bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Impact of Diabetes and African American Race in COVID-19 Severity
Authors: Arosemena Marilyn A , Pyzer Athalia , Yu Jovian , Flood Blake , Rouhani Sherin , Trujillo Jonathan , Gajewski Thomas , Casimiro Isabel 
Published: May 2021

Abstract
Introduction: COVID-19, an illness caused by the novel coronavirus usually presents as a mild to moderate flu like illness, but can lead to pneumonia, acute respiratory distress syndrome and death in some patients. Since the onset of the COVID-19 pandemic there has been special attention towards patients with diabetes. Not only is diabetes highly prevalent in patients with COVID-19, but diabetes has been reported as a significant predictor of morbidity and mortality. Furthermore, race seems to be a predictor of severity with black people dying at 2.3 times the rate of white people. Methods: Here we performed a retrospective study of 524 cases of COVID-19 at an academic center in Chicago between March 2020 until August 2020. Data were obtained from patients that consented to the study to examine the relationship between diabetes, BMI, age, and race with degree of COVID-19 severity. Not all patients had all clinical and demographic data available. COVID-19 severity was determined using a severity index obtained from the measured SpO2 divided by the FiO2/fraction of inspired oxygen times 100. Numbers ≥ 315 mmHg were defined as low severity with patients generally requiring outpatient care, while 235–314 mm Hg were classified as moderate severity generally requiring inpatient care and≤ 234 mm Hg indicated high severity generally requiring intubation/ICU care. The Pearson correlation coefficient was used for linear correlation analyses. Proportion for categorical values were compared using the Chi squared test, the means for continuous variables were compared using two-tailed t tests or one way ANOVA (with Tukey post-test) for comparisons involving more than two conditions. A multiple linear regression model was used to assess the contribution of different variables. Differences were considered statistically significant at p&lt;0.05 Results: Among 120 patients with an A1c, 55 (46%) patients had diabetes and 65 (54%) did not have diabetes. More patients with a high severity index were seen in the cohort with diabetes compared to those without diabetes (72% compared to 28% p=0.004). Univariate analyses revealed statistically significant positive correlations with higher COVID-19 severity and older age, BMI, and African American race. ANOVA analysis revealed a statistically significant difference between increasing BMI and worse severity category with a BMI mean of 29.3 kg/m2 in the low severity category compared to 34.9 kg/m2 in the moderate severity category (p=0.006). A multi-variate analysis adjusting for all variables revealed that A1c, older age and race were positively associated with higher COVID-19 severity. Conclusion: Increased A1c, older age and race are positively and independently associated with a higher COVID-19 severity index. Further research regarding the relationship between COVID-19 and these associations is urgently needed.
A Case of Autoimmune Hypoglycemia (Insulin Autoimmune Syndrome)
Authors: Mon Myint Myat Su , Htun Kyaw Wynn , Mulla Awais , Moe Khaing , Mukherji Rajat , Kazeem Saka 
Published: May 2021

Abstract
Introduction: Insulin Autoimmune Syndrome (IAS) is a condition caused by Insulin Autoantibody (IAA). IAS was initially reported in 1970 by Yukimasa Hirata from Japan. From 1970 to 2009, 380 cases were reported worldwide. We report a case of IAS in an African-American man who had recurrent episodes of syncope secondary to hypoglycemia. Case Report: A 50-year-old African American man with hypertension presented to emergency room after syncope. His initial blood glucose (BG) was 27 mg/dl. After Dextrose and glucagon injection, BG became 270 and he regained consciousness without any deficit. Vital signs and physical examination were unremarkable. He was not on any medication, and had no access to insulin or oral hypoglycemic agents. No family history of endocrine disorders, malignancy or autoimmune diseases were reported. He had been hospitalized two times for syncope secondary to hypoglycemia. During hospitalization, fasting insulin level was &gt;1000 IU/ml with high C-peptide (3.5ng/ml). Hypoglycemic agents assay was negative. During outpatient follow-ups, fasting labs showed C-peptide 1.59 ng/ml, Insulin antibody 37.6 U/ml while venous BG was 65 mg/dl. Random BG at different occasions were 65, 68 and 55 mg/dl. HbA1C was normal. BMI was gradually increased from 32.4 to 34.8 in 6 months. During the third hospitalization, fasting venous BG were 45 and 57 on two different days, Insulin was 2111 IU/ml and C-Peptide was 1.78 ng/ml. Other labs including cortisol and TSH were normal. CT abdomen was unremarkable.
Discussion: In IAS, Insulin secreted after meal is bound by IAA. It causes hyperglycemia unchecked which triggers further insulin secretion. When the bound insulin dissociates from antibodies, it causes significant hyperinsulinemia and subsequent hypoglycemia. IAS can occur regardless of previous insulin exposure, as a solitary autoimmune manifestation or in association with other autoimmune disorders. It can be induced by drugs that contain sulfhydryl group. Etiology of IAS is still not fully understood but there are theories that genetic predisposition such as class II Human Leukocyte Antigen (HLA) and environmental triggers such as medications, viruses, hematological diseases etc. might play a role. In our patient, failure to test IAA in past admissions and lack of continuity of care delayed the diagnosis.
Conclusion: IAS should be considered especially in those who have no clear etiology of hypoglycemia in order to avoid unnecessary diagnostic and therapeutic procedures. Gold standard test for definitive diagnosis is IAA. As IAS is frequently self-remitting, supportive management is usually recommended. In severe cases, pharmacotherapies that reduce insulin secretion and immunosuppressants are occasionally necessary. But there is still no study that compares different treatment measures.
A Case of Diabetic Keto Acidosis From Alpelisib
Authors: Thumma Soumya P , Manchala Venkata R , Motahari Hooman , Shah Aashka M , Menon Lakshmi 
Published: May 2021

Abstract
Introduction: Alpelisib is a phosphatidylinositol-3-kinase (PI3K) inhibitor, approved for the treatment of hormone receptor positive, human epidermal growth factor receptor-2 negative, PIK3CA-mutated metastatic breast cancer. While hyperglycemia is a known side effect of this drug, diabetes ketoacidosis (DKA) is rare. Only one case was previously reported in the literature to our knowledge. Here, we report a patient with prediabetes who presented with DKA after initiation of Alpelisib. Case Presentation: A 48 y.o. woman with metastatic left breast cancer was started on Alpelisib 300mg/day. HbA1C prior to the initiation of Alpelisib was in the prediabetes range at 5.7% with a fasting glucose of 106 mg/dL. Three weeks later, she presented to the ER with abdominal pain, nausea and vomiting. Vitals were notable for sinus tachycardia of 130 bpm. Exam was notable for diminished lung sounds over left lower chest. Labs revealed elevated serum glucose of 302 mg/dL, anion gap metabolic acidosis (anion gap 19, bicarbonate 10) and elevated beta hydroxy butyrate of 7.58 (normal &lt; 0.27 mmol/L) consistent with DKA. Intravenous insulin infusion per DKA protocol was initiated and Alpelisib was held. She was bridged and subsequently transitioned to insulin glargine with insulin lispro sliding scale. Her C-peptide was 1.47 ng/mL (normal 0.90 - 4.30 ng/mL) with negative anti-GAD antibody. She developed multiple episodes of symptomatic hypoglycemia despite reduced insulin doses, requiring eventual discontinuation of insulin, followed by stabilization of blood glucose levels. Subsequent hospital course was complicated by acute respiratory failure from malignant pleural effusion due to which hospice care was initiated. Discussion: Hyperglycemia, diarrhea, nausea and rash are common side effects of PI3K inhibitors. Insulin binds to insulin receptor substrate which activates PI3K, which in turn activates protein kinase B resulting in the translocation of the glucose transporter GLUT4 to the plasma membrane causing glucose uptake. Alpelisib inhibits PI3K resulting in hyperglycemia through decreased glucose uptake. Hyperglycemia was reported in 51–65% of the patients treated with Alpelisib. Patients with prediabetes are at increased risk of worsening hyperglycemia. Hyperosmolar and ketoacidotic states are rare, usually encountered in patients with pre-existing diabetes. DKA can be a presenting manifestation in patients with mildly impaired glucose tolerance as in our case, highlighting the importance of screening for diabetes prior to initiation and monitoring glycemic control during therapy. Once hyperglycemia is detected, prompt initiation of oral hypoglycemic agent metformin (first line) or insulin therapy is recommended depending on the severity of the hyperglycemia. Dose reduction or eventual discontinuation of Alpelisib therapy may be necessary based on the severity of hyperglycemia.
A Novel Homozygous WRN Mutation Identified in a Middle Aged Man With Diabetes Mellitus Complicated By Multiple Features of Accelerated Aging
Authors: Jaafar Batoul , Nasrallah Mona , Oshima Junko , Lessel Davor 
Published: May 2021

Abstract
Background: Werner syndrome (WS; MIM# 277700) is a rare genetic disorder characterized by accelerated aging and predisposition to cancers. The causal gene, WRN, encodes a multifunctional nuclear protein that belongs to the RecQ family of DNA helicases. The earliest sign of WS is short stature due to the lack of pubertal growth spurt. In addition to the aged-appearance, WS patients typically develop functional declines of multiple organs including the endocrine system in their middle ages. Frequent Endocrine disorders include Type 2 Diabetes (T2D), dyslipidemia (DL), hypothyroidism, hypogonadism and osteoporosis. Most common causes of deaths are myocardial infarction and cancers in their 50s. Clinical Case: A 54-year old man was admitted for right wrist septic arthritis. His medical history was pertinent for premature cataract diagnosed in his 2nd decade. He had uncontrolled T2D (peak HbA1C level 10%) since the age of 32 years, treated with oral hypoglycemics including glimepiride, sitagliptin and metformin then shifted to insulin over the past 2 years. He also had DL since the age of 41 years, characterized by hypertriglyceridemia (766 mg/dL) with very low HDL (7 mg/dL). At age 50, he was diagnosed with hypothyroidism and negative anti-TPO antibodies. Moreover, he had refractory bilateral leg ulcers that manifested at the age of 35 years requiring multiple debridments, premature coronary artery disease at the age of 38 years and ischemic cardiomyopathy. On examination, his height was 154 cm and weight 42 kgs. He had prominent eyes, a pinched nose, grey and sparse scalp hair with absence of eyebrows and eyelashes. Hoarse voice was easily noticeable. He had very thin limbs, flat feet, central fat distribution and muscle wasting. Skin was shiny, tight, and atrophic with overlying hypermelanosis. Old bilateral hyperkeratotic deep feet ulcers were noticed with variable necrosis. Blood chemistry testing showed: HbA1C 8.2%, disturbed lipid profile, TG 341 mg/dL, HDL 17 mg/dL, LDL 155 mg/dL, and TSH 21 µU/mL (0.2 - 4.2 µU/mL). MRI of the foot revealed Achilles’ tendon calcification. His parents were 2nd degree cousins and had normal features. Three of his siblings had similar features and premature death. His diabetes was atypical due to his low BMI, high insulin requirements and the relatively early onset. WS was suspected based on the overall features of accelerated aging with characteristic deep leg ulcers and the family history. Genetic sequence analysis revealed a novel pathogenic homozygous nonsense variant mutation c.1111G&gt;T, p.Glu371* of the WRN gene.
Conclusion: Werner syndrome is a rare genetic disease, but it carries high morbidity and mortality burden, in addition to impaired quality of life. It should be highly suspected in patients with atypical T2D, DL, premature coronary disease, refractory leg ulcers with features of accelerated aging and short stature.
Alpelisib-Induced Hyperglycemia- A Small Case Series
Authors: Ekanayake Preethika Subashini , Gerwer Johanna Elizabeth , McCowen Karen Clare 
Published: May 2021

Abstract
The phosphoinositide-3-kinase (PI3K) family consists of highly conserved enzymes that are key intermediaries in signal transduction regulating cell survival and mitogenesis. This axis has been implicated in many types of cancers. In 2019 Alpelisib (Piqray), a reversible inhibitor specific to the PI3Kα subunit, in combination with fulvestrant, was approved to treat hormone receptor positive, human epidermal growth factor receptor 2 (Her2) negative, PI3K mutated breast cancer. This approval followed SOLAR-1 trial results showing a 35% risk reduction in cancer progression or death with alpelisib-fulvestrant compared to placebo in a cohort with PI3K mutated breast cancer. PI3K also plays a critical role in the insulin signaling pathway and alpelisib has been shown to cause a dose dependent rise in plasma glucose, insulin and c-peptide. Here we present a case series of severe hyperglycemia induced by alpelisib.
A 44-year-old woman with ER+/Her2(-)/PI3K positive metastatic breast cancer was started on alpelisib. Previously, HbA1C was 5.4%. Hyperglycemia developed and HbA1c rose to 9.0% within 6 months of alpelisib 300mg daily. She started metformin and empagliflozin, which she was unable to tolerate due to nausea and vomiting. Her self-monitored blood glucoses were 300-400mg/dL within hours after her morning alpelisib dose. We discontinued empagliflozin when she developed metabolic acidosis with an increased anion gap. However, prior to any dose reduction, oncology discontinued alpelisib due to evidence of cancer progression. A week later, her glucoses normalized.
Second case is of a 64-year-old woman with stage IV ER+/Her2(-)/PI3K mutated breast cancer with bony metastases, who was started on alpelisib 250mg. Her prior HbA1C was 5.5%. Ten days after initiation of alpelisib, she developed grade 3 hyperglycemia (blood glucoses 200-500mg/dL). She was started on metformin 2000mg with alpelisib dosed at noon. However, she noted a marked rise in blood glucose in the afternoon, few hours following alpelisib dose. Thus, moving the alpelisib to bedtime allowed better control of glycemia by using overnight basal insulin.
Similarly, a 37-year-old woman with a history of ER+/HER2(-) stage IV metastatic breast cancer to the liver, with PI3K mutation was found to have acute, severe hyperglycemia with blood glucose of 300mg/dL, despite HbA1C being only 4.7%. This was attributed to initiation of alpelisib 2 days prior to admission. Given the severity of her insulin resistance (requiring &gt; 100 units of insulin daily), alpelisib dose was reduced from 300mg to 150mg/day. On discharge, she was placed on metformin, dulaglutide, and basal and prandial insulins. Her HbA1C rose to 9.4% within 3 months of alpelisib initiation.
This case series demonstrate the unique challenges in managing alpelisib induced reversible hyperglycemia.
An Atypical Case of Latent Autoimmune Diabetes of Adults
Authors: Kim Keun Young , Manem Raveena , Sun Chenyu , Qureshi Faisal 
Published: May 2021

Abstract
Introduction: Latent autoimmune diabetes of adults (LADA) is an adult-onset, slowly progressing subtype of autoimmune type 1 diabetes mellitus (T1DM), that is often misdiagnosed as T2DM. We present an atypical case of LADA that was presented in an uncommonly late age with high titres of anti-glutamic acid decarboxylase antibodies(GADA). Clinical Case: A 78 year old male presented with alcohol intoxication and hyperglycemia. His serum glucose was 441mg/dL with negative urine ketones. Arterial blood gas showed pH 7.36, HCO3- 20mmol/L, pCO2 37.1mmHg. Anion gap was 11. HbA1c level was 16%. His body weight was 43.2kg with a BMI of 16.6. He was having polyuria and polydipsia, and was recently diagnosed with T2DM. His low BMI and symptoms raised suspicion for LADA. GADA titres revealed to be greater than 250IU/mL. A diagnosis of LADA was made. He was discharged on insulin. Conclusion: LADA shares the same genetic and autoimmune profiles with T1DM, but its insidious presentation overlaps with that of T2DM, often delaying diagnosis and adequate treatment. Our case of confirmed LADA at a late age of 78 is atypical, but warrants that adults newly diagnosed with diabetes should be screened for LADA if there are atypical findings. Among the anti-islet antibodies, GADAs are the most sensitive self antigen-antibody markers of autoimmune diabetes. The GADA titre is often used to stratify the risk of progression to insulin dependence in LADA, as a higher titre suggests severe β-cell loss in the pancreas. High GADA titres at the time of diagnosis at an elderly age is also an uncommon finding for LADA. Autoimmune diseases with aggressive autoimmune responses present early, while indolent progressions lead to late onset of symptoms and diagnosis. Thus it is unusual for our patient to have significantly high GADA levels. As pathophysiology of LADA is yet to be understood, further research may reveal the autoimmune process of GADA and the role of titres in disease activity and progression. There are no current therapeutic guidelines for LADA. Our patient was eventually discharged on insulin given his high HbA1c with high titres of GADA, but there were questions regarding the use of oral glycemic control agents due to his history of noncompliance. The use of oral agents for LADA remains an area of ongoing research. The general understanding is that due to its autoimmune etiology, insulin is eventually required. Early insulin therapy preserves residual β-cell function, improves glycemic control, and reduces the risk of long-term complications. As treatment goals of LADA would be to improve glycemic control with preserving residual β-cell function, further research may establish treatment guidelines for LADA. Monitoring anti-islet antibodies and c-peptide titres may play a role in establishing the timing to introduce oral agents and/or insulin for optimal treatment of LADA.
Autoimmune Diabetes After Initiation of Nivolumab in a Patient With Hepatocellular Carcinoma
Authors: Cristiano Elizabeth A , Grdinovac Kristine , Bhattacharya Rajib 
Published: May 2021

Abstract
Background: Immune checkpoint inhibitors have become an integral part of oncologic treatment, and their role is rapidly evolving. Nivolumab is an immune checkpoint inhibitor to anti-programmed cell death protein-1 (PD-1), which blocks PD-L1 from binding to PD-1, allowing the T cell to activate. While nivolumab has been shown to improve outcomes in certain malignancies, anti-PD-1 therapy can cause multiple endocrinopathies, including autoimmune diabetes (AD). Case: Here we present a 60-year-old male with a past medical history of end-stage liver disease secondary to hepatitis C and hepatocellular carcinoma (HCC). After undergoing transarterial chemoembolization for HCC, nivolumab was initiated. The patient initially tolerated the immunotherapy well. However, after three cycles, the patient acutely developed nausea, vomiting, lethargy and confusion. On presentation, he was afebrile, blood pressure of 85/46 mmHg, and a heart rate of 92 bpm. Exam was significant for abnormal mentation, and diffuse guarding of the abdomen. Laboratory workup showed hyperglycemia (1,178 mg/dL), positive serum ketones (beta-hydroxybutyrate 11.4 mmol/L), anion gap metabolic acidosis (AG 31, CO2 7 mmol/L), anemia, thrombocytopenia, acute kidney injury, leukocytosis, and elevated lipase. He was admitted to the intensive care unit, and further workup for acute pancreatitis was unrevealing. C-peptide was low (0.8 ng/mL) with corresponding hyperglycemia (1,055 mg/dL). GAD-65, islet cell, and insulin antibodies were undetectable. Hemoglobin A1c was 8.0%. Blood sugars from the previous one and a half years were in normal range. The patient was ultimately diagnosed with DKA and AD secondary to anti-PD-1 therapy. Discussion: This case is representative of AD secondary to nivolumab. While there have been many cases of AD reported after nivolumab, this is the fifth case that has been reported in a patient being treated for HCC. Our patient presented acutely in DKA with no prior diagnosis of diabetes. His antibody testing was undetectable, C-peptide was low in the context of hyperglycemia, and he continued to require insulin therapy until his passing. Prior case reports have demonstrated that the majority of patients with AD related to anti-PD-1 therapy present in DKA, while less than half have detectable diabetes autoantibodies. Specific haplotypes and diabetes autoantibodies have been postulated as risk factors for AD secondary to anti-PD-1 therapy. However, this does not explain the pathology behind a number of patients who have neither of these risk factors. While AD is a rare complication of nivolumab (&lt;1%), this case identifies the need for patients and clinicians to be aware of and discuss the risk of AD after starting nivolumab. Future research is needed to identify risk factors for patients at highest risk of developing AD related to anti-PD-1 therapy and reporting every case encountered is the first step.