Search

Mitotic count in breast cancer is an important prognostic marker. Unfortunately, substantial inter- and intraobserver variation exists when pathologists manually count mitotic figures. To alleviate this problem, we developed a new technique incorporating both haematoxylin and eosin (HE) and phosphorylated histone H3 (PHH3), a marker highly specific to mitotic figures, and compared it to visual scoring of mitotic figures using HE only.Two full-face sections from 97 cases were cut, one stained with HE only, and the other was stained with PHH3 and counterstained with HE (PHH3-HE). Counting mitoses using PHH3-HE was compared to traditional mitoses scoring using HE in terms of reproducibility, scoring time, and the ability to detect mitosis hotspots. We assessed the agreement between manual and image analysis-assisted scoring of mitotic figures using HE and PHH3-HE-stained cells. The diagnostic performance of PHH3 in detecting mitotic figures in terms of sensitivity and specificity was measured. Finally, PHH3 replaced the mitosis score in a multivariate analysis to assess its significance.Pathologists detected significantly higher mitotic figures using the PHH3-HE (median ± SD, 20 ± 33) compared with HE alone (median ± SD, 16 ± 25), P 0.001. The concordance between pathologists in identifying mitotic figures was highest when using the dual PHH3-HE technique; in addition, it highlighted mitotic figures at low power, allowing better agreement on choosing the hotspot area (k = 0.842) in comparison with standard HE (k = 0.625). A better agreement between image analysis-assisted software and the human eye was observed for PHH3-stained mitotic figures. When the mitosis score was replaced with PHH3 in a Cox regression model with other grade components, PHH3 was an independent predictor of survival (hazard ratio [HR] 5.66, 95% confidence interval [CI] 1.92-16.69; P = 0.002), and even showed a more significant association with breast cancer-specific survival (BCSS) than mitosis (HR 3.63, 95% CI 1.49-8.86; P = 0.005) and Ki67 (P = 0.27).Using PHH3-HE-stained slides can reliably be used in routine scoring of mitotic figures and integrating both techniques will compensate for each other's limitations and improve diagnostic accuracy, quality, and precision.

Background: In atrial fibrillation patients undergoing left atrial appendage occlusion with a Watchman device, surveillance imaging with a transesophageal echocardiogram (TEE) is typically performed at 45 days and 1 year to evaluate for device-related thrombus (DRT) and peri-device leak (PDL) before cessation of oral anticoagulation. The incidence of these complications is relatively low, and the ideal timing and duration of surveillance is unknown. We sought to evaluate the incidence of DRT and PDL after Watchman placement at 45 days and 1 year to determine the necessity of surveillance TEEs. Methods: We retrospectively analyzed 361 patients who received a Watchman device between January 2016 and January 2020. Baseline clinical and echocardiographic data, post-procedure antithrombotic therapy and surveillance echocardiographic data were collected from the NCDR LAAO Registry. Nested backward variable elimination regression was performed to derive independent predictors of the composite outcome of DRT and PDL. Results: A total of 286 patients who had post-procedure TEEs were included in the analysis. At 45 days, 9 patients had DRT (3.2%) and 44 patients had PDL (15.0%). At 1 year, 5 patients had DRT (5.6%) and 8 patients had PDL (8.9%). All DRT at 45 days was treated with continued anticoagulation while no change in protocol occurred with PDL. All DRT at 1 year occurred in new patients without prior thrombus. A history of prior transient ischemic attack (TIA) and thromboembolism were significantly associated with DRT or PDL at 1 year. Conclusions: We identified several patients with device-related complications at 45 days and 1 year despite appropriate device sizing and adequate use of antithrombotic therapy. The incidence of DRT increased from 45 days to 1 year and occurred in patients without prior thrombus. These findings highlight the importance of surveillance imaging and suggest the potential need for extended surveillance in select patients.

Diabetes mellitus is a rapidly rising metabolic disorder with important systemic complications. Global figures have demonstrated the prevalence of diabetes mellitus has almost quadrupled from 108 million in 1980 to 422 million in 2014, with a current prevalence of over 525 million. Of the male sexual dysfunction resulting from diabetes mellitus, significant focus is afforded to erectile dysfunction. Nevertheless, ejaculatory dysfunction constitutes important sexual sequelae in diabetic men, with up to 35%-50% of men with diabetes mellitus suffering from ejaculatory dysfunction. Despite this, aspects of its pathophysiology and treatment are less well understood than erectile dysfunction. The main disorders of ejaculation include premature ejaculation, delayed ejaculation, anejaculation and retrograde ejaculation. Although ejaculatory dysfunction in diabetes mellitus can have complex multifactorial aetiology, understanding its pathophysiological mechanisms has facilitated the development of therapies in the management of ejaculatory dysfunction. Most of our understanding of its pathophysiology is derived from diabetic animal models; however, observational studies in humans have also provided useful information in elucidating important associative factors potentially contributing to ejaculatory dysfunction in diabetic men. These have provided the potential for more tailored treatment regimens in patients depending on the ejaculatory disorder, other co-existing sequelae of diabetes mellitus, specific metabolic factors as well as the need for fertility treatment. However, evidence for treatment of ejaculatory dysfunction, especially delayed ejaculation and retrograde ejaculation, is based on low-level evidence comprising small sample-size series and retrospective or cross-sectional studies. Whilst promising findings from large randomised controlled trials have provided strong evidence for the licensed treatment of premature ejaculation, similar robust studies are needed to accurately elucidate factors predicting ejaculatory dysfunction in diabetes mellitus, as well as for the development of pharmacotherapies for delayed ejaculation and retrograde ejaculation. Similarly, more contemporary robust data are required for fertility outcomes in these patients, including methods of sperm retrieval and assisted reproductive techniques in retrograde ejaculation.

Erectile dysfunction is associated with diabetes mellitus with an estimated prevalence of 52.5% in the diabetic population. The first-line therapy for erectile dysfunction is phosphodiesterase type 5 inhibitors, but data suggest that diabetic men may be less responsive than non-diabetic men. Thus, other treatments, including intracavernosal injections, intraurethral prostaglandin, vacuum erection devices and penile prosthetic surgery, should be considered in management of diabetic men with erectile dysfunction refractory to phosphodiesterase type 5 inhibitors. Furthermore, combination therapy of phosphodiesterase type 5 inhibitors and other oral treatments such as arginine or l-carnitine may have synergistic effects resulting in better outcomes. In addition, there are novel therapies such as low-intensity shockwave therapy and stem-cell therapy, which may also be effective in targeted treatment modalities. Furthermore, studies suggest that erectile dysfunction can be improved by targeting concurrent comorbidities or metabolic diseases such as depression, hypertension, hypogonadism, and dyslipidaemia. We present an evidence-based narrative review focusing on the management of erectile dysfunction in diabetic men who have not responded to phosphodiesterase type 5 inhibitors.Both clinicians and patients should be aware of the different management options in diabetic patients who have not responded to phosphodiesterase type 5 inhibitors.

Chronic kidney disease (CKD) and end-stage renal disease are considered independent risk factors for developing atrial fibrillation (AF). Percutaneous occlusion of left atrial appendage (LAAC) using WATCHMAN device is a widely accepted alternative to anticoagulation therapy to prevent ischemic stroke in AF in patients who are not candidates for anticoagulation. There is limited data regarding the utilization and periprocedural safety of this intervention in patients with CKD/ESRD.We retrospectively reviewed all hospitalizations from 2016 to 2017 with (ICD-10) procedure diagnosis code of LAA closure using WATCHMAN procedure with and without a secondary diagnosis of CKD/ESRD in acute-care hospitals across the United States using the national inpatient sample. Demographic variables (gender, race, income, hospital characteristics, medical comorbidities) were collected and compared. The primary outcomes were inpatient mortality, hospital length, and cost of stay.There were over 71 million discharges included in the combined 2016 and 2017 NIS database. Sixteen thousand five hundred five hospitalizations were for adult patients with a procedure code for LAA closure via watchman procedure. Of 16,505 patients, 3245 (19.66%) had CKD and ESRD. There was no statistically significant difference in mortality, length, and cost of stay in patients with and without CKD/ESRD. There were no statistically significant differences in periprocedural cerebrovascular accidents in both groups.Patients with and without ESRD/CKD who undergo LAA occlusion with Watchman have similar procedure related, in-hospital mortality, and complications.

Purpose of this study was to prepare chitosan/tamarind crosslinked poly (methacrylic acid) hydrogels for pH responsive delivery of cytarabine by using aqueous free radical polymerization technique. Polymers were chemically cross-linked with monomer (methacrylic acid) using methylene bisacrylamide as cross-linking agent and ammonium per sulphate as a reaction initiator in aqueous medium. Developed hydrogels were characterized for morphology, physical existence, drug loading (%), compositional and structural analysis, thermal behavior and stability, drug release analysis (pH 1.2 and pH 7.4), and in vivo release kinetics. pH sensitive behavior was established by observing swelling and release behavior at different pH values (1.2 and 7.4). Biocompatibility of network was evaluated through acute oral toxicity studies in rabbits. Results revealed that cytarabine was efficiently loaded in prepared hydrogels with an entrapment efficiency of 54.67%-108.59%. Highest swelling ratio of 38.67 was noticed at pH 7.4. Maximum pH sensitive behavior was seen at pH 7.4 showing maximum drug release up to 94.51%. All developed formulations followed zero order release as confirmed from regression coefficient (R

Hospitalization for heart failure (HF) constitutes a major healthcare and economic burden. Trends and characteristics of hospitalizations for HF for the recent years are not clear. We sought to determine the trends and characteristics of hospitalization for HF in the United States.A retrospective analysis of the National Inpatient Sample weighted data between 1 January 2004 and 31 December 2018, which included hospitalized adults ≥ 18 years with primary discharge diagnosis of HF using International Classification of Diseases-9/10 administrative codes. Main outcomes were trends in hospitalizations for HF (per 1000 person) and inpatient mortality (%) between 2004 and 2018.Hospitalizations for HF have been increasing across both sexes and age groups since 2013, whereas inpatient mortality has been decreasing over the study period. Blacks have the highest risk of hospitalization for HF, and Whites have the highest in-hospital mortality. There are significant racial and geographic disparities related to hospitalizations for HF.

Background The prevalence of alcohol use disorder (AUD) is estimated to be ten times higher amongst individuals in the criminal justice system compared to the general population. Alcohol use is also one of the strongest modifiable risk factors for recidivism. One intervention that has been shown to be effective in reducing alcohol consumption in the general population is medication assisted treatment (MAT) (e.g., naltrexone, disulfiram), and this critical review synthesized the existing evidence on MAT for AUD in correctional settings. Methods Empirical, peer-reviewed studies on approved medications for AUD in correctional populations were searched in major databases. One hundred and sixty-two articles were initially screened, and 14 eligible articles were included in the final review. Four articles examined disulfiram, and ten articles examined naltrexone. Results The studies on disulfiram were considerably older, predating contemporary scientific standards. In terms of outcomes, disulfiram in combination with substantial contingencies in a supervised setting significantly reduced alcohol-related measures of consumption and recidivism, and had acceptable safety and tolerability. All naltrexone studies showed significant reductions on alcohol-related measures, but the effects on recidivism were mixed. The naltrexone studies indicated that it was highly acceptable and well-tolerated. In addition, offenders receiving naltrexone had significantly greater medication adherence, treatment attendance and treatment duration compared to placebo. Conclusions A small number of studies on pharmacological interventions for AUD in the correctional population suggest that MAT is useful for addressing alcohol consumption, although report mixed results regarding recidivism. On balance, the evidence was more convincing for naltrexone in reducing alcohol-related outcomes than disulfiram and it may also be a more feasible intervention in correctional settings. Further research on MAT to address AUD in correctional populations with larger sample sizes, longer duration, and in combination with behavioural interventions is warranted.

OBJECTIVE To describe the real-world treatment persistence (defined as the continuation of medication for the prescribed treatment duration), demographics and clinical characteristics, and treatment patterns for patients prescribed erenumab for migraine prevention in Canada. BACKGROUND The effectiveness of prophylactic migraine treatments is often undermined by poor treatment persistence. In clinical trials, erenumab has demonstrated efficacy and tolerability as a preventive treatment, but less is known about the longer term treatment persistence with erenumab. METHODS This is a real-world retrospective cohort study where a descriptive analysis of secondary patient data was conducted. Enrollment and prescription data were extracted from a patient support program for a cohort of patients prescribed erenumab in Canada between September 2018 and December 2019 and analyzed for persistence, baseline demographics, clinical characteristics, and treatment patterns. Descriptive analyses and unadjusted Kaplan-Meier (KM) curves were used to summarize the persistence and dose escalation/de-escalation at different timepoints. RESULTS Data were analyzed for 14,282 patients. Median patient age was 47 years, 11,852 (83.0%) of patients were female, and 9443 (66.1%) had chronic migraine at treatment initiation. Based on KM methods, 71.0% of patients overall were persistent to erenumab 360 days after treatment initiation. Within 360 days of treatment initiation, it is estimated that 59.3% (KM-derived) of patients who initiated erenumab at 70 mg escalated to 140 mg, and 4.4% (KM-derived) of patients who initiated at 140 mg de-escalated to 70 mg. CONCLUSIONS The majority of patients prescribed erenumab remained persistent for at least a year after treatment initiation, and most patients initiated or escalated to a 140 mg dose. These results suggest that erenumab is well tolerated, and its uptake as a new class of prophylactic treatment for migraine in real-world clinical practice is not likely to be undermined by poor persistence when coverage for erenumab is easily available.

Male hypogonadism (MH) is a common endocrine disorder. However, uncertainties and variations in its diagnosis and management exist. There are several current guidelines on testosterone replacement therapy that have been driven predominantly by single disciplines. The Society for Endocrinology commissioned this new guideline to provide all care providers with a multidisciplinary approach to treating patients with MH. This guideline has been compiled using expertise from endocrine (medical and nursing), primary care, clinical biochemistry, urology and reproductive medicine practices. These guidelines also provide a patient perspective to help clinicians best manage MH.

Frailty is a distinctive health state in which the ability of older people to cope with acute stressors is compromised by an increased vulnerability brought by age-associated declines in physiological reserve and function across multiple organ systems. Although closely associated with age, multimorbidity, and disability, frailty is a discrete syndrome that is associated with poorer outcomes across a range of medical conditions. However, its role in cerebrovascular disease and stroke has received limited attention. The estimated rise in the prevalence of frailty associated with changing demographics over the coming decades makes it an important issue for stroke practitioners, cerebrovascular research, clinical service provision, and stroke survivors alike. This review will consider the concept and models of frailty, how frailty is common in cerebrovascular disease, the impact of frailty on stroke risk factors, acute treatments, and rehabilitation, and considerations for future applications in both cerebrovascular clinical and research settings.

To systematically review the literature to determine the benefits and harms of the surgical techniques used for the correction of adult-acquired buried penis (AABP).The systematic review was registered in the PROSPERO database (CRD42021267440) and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The Pariser system was used to classify surgical procedures.In total, 170 studies were identified and screened, and 21 studies (570 patients) were included. In general, high-complexity reconstructive procedures (categoryIII) were performed, with split-thickness skin grafts for shaft reconstruction. The pooled mean operating time was 192.2 min and the mean estimated blood loss range was 57-326 mL. No intra-operative complications were recorded. The incidence of postoperative complications varied across studies (0-80.8%), withGrade 4 complications reported in 3.1-3.7% of cases. Wound infection and genital lymphoedema were reported in 4.7-33% and 7.1-60% of cases, respectively. The incidence of graft contracture and partial/total loss was 2.4-14.3% and 1.5-21%, respectively. The incidence of recurrence was not systematically reported and ranged from 5.2% to 13%. Postoperative evaluation of functional outcomes demonstrated significant improvements in sexual function, urinary function and cosmesis. Assessment of risk of bias demonstrated a high risk of bias across all studies.Surgical management of AABP has a high incidence of complications but results in satisfactory outcomes, with significant improvement in patients' quality of life. The high incidence of graft-related complications should be taken into account when counselling patients and AABP care should be centralized to high-volume centres.

OBJECTIVE Medication access and adherence are important determinants of health outcomes. We investigated factors associated with access and cost-related nonadherence to prescriptions in a population-based cohort of systemic lupus erythematosus (SLE) patients and controls. METHODS Detailed sociodemographic and prescription data were collected by structured interview in 2014-2015 from participants in the Michigan Lupus Epidemiology and Surveillance (MILES) cohort. We compared access between cases and frequency-matched controls and examined associated factors in separate multivariable logistic regression models. RESULTS A total of 654 participants (462 SLE patients, 192 controls) completed the baseline visit; 584 (89%) were female, 285 (44%) were Black, and the mean age was 53 years. SLE patients and controls reported similar frequencies of being unable to access prescribed medications (12.1% versus 9.4%, respectively; P was not significant). SLE patients were twice as likely as controls to report cost-related prescription nonadherence in the preceding 12 months to save money (21.7% versus 10.4%; P = 0.001) but were also more likely to ask their doctor for lower cost alternatives (23.8% versus 15.6%; P = 0.02). Disparities were found in association with income, race, and health insurance status, but the main findings persisted after adjusting for these and other variables in multivariable models. CONCLUSION SLE patients were more likely than controls from the general population to report cost-related prescription nonadherence, including skipping doses, taking less medicine, and delaying filling prescriptions; yet