The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention.

Maintenance of proper levels of the methyl donor S-adenosylmethionine (SAM) is critical for a wide variety of biological processes. We demonstrate that the N6-adenosine methyltransferase METTL16 regulates expression of human MAT2A, which encodes the SAM synthetase expressed in most cells. Upon SAM depletion by methionine starvation, cells induce MAT2A expression by enhanced splicing of a retained intron. Induction requires METTL16 and its methylation substrate, a vertebrate conserved hairpin (hp1) in the MAT2A 3' UTR. Increasing METTL16 occupancy on the MAT2A 3' UTR is sufficient to induce efficient splicing. We propose that, under SAM-limiting conditions, METTL16 occupancy on hp1 increases due to inefficient enzymatic turnover, which promotes MAT2A splicing. We further show that METTL16 is the long-unknown methyltransferase for the U6 spliceosomal small nuclear RNA (snRNA). These observations suggest that the conserved U6 snRNA methyltransferase evolved an additional function in vertebrates to regulate SAM homeostasis.

Recent Trends in Admission Diagnosis and Related Mortality in the Medically Critically Ill.

PURPOSE: With decades of declining ICU mortality, we hypothesized that the outcomes and distribution of diseases cared for in the ICU have changed and we aimed to further characterize them. STUDY DESIGN AND METHODS: A retrospective cohort analysis of 287,154 nonsurgical-critically ill adults, from 237 U.S. ICUs, using the manually abstracted Cerner APACHE Outcomes database from 2008 to 2016 was performed. Surgical patients, rare admission diagnoses (<100 occurrences), and low volume hospitals (<100 total admissions) were excluded. Diagnoses were distributed into mutually exclusive organ system/disease-based categories based on admission diagnosis. Multi-level mixed-effects negative binomial regression was used to assess temporal trends in admission, in-hospital mortality, and length of stay (LOS). RESULTS: The number of ICU admissions remained unchanged (IRR 0.99, 0.98-1.003) while certain organ system/disease groups increased (toxicology [25%], hematologic/oncologic [55%] while others decreased (gastrointestinal [31%], pulmonary [24%]). Overall risk-adjusted in-hospital mortality was unchanged (IRR 0.98, 0.96-1.0004). Risk-adjusted ICU LOS (Estimate -0.06 days/year, -0.07 to -0.04) decreased. Risk-adjusted mortality varied significantly by disease. CONCLUSION: Risk-adjusted ICU mortality rate did not change over the study period, but there was evidence of shifting disease burden across the critical care population. Our data provides useful information regarding future ICU personnel and resource needs.

National Trends and Variation of Functional Status Deterioration in the Medically Critically Ill.

OBJECTIVES: Physical and psychologic deficits after an ICU admission are associated with lower quality of life, higher mortality, and resource utilization. This study aimed to examine the prevalence and secular changes of functional status deterioration during hospitalization among nonsurgical critical illness survivors over the past decade. DESIGN: We performed a retrospective longitudinal cohort analysis. SETTING: Analysis performed using the Cerner Acute Physiology and Chronic Health Evaluation outcomes database which included manually abstracted data from 236 U.S. hospitals from 2008 to 2016. PATIENTS: We included nonsurgical adult ICU patients who survived their hospitalization and had a functional status documented at ICU admission and hospital discharge. Physical functional status was categorized as fully independent, partially dependent, or fully dependent. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Functional status deterioration occurred in 38,116 patients (29.3%). During the past decade, functional status deterioration increased in each disease category, as well as overall (prevalence rate ratio, 1.15; 95% CI, 1.13-1.17; p < 0.001). Magnitude of functional status deterioration also increased over time (odds ratio, 1.03; 95% CI, 1.03-1.03; p < 0.001) with hematological, sepsis, neurologic, and pulmonary disease categories having the highest odds of severe functional status deterioration. CONCLUSIONS: Following nonsurgical critical illness, the prevalence of functional status deterioration and magnitude increased in a nationally representative cohort, despite efforts to reduce ICU dysfunction over the past decade. Identifying the prevalence of functional status deterioration and primary etiologies associated with functional status deterioration will elucidate vital areas for further research and targeted interventions. Reducing ICU debilitation for key disease processes may improve ICU survivor mortality, enhance quality of life, and decrease healthcare utilization.

Balance between MAT2A intron detention and splicing is determined cotranscriptionally.

Transcriptome analysis of human cells has revealed that intron retention controls the expression of a large number of genes with diverse cellular functions. Detained introns (DI) constitute a subgroup of transcripts with retained introns that are not exported to the cytoplasm but instead remain in the nucleus. Previous studies reported that the splicing of DIs in the CLK1 transcript is post-transcriptionally induced to produce mature mRNA in the absence of new transcription. Thus, CLK1-DI serves as a precursor or "reservoir" for the CLK1 mRNA. However, whether this is a universal mechanism for gene regulation by intron detention remains unknown. The MAT2A gene encodes S-adenosylmethionine (SAM) synthetase and it contains a DI that is regulated in response to intracellular SAM levels. We used three independent assays to assess the precursor-product relationship between MAT2A-DI and MAT2A mRNA. In contrast to CLK1-DI, these data support a model in which the MAT2A-DI transcript is not a precursor to mRNA but is instead a "dead-end" RNA fated for nuclear decay. Additionally, we show that in SAM-deprived conditions the cotranscriptional splicing of MAT2A detained introns increases. We conclude that polyadenylated RNAs with DIs can have at least two distinct fates. They can serve as nuclear reservoirs of pre-mRNAs available for rapid induction by the cell, or they constitute dead-end RNAs that are degraded in the nucleus.

Respiratory Tract Colonization by Candida species Portends Worse Outcomes in Immunocompromised Patients.

BACKGROUND: The significance and clinical management of Candida colonization of the respiratory tract are ill-defined. We now report the frequency of Candida species from the lower respiratory tract in hematopoietic stem cell transplant recipients (HSCT) undergoing bronchoscopy with broncheoalveolar lavage (BAL) for pneumonitis post-HSCT. METHODS: The University of Michigan Clinical Microbiology Lab Database was queried for all respiratory cultures positive for Candida species between 2000-2012. We concurrently performed a retrospective analysis of 515 HSCT recipients with pneumonitis at our institution between 2001-2012. RESULTS: During this twelve-year period, there were 2524 unique Candida isolates (78% Candida albicans). Of the 515 HSCT patients with suspected pneumonitis,127 (24.7%) HSCT subjects were culture positive for a fungal pathogen, with Candida species identified in 27 cases (5.2%). When compared with other HSCT subjects, those cultures positive for Candida had significantly increased mortality (p=0.04). CONCLUSIONS: Candida sp. are commonly cultured from the respiratory tract of HSCT recipients, with increased mortality in affected patients. While there is insufficient evidence for anti-fungal treatment of Candida species colonization, the presence of the yeast may be useful as a surrogate marker of disease severity.

The use of peripheral vasopressors and its implications for hospital medicine.

Vasopressor medications for circulatory shock have historically been administered through central venous catheters due to concern for extravasation injury when given peripherally. However, recent studies have demonstrated the safety of peripheral administration of vasopressor medications at lower doses and for a limited duration. Peripheral use of vasopressors is appealing to both patients and providers, as obtaining central access is an invasive procedure associated with the risk of pneumothorax, bleeding, and infection. Furthermore, waiting to initiate these medications until central access is obtained can lead to delays in care. Conversely, valid concerns remain regarding the risk of tissue extravasation associated with peripheral vasopressors, which can be life and limb threatening. We discuss the guidelines and data for optimal dose, duration, intravenous line (IV) size, IV location, and nursing IV site monitoring for peripheral vasopressors. We then explore adverse events associated with peripheral vasopressors. Finally, we describe how this practice change may impact hospital medicine providers.

High PEEP extubation as guided by esophageal manometry.

The ventilatory management of morbidly obese patients presents an ongoing challenge in the Intensive Care Unit (ICU) as multiple physiologic changes in the respiratory system complicate weaning efforts and make extubation more difficult, often leading to increased time on the ventilator. We report the case of a young adult male who presented to our ICU on two separate occasions with hypoxemic respiratory failure requiring intubation. Esophageal manometry (EM) guided positive end expiratory pressure (PEEP) titration was utilized during both ICU admissions to improve oxygenation and aid in extubation with spontaneous breathing trials performed on higher-than-normal PEEP settings and successful liberation on both occasions.

Physicians' Clinical Behavior During Fluid Evaluation Encounters.

We sought to identify factors affecting physicians' cognition and clinical behavior when evaluating patients that may need fluid therapy. BACKGROUND: Proponents of dynamic fluid responsiveness testing advocate measuring cardiac output or stroke volume after a maneuver to prove that further fluids will increase cardiac output. However, surveys suggest that fluid therapy in clinical practice is often given without prior responsiveness testing. DESIGN: Thematic analysis of face-to-face structured interviews. SETTING: ICUs and medical-surgical wards in acute care hospitals. SUBJECTS: Intensivists and hospitalist physicians. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We conducted 43 interviews with experienced physicians in 19 hospitals. Hospitalized patients with hypotension, tachycardia, oliguria, or elevated serum lactate are commonly seen by physicians who weigh the risks and benefits of more fluid therapy. Encounters are often with unfamiliar patients and evaluation and decisions are completed quickly without involving other physicians. Dynamic testing for fluid responsiveness is used much less often than static methods and fluid boluses are often ordered with no testing at all. This approach is rationalized by factors that discourage dynamic testing: unavailability of equipment, time to obtain test results, or lack of expertise in obtaining valid data. Two mental calculations are particularly influential: physicians' estimate of the base rate of fluid responsiveness (determined by physical examination, chart review, and previous responses to fluid boluses) and physicians' perception of patient harm if 500 or 1,000 mL fluid boluses are ordered. When the perception of harm is low, physicians use heuristics that rationalize skipping dynamic testing. LIMITATIONS: Geographic limitation to hospitals in Minnesota, United States. CONCLUSIONS: If dynamic responsiveness testing is to be used more often in routine clinical practice, physicians must be more convinced of the benefits of dynamic testing, that they can obtain valid results quickly and believe that even small fluid boluses harm their patients.

Patient Outcomes and Unit Composition With Transition to a High-Intensity ICU Staffing Model: A Before-and-After Study.

Provider staffing models for ICUs are generally based on pragmatic necessities and historical norms at individual institutions. A better understanding of the role that provider staffing models play in determining patient outcomes and optimizing use of ICU resources is needed. OBJECTIVES: To explore the impact of transitioning from a low- to high-intensity intensivist staffing model on patient outcomes and unit composition. DESIGN SETTING AND PARTICIPANTS: This was a prospective observational before-and-after study of adult ICU patients admitted to a single community hospital ICU before (October 2016-May 2017) and after (June 2017-November 2017) the transition to a high-intensity ICU staffing model. MAIN OUTCOMES AND MEASURES: The primary outcome was 30-day all-cause mortality. Secondary outcomes included in-hospital mortality, ICU length of stay (LOS), and unit composition characteristics including type (e.g., medical, surgical) and purpose (ICU-specific intervention vs close monitoring only) of admission. RESULTS: For the primary outcome, 1,219 subjects were included (779 low-intensity, 440 high-intensity). In multivariable analysis, the transition to a high-intensity staffing model was not associated with a decrease in 30-day (odds ratio [OR], 0.90; 95% CI, 0.61-1.34; p = 0.62) or in-hospital (OR, 0.89; 95% CI, 0.57-1.38; p = 0.60) mortality, nor ICU LOS. However, the proportion of patients admitted to the ICU without an ICU-specific need did decrease under the high-intensity staffing model (27.2% low-intensity to 17.5% high-intensity; p < 0.001). CONCLUSIONS AND RELEVANCE: Multivariable analysis showed no association between transition to a high-intensity ICU staffing model and mortality or LOS outcomes; however, the proportion of patients admitted without an ICU-specific need decreased under the high-intensity model. Further research is needed to determine whether a high-intensity staffing model may lead to more efficient ICU bed usage.

Successful hemostasis in refractory alveolar hemorrhage using low-dose recombinant activated factor VII.

Diffuse alveolar hemorrhage (DAH) is a life-threatening condition requiring prompt recognition. Conventional therapy, even when initiated early, may not have an immediate effect, and in severe cases, bleeding can persist despite treatment. We report the case of a previously healthy 33-year-old male who developed DAH secondary to granulomatosis with polyangiitis, resulting in respiratory failure and the need for mechanical ventilation. High-dose corticosteroids, plasma exchange, and remission induction with cyclophosphamide failed to control bleeding, leading to severely impaired gas exchange. 20 mcg/kg of systemic recombinant activated Factor VII (rFVIIa), a dose lower than previously reported for management of DAH, resulted in hemostasis and improved oxygenation after only three doses. No complications were observed, and our patient was liberated from ventilatory support eight days later. In the setting of DAH with refractory bleeding, hemostasis may be achievable with a lower dose of rFVIIa than commonly used, potentially mitigating the risk of dose-dependent side effects.

Factors Associated with Mortality in Patients with COVID-19 Receiving Prolonged Ventilatory Support.

Background: Since its emergence in early 2020, coronavirus disease 2019 (COVID-19)-associated pneumonia has caused a global strain on intensive care unit (ICU) resources with many intubated patients requiring prolonged ventilatory support. Outcomes for patients with COVID-19 who receive prolonged intubation (>21 days) and possible predictors of mortality in this group are not well established. Patients and Methods: Data were prospectively collected from adult patients with COVID-19 requiring mechanical ventilation from March 2020 through December 2021 across a system of 11 hospitals. The primary end point was in-hospital mortality. Factors associated with mortality were evaluated using univariable and multivariable logistic regression analyses. Results: Six hundred six patients were placed on mechanical ventilation for COVID-19 pneumonia during the study period, with in-hospital mortality of 40.3% (n = 244). Increased age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.03-1.09), increased creatinine (OR, 1.40; 95% CI, 1.08-1.82), and receiving corticosteroids (OR, 2.68; 95% CI, 1.20-5.98) were associated with mortality. Intubations lasting longer than 21 days (n = 140) had a lower in-hospital mortality of 25.7% (n = 36; p < 0.001). Increasing Elixhauser comorbidity index (OR, 1.12; 95% CI, 1.04-1.19) and receiving corticosteroids (OR, 1.92; 95% CI, 1.06-3.47) were associated with need for prolonged ventilation. In this group, increased age (OR, 1.06; 95% CI, 1.01-1.08) and non-English speaking (OR, 3.74; 95% CI, 1.13-12.3) were associated with mortality. Conclusions: In-hospital mortality in mechanically ventilated patients with COVID-19 pneumonia occurs primarily in the first 21 days after intubation, possibly related to the early active inflammatory process. In patients on prolonged mechanical ventilation, increased age and being non-English speaking were associated with mortality.

Ketamine Infusion for Sedation and Analgesia during Mechanical Ventilation in the ICU: A Multicenter Evaluation.

Methods: We reviewed the electronic medical record of critically ill adults who received a continuous infusion of ketamine for ≥24 hours during invasive mechanical ventilation in three hospitals over a two-year period. We captured data including ketamine indication, dose, unintended effects, and adjustments to coadministered sedatives or opioids. We analyzed these data to determine the incidence of reported unintended effects of ketamine infusion (primary outcome) and changes in exposure to coadministered sedatives or opioids during ketamine use (secondary outcome). Results: 95 mechanically ventilated adults received a ketamine infusion for a median duration of 75 hours (interquartile range [IQR] 44-115) at a mean ± standard deviation (SD) infusion rate of 1.3 ± 0.5 mg/kg/hour for the first 24 hours. At least one unintended effect attributed to ketamine was documented in 24% of cases, most frequently tachycardia (6%) and sialorrhea (6%). Other sedative or opioid infusions were administered with ketamine in 76% and 92% of cases, respectively. Comparing the total amount of sedative or opioid administered in the 24 hours prior to ketamine infusion with the total amount administered during the first 24 hours on ketamine, there were no significant differences in propofol, midazolam, or dexmedetomidine exposure, but the average fentanyl exposure was higher after ketamine (2740 ± 1812 mcg) than before (1975 ± 1860 mcg) (absolute difference 766 mcg, 95% confidence interval [CI] 442 to 1089 mcg). Conclusions: In this multicenter cohort of critically ill, mechanically ventilated adults, ketamine infusion was primarily used as an adjunct to conventional sedative and opioid infusions, with noticeable but unintended effects potentially related to ketamine in nearly one-quarter of cases.

Benefits of collaborative patient care rounds in the intensive care unit.

BACKGROUND: Improving care of critically ill patients requires using an interprofessional care model and care standardisation. OBJECTIVES: Determine whether collaborative patient care rounds in the intensive care unit increases practice consistency with respect to common considerations such as delirium prevention, device use, and indicated prophylaxis, among others. Secondary objective to assess whether collaborative interprofessional format improved nursing perceptions of collaboration. METHODS: Single centre, pre- and post- intervention design. collaborative patient care rounding format implemented in three intensive care units in an academic tertiary care centre. format consisted of scripted nursing presentation, provider checklist of additional practice considerations, and daily priority goals documentation. measurements included nursing participation, consideration of selected practice items, daily goal verbalisation, and nursing perception of collaboration. RESULTS: Pre- and post-intervention measurements indicate gains in consideration of eight of thirteen bundle items (p < 0.05), with the greatest gains seen in nurse-presented items. Increases were observed in verbalisation of daily goals (59.8% versus 89.1%, p < 0.0001), nurse participation (83.9% versus 91.8%, p = 0.056), and nurse collaboration ratings (p < 0.0001). CONCLUSION: This study describes implementation of collaborative patient care rounds with corresponding increases in consideration of selected practice items, verbalisation of daily goals, and perceptions of collaboration.

Discordant Cardiopulmonary Resuscitation and Code Status at Death.

CONTEXT: One fundamental way to honor patient autonomy is to establish and enact their wishes for end-of-life care. Limited research exists regarding adherence with code status. OBJECTIVES: This study aimed to characterize cardiopulmonary resuscitation (CPR) attempts discordant with documented code status at the time of death in the U.S. and to elucidate potential contributing factors. METHODS: The Cerner Acute Physiology and Chronic Health Evaluation (APACHE) outcomes database, which includes 237 U.S. hospitals that collect manually abstracted data from all critical care patients, was queried for adults admitted to intensive care units with a documented code status at the time of death from January 2008 to December 2016. The primary outcome was discordant CPR at death. Multivariable logistic regression models were used to identify patient-level and hospital-level associated factors after adjustment for age, hospital, and illness severity (APACHE III score). RESULTS: A total of 21,537 patients from 56 hospitals were included. Of patients with a do-not-resuscitate code status, 149 (0.8%) received CPR at death, and associated factors included black race, higher APACHE III score, or treatment in small or nonteaching hospitals. Of patients with a full code status, 203 (9.0%) did not receive CPR at death, and associated factors included higher APACHE III score, primary neurologic or trauma diagnosis, or admission in a more recent year. CONCLUSION: At the time of death, 1.6% of patients received or did not undergo CPR in a manner discordant with their documented code statuses. Race and institutional factors were associated with discordant resuscitation, and addressing these disparities may promote concordant end-of-life care in all patients.

Morbidity and Mortality Trends of Pancreatitis: An Observational Study.

Background: Pancreatitis accounts for more than $2.5 billion of healthcare costs and remains the most common gastrointestinal (GI) admission. Few contemporary studies have assessed temporal trends of incidence, complications, management, and outcomes for acute pancreatitis in hospitalized patients at the national level. Methods: We used data from one of the largest hospital-based databases available in the United States, the Healthcare Cost and Utilization Project's (HCUP) State Inpatient Database, from 10 states between 2008 and 2015. We included patients with a diagnosis of acute pancreatitis (ICD-9 CM 577.0). Patient- and hospital-level data were used to estimate incidence and inpatient mortality rates. Results: From 80,736,256 hospitalizations, 929,914 (1.15%) cases of acute pancreatitis were identified, 186,226 (20.2%) of which were caused by gallbladder disease). The median age was 53 years (interquartile range [IQR], 41-67) and 50.8% were men. In-hospital mortality was 2.5% and crude mortality rates declined from 2.9% to 2.0% over the study period. Admission year remained significant after adjusting for patient demographics and comorbidities (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.89-0.90; p < 0.001). Gallbladder disease was associated with decreased odds of mortality (OR, 0.60; 95% CI, 0.57-0.62). Median length of stay was four days (IQR, 2-7) and decreased over time. The rates of surgical and endoscopic interventions were highest in 2011 (peak incidence of 16.1% and 9.5%, respectively) and have been decreasing since. Surgical providers were, on average, more likely than medical providers to perform surgery in both those with and without gallbladder disease etiology (gallbladder disease OR, 7.11; 95% CI, 5.46-9.25; non-gallbladder disease OR, 20.50; 95% CI, 16.81-25.01), endoscopy (gallbladder disease OR, 1.22; 95% CI, 0.87-1.72; non-gallbladder disease OR, 1.60; 95% CI, 1.18-2.16), or both (gallbladder disease OR, 7.00; 95% CI, 5.22-9.37; non-gallbladder disease OR, 8.85; 95% CI, 5.61-13.96). Conclusions: The incidence of pancreatitis, from 2008 to 2015, has increased whereas inpatient mortality (i.e., case fatality) has decreased. Understanding temporal trends in outcomes and management along with provider, hospital, and regional variation can better identify areas for future research and collaboration in managing these patients.

Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis.

BACKGROUND: Type 2 diabetes and obesity, as states of chronic inflammation, are risk factors for severe COVID-19. Metformin has cytokine-reducing and sex-specific immunomodulatory effects. Our aim was to identify whether metformin reduced COVID-19-related mortality and whether sex-specific interactions exist. METHODS: In this retrospective cohort analysis, we assessed de-identified claims data from UnitedHealth Group (UHG)'s Clinical Discovery Claims Database. Patient data were eligible for inclusion if they were aged 18 years or older; had type 2 diabetes or obesity (defined based on claims); at least 6 months of continuous enrolment in 2019; and admission to hospital for COVID-19 confirmed by PCR, manual chart review by UHG, or reported from the hospital to UHG. The primary outcome was in-hospital mortality from COVID-19. The independent variable of interest was home metformin use, defined as more than 90 days of claims during the year before admission to hospital. Covariates were comorbidities, medications, demographics, and state. Heterogeneity of effect was assessed by sex. For the Cox proportional hazards, censoring was done on the basis of claims made after admission to hospital up to June 7, 2020, with a best outcome approach. Propensity-matched mixed-effects logistic regression was done, stratified by metformin use. FINDINGS: 6256 of the 15 380 individuals with pharmacy claims data from Jan 1 to June 7, 2020 were eligible for inclusion. 3302 (52·8%) of 6256 were women. Metformin use was not associated with significantly decreased mortality in the overall sample of men and women by either Cox proportional hazards stratified model (hazard ratio [HR] 0·887 [95% CI 0·782-1·008]) or propensity matching (odds ratio [OR] 0·912 [95% CI 0·777-1·071], p=0·15). Metformin was associated with decreased mortality in women by Cox proportional hazards (HR 0·785, 95% CI 0·650-0·951) and propensity matching (OR 0·759, 95% CI 0·601-0·960, p=0·021). There was no significant reduction in mortality among men (HR 0·957, 95% CI 0·82-1·14; p=0·689 by Cox proportional hazards). INTERPRETATION: Metformin was significantly associated with reduced mortality in women with obesity or type 2 diabetes who were admitted to hospital for COVID-19. Prospective studies are needed to understand mechanism and causality. If findings are reproducible, metformin could be widely distributed for prevention of COVID-19 mortality, because it is safe and inexpensive. FUNDING: National Heart, Lung, and Blood Institute; Agency for Healthcare Research and Quality; Patient-Centered Outcomes Research Institute; Minnesota Learning Health System Mentored Training Program, M Health Fairview Institutional Funds; National Center for Advancing Translational Sciences; and National Cancer Institute.

A Method for Balancing Provider Schedules in Outpatient Specialty Clinics.

Background. Variability in outpatient specialty clinic schedules contributes to numerous adverse effects including chaotic clinic settings, provider burnout, increased patient waiting times, and inefficient use of resources. This research measures the benefit of balancing provider schedules in an outpatient specialty clinic. Design. We developed a constrained optimization model to minimize the variability in provider schedules in an outpatient specialty clinic. Schedule variability was defined as the variance in the number of providers scheduled for clinic during each hour the clinic is open. We compared the variance in the number of providers scheduled per hour resulting from the constrained optimization schedule with the actual schedule for three reference scenarios used in practice at M Health Fairview's Clinics and Surgery Center as a case study. Results. Compared to the actual schedules, use of constrained optimization modeling reduced the variance in the number of providers scheduled per hour by 92% (1.70-0.14), 88% (1.98-0.24), and 94% (1.98-0.12). When compared with the reference scenarios, the total, and per provider, assigned clinic hours remained the same. Use of constrained optimization modeling also reduced the maximum number of providers scheduled during each of the actual schedules for each of the reference scenarios. The constrained optimization schedules utilized 100% of the available clinic time compared to the reference scenario schedules where providers were scheduled during 87%, 92%, and 82% of the open clinic time, respectively. Limitations. The scheduling model's use requires a centralized provider scheduling process in the clinic. Conclusions. Constrained optimization can help balance provider schedules in outpatient specialty clinics, thereby reducing the risk of negative effects associated with highly variable clinic settings.