Estimating Glycemia From HbA1c and CGM: Analysis of Accuracy and Sources of Discrepancy.

OBJECTIVE: To examine the accuracy of different periods of continuous glucose monitoring (CGM), hemoglobin A1c (HbA1c), and their combination for estimating mean glycemia over 90 days (AG90). RESEARCH DESIGN AND METHODS: We retrospectively studied 985 CGM periods of 90 days with <10% missing data from 315 adults (86% of whom had type 1 diabetes) with paired HbA1c measurements. The impact of mean red blood cell age as a proxy for nonglycemic effects on HbA1c was estimated using published theoretical models and in comparison with empirical data. Given the lack of a gold standard measurement for AG90, we applied correction methods to generate a reference (eAG90) that we used to assess accuracy for HbA1c and CGM. RESULTS: Using 14 days of CGM at the end of the 90-day period resulted in a mean absolute error (95th percentile) of 14 (34) mg/dL when compared with eAG90. Nonglycemic effects on HbA1c led to a mean absolute error for average glucose calculated from HbA1c of 12 (29) mg/dL. Combining 14 days of CGM with HbA1c reduced the error to 10 (26) mg/dL. Mismatches between CGM and HbA1c >40 mg/dL occurred more than 5% of the time. CONCLUSIONS: The accuracy of estimates of eAG90 from limited periods of CGM can be improved by averaging with an HbA1c-based estimate or extending the monitoring period beyond ∼26 days. Large mismatches between eAG90 estimated from CGM and HbA1c are not unusual and may persist due to stable nonglycemic factors.

Hematologic setpoints are a stable and patient-specific deep phenotype.

The complete blood count is an important screening tool for healthy adults and is the most commonly ordered test at periodic physical exams. However, results are usually interpreted relative to one-size-fits-all reference intervals, undermining the goal of precision medicine to tailor medical care to the needs of individual patients based on their unique characteristics. Here we show that standard complete blood count indices in healthy adults have robust homeostatic setpoints that are patient-specific and stable, with the typical healthy adult's set of 9 blood count setpoints distinguishable from 98% of others, and with these differences persisting for decades. These setpoints reflect a deep physiologic phenotype, enabling improved detection of both acquired and genetic determinants of hematologic regulation, including discovery of multiple novel loci via GWAS analyses. Patient-specific reference intervals derived from setpoints enable more accurate personalized risk assessment, and the setpoints themselves are significantly correlated with mortality risk, providing new opportunities to enhance patient-specific screening and early intervention. This study shows complete blood count setpoints are sufficiently stable and patient-specific to help realize the promise of precision medicine for healthy adults.

Computer vision quantitation of erythrocyte shape abnormalities provides diagnostic, prognostic, and mechanistic insight.

Examination of red blood cell (RBC) morphology in peripheral blood smears can help diagnose hematologic diseases, even in resource-limited settings, but this analysis remains subjective and semiquantitative with low throughput. Prior attempts to develop automated tools have been hampered by their poor reproducibility and limited clinical validation. Here, we present a novel, open-source machine-learning approach (denoted as RBC-diff) to quantify abnormal RBCs in peripheral smear images and generate an RBC morphology differential. RBC-diff cell counts showed high accuracy for single-cell classification (mean AUC, 0.93) and quantitation across smears (mean R2, 0.76 compared with experts, interexperts R2, 0.75). RBC-diff counts were concordant with the clinical morphology grading for 300 000+ images and recovered the expected pathophysiologic signals in diverse clinical cohorts. Criteria using RBC-diff counts distinguished thrombotic thrombocytopenic purpura and hemolytic uremic syndrome from other thrombotic microangiopathies, providing greater specificity than clinical morphology grading (72% vs 41%; P < .001) while maintaining high sensitivity (94% to 100%). Elevated RBC-diff schistocyte counts were associated with increased 6-month all-cause mortality in a cohort of 58 950 inpatients (9.5% mortality for schist. >1%, vs 4.7% for schist; <0.5%; P < .001) after controlling for comorbidities, demographics, clinical morphology grading, and blood count indices. RBC-diff also enabled the estimation of single-cell volume-morphology distributions, providing insight into the influence of morphology on routine blood count measures. Our codebase and expert-annotated images are included here to spur further advancement. These results illustrate that computer vision can enable rapid and accurate quantitation of RBC morphology, which may provide value in both clinical and research contexts.

Cardiovascular Risk Assessment Using Artificial Intelligence-Enabled Event Adjudication and Hematologic Predictors.

BACKGROUND: Researchers routinely evaluate novel biomarkers for incorporation into clinical risk models, weighing tradeoffs between cost, availability, and ease of deployment. For risk assessment in population health initiatives, ideal inputs would be those already available for most patients. We hypothesized that common hematologic markers (eg, hematocrit), available in an outpatient complete blood count without differential, would be useful to develop risk models for cardiovascular events. METHODS: We developed Cox proportional hazards models for predicting heart attack, ischemic stroke, heart failure hospitalization, revascularization, and all-cause mortality. For predictors, we used 10 hematologic indices (eg, hematocrit) from routine laboratory measurements, collected March 2016 to May 2017 along with demographic data and diagnostic codes. As outcomes, we used neural network-based automated event adjudication of 1 028 294 discharge summaries. We trained models on 23 238 patients from one hospital in Boston and evaluated them on 29 671 patients from a second one. We assessed calibration using Brier score and discrimination using Harrell's concordance index. In addition, to determine the utility of high-dimensional interactions, we compared our proportional hazards models to random survival forest models. RESULTS: Event rates in our cohort ranged from 0.0067 to 0.075 per person-year. Models using only hematology indices had concordance index ranging from 0.60 to 0.80 on an external validation set and showed the best discrimination when predicting heart failure (0.80 [95% CI, 0.79-0.82]) and all-cause mortality (0.78 [0.77-0.80]). Compared with models trained only on demographic data and diagnostic codes, models that also used hematology indices had better discrimination and calibration. The concordance index of the resulting models ranged from 0.75 to 0.85 and the improvement in concordance index ranged up to 0.072. Random survival forests had minimal improvement over proportional hazards models. CONCLUSIONS: We conclude that low-cost, ubiquitous inputs, if biologically informative, can provide population-level readouts of risk.

Primary Prostatic Carcinoma With De Novo Diffuse Neuroendocrine Differentiation.

The 2016 World Health Organization classification of prostate cancer with neuroendocrine (NE) differentiation includes NE cells in usual prostate cancer, adenocarcinoma with Paneth cell-like NE differentiation, well-differentiated NE tumor (carcinoid), small cell NE carcinoma, and large cell NE carcinoma. In this article, we report a rare case of primary prostatic carcinoma with de novo diffuse NE differentiation presenting with bilateral hydronephrosis in a 79-year-old man. This case did not fit into any of the existing classifications. The clinical, radiological, morphological, and immunohistochemical findings and response to androgen deprivation therapy (ADT) are presented. The proposed pathogenesis of NE differentiation via transdifferentiation from conventional prostatic adenocarcinoma whereby genomic alterations, coupled with ADT can induce lineage plasticity resulting in NE differentiation is described.

Dual Mobility in Total Hip Arthroplasty: Biomechanics, Indications and Complications-Current Concepts.

Dual-mobility (DM) articulations are increasingly utilized to prevent or manage hip instability after total hip arthroplasty (THA). DM cups offer enhanced stability due to the dual articulation resulting in larger jump distance and greater range of motion before impingement. Improvement in design features and biomaterials has contributed to increased interest in dual-mobility articulations due to lower risk of complications compared to their historic rates. The incidence of implant-specific complications like intra-prosthetic dislocation (IPD) and wear has reduced with newer-generation implants. DM THAs are used in primary THA in patients with high risk for dislocation, e.g. neuromuscular disorder, femoral neck fracture, spinopelvic deformity, etc. They offer an attractive alternative option to constrained liner for treatment of hip instability in revision THA. The medium- to short-term results with DM THA have been encouraging in primary and revision THA. However, there are concerns of fretting, corrosion and long-term survivorship with DM THA. Hence, longer-term studies and surveillance are required for the safe use of DM THA in clinical practice.

Association of Red Blood Cell Distribution Width With Mortality Risk in Hospitalized Adults With SARS-CoV-2 Infection.

Importance: Coronavirus disease 2019 (COVID-19) is an acute respiratory illness with a high rate of hospitalization and mortality. Biomarkers are urgently needed for patient risk stratification. Red blood cell distribution width (RDW), a component of complete blood counts that reflects cellular volume variation, has been shown to be associated with elevated risk for morbidity and mortality in a wide range of diseases. Objective: To investigate whether an association between mortality risk and elevated RDW at hospital admission and during hospitalization exists in patients with COVID-19. Design, Setting, and Participants: This cohort study included adults diagnosed with SARS-CoV-2 infection and admitted to 1 of 4 hospitals in the Boston, Massachusetts area (Massachusetts General Hospital, Brigham and Women's Hospital, North Shore Medical Center, and Newton-Wellesley Hospital) between March 4, 2020, and April 28, 2020. Main Outcomes and Measures: The main outcome was patient survival during hospitalization. Measures included RDW at admission and during hospitalization, with an elevated RDW defined as greater than 14.5%. Relative risk (RR) of mortality was estimated by dividing the mortality of those with an elevated RDW by the mortality of those without an elevated RDW. Mortality hazard ratios (HRs) and 95% CIs were estimated using a Cox proportional hazards model. Results: A total of 1641 patients were included in the study (mean [SD] age, 62[18] years; 886 men [54%]; 740 White individuals [45%] and 497 Hispanic individuals [30%]; 276 nonsurvivors [17%]). Elevated RDW (>14.5%) was associated with an increased mortality risk in patients of all ages. The RR for the entire cohort was 2.73, with a mortality rate of 11% in patients with normal RDW (1173) and 31% in those with an elevated RDW (468). The RR in patients younger than 50 years was 5.25 (normal RDW, 1% [n = 341]; elevated RDW, 8% [n = 65]); 2.90 in the 50- to 59-year age group (normal RDW, 8% [n = 256]; elevated RDW, 24% [n = 63]); 3.96 in the 60- to 69-year age group (normal RDW, 8% [n = 226]; elevated RDW, 30% [104]); 1.45 in the 70- to 79-year age group (normal RDW, 23% [n = 182]; elevated RDW, 33% [n = 113]); and 1.59 in those ≥80 years (normal RDW, 29% [n = 168]; elevated RDW, 46% [n = 123]). RDW was associated with mortality risk in Cox proportional hazards models adjusted for age, D-dimer (dimerized plasmin fragment D) level, absolute lymphocyte count, and common comorbidities such as diabetes and hypertension (hazard ratio of 1.09 per 0.5% RDW increase and 2.01 for an RDW >14.5% vs ≤14.5%; P < .001). Patients whose RDW increased during hospitalization had higher mortality compared with those whose RDW did not change; for those with normal RDW, mortality increased from 6% to 24%, and for those with an elevated RDW at admission, mortality increased from 22% to 40%. Conclusions and Relevance: Elevated RDW at the time of hospital admission and an increase in RDW during hospitalization were associated with increased mortality risk for patients with COVID-19 who received treatment at 4 hospitals in a large academic medical center network.

Minimally invasive and standard total knee arthroplasty result in similar clinical outcomes at a minimum of five-year follow-up.

BACKGROUND: Although a minimally invasive total knee arthroplasty (MIS-TKA)fails to show superior short-term clinical results over a standard technique, the longer-term outcomes remain unknown. OBJECTIVE: Evaluate the intermediate clinical outcomes of MIS-TKA, comparing to those of standard technique. MATERIAL AND METHOD: The authors retrospectively collected data from the patients who underwent uncomplicated total knee arthroplasty between March 2004 and December 2005. Patients with a body mass index (BMI) over 30 kg/m2 or with severe deformity and those who required a complex surgical procedure were excluded. Patients were divided into 2 groups based on the surgical approach: 27patients (31 knees) and 26 patients (33 knees) for the MIS-TKA and standard TKA, respectively. Pre- and perioperative data were collected. Clinical and functional outcomes were followed-up to a minimum of 5 years. RESULTS: The means follow-up in the MIS- and standard TKA groups were 73 and 74 months, respectively. Pre- and perioperative data did not show any differences between the two groups except for more females and lower BMI in the MIS-TKA group. At 2- and 5-year post-operative follow-up, the knee society pain and functional scores improved significantly in both groups (p < 0.001). There were no differences in the postoperative alignment, range of motion and the knee society scores between MIS- and standard TKA. In addition, post-operative complications were similar in both groups (2 manipulations under anesthesia and 1 traumatic rupture of patellar tendon in each group). CONCLUSION: The present study showed that there were no differences in the intermediate-term post-operative function between MIS-TKA and standard TKA in a well-selected patient population. Thus, orthopedic surgeons should not compromise their surgical exposure by using small and unfamiliar surgical technique. Since MIS-technique may increase the postoperative complication rate, a long-term study to evaluate the results of MIS-TKA is still needed.

High revision rate after total elbow arthroplasty with a linked semiconstrained device.

The clinical results of semiconstrained total elbow arthroplasty have been encouraging, especially in rheumatoid arthritis. This article presents medium-term clinical results, revision rates, and reasons for revision of a semiconstrained linked total elbow device (Solar Total Elbow; Stryker, Mahwah, New Jersey). We retrospectively reviewed 17 consecutive total elbow arthroplasty patients operated on between February 1994 and March 2001. Thirteen patients were available for clinical evaluation with an average follow-up of 8.4 years (range, 4-12.6 years). The presenting diagnosis was posttraumatic arthritis in 6 patients, rheumatoid arthritis in 6, and gouty arthritis in 1, with an average patient age of 63.4 years. The results were analyzed with regard to complications following the procedure, functional outcome using the Mayo Elbow Performance Score (MEPS), and radiological evaluation at latest follow-up. The mean MEPS improved from 32.1 to 65 at latest follow-up. Three patients had excellent results, 5 had good results, 1 had a fair result, and 4 had poor results. Seven patients required at least 1 revision surgery, including 2 with humeral component loosening, 2 with ulnar component loosening, and 2 with bushing failure. One patient required resection arthroplasty for deep periprosthetic infection. Three patients eventually sustained periprosthetic fractures. Five patients with rheumatoid arthritis and 2 patients with posttraumatic arthritis underwent revision surgery. Poor clinical outcomes and a high revision rate were noted in patients with posttraumatic arthritis. Further comparative studies with other semiconstrained devices are necessary to determine their clinical effectiveness in patients with rheumatoid arthritis.

Age at onset-dependent presentations of premature hip osteoarthritis, avascular necrosis of the femoral head, or Legg-Calvé-Perthes disease in a single family, consequent upon a p.Gly1170Ser mutation of COL2A1.

OBJECTIVE: To identify the genetic abnormality responsible for osteoarthritis (OA), avascular necrosis (AVN) of the femoral head, and Legg-Calvé-Perthes disease in a single family, and to determine factors responsible for the distinct phenotypes manifested by different family members. METHODS: Forty-two members of a 5-generation family were recruited and investigated. Diagnosis was made by independent orthopedic surgeons and radiologists. Histopathologic changes of the diseased tissue were examined. Linkage analysis was performed with markers spanning the COL2A1 locus. Haplotypes were constructed and mutation of the gene was detected. Structures of the wild-type and mutant proteins were modeled. RESULTS: Sixteen affected members were identified (5 with isolated precocious hip OA, 6 with AVN of the femoral head, and 5 with Legg-Calvé-Perthes disease). A p.Gly1170Ser mutation of COL2A1 cosegregated with the 3 diseases and was absent in controls. Of note, age at onset in relation to the closure status of the femoral head epiphysis was associated with the diseases, with Legg-Calvé-Perthes disease presenting prior to closure (at ages 6-14 years), AVN of the femoral head presenting during closure (at ages 15-18 years), and precocious OA of the hip presenting after closure (at ages 21-34 years). Molecular modeling predicted that the serine-to-glycine substitution loosens the helical structure of the protein. CONCLUSION: The p.Gly1170Ser mutation of COL2A1 in the family described is responsible for pathology confined to the hip joint, which presents as isolated precocious hip OA, AVN of the femoral head, or Legg-Calvé-Perthes disease. Age at onset in relation to closure of the femoral head epiphysis appears to be a critical factor in determining disease pattern.

Deep infection of a total knee implant as a complication of disseminated pneumococcal sepsis. A case report and review of literature.

Pneumoccal infection of a total knee replacement is rare. We present a case of hematogeous pneumoccocal infection of a revision total knee arthroplasty as a complication of disseminated pneumoccocal sepsis. The patient was successfully treated with two stage reimplantation in addition to 8 weeks of intravenous moxifloxacin and penicillin, and remains infection free and functions well over 3 years postoperatively.

Comparison of scars from total hip replacements done with a standard or a mini-incision.

UNLABELLED: Scar cosmesis is one of the proposed benefits of mini-incision total hip replacement as opposed to standard-incision procedures; however, there has been no scientific proof of this clinical outcome. The cosmetic appearances of healed incisions of 34 primary total hip replacement procedures done by one surgeon using either a mini-incision (20 procedures) or a standard-length incision (14 procedures) were compared at an average of 2 years postoperatively. Each scar's appearance was graded independently by two plastic surgeons using a standardized rating system. Patients answered a questionnaire regarding their subjective assessment of their scar. The blinded observers found that more mini-scars (six of 20) were rated poor than standard scars (one of 14) and that more standard-incision patients had scars that were rated good. More mini-incision patients (two of 20 versus zero of 14) had wound-healing problems. All the patients thought that their hip scar was acceptable in appearance, but 30 of 31 patients rated the relief of pain and total hip replacement longevity as higher priorities than scar cosmesis. The cosmesis of mini-incision total hip replacement scars may be inferior to standard-incision scars because of skin and soft tissue damage produced by high retractor pressures needed for exposure using a limited skin incision. LEVEL OF EVIDENCE: Therapeutic study, Level II-2 (prospective comparative study). See the Guidelines for Authors for a complete description of levels of evidence.

Comparison of primary total hip replacements performed with a standard incision or a mini-incision.

BACKGROUND: Primary total hip replacement performed through an incision that is

Unconstrained shoulder arthroplasty.

OBJECTIVE: To evaluate the results of 36 unconstrained shoulder arthroplasties. METHODS: In the series, 24 total and 12 hemi-arthroplasties of the shoulders were performed with unconstrained shoulder prostheses in 29 patients who suffered from glenohumeral degenerative arthritis, rheumatoid arthritis, avascular necrosis and proximal fracture of humerus, respectively. Follow-up averaged 6.2 years. All patients were evaluated pre- and post-operatively using the rating system of the Society of American Shoulder and Elbow Surgeons which assesses the severity of pain, strength of muscles around shoulder, stability, range of motion and functional activities of daily living. Radiolucent line and migration of prostheses were observed postoperatively on X-rays. RESULTS: Postoperatively, the rate of pain relief was 91.3%, and active range of motion increased by 47 in forward flexion, 43 in abduction, 30 in external rotation, and 4 segments in internal rotation. Preoperatively the average points of 6 functional activities patients could perform was 0.8, and postoperatively 3.1. On postoperative X-ray, proximal migration of the humerus was seen in 8 shoulders, 6 of which had either a torn or absent rotator cuff. Radiolucent lines were seen around 1 humeral component and 9 glenoid components. One humeral and 2 glenoid components loosened. CONCLUSIONS: These results suggest that unconstrained shoulder arthroplasty is a satisfactory and safe technique.