Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Systematic Review and Network Meta-analysis for the American College of Physicians.

BACKGROUND: Newer diabetes medications may have beneficial effects on mortality, cardiovascular outcomes, and renal outcomes. PURPOSE: To evaluate the effectiveness, comparative effectiveness, and harms of sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, and long-acting insulins as monotherapy or combination therapy in adults with type 2 diabetes mellitus (T2DM). DATA SOURCES: MEDLINE and EMBASE for randomized controlled trials (RCTs) published from 2010 through January 2023. STUDY SELECTION: RCTs lasting at least 52 weeks that included at least 500 adults with T2DM receiving eligible medications and reported any outcomes of interest. DATA EXTRACTION: Data were abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE) were done. DATA SYNTHESIS: A total of 130 publications from 84 RCTs were identified. CoE was appraised using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria for direct, indirect, and network meta-analysis (NMA); the highest CoE was reported. Compared with usual care, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (high CoE) and major adverse cardiovascular events (MACE) (moderate to high CoE), SGLT2 inhibitors reduce progression of chronic kidney disease (CKD) and heart failure hospitalizations and GLP1 agonists reduce stroke (high CoE), and SGLT2 inhibitors reduce serious adverse events and severe hypoglycemia (high CoE). The threshold for minimally important differences, which was predefined with the American College of Physicians Clinical Guidelines Committee, was not met for these outcomes. Compared with usual care, insulin, tirzepatide, and DPP4 inhibitors do not reduce all-cause mortality (low to high CoE). Compared with insulin, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (low to moderate CoE). Compared with DPP4 inhibitors, GLP1 agonists reduce all-cause mortality (moderate CoE). Compared with DPP4 inhibitors and sulfonylurea (SU), SGLT2 inhibitors reduce MACE (moderate to high CoE). Compared with SU and insulin, SGLT2 inhibitors and GLP1 agonists reduce severe hypoglycemia (low to high CoE). LIMITATIONS: Infrequent direct comparisons between drugs of interest; sparse data for NMA on most outcomes; possible incoherence due to differences in baseline patient characteristics and usual care; insufficient data on predefined subgroups, including demographic subgroups, patients with prior cardiovascular disease, and treatment-naive persons. CONCLUSION: In adults with T2DM, SGLT2 inhibitors and GLP1 agonists (but not DPP4 inhibitors, insulin, or tirzepatide) reduce all-cause mortality and MACE compared with usual care. SGLT2 inhibitors reduce CKD progression and heart failure hospitalization and GLP1 agonists reduce stroke compared with usual care. Serious adverse events and severe hypoglycemia are less frequent with SGLT2 inhibitors and GLP1 agonists than with insulin or SU. PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD42022322129).

Cost-Effectiveness of Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Systematic Review of Cost-Effectiveness Studies for the American College of Physicians.

BACKGROUND: In the United States, costs of antidiabetes medications exceed $327 billion. PURPOSE: To systematically review cost-effectiveness analyses (CEAs) of newer antidiabetes medications for type 2 diabetes. DATA SOURCES: Bibliographic databases from 1 January 2010 through 13 July 2023, limited to English. STUDY SELECTION: Nonindustry-funded CEAs, done from a U.S. perspective that estimated cost per quality-adjusted life-year (QALY) gained for newer antidiabetic medications. Two reviewers screened the literature; disagreements were resolved with a third reviewer. DATA EXTRACTION: Cost-effectiveness analyses were reviewed for treatment comparisons, model inputs, and outcomes. Risk of bias (RoB) of the CEAs was assessed using Drummond criteria and certainty of evidence (CoE) was assessed using GRADE (Grading of Recommendations Assessment, Development, and Evaluations). Certainty of evidence was determined using cost per QALY thresholds predetermined by the American College of Physicians Clinical Guidelines Committee; low (>$150 000), intermediate ($50 to $150 000), or high (<$50 000) value per QALY compared with the alternative. DATA SYNTHESIS: Nine CEAs were eligible (2 low, 1 high, and 6 some concerns RoB), evaluating glucagon-like peptide-1 agonists (GLP1a), dipeptidyl peptidase-4 inhibitors (DPP4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucose-dependent insulinotropic peptide agonist (GIP/GLP1a), and insulin. Comparators were metformin, sulfonylureas, neutral protamine Hagedorn (NPH) insulin, and others. Compared with metformin, GLP1a and SGLT2i are low value as first-line therapy (high CoE) but may be of intermediate value when added to metformin or background therapy compared with adding nothing (low CoE). Insulin analogues may be similarly effective but more expensive than NPH insulin (low CoE). The GIP/GLP1a value is uncertain (insufficient CoE). LIMITATIONS: Cost-effectiveness analyses varied in methodological approach, assumptions, and drug comparisons. Risk of bias and GRADE method for CEAs are not well established. CONCLUSION: Glucagon-like peptide-1 agonists and SGLT2i are of low value as first-line therapy but may be of intermediate value when added to metformin or other background therapy compared with adding nothing. Other drugs and comparisons are of low or uncertain value. Results are sensitive to drug effectiveness and cost assumptions. PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD42022382315).

Reporting of Incidental Thyroid Nodules on Chest Computed Tomography and the Impact on Nodule Evaluation: A Retrospective Cohort Study.

Introduction: Thyroid incidentalomas are frequently identified thyroid nodules viewed on nonthyroid dedicated imaging studies. Clinical guidelines recommend evaluation of all thyroid incidentalomas to risk stratify for cancer. This study examined how thyroid incidentalomas are reported on chest computed tomography (CT) and determined the association of reporting location with likelihood of evaluation and risk of long-term outcomes. Methods: Retrospective cohort of 1460 previously identified Veterans with thyroid incidentalomas on chest CT from a single VA institution between 1995 and 2016. Reporting of the incidentaloma was categorized as either in the body of the report alone or in the impression. Demographic data, vital status, thyroid ultrasound, endocrinology consult, thyroid nodule fine needle aspiration, thyroid surgery, thyroid cancer diagnosis, and death from thyroid cancer were abstracted. Results: Among the 1460 Veterans (mean age 70.4 years and 94.9% male) in the cohort, 707 incidentalomas (48.4%) were reported in the impression and 753 (51.6%) were reported in the body section. Veterans with thyroid incidentalomas reported in the impression versus body were significantly more likely to be evaluated within 6 months (35.5% vs. 5.1%; p ≤ 0.001), 12 months (38.5% vs. 6.5%; p ≤ 0.001), and at any time during the follow-up period (47.8% vs. 13.2%; p ≤ 0.001). Veterans with thyroid incidentalomas reported in the impression versus body were more likely to undergo thyroidectomy (18 [2.6%] vs. 6 [0.8%]; p = 0.009), but there was no difference in the proportion of Veterans diagnosed with thyroid cancer (11 [1.6%] vs. 6 [0.8%]; p = 0.18), thyroid-cancer related mortality (4 [0.6%] vs. 1 [0.1%]; p = 0.16), or all-cause mortality (63.2% vs. 66.5%; p = 0.19). Conclusions: Thyroid incidentalomas on chest CT are inconsistently reported and often receive no subsequent evaluation. The location of reporting affects whether clinical evaluation is performed, yet reporting does not affect the proportion of Veterans who died of any cause and may have little effect on the proportion of Veterans who received a diagnosis of thyroid cancer or died from thyroid cancer. These findings suggest that the guideline recommendation to evaluate all thyroid incidentalomas should be reevaluated.

Ectopic Pleural Parathyroid Adenoma Causing Recurrent Primary Hyperparathyroidism.

Ectopic parathyroid glands can cause primary hyperparathyroidism (PHPT) in up to 16% of cases. These can lead to recurrent/persistent PHPT, and multiple cases have been described in the literature. We present a case of a pleural parathyroid adenoma leading to persistent PHPT. The ectopic location of the parathyroid glands is a result of their migration during development and is next to tissues they share a common embryologic origin with. The pleural location of the parathyroid adenoma in our patient was highly unusual, as the pleura have an embryologically distinct origin from the parathyroids. This was likely the result of incomplete removal of a previous mediastinal adenoma or seeding of abnormal cells in the surrounding tissue due to capsular breach (parathyromatosis). These can lead to recurrent/persistent PHPT. Parathyromatosis can lead to the presence of adenomas in highly unusual locations, making diagnosis and treatment difficult. To our knowledge, this is the first reported case in the literature of pleural adenoma causing persistent PHPT.

Prevalence of Thyroid Incidentalomas from 1995 to 2016: A Single-Center, Retrospective Cohort Study.

BACKGROUND: Incidental detection of thyroid nodules on nonthyroid imaging may contribute to increased diagnosis of thyroid cancer. We investigated the prevalence of thyroid incidentalomas across imaging modalities among a predominately male veteran population. METHODS: Thyroid nodules were identified on nonthyroid-directed radiology reports using natural language processing. All reports from 1995 to 2016 for chest computed tomography (CT), carotid ultrasound (US), and neck magnetic resonance imaging (MRI) were reviewed. Individuals with multiple studies were included at their initial study and duplicates removed. RESULTS: A total of 25 763 carotid US, 23 526 chest CTs with contrast, 39 262 noncontrast chest CTs, and 9503 MRIs were reviewed. With duplicates removed, 14 642 carotid US, 12 923 chest CTs with contrast, 17 416 noncontrast chest CTs, and 6926 MRIs were included. Mean age was 66.2 years and 1834 were female (3.53%). Thyroid nodules were reported on 0.84% carotid US, 3.45% MRIs, 5.84% chest CTs with contrast, and 5.14% noncontrast chest CTs. Women had a higher rate of thyroid nodules on MRI (6.46% vs 3.20%, P = .003), chest CT with contrast (9.80% vs 5.72%, P = .007), and noncontrast chest CT (8.77% vs 5.02%, P = .002), but not on carotid US (1.99% vs 0.81%, P = .12). Incidentaloma prevalence increased with age on MRI, chest CT with or without contrast, but not on carotid US, and were more commonly reported from 2007 to 2016 compared to before 2007 across all modalities. CONCLUSIONS: Thyroid incidentalomas are commonly reported, are more common among women, and increase with age. The rate of reported incidental thyroid nodules is increasing, likely contributing to the increase in thyroid cancer.

THYROID STORM WITH COMA IN A PATIENT WITH METASTATIC THYROID CARCINOMA AND GRAVES DISEASE: WON THE BATTLE BUT LOST THE WAR.

OBJECTIVE: To describe the background and events that may precipitate thyroid storm (TS) with coma as well as the course of treatment intervention and our patient's response to treatment. METHODS: We present a case of TS with coma including precipitants, thyroid function tests, thyroid ultrasound, computed tomography findings, course, treatment, and outcome. RESULTS: A 71-year-old woman was hospitalized with back pain and right leg weakness due to a newly diagnosed, 12.4-cm sacral tumor. The tumor had metastasized from poorly differentiated papillary thyroid carcinoma. The patient developed TS characterized by thyrotoxicosis with fever, tachycardia, and mental status change progressing to coma over several days. Treatment including antithyroid drugs, steroids, saturated solution of potassium iodide, L-carnitine, therapeutic plasma exchange, and thyroidectomy reversed the prolonged coma and TS, but left residual flaccid quadriplegia. The patient eventually died. CONCLUSION: This patient presented with multiple rare causes of TS (computed tomography contrast and Graves disease in the setting of high-volume thyroid cancer) and a rare manifestation of TS (coma). The TS included fever, tachycardia, and rapid onset of prolonged coma in the setting of thyrotoxicosis. Precipitants of the TS may have included enlarged thyroid tissue from goiter, distant metastasis, the operation, computed tomography contrast exposure, and high levels of thyroid-stimulating immunoglobulin. Multifaceted treatments, most importantly therapeutic plasma exchange, resolved the coma and TS, but the patient still succumbed to comorbidity. We agree with the Japan Thyroid Association recommendation for therapeutic plasma exchange in patients with TS, especially those in a coma who do not awaken within 24 to 48 hours of starting conventional TS treatment.

SYMPTOMATIC PITUITARY METASTASES: TWO CASE REPORTS WITH CONTRASTING CLINICAL PRESENTATIONS.

OBJECTIVE: To report 2 interesting cases of pituitary metastasis (PM) with differing presentations, and briefly review the literature regarding the incidence, presentation, and natural history of PMs. METHODS: Case report and literature review. RESULTS: Patient 1 had known widely metastatic papillary thyroid cancer and presented with signs and symptoms of anterior pituitary dysfunction. He was found to have an undetectable AM cortisol. Further lab evaluation showed complete anterior panhypopituitarism. Pituitary magnetic resonance imaging (MRI) revealed an infiltrative pituitary lesion, which was presumed to be a meta-static lesion from his thyroid cancer. Patient 2 presented with an acute increase in urinary frequency and polydipsia. Water deprivation testing confirmed central diabetes insipidus (DI). Brain MRI showed an infiltrative pituitary lesion, which was the first sign of recurrent metastatic colon cancer. Subsequently, he developed the rapid onset of complete anterior panhypopituitarism. Review of the literature shows that when PMs produce symptoms, the most common presentation has traditionally been central DI. However, this is shifting as the incidence of anterior dysfunction and cranial nerve abnormalities is rising in more recent reviews. CONCLUSION: Central DI has traditionally been the most common presenting symptom of PM, however symptoms reflective of anterior pituitary dysfunction and cranial nerve abnormalities are being reported with increasing frequency. PM should remain in the differential in any form of pituitary dysfunction.

Feasibility of clinical detection of cervical dysplasia using angle-resolved low coherence interferometry measurements of depth-resolved nuclear morphology.

This study sought to establish the feasibility of using in situ depth-resolved nuclear morphology measurements for detection of cervical dysplasia. Forty enrolled patients received routine cervical colposcopy with angle-resolved low coherence interferometry (a/LCI) measurements of nuclear morphology. a/LCI scans from 63 tissue sites were compared to histopathological analysis of co-registered biopsy specimens which were classified as benign, low-grade squamous intraepithelial lesion (LSIL), or high-grade squamous intraepithelial lesion (HSIL). Results were dichotomized as dysplastic (LSIL/HSIL) versus non-dysplastic and HSIL versus LSIL/benign to determine both accuracy and potential clinical utility of a/LCI nuclear morphology measurements. Analysis of a/LCI data was conducted using both traditional Mie theory based processing and a new hybrid algorithm that provides improved processing speed to ascertain the feasibility of real-time measurements. Analysis of depth-resolved nuclear morphology data revealed a/LCI was able to detect a significant increase in the nuclear diameter at the depth bin containing the basal layer of the epithelium for dysplastic versus non-dysplastic and HSIL versus LSIL/Benign biopsy sites (both p < 0.001). Both processing techniques resulted in high sensitivity and specificity (>0.80) in identifying dysplastic biopsies and HSIL. The hybrid algorithm demonstrated a threefold decrease in processing time at a slight cost in classification accuracy. The results demonstrate the feasibility of using a/LCI as an adjunctive clinical tool for detecting cervical dysplasia and guiding the identification of optimal biopsy sites. The faster speed from the hybrid algorithm offers a promising approach for real-time clinical analysis.

Evaluation of hybrid algorithm for analysis of scattered light using ex vivo nuclear morphology measurements of cervical epithelium.

We evaluate a new hybrid algorithm for determining nuclear morphology using angle-resolved low coherence interferometry (a/LCI) measurements in ex vivo cervical tissue. The algorithm combines Mie theory based and continuous wavelet transform inverse light scattering analysis. The hybrid algorithm was validated and compared to traditional Mie theory based analysis using an ex vivo tissue data set. The hybrid algorithm achieved 100% agreement with pathology in distinguishing dysplastic and non-dysplastic biopsy sites in the pilot study. Significantly, the new algorithm performed over four times faster than traditional Mie theory based analysis.

Wavelet transform fast inverse light scattering analysis for size determination of spherical scatterers.

We present a fast approach for size determination of spherical scatterers using the continuous wavelet transform of the angular light scattering profile to address the computational limitations of previously developed sizing techniques. The potential accuracy, speed, and robustness of the algorithm were determined in simulated models of scattering by polystyrene beads and cells. The algorithm was tested experimentally on angular light scattering data from polystyrene bead phantoms and MCF-7 breast cancer cells using a 2D a/LCI system. Theoretical sizing of simulated profiles of beads and cells produced strong fits between calculated and actual size (r(2) = 0.9969 and r(2) = 0.9979 respectively), and experimental size determinations were accurate to within one micron.

Measuring dilution of microbicide gels with optical imaging.

We present a novel approach for measuring topical microbicide gel dilution using optical imaging. The approach compares gel thickness measurements from fluorimetry and multiplexed low coherence interferometry in order to calculate dilution of a gel. As a microbicide gel becomes diluted at fixed thickness, its mLCI thickness measurement remains constant, while the fluorimetry signal decreases in intensity. The difference between the two measurements is related to the extent of gel dilution. These two optical modalities are implemented in a single endoscopic instrument that enables simultaneous data collection. A preliminary validation study was performed with in vitro placebo gel measurements taken in a controlled test socket. It was found that change in slope of the regression line between fluorimetry and mLCI based measurements indicates dilution. A dilution calibration curve was then generated by repeating the test socket measurements with serial dilutions of placebo gel with vaginal fluid simulant. This methodology can provide valuable dilution information on candidate microbicide products, which could substantially enhance our understanding of their in vivo functioning.

Model of fission yeast cell shape driven by membrane-bound growth factors and the cytoskeleton.

Fission yeast serves as a model for how cellular polarization machinery consisting of signaling molecules and the actin and microtubule cytoskeleton regulates cell shape. In this work, we develop mathematical models to investigate how these cells maintain a tubular shape of approximately constant diameter. Many studies identify active Cdc42, found in a cap at the inner membrane of growing cell tips, as an important regulator of local cell wall remodeling, likely through control of exocyst tethering and the targeting of other polarity-enhancing structures. First, we show that a computational model with Cdc42-dependent local cell wall remodeling under turgor pressure predicts a relationship between spatial extent of growth signal and cell diameter that is in agreement with prior experiments. Second, we model the consequences of feedback between cell shape and distribution of Cdc42 growth signal at cell tips. We show that stability of cell diameter over successive cell divisions places restrictions on their mutual dependence. We argue that simple models where the spatial extent of the tip growth signal relies solely on geometrical alignment of confined microtubules might lead to unstable width regulation. Third, we study a computational model that combines a growth signal distributed over a characteristic length scale (as, for example, by a reaction-diffusion mechanism) with an axis-sensing microtubules system that places landmarks at positions where microtubule tips touch the cortex. A two-dimensional implementation of this model leads to stable cell diameter for a wide range of parameters. Changes to the parameters of this model reproduce straight, bent, and bulged cell shapes, and we discuss how this model is consistent with other observed cell shapes in mutants. Our work provides an initial quantitative framework for understanding the regulation of cell shape in fission yeast, and a scaffold for understanding this process on a more molecular level in the future.

In vivo optical imaging of human vaginal gel thickness distributions with a probe-based, dual-modality instrument.

ABSTRACT. We used a probe-based dual-modality optical imaging instrument to measure in vivo coating thickness distributions of a gel distributed along the vaginal lumen, in a clinical study. The gel was a surrogate for one delivering an anti-HIV topical microbicide. Imaging data from Fourier-domain multiplexed low-coherence interferometry (mLCI) and fluorimetric measurements were compared to assess the feasibility and accuracy of mLCI in measuring in vivo gel coating thickness distributions. In each study session, 3.5 mL of Replens gel was inserted to the vaginal fornix while the participant was supine. The participant either: 1. remained supine (10 or 60 min); or 2. sat up (1 min), stood up (1 min), sat down (1 min) and returned to the supine position; net elapsed time was 10 or 60 min after which the gel distribution was imaged. Local coating thickness distributions were qualitatively and quantitatively similar. Here mLCI did not accurately measure thicker gel coatings (>0.8 mm), a limitation not seen with fluorimetry. However, mLCI is capable of measuring in vivo microbicide gel distributions with resolution on the order of 10 µm, without the need for exogenous contrast agents, and can accurately capture relevant summary coating measures in good agreement with fluorimetry.

Oscillatory dynamics of Cdc42 GTPase in the control of polarized growth.

Cells promote polarized growth by activation of Rho-family protein Cdc42 at the cell membrane. We combined experiments and modeling to study bipolar growth initiation in fission yeast. Concentrations of a fluorescent marker for active Cdc42, Cdc42 protein, Cdc42-activator Scd1, and scaffold protein Scd2 exhibited anticorrelated fluctuations and oscillations with a 5-minute average period at polarized cell tips. These dynamics indicate competition for active Cdc42 or its regulators and the presence of positive and delayed negative feedbacks. Cdc42 oscillations and spatial distribution were sensitive to the amounts of Cdc42-activator Gef1 and to the activity of Cdc42-dependent kinase Pak1, a negative regulator. Feedbacks regulating Cdc42 oscillations and spatial self-organization appear to provide a flexible mechanism for fission yeast cells to explore polarization states and to control their morphology.

Chromium infusion in hospitalized patients with severe insulin resistance: a retrospective analysis.

OBJECTIVE: To investigate the effects of intravenous chromium on serum glucose and insulin infusion rates in hospitalized patients with severe insulin resistance. METHODS: In this retrospective study, we reviewed hospital records from January 1, 2008, to December 1, 2008, to identify patients for whom intravenous chromium was ordered at our academic medical center. To be included, patients were required to demonstrate profound insulin resistance and uncontrolled hyperglycemia (defined as the inability to achieve a blood glucose value less than 200 mg/dL during the 12 hours before chromium was given despite administration of continuous insulin infusion at a rate of 20 or more units/h) and to have received a continuous infusion of chromium chloride at 20 mcg/h for 10 to 15 hours for a total dose of 200 to 240 mcg. RESULTS: Fourteen patients met our inclusion criteria. Over the hour preceding intravenous chromium infusion, the mean ± standard deviation rate of insulin infusion was 31 ± 15 units/h, and blood glucose was 326 ± 86 mg/dL. Twelve hours after the initiation of chromium, these values were 16 ± 16 units/h and 162 ± 76 mg/dL, respectively (P = .011 for difference in mean insulin rate from baseline, P<.001 for difference in mean blood glucose from baseline) and 24 hours after, these values were 12 ± 15 units/h and 144 ± 48 mg/dL, respectively (P<.001 for both). CONCLUSIONS: Intravenous chromium decreases insulin needs and improves glucose control at 12 and 24 hours compared with baseline values. Chromium appears to improve hyperglycemia and insulin resistance in acutely ill patients and represents a potential new therapy. Future prospective randomized controlled trials are needed to confirm these results.

A systems-biology approach to yeast actin cables.

We focus on actin cables in yeast as a model system for understanding cytoskeletal organization and the workings of actin itself. In particular, we highlight quantitative approaches on the kinetics of actin-cable assembly and methods of measuring their morphology by image analysis. Actin cables described by these studies can span greater lengths than a thousand end-to-end actin-monomers. Because of this difference in length scales, control of the actin-cable system constitutes a junction between short-range interactions - among actin-monomers and nucleating, polymerization-facilitating, side-binding, severing, and cross-linking proteins - and the emergence of cell-scale physical form as embodied by the actin cables themselves.

Time-resolved imaging refractometry of microbicidal films using quantitative phase microscopy.

Quantitative phase microscopy is applied to image temporal changes in the refractive index (RI) distributions of solutions created by microbicidal films undergoing hydration. We present a novel method of using an engineered polydimethylsiloxane structure as a static phase reference to facilitate calibration of the absolute RI across the entire field. We present a study of dynamic structural changes in microbicidal films during hydration and subsequent dissolution. With assumptions about the smoothness of the phase changes induced by these films, we calculate absolute changes in the percentage of film in regions across the field of view.