The circadian timing of food intake and the composition of dietary protein sources may jointly influence metabolic regulation. Our aim was to examine the effects of a dairy-enriched vs non-dairy isoenergetic diet with structured meal timing on circadian clock gene expression, glycaemic management and appetite regulation in individuals with type 2 diabetes. In a randomised, crossover trial, 25 participants with type 2 diabetes and HbA1c ≥48 mmol/mol (6.5

Multiple endocrine neoplasia type 2 (MEN2) is caused by germline pathogenic variants (PVs) in the RET proto-oncogene, leading to medullary thyroid carcinoma (MTC), pheochromocytoma, and primary hyperparathyroidism (PHPT). RET p.Lys666Asn is a rare PV, but its clinical significance remains incompletely understood. The purpose of this study is to expand the clinical understanding of the RET Lys666Asn variant. Index patients carrying the RET Lys666Asn variant were identified through clinical genetic testing in two referral medical centers. Comprehensive clinical evaluation, biochemical screening, and imaging studies were performed to assess the presence of MTC, pheochromocytoma, and PHPT of the index patients and carrier family members. We performed a literature search on Lys666Asn carriers and their clinical manifestations. Ten individuals from five families were identified as carriers of the RET Lys666Asn variant. The median age at diagnosis was 43.7 years (range 2–75 years). Only one individual presented with pheochromocytoma, diagnosed at age 54. The rate of MTC, pheochromocytoma, and PHPT was 0 (0–0.26), 0.1 (0.01–0.39), and 0 (0–0.26), respectively. In a pooled analysis of cases reported in the literature, MTC, pheochromocytoma, and PHPT rate are 0.42 (0.28–0.57), 0.11 (0.04–0.22), and 0.03 (0–0.12), respectively. MTC had a wide age range at presentation (20–70 years). The RET Lys666Asn variant is associated with lower event rate of MEN2-related tumors compared to classical MEN2 variants, particularly MTC and pheochromocytoma. Despite its rarity, pheochromocytoma cannot be excluded in carriers, underscoring the need for individualized screening protocols based on specific RET variants.

Introduction: This study evaluates the efficacy of a nurse practitioner-managed, computer algorithm-supported institutional fracture liaison service (FLS) that provides treatment recommendations for patients with hip fractures. Methods: A retrospective study included patients hospitalized in the Orthopedic ward with hip fractures between April 1 and October 31. The decision-making algorithm recommends zoledronic acid as the default medication, except for patients younger than 65 years, with estimated glomerular filtration rate (eGFR) <35 or prior osteoporosis therapy, who are ordered to undergo endocrinology consultation. Patients with vitamin D deficiency/insufficiency are given a loading dose. Results: Two hundred and eight hip fracture patients were identified. The cohort was predominantly female (137/208, 65.9%); the mean age was 79.9 ± 9.6 years. Nurse practitioner evaluation was performed in 200/208 patients (96.2%). The algorithm provided a treatment recommendation in 140 out of 200 (70.0%), while 60 out of 200 (30.0%) required an endocrinology consultation. A Vitamin D loading dose was given in 89/99 (89.9%) deficiency and 44/62 (71.0%) insufficiency cases. Conclusions: This simplified algorithm-based FLS model demonstrated practicality and feasibility in providing therapeutic recommendations with minimal physician intervention.

IntroductionCirculating microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and play key roles in metabolic diseases, including diabetes. This study aimed to identify circulating miRNA signatures linked to glycemic status, vitamin D deficiency, aspirin consumption, and platelet activity in individuals with type 2 diabetes, prediabetes, and healthy controls.MethodsPlasma samples from 24 participants (14 with diabetes, 2 prediabetic, and 8 non-diabetic controls) were analyzed using next-generation sequencing to assess differences in miRNA expression.ResultsAlthough principal component analysis showed no group separation, pairwise testing identified 131 miRNAs that were significantly altered between the diabetic and control groups, as well as 141 miRNAs between the prediabetic and control groups (FDR <0.05), with 56 overlapping between contrasts. Fourteen miRNAs in the pre-diabetic group and twelve in the diabetic group overlapped with literature-supported candidates, reinforcing their clinical relevance. In the direct diabetes vs. prediabetes comparison, no miRNAs passed FDR. Still, consistent trend-level decreases in diabetes were observed for hsa-miR-4776-5p, hsa-miR-6778-3p, and hsa-miR-5002-3p, which were among the most upregulated in prediabetes vs. controls. Sex-stratified analyses revealed distinct miRNA expression patterns, emphasizing the influence of biological sex on miRNA regulation in glucose metabolism. Correlation analyses highlighted miRNAs associated with glucose/HbA1c, alongside relationships among vitamin D status, glycemia, and platelet function.DiscussionCollectively, these data highlight the exploratory potential of circulating miRNAs as candidate early biomarkers for glycemic dysregulation, providing a foundation for future validation and development of improved diagnostic and preventive strategies for type 2 diabetes.

BACKGROUND:Non-surgical treatment of appendicitis carries the risk of missed tumors, such as appendiceal neuroendocrine neoplasms (ANEN), the most common appendiceal tumor. The aim of this study is to identify radiological features of ANEN that will distinguish them from simple acute appendicitis. METHODS:Data were extracted from a database of 8327 appendectomies conducted during 2005-2018. Pre-operative computerized tomography (CT) or ultrasound (US) scans of patients with ANEN and a random sample of patients with simple appendicitis were compared. Patients with other appendiceal tumors were excluded. All images were reviewed by a blinded, experienced radiologist. RESULTS:Thirty-five ANEN (20 CT, 15 US) were compared to 50 cases with simple appendicitis (30 CT, 20 US). Age was similar between study groups (33.8 ± 19.2 vs. 35.2 ± 17.9, respectively, p = 0.378); female gender was more prevalent in the ANEN group (65.7% vs. 38.3%, p = 0.017). ANEN size per pathology report was 17.0 ± 13.4 mm, and mesoappendix invasion was evident in 37.1%. Appendiceal diameter, regional lymph node number, and size were similar. Evidence of solid tissue in the appendiceal lumen per CT was more prevalent in the ANEN group compared to controls (7/20 [35%] vs. 2/30 [6.7%], p = 0.0008). CONCLUSIONS:Although the majority of ANEN cannot be identified in pre-appendectomy imaging, 35% of cases demonstrate the presence of solid tissue in the appendiceal lumen. This finding may distinguish these patients from those with simple appendicitis and should lead to early surgical intervention, or close and more cautious surveillance if a conservative approach is chosen.

The circadian clock gene system plays a pivotal role in coordinating the daily rhythms of most metabolic processes. It is synchronized with the light-dark cycle and the eating-fasting schedule. Notably, the interaction between meal timing and circadian clock genes (CGs) allows for optimizing metabolic processes at specific times of the day. Breakfast has a powerful resetting effect on the CG network. A misaligned meal pattern, such as skipping breakfast, can lead to a discordance between meal timing and the endogenous CGs, and is associated with obesity and T2D. Conversely, concentrating most calories and carbohydrates (CH) in the early hours of the day upregulates metabolic CG expression, thus promoting improved weight loss and glycemic control. Recently, it was revealed that microorganisms in the gastrointestinal tract, known as the gut microbiome (GM), and its derived metabolites display daily oscillation, and play a critical role in energy and glucose metabolism. The timing of meal intake coordinates the oscillation of GM and GM-derived metabolites, which in turn influences CG expression, playing a crucial role in the metabolic response to food intake. An imbalance in the gut microbiota (dysbiosis) can also reciprocally disrupt CG rhythms. Evidence suggests that misaligned meal timing may cause such disruptions and can lead to obesity and hyperglycemia. This manuscript focuses on the reciprocal interaction between meal timing, GM oscillation, and circadian CG rhythms. It will also review studies demonstrating how aligning meal timing with the circadian clock can reset and synchronize CG rhythms and GM oscillations. This synchronization can facilitate weight loss and improve glycemic control in obesity and those with T2D.

Pancytopenia is defined as a reduction in red blood cells, white blood cells, and platelets, and can pose as a diagnostic challenge due to the multitude of causes. Myxedema coma is the manifestation of severe untreated hypothyroidism. This case report presents a rare instance of myxedema coma-associated pancytopenia in a 53-year-old man with a history of untreated hypothyroidism. The patient presented with altered mental status and vital instability, and on further workup was found to have pancytopenia. During his hospital stay his symptomatic hypothyroidism was identified, and he was treated with intravenous levothyroxine, hydrocortisone, and supportive care. The patient’s clinical status improved gradually, with normalized blood counts upon discharge. This case underscores the significance of considering myxedema coma in the differential diagnosis of pancytopenia, especially in older patients with limited healthcare access. Increased awareness of this association can aid clinicians in timely diagnosis and management, preventing potential complications associated with untreated hypothyroidism.

OBJECTIVE:Diabetic ketoacidosis (DKA) is a rare side effect related to sodium-glucose cotransporter-2 inhibitors (SGLT2I). This study investigated the incidence of people with diabetes hospitalized because of DKA after the implementation of SGLT2I (2015-2019), compared with the pre-SGLT2I era.METHODS:In this retrospective cohort study, medical records of all adult patients hospitalized with a diagnosis of DKA in a tertiary referral center from 2011-2019 were reviewed. The incidence of DKA was compared between the periods 2011-2014 and 2015-2019. Demographic and clinical data of patients hospitalized with DKA as well as SGLT2I use were extracted.RESULTS:During 2011-2019, there were 186 hospitalizations because of DKA. The rate of hospitalization was stable during 2011-2019 at 0.22% ± 0.04% (95% CI, 0.18-0.25). The clinical characteristics of people hospitalized with DKA in 2011-2014 were similar to those of people hospitalized during 2015-2019. Only 7 people (6.1%) in the 2015-2019 cohort had SGLT2I-related DKA, and their clinical characteristics were similar to those of the rest of the cohort.CONCLUSIONS:The rate of hospitalizations because of DKA remained stable before and 5 years after SGLT2I were implemented for the treatment of type 2 diabetes mellitus. Larger, multi-institutional studies with longer follow-ups are needed to study the effect of SGLT2I on the rate of hospitalizations because of DKA among people with diabetes. Although DKA events associated with SGLT2I are rare, they should be strongly considered in the differential diagnosis of people treated with these medications.

Introduction Although appendicitis occurs in approximately 1:1000 pregnancies, appendiceal neuroendocrine neoplasm (ANEN) diagnosis during pregnancy is very rare. Data on presentation, treatment and prognosis is scarce. Aim To describe ANEN cases diagnosed during pregnancy. Materials and methods A retrospective appraisal of 7 consecutive ANEN patients diagnosed during pregnancy from four Israeli tertiary medical centers and comparison with 17 cases described in the literature from 1965-2021. Results Age at ANEN diagnosis was 26.4 ± 3.5 years (range 21-33). Patients were diagnosed between gestational weeks 6-40, most frequently in the third trimester (53%). The most common presenting symptom was abdominal pain. Tumor size was 14.3 ± 8.9mm (range 3-45mm). In patients from our series appendiceal base involvement was reported in 2/7; mesoappendiceal invasion in 5/7; lympho-vascular invasion in 2/7. Ki67 staining was reported in 6/7 cases and ranged from 1-10%. Pathology details were lacking in most of the previously published cases. All 7 pregnancies in our series resulted in term delivery with no complications, whereas in historical cases there were one first trimester abortion, one ectopic pregnancy, and one stillbirth. Right hemicolectomy was performed in 5/7 patients in our series and reported in 2/17 historical cases. All hemicolectomies were performed after delivery, 3-16 months after appendectomy. Local metastases were reported in two cases. Follow-up duration was 7-98 months for our patients and 3-48 months in 5 historical cases. No disease recurrence, distant metastases or mortality were noted. Conclusions To the best of our knowledge, this is the largest series describing the extremely rare diagnosis of ANEN during pregnancy. Although pathologic characteristics varied, pregnancy outcomes were usually favorable and long-term prognosis was excellent. This data may suggest that a conservative approach to patients with ANEN diagnosis during pregnancy can be considered.

The trend of fasting until noon (omission or delayed breakfast) is increasingly prevalent in modern society. This eating pattern triggers discordance between endogenous circadian clock rhythms and the feeding/fasting cycle and is associated with an increased incidence of obesity and T2D. Although the underlying mechanism of this association is not well understood, growing evidence suggests that fasting until noon, also known as an "extended postabsorptive state", has the potential to cause a deleterious effect on clock gene expression and to disrupt regulation of body weight, postprandial and overall glycemia, skeletal muscle protein synthesis, and appetite, and may also lead to lower energy expenditure. This manuscript overviews the clock gene-controlled glucose metabolism during the active and resting phases and the consequences of postponing until noon the transition from postabsorptive to fed state on glucose metabolism, weight control, and energy expenditure. Finally, we will discuss the metabolic advantages of shifting more energy, carbohydrates (CH), and proteins to the early hours of the day.

Background: Cytological limitations pose a challenge to preoperative diagnosis of medullary thyroid carcinoma (MTC) and therefore, a significant subset of patients is only diagnosed postoperatively. The objective of this study was to investigate the impact of knowledge of a preoperative MTC diagnosis on disease management and outcomes.Methods: Multicenter, retrospective, cohort study of MTC patients treated in Israel from January 2000 to June 2021. We compared cohorts of patients according to the presence or absence of a preoperative MTC diagnosis.Results: Ninety-four patients with histologically confirmed MTC were included (mean age 56.2 +/- 14.3 years, 43% males). Fifty-three patients (56%) had a preoperative MTC diagnosis (preop-Dx group), and 41 (44%) were confirmed only postoperatively (no-Dx group). The extent of surgical resection, including completion procedures, was as follows: total thyroidectomy in 83% versus 100% (p = 0.002), central lymph node dissection (LND) in 46% versus 98% (p < 0.001), ipsilateral lateral LND in 36% versus 79% (p < 0.001), and contralateral lateral LND in 17% versus 28% (NS), in the no-Dx versus the preop-Dx group, respectively. Pathology confirmed a smaller median tumor size of 16 +/- 17.4 mm versus 23 +/- 14.0 mm (p = 0.09), a higher proportion of micro-MTC (size <= 10 mm) 32% versus 15% (p = 0.03), and a higher rate of co-occurrence of follicular cell-derived carcinoma 24% versus 4% (p = 0.003), in the no-Dx compared to the preop-Dx group, respectively. The rates of extrathyroidal and extranodal tumor extension were not significantly different between the groups. At the last follow-up, the biochemical cure was attained in 55% [CI 0.38-0.71] compared to 64% [CI 0.50-0.77] of the no-Dx and the preop-Dx group, respectively (p = 0.41). After the exclusion of patients with micro-MTC, biochemical cure was more commonly achieved in the preop-Dx group (33% [CI 0.14-0.52] vs. 62% [CI 0.46-0.77], p = 0.04). Preop-Dx patients had improved overall survival compared to the no-Dx group (log-rank p = 0.04) over a median follow-up of 82 months (interquartile range [IQR] 30-153).Conclusions: Preoperatively, the diagnosis of MTC is often missed. An accurate preoperative diagnosis of MTC may enable guideline-concordant surgical treatment and ultimately contribute to an overall survival benefit in MTC patients.

ObjectiveTo determine genealogical, clinical and pathological characteristics of a cohort with Cys618Arg mutation from an Israeli multicenter MTC study.MethodsRetrospective database analysis examining RET mutations and comparing Cys618Arg and Cys634Arg/Thr/Tyr subgroups.ResultsGenetic testing was performed in 131/275 MTC patients (47.6%). RET mutations were found in 50/131 (38.2%), including Cys618Arg (28/50 cases,56%), and Cys634Arg/Thr/Tyr (15/50,30%). Through genealogical study, 31 MTC patients were found descendants of one family of Jewish Moroccan descent, accounting for 27/28 patients with documented Cys618Arg mutation and 4 patients without available genetic testing. Familial Cys618Arg cases (n=31) and Cys634Arg/Thr/Tyr cases (n=15, from 6 families) were compared. Although surgical age was similar (25.7 vs 31.3 years, p=0.19), the Cys618Arg group had smaller tumors (8.9mm vs 18.5mm, p=0.004) and lower calcitonin levels (33.9 vs 84.5 X/ULN, p=0.03). Youngest ages at MTC diagnosis were 8 and 3 years in Cys618Arg and Cys634Arg/Thr/Tyr cohorts, respectively. Long-term outcome was similar between groups. The Cys618Arg cohort had lower rates of pheochromocytoma (6.5% vs 53.3%, p=0.001) and primary hyperparathyroidism (3.2% vs 33.3%, p=0.01).ConclusionThis is the first description of RET mutation distribution in Israel. Of 131 tested MTC patients, Cys618Arg was the predominant mutation. To the best of our knowledge, this is the largest cohort of Cys618Arg mutation described. For Cys618Arg and Cys634Arg/Thr/Tyr cohorts, MTC was diagnosed earlier than expected, likely due to familial genetic screening, and MTC outcomes were similar between groups. International studies are necessary to further characterize the clinical features of Cys618 mutations due to their relative rarity.

Background Whole-body scan (WBS) is indicated for selected patients in the follow-up of differentiated thyroid cancer (DTC). Aim The aim of this study was to evaluate the incidence of positive WBS in patients with negative stimulated thyroglobulin (sTg), to define the clinical characteristics of this group, and the association with disease outcome. Methods DTC patients who underwent surveillance with simultaneous sTg and WBS were included. Results Two hundred seventy-two patients were included. Age at diagnosis was 46.5 +/- 15.2 years, 79% were female. Mean duration of follow-up was 11.6 +/- 6.8 years. Patients were categorised according to stimulation test results: sTg(-)/WBS(-) in 192/272 (70.6%); sTg(+) regardless of WBS results in 33/272 (12.1%); and sTg(-)/WBS(+) in 47/272 (17.3%) subjects. sTg > 10 mg/dl was considered positive. The three groups had similar demographic and pathologic characteristics. During follow-up, additional treatment was given in 77 patients (28.3%). Twelve (4.4%) developed distant metastases; 16 patients (5.8%) died. No deaths were disease-related. There was no difference in mortality rate between categories (P = 0.182). On multivariate analysis, additional treatment was associated with male gender (P = 0.046) and positive stimulation test results, either sTg (P < 0.001) or WBS (P < 0.001). Of the 47 WBS(+)/sTg(-) patients, 7(15%) were treated due to positive WBS results, including two who underwent additional surgery. Conclusion A substantial proportion of stimulation test results were discordant. There was a significant association between WBS results and administration of additional treatment. Routine WBS had additional value for a small proportion of patients with no other evidence for disease and no indication for WBS.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Stefano Partelli , Sara Massironi , Alessandro Zerbi, Patricia Niccoli, Wooil Kwon , Luca Landoni, Francesco Panzuto, Ales Tomazic, Alberto Bongiovanni, Gregory Kaltsas, Alain Sauvanet, Emilio Bertani, Vincenzo Mazzaferro , Martyn Caplin, Thomas Armstrong, Martin O. Weickert, John Ramage, Eva Segelov , Giovanni Butturini, Stefan Staettner, Mauro Cives, Andrea Frilling, Carol Anne Moulton, Jin He , Florian Boesch, Andreas Selberheer, Orit Twito, Antonio Castaldi , Claudio G. De Angelis, Sebastien Gaujoux , Katharina Holzer, Colin H. Wilson, Hussein Almeamar, Emanuel Vigia, Francesca Muffatti, Martina Lucà, Andrea Lania, Jacques Ewald, Hongbeom Kim , Roberto Salvia, Maria Rinzivillo, Alojz Smid, Andrea Gardini, Marina Tsoli, Olivia Hentic, Samuele Colombo, Davide Citterio, Christos Toumpanakis, Emma Ramsey, Harpal S. Randeva, Ray Srirajaskanthan, Daniel Croagh, Paolo Regi, Silvia Gasteiger, Pietro Invernizzi, Cristina Ridolfi, Marc Giovannini, Jin-Young Jang, Claudio Bassi and Massimo Falconi*

Objective: Anemia is a known complication of diabetes mellitus (DM); however, its prevalence and prognostic relevance in patients with DM and pre-DM with normal kidney function have not been well defined. This study assessed the prevalence of anemia in patients with DM and pre-DM and evaluated its association with clinical outcomes during a 4-year follow-up period. Methods: This retrospective analysis included patients with DM and pre-DM referred to the Meir Medical Center Endocrine Institute in 2015. Patients with an estimated glomerular filtration rate (eGFR) of <60 mL/min or any other recognized cause of anemia were excluded. The risk of developing microvascular or macrovascular complications or of death during the 4-year follow-up period was determined. Results: A total of 622 patients (408 with DM and 214 with pre-DM) were included. The mean age of the patients was 64 +/- 10.6 years, and 70% were women. The baseline hemoglobin A1C level was 7.1% +/- 1.7% (54 mmol/mol), and the eGFR was 86.1 +/- 15.3 mL/min. At the time of inclusion, 77 patients (19%) with DM and 23 (11%) with pre-DM had anemia (hemoglobin level 11.9 +/- 0.8 and 11.8 +/- 0.8 g/dL, respectively), compared with normal hemoglobin levels of 13.8 +/- 0.9 and 13.7 +/- 0.9 g/dL, respectively, in the others. A multivariable analysis demonstrated an inverse correlation between baseline hemoglobin (as a continuous variable) and mortality (P = .035), microvascular complications (P = .003), and eGFR decline (P < .001) but not between baseline hemoglobin and macrovascular complications (P = .567). Conclusion: This study found a significant prevalence of anemia unrelated to renal failure, both in patients with DM and pre-DM. Anemia in these patients is associated with the development of microvascular complications, eGFR decline, and mortality. These results underscore the need for intensive lifestyle and pharmacologic interventions in these patients. (c) 2021 AACE. Published by Elsevier Inc. All rights reserved.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Background Although patients with diabetes mellitus (DM) are at higher risk of hip fracture, data regarding the effect of DM on rehabilitation outcomes are limited.Methods A retrospective single-centre study was conducted comparing elderly diabetic and non-diabetic patients with recent hip fracture, admitted to geriatric rehabilitation, 2014–2019. The functional independence measure (FIM) was used to assess physical and cognitive function. Delta-FIM was calculated by subtracting admission FIM from discharge FIM. One-year mortality, hospitalizations and fractures were assessed.Results Six-hundred-thirty elderly patients, post-hip fracture were included, mean age 83 ± 7 years, 70.5% (444) women. Among them, 193 (30.6%) had type 2 DM, HbA1c 6.6 ± 1.25%. They were younger (81.4 vs. 84.3 years, p < .01) and had more co-morbidities including hypertension, chronic kidney disease, ischaemic heart disease and cerebrovascular disease. Baseline cognitive and motor scores were similar between groups. Delta motor-FIM was similar between diabetics and non-diabetics (15.56 ± 8.95 and 14.78 ± 8.79, respectively, p = .35). Multivariate regression analysis showed motor-FIM improvement was associated with higher BMI, male sex, and younger age, but not with DM. Cognitive FIM did not change significantly during rehabilitation in either group. Similar rates of patients were discharged to nursing care facilities. There was no difference in 1-year hospitalization or fracture rates. One-year, all-cause mortality was higher among diabetic patients (10.9 vs. 6.6%, respectively, p = .07). After adjusting for covariates, DM was associated with higher mortality risk (odds ratio = 2.78, 95% CI [1.28, 6.04], p = .01).Conclusions Patients with well-controlled DM have similar post-hip fracture rehabilitation potential compared with non-diabetics, despite more co-morbidities. These results support resource allocation for post-hip fracture rehabilitation among patients with DM. The higher 1-year all-cause mortality in patients with DM reinforces the need for close follow-up and control of co-morbidities in this population.