Atlantic Health System

BACKGROUND: In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients. METHODS: In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis. RESULTS: In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation. CONCLUSIONS: Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.).

RECOMMENDATION 1: Clinicians should conduct a focused history and physical examination to help place patients with low back pain into 1 of 3 broad categories: nonspecific low back pain, back pain potentially associated with radiculopathy or spinal stenosis, or back pain potentially associated with another specific spinal cause. The history should include assessment of psychosocial risk factors, which predict risk for chronic disabling back pain (strong recommendation, moderate-quality evidence). RECOMMENDATION 2: Clinicians should not routinely obtain imaging or other diagnostic tests in patients with nonspecific low back pain (strong recommendation, moderate-quality evidence). RECOMMENDATION 3: Clinicians should perform diagnostic imaging and testing for patients with low back pain when severe or progressive neurologic deficits are present or when serious underlying conditions are suspected on the basis of history and physical examination (strong recommendation, moderate-quality evidence). RECOMMENDATION 4: Clinicians should evaluate patients with persistent low back pain and signs or symptoms of radiculopathy or spinal stenosis with magnetic resonance imaging (preferred) or computed tomography only if they are potential candidates for surgery or epidural steroid injection (for suspected radiculopathy) (strong recommendation, moderate-quality evidence). RECOMMENDATION 5: Clinicians should provide patients with evidence-based information on low back pain with regard to their expected course, advise patients to remain active, and provide information about effective self-care options (strong recommendation, moderate-quality evidence). RECOMMENDATION 6: For patients with low back pain, clinicians should consider the use of medications with proven benefits in conjunction with back care information and self-care. Clinicians should assess severity of baseline pain and functional deficits, potential benefits, risks, and relative lack of long-term efficacy and safety data before initiating therapy (strong recommendation, moderate-quality evidence). For most patients, first-line medication options are acetaminophen or nonsteroidal anti-inflammatory drugs. RECOMMENDATION 7: For patients who do not improve with self-care options, clinicians should consider the addition of nonpharmacologic therapy with proven benefits-for acute low back pain, spinal manipulation; for chronic or subacute low back pain, intensive interdisciplinary rehabilitation, exercise therapy, acupuncture, massage therapy, spinal manipulation, yoga, cognitive-behavioral therapy, or progressive relaxation (weak recommendation, moderate-quality evidence).

Electromechanical actuators based on sheets of single-walled carbon nanotubes were shown to generate higher stresses than natural muscle and higher strains than high-modulus ferroelectrics. Like natural muscles, the macroscopic actuators are assemblies of billions of individual nanoscale actuators. The actuation mechanism (quantum chemical-based expansion due to electrochemical double-layer charging) does not require ion intercalation, which limits the life and rate of faradaic conducting polymer actuators. Unlike conventional ferroelectric actuators, low operating voltages of a few volts generate large actuator strains. Predictions based on measurements suggest that actuators using optimized nanotube sheets may eventually provide substantially higher work densities per cycle than any previously known technology.

BACKGROUND: Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. METHODS: We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end point was clinical response. Secondary end points included toxic effects and progression-free survival. RESULTS: The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine-interleukin-2 group, as compared with the interleukin-2-only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P=0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P=0.008). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P=0.06). CONCLUSIONS: In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine and interleukin-2 than with interleukin-2 alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00019682.).

Abstract Variants of UNC13A , a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia 1–3 , two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43 4,5 . Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A , resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.

Colorectal cancer (CRC) is the third most common cancer and third leading cause of cancer death in both men and women and second leading cause of cancer death when men and women are combined in the United States (US). Almost two-thirds of CRC survivors are living 5 years after diagnosis. Considering the recent decline in both incidence and mortality, the prevalence of CRC survivors is likely to increase dramatically over the coming decades with the increase in rates of CRC screening, further advances in early detection and treatment and the aging and growth of the US population. Survivors are at risk for a CRC recurrence, a new primary CRC, other cancers, as well as both short-term and long-term adverse effects of the CRC and the modalities used to treat it. CRC survivors may also have psychological, reproductive, genetic, social, and employment concerns after treatment. Communication and coordination of care between the treating oncologist and the primary care clinician is critical to effectively and efficiently manage the long-term care of CRC survivors. The guidelines in this article are intended to assist primary care clinicians in delivering risk-based health care for CRC survivors who have completed active therapy.

PURPOSE: Effective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product. METHODS: We conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1. RESULTS: Sixty-six patients received a mean of 3.3 prior therapies (anti-programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti-PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2. CONCLUSION: Lifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti-PD-1 or PD-L1 therapy subset.

Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma. Design, Setting, and Participants: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. Interventions: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. Main Outcomes and Measures: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. Results: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03). Conclusions and Relevance: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone. Trial Registration: ClinicalTrials.gov Identifier: NCT00045968.

Trials of coronavirus disease 2019 (COVID-19) vaccination included limited numbers of children, so they may not have detected rare but important adverse events in this population. We report 7 cases of acute myocarditis or myopericarditis in healthy male adolescents who presented with chest pain all within 4 days after the second dose of Pfizer-BioNTech COVID-19 vaccination. Five patients had fever around the time of presentation. Acute COVID-19 was ruled out in all 7 cases on the basis of negative severe acute respiratory syndrome coronavirus 2 real-time reverse transcription polymerase chain reaction test results of specimens obtained by using nasopharyngeal swabs. None of the patients met criteria for multisystem inflammatory syndrome in children. Six of the 7 patients had negative severe acute respiratory syndrome coronavirus 2 nucleocapsid antibody assay results, suggesting no previous infection. All patients had an elevated troponin. Cardiac MRI revealed late gadolinium enhancement characteristic of myocarditis. All 7 patients resolved their symptoms rapidly. Three patients were treated with nonsteroidal antiinflammatory drugs only, and 4 received intravenous immunoglobulin and corticosteroids. In this report, we provide a summary of each adolescent's clinical course and evaluation. No causal relationship between vaccine administration and myocarditis has been established. Continued monitoring and reporting to the US Food and Drug Administration Vaccine Adverse Event Reporting System is strongly recommended.

Cells with sphere forming capacity, spheroid cells, are present in the malignant ascites of patients with epithelial ovarian cancer (EOC) and represent a significant impediment to efficacious treatment due to their putative role in progression, metastasis and chemotherapy resistance. The exact mechanisms that underlie EOC metastasis and drug resistance are not clear. Understanding the biology of sphere forming cells may contribute to the identification of novel therapeutic opportunities for metastatic EOC. Here we generated spheroid cells from human ovarian cancer cell lines and primary ovarian cancer. Xenoengraftment of as few as 2000 dissociated spheroid cells into immune-deficient mice allowed full recapitulation of the original tumor, whereas >10(5) parent tumor cells remained non-tumorigenic. The spheroid cells were found to be enriched for cells with cancer stem cell-like characteristics such as upregulation of stem cell genes, self-renewal, high proliferative and differentiation potential, and high aldehyde dehydrogenase (ALDH) activity. Furthermore, spheroid cells were more aggressive in growth, migration, invasion, scratch recovery, clonogenic survival, anchorage-independent growth, and more resistant to chemotherapy in vitro. (13)C-glucose metabolic studies revealed that spheroid cells route glucose predominantly to anaerobic glycolysis and pentose cycle to the detriment of re-routing glucose for anabolic purposes. These metabolic properties of sphere forming cells appear to confer increased resistance to apoptosis and contribute to more aggressive tumor growth. Collectively, we demonstrated that spheroid cells with cancer stem cell-like characteristics contributed to tumor generation, progression and chemotherapy resistance. This study provides insight into the relationship between tumor dissemination and metabolic attributes of human cancer stem cells and has clinical implications for cancer therapy.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.

OBJECTIVE: Children with chronic abdominal pain of nonorganic origin, termed functional abdominal pain (FAP), experience school absences and social withdrawal and report impaired physical ability. The aim of this study was to assess patients' and parents' perceptions of health-related quality of life (QoL) for children with FAP. METHODS: Between October 2002 and November 2003, 209 children (including 125 girls; age: 11.2 +/- 3.5 years) and 209 parents were recruited from a pediatric referral center. At the time of their initial evaluations, participants completed a validated, health-related QoL instrument (Pediatric Quality of Life Inventory), which was scored on a scale of 0 (poor) through 100 (best). Children with FAP (n = 65) and their families were compared with control groups of healthy children (n = 46) and children with histologically proven inflammatory bowel disease (IBD) (n = 42) or gastroesophageal reflux disease (GERD) (n = 56). RESULTS: Children with FAP had self-reported QoL scores (score: 78) that were similar to those for children with GERD (score: 80) or IBD (score: 84). Children with FAP had lower QoL scores than did healthy children (score: 88). Parents of children with FAP reported lower QoL scores, compared with their children's scores (scores: 70 vs 78). CONCLUSIONS: Children with FAP reported lower QoL, compared with their healthy peers, and had the same QoL scores as did children with IBD or GERD. Parents' perceptions of QoL for children with FAP were lower than their children's self-reported scores. These findings highlight the clinical significance of FAP and may provide insight into one facet of the disease's biopsychosocial etiology.

PURPOSE: To conduct an update of the ASCO venous thromboembolism (VTE) guideline. METHODS: After publication of potentially practice-changing clinical trials, identified through ASCO's signals approach to updating, an updated systematic review was performed for two guideline questions: perioperative thromboprophylaxis and treatment of VTE. PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) published between November 1, 2018, and June 6, 2022. RESULTS: Five RCTs provided information that contributed to changes to the 2019 recommendations. Two RCTs addressed direct factor Xa inhibitors (either rivaroxaban or apixaban) for extended thromboprophylaxis after surgery. Each of these postoperative trials had important limitations but suggested that these two oral anticoagulants are safe and effective in the settings studied. An additional three RCTs addressed apixaban in the setting of VTE treatment. Apixaban was effective in reducing the risk of recurrent VTE, with a low risk of major bleeding. RECOMMENDATIONS: Apixaban and rivaroxaban were added as options for extended pharmacologic thromboprophylaxis after cancer surgery, with a weak strength of recommendation. Apixaban was also added as an option for the treatment of VTE, with high quality of evidence and a strong recommendation.Additional information is available at www.asco.org/supportive-care-guidelines.

We conducted a systematic review of the literature about home telehealth for chronic obstructive pulmonary disease (COPD) compared with usual care. An electronic literature search identified 6241 citations. From these, nine original studies (10 references) relating to 858 patients were selected for inclusion in the review. Four studies compared home telemonitoring with usual care, and six randomized controlled trials compared telephone support with usual care. Clinical heterogeneity was present in many of the outcomes measured. Home telehealth (home telemonitoring and telephone support) was found to reduce rates of hospitalization and emergency department visits, while findings for hospital bed days of care varied between studies. However, the mortality rate was greater in the telephone-support group compared with usual care (risk ratio = 1.21; 95% CI: 0.84 to 1.75). Home telehealth interventions were similar or better than usual care for quality of life and patient satisfaction outcomes.

BACKGROUND: Patients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% in 66 patients who progressed after ICI and targeted therapy. Herein, we report independent review committee (IRC)-assessed outcomes of 153 patients treated with lifileucel in a large multicenter Phase 2 cell therapy trial in melanoma. METHODS: Eligible patients had advanced melanoma that progressed after ICI and targeted therapy, where appropriate. Melanoma lesions were resected (resected tumor diameter ≥1.5 cm) and shipped to a central good manufacturing practice facility for 22-day lifileucel manufacturing. Patients received a non-myeloablative lymphodepletion regimen, a single lifileucel infusion, and up to six doses of high-dose interleukin-2. The primary endpoint was IRC-assessed ORR (Response Evaluation Criteria in Solid Tumors V.1.1). RESULTS: The Full Analysis Set consisted of 153 patients treated with lifileucel, including longer-term follow-up on the 66 patients previously reported. Patients had received a median of 3.0 lines of prior therapy (81.7% received both anti-programmed cell death protein 1 and anti-cytotoxic lymphocyte-associated protein 4) and had high disease burden at baseline (median target lesion sum of diameters (SOD): 97.8 mm; lactate dehydrogenase (LDH) >upper limit of normal: 54.2%). ORR was 31.4% (95% CI: 24.1% to 39.4%), with 8 complete responses and 40 partial responses. Median duration of response was not reached at a median study follow-up of 27.6 months, with 41.7% of the responses maintained for ≥18 months. Median overall survival and progression-free survival were 13.9 and 4.1 months, respectively. Multivariable analyses adjusted for Eastern Cooperative Oncology Group performance status demonstrated that elevated LDH and target lesion SOD >median were independently correlated with ORR (p=0.008); patients with normal LDH and SOD <median had greater likelihood of response than those with either (OR=2.08) or both (OR=4.42) risk factors. The most common grade 3/4 treatment-emergent adverse events (≥30%) were thrombocytopenia (76.9%), anemia (50.0%), and febrile neutropenia (41.7%). CONCLUSIONS: Investigational lifileucel demonstrated clinically meaningful activity in heavily pretreated patients with advanced melanoma and high tumor burden. Durable responses and a favorable safety profile support the potential benefit of one-time lifileucel TIL cell therapy in patients with limited treatment options in ICI-refractory disease.

RECOMMENDATION 1: In patients with serious illness at the end of life, clinicians should regularly assess patients for pain, dyspnea, and depression. (Grade: strong recommendation, moderate quality of evidence.) RECOMMENDATION 2: In patients with serious illness at the end of life, clinicians should use therapies of proven effectiveness to manage pain. For patients with cancer, this includes nonsteroidal anti-inflammatory drugs, opioids, and bisphosphonates. (Grade: strong recommendation, moderate quality of evidence.) RECOMMENDATION 3: In patients with serious illness at the end of life, clinicians should use therapies of proven effectiveness to manage dyspnea, which include opioids in patients with unrelieved dyspnea and oxygen for short-term relief of hypoxemia. (Grade: strong recommendation, moderate quality of evidence.) RECOMMENDATION 4: In patients with serious illness at the end of life, clinicians should use therapies of proven effectiveness to manage depression. For patients with cancer, this includes tricyclic antidepressants, selective serotonin reuptake inhibitors, or psychosocial intervention. (Grade: strong recommendation, moderate quality of evidence.) RECOMMENDATION 5: Clinicians should ensure that advance care planning, including completion of advance directives, occurs for all patients with serious illness. (Grade: strong recommendation, low quality of evidence.).

BACKGROUND: Tight blood glucose control has been correlated with a reduction in diabetes complications. Adherence to antidiabetic medications is crucial to achieving blood glucose control. OBJECTIVE: To assess the relationship between good glucose control [glycosylated hemoglobin (HbA1c) levels] and adherence to prescribed treatment in patients on a stable medication regimen for type 2 diabetes. METHODS: The Morisky survey, a 4-item questionnaire that predicts patient medication-taking behavior, was used to assess adherence in 301 patients. The relationship of HbA1c to Morisky score was evaluated, controlling for other variables related to patient demographics and clinical characteristics. Data were analyzed using a general linear model on log (HbA1c). RESULTS: Unadjusted mean HbA1c values (capped at 14.0%) for patients with Morisky scores of 0 or 1, 2, 3, and 4 were 8.92%, 8.67%, 7.74%, and 7.60%, respectively. Of all patients, 13.0%, 14.0%, 24.3%, and 48.8% had scores of 0 or 1, 2, 3, and 4, respectively. Good adherence (Morisky score > or = 3) was associated with a 10% lower total HbA1c (p = 0.0003) adjusted for all other factors in the model. Duration of diabetes (5-10 y) and presence of diabetes complications were also significantly associated with HbA1c (p = 0.026 and 0.002, respectively). Adherence was poor in 27% of patients. CONCLUSIONS: This study found that patients with a higher score on the Morisky scale had a lower associated HbA1c measurement. The Morisky score may be an efficient tool for identifying patients with poor medication-taking behavior who can then be targeted for directed adherence counseling services.

BACKGROUND: Physicians commonly screen for prostate cancer by using prostate-specific antigen (PSA) and digital rectal examination (DRE). The usefulness of these screening mechanisms is not well established, however. A meta-analysis of PSA and DRE to detect prostate carcinoma was conducted with a focus on sensitivity, specificity, and positive predictive value. METHODS: A literature search of OVID database (1966 to November 1999) using the medical subject headings "prostate-specific antigen" and "mass screening," as well as "prostate carcinoma," was performed. Thirteen articles were selected for the meta-analysis in this study. Most studies included asymptomatic men older than 50 years from various countries. Pooled results were calculated from the individual reports for sensitivity, specificity, and positive predictive value for PSA and DRE based on biopsy result as the reference standard. RESULTS: The overall detection rate of prostate carcinoma was 1.8% based on a positive biopsy. Of the prostate carcinoma detected, 83.4% was localized. The pooled sensitivity, specificity, and positive predictive value for PSA were 72.1%, 93.2% and 25.1%, respectively; and for DRE were 53.2%, 83.6% and 17.8%, respectively. CONCLUSIONS: There were two major outcomes of this meta-analysis. One was the potential for detecting early-stage prostate cancer with these screening tests, because 83.4% of total cancers detected were localized. The second important outcome was that the overall sensitivity, specificity, and positive predictive value for PSA were higher than those for DRE when used as a screening tool to detect prostate cancer. When a patient has abnormal findings using PSA and DRE, the chance of cancer is 1 in 4 or 5. Conversely, when findings from PSA and DRE are normal, the chance of missing a cancer is about 10%.

Importance: The major North American professional sports leagues were among the first to return to full-scale sport activity during the coronavirus disease 2019 (COVID-19) pandemic. Given the unknown incidence of adverse cardiac sequelae after COVID-19 infection in athletes, these leagues implemented a conservative return-to-play (RTP) cardiac testing program aligned with American College of Cardiology recommendations for all athletes testing positive for COVID-19. Objective: To assess the prevalence of detectable inflammatory heart disease in professional athletes with prior COVID-19 infection, using current RTP screening recommendations. Design, Setting, and Participants: This cross-sectional study reviewed RTP cardiac testing performed between May and October 2020 on professional athletes who had tested positive for COVID-19. The professional sports leagues (Major League Soccer, Major League Baseball, National Hockey League, National Football League, and the men's and women's National Basketball Association) implemented mandatory cardiac screening requirements for all players who had tested positive for COVID-19 prior to resumption of team-organized sports activities. Exposures: Troponin testing, electrocardiography (ECG), and resting echocardiography were performed after a positive COVID-19 test result. Interleague, deidentified cardiac data were pooled for collective analysis. Those with abnormal screening test results were referred for additional testing, including cardiac magnetic resonance imaging and/or stress echocardiography. Main Outcomes and Measures: The prevalence of abnormal RTP test results potentially representing COVID-19-associated cardiac injury, and results and outcomes of additional testing generated by the initial screening process. Results: The study included 789 professional athletes (mean [SD] age, 25 [3] years; 777 men [98.5%]). A total of 460 athletes (58.3%) had prior symptomatic COVID-19 illness, and 329 (41.7%) were asymptomatic or paucisymptomatic (minimally symptomatic). Testing was performed a mean (SD) of 19 (17) days (range, 3-156 days) after a positive test result. Abnormal screening results were identified in 30 athletes (3.8%; troponin, 6 athletes [0.8%]; ECG, 10 athletes [1.3%]; echocardiography, 20 athletes [2.5%]), necessitating additional testing; 5 athletes (0.6%) ultimately had cardiac magnetic resonance imaging findings suggesting inflammatory heart disease (myocarditis, 3; pericarditis, 2) that resulted in restriction from play. No adverse cardiac events occurred in athletes who underwent cardiac screening and resumed professional sport participation. Conclusions and Relevance: This study provides large-scale data assessing the prevalence of relevant COVID-19-associated cardiac pathology with implementation of current RTP screening recommendations. While long-term follow-up is ongoing, few cases of inflammatory heart disease have been detected, and a safe return to professional sports activity has thus far been achieved.

BACKGROUND: encephalopathy and explored potential prospects of personalised medicine. METHODS: variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. CONCLUSIONS: encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.