Medical student intentions to practice internal medicine in underserved areas associated with debt, identity and extracurricular participation.

BACKGROUND: Currently, Internal Medicine (IM) physicians do not reflect the ethno-racial diversity of the US population. Moreover, there is a shortage of IM physicians in Medically Underserved Areas (MUAs) in the US. The purpose of this study was to determine factors that influence medical students' intent to practice IM in MUAs. We hypothesized students with intentions to pursue a career in IM and work in MUAs were more likely than their peers to identify as underrepresented in medicine (URiM), report greater student debt loads, and report medical school experiences in cultural competencies. METHODS: We analyzed de-identified data of 67,050 graduating allopathic medical students who completed the Association of American Medical Colleges' (AAMC) Medical School annual Graduation Questionnaire (GQ) between 2012-2017 by multivariate logistic regression models, examining intent to practice IM in MUAs based on respondent characteristics. RESULTS: Of 8,363 students indicating an intent to pursue IM, 1,969 (23.54%) students also expressed an intent to practice in MUAs. Students awarded scholarships, (aOR: 1.23, [1.03-1.46]), with debt greater than $300,000 (aOR: 1.54, [1.21-1.95], and self-identified non-Hispanic Black/African American (aOR: 3.79 [2.95-4.87]) or Hispanic (aOR: 2.53, [2.05-3.11]) students were more likely than non-Hispanic White students to indicate intent to practice in MUAs. This pattern also existed for students who participated in a community-based research project (aOR: 1.55, [1.19-2.01]), had experiences related to health disparities (aOR: 2.13, [1.44-3.15]), or had experiences related to global health (aOR: 1.75, [1.34-2.28]). CONCLUSIONS: We identified experiences and characteristics that associate with intention to practice IM in MUAs, which can aid future curricular redesign by medical schools to expand and deepen comprehension of health disparities, access to community-based research, and global health experiences. Loan forgiveness programs and other initiatives to increase recruitment and retention of future physicians should also be developed.

Role of Depression in Total Knee Arthroplasty: A Retrospective Analysis of Perioperative Outcomes in Patients in the United States.

We evaluate the patient demographics, perioperative outcomes, in-hospital complications, and assess recent national trends in clinically depressed and non-depressed patients undergoing primary total knee arthroplasty (TKA). Using the National Hospital Discharge Survey from 2001 and 2010, patients undergoing primary TKA in the United States were identified based upon the diagnosis of depression. Differences in gender, patient-demographics, comorbidities, complications, length of stay, and discharge disposition were analyzed. A total of 32,761 TKA patients were identified, consisting of 1,880 patients with a diagnosis of depression and 30,881 patients without. The depression group had an average age significantly younger than the non-depression cohort (p < 0.01). The depression group contained a significantly greater percentage of females when compared to the non-depression group. The non-depression group had a significantly greater percentage of African-Americans (p < 0.01), and a significantly smaller percentage of Caucasians (p < 0.01). Our findings contribute to the literature on the role of depression on perioperative outcomes of TKA. (Journal of Surgical Orthopaedic Advances 30(1):007-009, 2021).

A Comprehensive Review of Analgesia and Pain Modalities in Hip Fracture Pathogenesis.

PURPOSE OF REVIEW: Hip fracture is common in the elderly population, painful and costly. The present investigation was undertaken to review epidemiology, socio-economic and medical implications, relevant anatomy, and anesthetic and pain modalities of hip fracture. RECENT FINDINGS: A literature search of PubMed, Ovid Medline, and Cochrane databases was conducted in December 2018 to identify relevant published clinical trials, review articles, and meta-analyses studies related to anesthetic and pain modalities of hip fracture. The acute pain management in these situations is often challenging. Common issues associated with morbidity and mortality include patients' physiological decrease in function, medical comorbidities, and cognitive impairment, which all can confound and complicate pain assessment and treatment. Perioperative multidisciplinary and multimodal approaches require medical, surgical, and anesthesiology teams employing adequate preoperative optimization. Reduction in pain and disability utilizing opioid and non-opioid therapies, regional anesthesia, patient-tailored anesthetic approach, and delirium prevention strategies seems to ensure best outcomes.

Gender Role in Total Knee Arthroplasty: A Retrospective Analysis of Perioperative Outcomes in US Patients.

BACKGROUND: Women present later than men for total knee arthroplasty (TKA) with more severe osteoarthritic disease but achieve comparable functional improvement and implant survival and also lower rates of revision. Despite these findings, there is significant underutilization of the procedure for women compared to men. METHODS: We conducted a retrospective study to address the lack of information in the literature concerning the immediate and short-term perioperative outcomes between genders. The National Hospital Discharge Survey was evaluated between 2001 and 2010 for men and women undergoing primary TKA in the United States. Differences in gender, patient demographics, comorbidities, complications, length of stay, and discharge disposition were analyzed and identified. RESULTS: The growth in TKA was 145% for men and 131% for women over the 10-year period. Women presented with significantly higher rates of obesity, morbid obesity, postoperative transfusion rate, and length of stay. In contrast, men showed a greater proportion of diabetes, postoperative wound infections, and increased mortality rates. Males were also more likely to be discharged to home, whereas females were more likely to be discharged to rehabilitation facilities. CONCLUSION: Our findings provide important insight into the perioperative outcomes that may be influencing gender disparity in TKA.

Biomechanical evaluation of a central collinear entry reconstruction nail for femoral neck fracture prophylaxis.

INTRODUCTION: Reconstruction nails are commonly used to treat proximal femur fractures, with cephalic screw placement for femoral neck "prophylaxis" becoming standard practice. These implants are traditionally introduced through piriformis fossa (PF) or greater trochanter (GT) entry portals. A third "central collinear" (CC) portal has been proposed that allows entry along the femoral anatomic axis and central placement of cephalic screws. The present study aimed to quantify and compare the CC portal femoral neck strength with the two traditional (PF and GT) entry portals. MATERIALS AND METHODS: Eighteen cadaveric femur specimens (nine matched pairs) were divided into three groups using a balanced incomplete block design to control for variations in age and sex: (1) GT, (2) CC, and (3) PF entry points. Specimens and implants were cut to a standard length and instrumented with straight or valgus bend nails of appropriate laterality and two cephalic screws. Specimens were mounted on a custom jig replicating load distribution along the mechanical axis. A 100 N compressive preload was applied to the femoral head, followed by loading to failure at a rate of 10 mm/s until fracture, indicated by 30 % drop in axial force. RESULTS: THE THREE ENTRY POINTS DID NOT DIFFER IN LOAD-TO-FAILURE: GT (6378.7 ± 1494.9 N), P (6912.4 ± 4924.1 N) and CC (7044.2 ± 2911.4 N) (P = 0.948) or maximum displacement, stiffness, and toughness. Most PF specimens failed at the basicervical neck, whereas most GT specimens failed at the subcapital neck; these differences were not significant. CC specimens failed evenly split between subcapital and basicervical. CONCLUSION: There were no significant difference in femoral neck load-to-failure after placement of a reconstruction nail through a CC entry portal when compared to both GT and PF entry. Clinically, this suggests the CC entry portal is a viable option when clinical considerations warrant its use.

In silico study to recognize novel angiotensin-converting-enzyme-I inhibitors by 2D-QSAR and constraint-based molecular simulations.

Cardiovascular diseases (CVD) such as heart failure, stroke, and hypertension affect 64.3 million people worldwide and are responsible for 30% of all deaths. Primary inhibition of the angiotensin-converting enzyme (ACE) is significant in the management of CVD. In the present study, the genetic algorithm-multiple linear regressions (GA-MLR) method is used to generate highly predictive and statistically significant (R2 = 0.70-0.75, Q2LOO=0.67-0.73, Q2LMO=0.66-0.72, CCCex=0.70-0.78) quantitative structure-activity relationships (QSAR) models conferring to OECD requirements using a dataset of 255 structurally diverse and experimentally validated ACE inhibitors. The models contain simply illustratable Padel, Estate, and PyDescriptors that correlate structural scaffold requisite for ACE inhibition. Also, constraint-based molecular docking reveals an interaction profile between ligands and enzymes which is then correlated with the essential structural features associated with the QSAR models. The QSAR-based virtual screening was utilized to find novel lead molecules from a designed database of 102 thiadiazole derivatives. The Applicability domain (AD), Molecular Docking, Molecular dynamics, and ADMET analysis suggest two compound D24 and D40 are inflexibly linked to the protein binding site and follows drug-likeness properties.Communicated by Ramaswamy H. Sarma.

CMS ESRD quality incentive program has not improved patient dialysis vascular access.

PURPOSE: Over 468,000 patients in the United States use hemodialysis to manage End Stage Renal Disease (ESRD). The purpose of this study was to determine whether the dialysis access Clinical Performance Measures (CPMs) of Centers for Medicare & Medicaid Services (CMS) ESRD Quality Incentive Program (QIP) have increased arteriovenous fistula (AVF) rates and decreased long-term tunneled hemodialysis catheter (TDC) rates among hemodialysis patients in United States. METHODS: Retrospective observational study: evaluated reported AVF and long-term TDC rates of 4804 dialysis facilities which reported dialysis access data as part of the ESRD QIP from Payment Year (PY) 2014-2020. Facilities were also sorted by specific additional criteria to examine disparities in dialysis access. RESULTS: Mean AVF rates of included facilities increased from 63.7% in PY 2014 to 67.2% in PY 2016 (p < 0.05), did not change in PY 2017 (p > 0.05), and declined significantly in PY 2018-2020 to 64.1% in PY 2020, near AVF rates at the inception of program. Long-term TDC rates decreased from 10.4% in PY 2014 to 9.88% in PY 2015 (p < 0.05), then increased in PY 2015-PY 2020 to rates higher than at the inception of program, at 11.8% in PY 2020 (p < 0.05). Facilities serving majority Black ZIP Code Tabulation Areas (ZCTAs) or ZCTAs with median income <$45,000 achieved significantly lower AVF rates (p < 0.05) with no significant difference in long-term TDC rates (p > 0.05). AVF rates correlated positively and long-term TDC rates correlated negatively with star rating of facilities (p < 0.05). CONCLUSION: As one of the first financial QIPs in healthcare, the ESRD QIP has not achieved the stated goals of the CMS to increase AVF access rates above 68% and reduce long-term TDC clinical rates below 10%. Systemic disparities in race, geographic region, economic status, healthcare access, and education of providers and patients prevent successful attainment of goal metrics.

Group A Streptococcal Endometritis and Toxic Shock causing Septic Pelvic Thrombophlebitis and Septic Pulmonary Emboli.

Group A Streptococcus (GAS) in the setting of postpartum endometritis can have severe and life-threatening complications. We report a rare case of septic pulmonary emboli that we surmised to have originated from septic pelvic thrombosis in the setting of GAS toxic shock syndrome (TSS) secondary to postpartum endometritis and intrauterine demise. Although the patient had source control with hysterectomy, she continued to have new septic emboli to the lungs seen on CT scans. CT scan of the pelvis demonstrated several filling defects in the renal and pelvic veins. The patient eventually responded well to anticoagulation in addition to antibiotics, which is similar to cases of Lemierre's syndrome. Additionally, we would like to bring attention to how important radiological findings can be missed if there is lack of interspecialty communication about the patient's clinical situation.

Identification of structural scaffold from interbioscreen (IBS) database to inhibit 3CLpro, PLpro, and RdRp of SARS-CoV-2 using molecular docking and dynamic simulation studies.

A novel coronavirus SARS-CoV-2 has caused a worldwide pandemic and remained a severe threat to the entire human population. Researchers worldwide are struggling to find an effective drug treatment to combat this deadly disease. Many FDA-approved drugs from varying inhibitory classes and plant-derived compounds are screened to combat this virus. Still, due to the lack of structural information and several mutations of this virus, initial drug discovery efforts have limited success. A high-resolution crystal structure of important proteins like the main protease (3CLpro) that are required for SARS-CoV-2 viral replication and polymerase (RdRp) and papain-like protease (PLpro) as a vital target in other coronaviruses still presents important targets for the drug discovery. With this knowledge, scaffold library of Interbioscreen (IBS) database was explored through molecular docking, MD simulation and postdynamic binding free energy studies. The 3D docking structures and simulation data for the IBS compounds was studied and articulated. The compounds were further evaluated for ADMET studies using QikProp and SwissADME tools. The results revealed that the natural compounds STOCK2N-00385, STOCK2N-00244, and STOCK2N-00331 interacted strongly with 3CLpro, PLpro, and RdRp, respectively, and ADMET data was also observed in the range of limits for almost all the compounds with few exceptions. Thus, it suggests that these compounds may be potential inhibitors of selected target proteins, or their structural scaffolds can be further optimized to obtain effective drug candidates for SARS-CoV-2. The findings of in-silico data need to be supported by in-vivo studies which could shed light on understanding the exact mode of inhibitory action.Communicated by Ramaswamy H. Sarma.

Prospecting for Cressa cretica to treat COVID-19 via in silico molecular docking models of the SARS-CoV-2.

The severe acute respiratory syndrome COVID-19 declared as a global pandemic by the World Health Organization has become the present wellbeing worry to the whole world. There is an emergent need to search for possible medications. Cressa cretica is reported to show antitubercular, antibacterial and expectorant property. In this research, we aim to prospect the COVID-19 main protease crystal structure (Mpro; PDB ID: 6LU7) and the active chemical constituents from Cressa cretica in order to understand the structural basis of their interactions. We examined the binding potential of active constituents of Cressa cretica plant to immensely conserved protein Mpro of SARS-CoV-2 followed by exploration of the vast conformational space of protein-ligand complexes by molecular dynamics (MD) simulations. The results suggest the effectiveness of 3,5-Dicaffeoylquinic acid and Quercetin against standard drug Remdesivir. The active chemical constituents exhibited good docking scores, and interacts with binding site residues of Mpro by forming hydrogen bond and hydrophobic interactions. 3,5-Dicaffeoylquinic acid showed the best affinity towards Mpro receptor which is one of the target enzymes required by SARS CoV-2 virus for replication suggesting it to be a novel research molecule. The potential of the active chemical constituents from Cressa cretica against the SARS-CoV-2 virus has best been highlighted through this study. Therefore, these chemical entities can be further scrutinized and provides direction for further consideration for in-vivo and in-vitro validations for the treatment of covid-19. Communicated by Ramaswamy H. Sarma.

Exploring the active constituents of Oroxylum indicum in intervention of novel coronavirus (COVID-19) based on molecular docking method.

The severe acute respiratory syndrome COVID-19 declared a global pandemic by WHO has become the present wellbeing worry to the whole world. There is an emergent need to search for possible medications. We report in this study a molecular docking study of eighteen Oroxylum indicum molecules with the main protease (Mpro) responsible for the replication of SARS-CoV-2 virus. The outcome of their molecular simulation and ADMET properties reveal four potential inhibitors of the enzyme (Baicalein-7-O-diglucoside, Chrysin-7-O-glucuronide, Oroxindin and Scutellarein) with preference of ligand Chrysin-7-O-glucuronide that has the second highest binding energy (- 8.6 kcal/mol) and fully obeys the Lipinski's rule of five. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13721-020-00279-y.

Estimation of benzathine penicillin G demand for congenital syphilis elimination with adoption of dual HIV/syphilis rapid diagnostic tests in eleven high burden countries.

BACKGROUND: WHO recommends use of rapid dual HIV/syphilis tests for screening pregnant women (PW) during antenatal care to prevent mother-to-child transmission. Scale-up of testing implies a need to accurately forecast and procure benzathine penicillin (BPG) to treat the additionally identified PW with syphilis. METHODS: Country-reported ANC coverage, PW syphilis screening and treatment coverage values in 2019 were scaled linearly to EMTCT targets by 2030 (constant increasing slope from 2019 figures to 95% in 2030) for 11 focus countries. Antenatal syphilis screening coverage was substituted with HIV screening coverage to estimate potential contribution of rapid dual HIV/syphilis tests in identifying additional PW with syphilis. BPG demand was calculated for 2019-2030 accordingly. RESULTS: The estimated demand for BPG (in 2.4 million unit vials) using current maternal syphilis prevalence and treatment coverage will increase from a baseline of 414,459 doses in 2019 to 683,067 doses (+65%) in 2021 assuming immediate replacement of single HIV test kits with rapid dual HIV/syphilis tests for these 11 countries. Continued scale up of syphilis screening and treatment coverage to reach elimination coverage of 95% will result in an estimated demand increase of 160%, (663,969 doses) from 2019 baseline for a total demand of 1,078,428 BPG doses by 2030. CONCLUSIONS: Demand for BPG will increase following adoption of rapid dual HIV/syphilis test kits due to increases in maternal diagnoses of syphilis. To eliminate congenital syphilis, MNCH clinical programs will need to synergize with disease surveillance programs to accurately forecast BPG demand with scale up of antenatal syphilis screening to ensure adequate treatment is available for pregnant women diagnosed with syphilis.

Methylprednisolone and 60 Days in Hospital Survival in Coronavirus Disease 2019 Pneumonia.

OBJECTIVES: To determine methylprednisolone's dose, duration, and administration from onset of symptoms and association with 60 days in hospital survival of coronavirus disease 2019 pneumonia. DESIGN: Cohort study. SETTING: Thirteen hospitals in New Jersey, United States during March to June 2020. PATIENTS: Seven-hundred fifty-nine hospitalized coronavirus disease 2019 patients. INTERVENTIONS: We performed a propensity matched cohort study between patients who received methylprednisolone and no methylprednisolone. Patients in the methylprednisolone group were further differentiated into dose (high dose and low dose), duration, and administration from onset of symptoms. MEASUREMENTS AND MAIN RESULTS: In the propensity matched sample, 99 out of 380 (26%) in no methylprednisolone, 69 out of 215 (31.9%) in low-dose methylprednisolone, and 74 out of 164 (55.2%) high-dose methylprednisolone expired. Overall median survival for no methylprednisolone (25.0 d), low-dose methylprednisolone (39.0 d), high-dose methylprednisolone (20.0 d), less than or equal to 7 days duration (19.0 d), 7-14 days duration (30.0 d), greater than 14 days duration (44.0 d), onset of symptoms less than or equal to 7 days (20.0 d), and onset of symptoms 7-14 days (27.0 d) were statistically significant (log-rank p ≤ 0.001). Multivariate Cox regression showed nursing home residents, coronary artery disease, and invasive mechanical ventilation were independently associated with mortality. Methylprednisolone was associated with reduced mortality compared with no methylprednisolone (hazard ratio, 0.40; 95% CI, 0.27-0.59; p < 0.001) but no added benefit with high dose. Low-dose methylprednisolone for 7-14 days was associated with reduced mortality compared with less than or equal to 7 days (hazard ratio, 0.45; 95% CI, 0.22-0.91; p = 0.0273), and no additional benefit if greater than 14 days (hazard ratio, 1.27; 95% CI, 0.60-2.69; p = 0.5434). Combination therapy with tocilizumab was associated with reduced mortality over monotherapy (p < 0.0116). CONCLUSIONS: Low-dose methylprednisolone was associated with reduced mortality if given greater than 7 days from onset of symptoms, and no additional benefit greater than 14 days. High dose was associated with higher mortality.

Prevalence of Gluteus Medius Pathology on Magnetic Resonance Imaging in Patients Undergoing Hip Arthroscopy for Femoroacetabular Impingement: Asymptomatic Tears Are Rare, Whereas Tendinosis Is Common.

BACKGROUND: There is a paucity of literature on asymptomatic gluteus medius pathology. Moreover, no studies have examined the prevalence of asymptomatic gluteus medius pathology. PURPOSE: To describe the prevalence of asymptomatic gluteus medius pathology in patients undergoing hip arthroscopy for femoroacetabular impingement. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A database search of our institution was performed for patients undergoing hip arthroscopy for labral treatment between February 2008 and January 2019. Patients were included if they had gluteus medius pathology identified through magnetic resonance imaging (MRI). Patients were deemed to be asymptomatic if they lacked greater trochanteric hip tenderness, abductor weakness, a positive Trendelenburg sign, or a positive Trendelenburg gait on physical examination. Patients were excluded if they were unwilling to participate or did not have a documented physical examination or MRI read in the database. RESULTS: A total of 2851 hips (2452 patients) met the inclusion/exclusion criteria. Gluteus medius pathology was found in 871 hips (30.6%) on MRI. Symptomatic gluteus medius pathology was observed in 414 (14.5%) hips, of which 305 (10.7%) had tendinosis, 99 (3.5%) had partial-thickness tears, and 10 (0.4%) had full-thickness tears. Asymptomatic gluteus medius pathology was observed in 457 (16.0%) hips, of which 408 (14.3%) had tendinosis and 49 (1.7%) had partial-thickness tears. No hips with full-thickness tears on MRI were asymptomatic. Patients with asymptomatic partial-thickness tears were significantly older than those with only tendinosis (45.3 vs 39.4 years, respectively; P = .001). Patients aged 40 years or older had a 2.11 (1.80-2.50) (P < .001) relative risk of asymptomatic pathology compared with patients younger than 40 years. CONCLUSION: Although there is a meaningful prevalence of asymptomatic gluteus medius tendinosis, the prevalence of asymptomatic gluteus medius tears is low. Treatment of gluteus medius tendinosis should therefore be based not solely on MRI findings but rather on a complete clinical evaluation. In contrast, MRI findings of partial or full-thickness gluteus medius tears may be more likely to have clinical significance.

Total Knee Arthroplasty in the Younger Patient.

The rate of total knee arthroplasty (TKA) utilization in younger patients (< 65 years old) is increasing. Little is known regarding demographics and in-hospital outcomes in this population. The National Hospital Discharge Survey (NHDS) database was searched using International Classification of Diseases, Ninth Revision (ICD-9) procedure codes for patients admitted to U.S. hospitals for unilateral primary TKA between 2001 and 2010. Patients were separated into young (< 65 years of age) and senior cohorts (≥ 65 years of age). ICD-9 diagnosis and procedure codes were used to identify demographics, hospital length of stay, in-hospital adverse events, mortality, and discharge disposition. Trends were evaluated by linear regression with Pearson correlation coefficient (r) and statistical comparisons were made using Student t-test and chi-square analysis. The young cohort accounted for 38.4% of TKAs performed from 2001 to 2005, increasing to 42.7% of TKAs from 2006 to 2010. They had a higher percentage of males (36.4 vs. 34.2%, p < 0.001). Rates of obesity (11.1 vs. 6.0%, p < 0.001) and morbid obesity (5.8 vs. 1.9%, p < 0.001) were significantly higher, yet they had less comorbidities (4.7 vs. 5.2, p < 0.001), and lower rates of transfusion (12.2 vs. 19.8%, p < 0.001), pulmonary embolism (PE) (0.31 vs. 0.49%, p < 0.020), and mortality (0.03 vs. 0.18%, p < 0.001). Patients < 65 years old undergoing TKA have almost double the rate of obesity of patients ≥ 65 years old. This could explain the higher rates of periprosthetic infection and aseptic mechanical failure seen in younger patients. However, the young cohort had a more favorable discharge disposition and lower mortality and risk of PE than elderly patients.

Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system.

Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases are a family of iron- and 2-oxoglutarate-dependent dioxygenases that negatively regulate the stability of several proteins that have established roles in adaptation to hypoxic or oxidative stress. These proteins include the transcriptional activators HIF-1alpha and HIF-2alpha. The ability of the inhibitors of HIF prolyl 4-hydroxylases to stabilize proteins involved in adaptation in neurons and to prevent neuronal injury remains unclear. We reported that structurally diverse low molecular weight or peptide inhibitors of the HIF prolyl 4-hydroxylases stabilize HIF-1alpha and up-regulate HIF-dependent target genes (e.g. enolase, p21(waf1/cip1), vascular endothelial growth factor, or erythropoietin) in embryonic cortical neurons in vitro or in adult rat brains in vivo. We also showed that structurally diverse HIF prolyl 4-hydroxylase inhibitors prevent oxidative death in vitro and ischemic injury in vivo. Taken together these findings identified low molecular weight and peptide HIF prolyl 4-hydroxylase inhibitors as novel neurological therapeutics for stroke as well as other diseases associated with oxidative stress.

Elevated expression of a regulator of the G2/M phase of the cell cycle, neuronal CIP-1-associated regulator of cyclin B, in Alzheimer's disease.

Adult neurons are generally accepted to be in a quiescent, nonproliferative state. However, it is becoming increasingly apparent that, in Alzheimer's disease (AD), alterations in cell cycle machinery, suggesting an attempt to reenter cell cycle, relate temporally and topographically to degenerating neurons. These findings, together with the fact that neurons lack the necessary components for completion of mitosis, have led to the notion that an ill-regulated attempt to reenter the cell cycle is associated with disease pathogenesis and, ultimately, neuronal degeneration. To understand better the role of such cell cycle abnormalities in AD, we undertook a study of CIP-1-associated regulator of cyclin B (CARB), a protein that associates with two key proteins, p21 and cyclin B, involved in cellular checkpoints in the cell cycle. Our results show that there are increases in CARB localized to intraneuronal neurofibrillary tangles and granulovacuolar degeneration in susceptible hippocampal and cortical neurons in AD. By marked contrast, CARB is found only at background levels in these neuronal populations in nondiseased age-matched controls. Our data not only provide another line of evidence indicative of cell cycle abnormalities in neurons in AD but also lend further credence to the hypothesis that susceptible neurons may be arrested at the G2/M phase of the cell cycle before they die. Therefore, therapeutics targeted toward initiators of the cell cycle are likely to prove of great efficacy for the treatment of AD.