m2, suggesting that its implementation should be routinely recommended from the first GWs.

Efficacy, Safety, and Satisfaction with the Accu-Chek Insight with Diabeloop Closed-Loop System in Subjects with Type 1 Diabetes: A Multicenter Real-World Study.

Aim: To evaluate the efficacy, safety and satisfaction of the closed-loop system Accu-Chek® Insight with Diabeloop™ (DBLG1™) in adults with type 1 diabetes (T1D) in real-world conditions. Methods: Patients with T1D using DBLG1 for at least 3 months were included. Glucometric parameters were analyzed at baseline, 1, 2, and 3 months after starting DBLG1. HbA1c was measured before and at 3 months. Technical issues and acute complications were recorded and patients completed a satisfaction questionnaire. Results: Sixty-two patients were included (43 women; age 44.2 ± 11 years; diabetes duration 24.6 ± 12 years; 40 used flash and 22 continuous glucose monitoring (CGM); 45 were on insulin pump and 17 on multiple daily injections). A significant improvement was observed in the CGM-derived glucose metrics early in the first month: Time in range (%TIR) 70-180 mg/dL (54.86 ± 17 vs. 72.23 ± 10.11); time above range level 1 (%TAR1) 180-250 mg/dL (26.26 ± 13.3 vs. 19.48 ± 6.78), time above range level 2 (%TAR2) > 250 mg/dL (12.02 ± 13.09 vs. 6.14 ± 5.23), time below range level 1 (%TBR 1) 54-70 mg/dL (5.73 ± 11.5 vs. 1.67 ± 1.3), time below range level 2 (%TBR2) < 54 mg/dL (1.18 ± 1.97 vs.0.44 ± 0.49), %CV (38.66 ± 7.53 vs. 29.63 ± 3.74), median glucose (168.57 ± 36 mg/dL vs. 154.63 ± 17.55 mg/dL), and %GMI (7.37 ± 0.91 vs. 7.02 ± 0.42). Also, HbA1c decreased significantly (7.45% ± 1.05% vs. 6.95% ± 0.7%). No acute complications or serious adverse events occurred. Similar improvement was observed regardless of prior therapy or the glucose monitoring system used. Three patients discontinued DBLG1 and 21 experienced technical issues. Overall, patient satisfaction was high. Adjustments of the settings were modified in general in the direction of greater aggressiveness. Conclusions: A significant improvement in glycemic control without serious adverse events and a high degree of patient satisfaction were observed in this first real-world study evaluating the closed-loop system, Accu-Chek Insight with Diabeloop.

The prevalence of primary and secondary hyperparathyroidism and its cardiometabolic implications in primary aldosteronism.

BACKGROUND: The aim of this study was to analyze the prevalence of primary and secondary hyperparathyroidism in patients with primary aldosteronism (PA), and its implication on cardiovascular and metabolic outcomes. METHODS: A retrospective study of patients with PA (exposed cohort, N.=44) and all hypertensive (EH) patients with adrenal lesions without PA nor other adrenal hypersecretion (non-exposed cohort, N.=41) on follow-up at our center between 2016 and 2020. RESULTS: The mean age of patients with PA and EH was 55.1±14.13 and 66.3±10.93 (P<0.001), and 50% of PA and 39.0% of EH were women (P=0.309). At diagnosis, the prevalence of primary hyperparathyroidism in PA was of 18.2%, and all were normocalcemic hyperparathyroidism cases. Globally, no differences were found in the prevalence of primary hyperparathyroidism compared to EH (18.2% vs. 29.3%, P=0.229), but hypercalcemic primary hyperparathyroidism was significantly more prevalent in EH patients than in PA (22.0% vs. 0%, P=0.001). There were 47.7% (N.=21) cases of secondary hyperparathyroidism in patients with PA (4 due to chronic kidney disease (CKD) and vitamin D deficiency, and 17 due to vitamin D deficiency alone). The cardiometabolic profile of patients with PA and hyperparathyroidism (N.=29) was similar to of those patients without hyperparathyroidism (N.=15) at diagnosis and after a median follow-up of 3.6 years (interquartile range 1.1-5.9). CONCLUSIONS: Although primary and secondary hyperparathyroidism are common in patients with PA, their prevalence was similar than the observed in EH patients. Primary hyperparathyroidism is usually mild in PA, appearing as normocalcemic forms. No negative implications of the hyperparathyroidism in the cardiometabolic profile of PA were observed.

An Early Mediterranean-Based Nutritional Intervention during Pregnancy Reduces Metabolic Syndrome and Glucose Dysregulation Rates at 3 Years Postpartum.

A Mediterranean diet (MedDiet)-based intervention reduces the rate of immediate postpartum maternal metabolic disorders. Whether these effects persist long-term remains to be determined. A total of 2526 normoglycemic women were randomized before the 12th gestational week (GW). IG women followed a MedDiet with extra virgin olive oil (EVOO) (>40 mL/day) and a handful of nuts daily, whereas CG women had to restrict all kinds of dietary fat. At 3 months postpartum, a motivational lifestyle interview was held. The endpoint of the study evaluated the rate of abnormal glucose regulation (AGR) and metabolic syndrome (MetS) at 3 years postpartum in women of the San Carlos cohort. A total of 369/625 (59%) CG women and 1031/1603 (64.3%) IG women were finally analyzed. At 3 months and 3 years postdelivery, the IG women showed higher adherence to the MedDiet, which was associated with lower values of body mass index (BMI) and lipid and glycemic profiles. Body weight change and waist circumference were lower in the IG women. After applying multiple regression analysis, the ORs (95%CI) resulted in AGR (3.18 (2.48-4.08); p < 0.001)/MetS (3.79 (1.81-7.95); p = 0.001) for women with GDM and higher OR for development of MetS in CG women (3.73 (1.77-7.87); p = 0.001). A MedDiet-based intervention early in pregnancy demonstrated persistent beneficial effects on AGR and MetS rates at 3 years postpartum.