Rank correlation inferences for clustered data with small sample size.

This paper develops methods to test for associations between two variables with clustered data using a U-Statistic approach with a second-order approximation to the variance of the parameter estimate for the test statistic. The tests that are presented are for clustered versions of: Pearsons χ 2 test, the Spearman rank correlation and Kendall's τ for continuous data or ordinal data and for alternative measures of Kendall's τ that allow for ties in the data. Shih and Fay use the U-Statistic approach but only consider a first-order approximation. The first-order approximation has inflated significance level in scenarios with small sample sizes. We derive the test statistics using the second-order approximations aiming to improve the type I error rates. The method applies to data where clusters have the same number of measurements for each variable or where one of the variables may be measured once per cluster while the other variable may be measured multiple times. We evaluate the performance of the test statistics through simulation with small sample sizes. The methods are all available in the R package cluscor.

Natural History and Evolution of Anti-Interferon-γ Autoantibody-Associated Immunodeficiency Syndrome in Thailand and the United States.

BACKGROUND: The natural history of anti-interferon-γ (IFN-γ) autoantibody-associated immunodeficiency syndrome is not well understood. METHODS: Data of 74 patients with anti-IFN-γ autoantibodies at Srinagarind Hospital, Thailand, were collected annually (median follow-up duration, 7.5 years). Annual data for 19 patients and initial data for 4 patients with anti-IFN-γ autoantibodies at the US National Institutes of Health were collected (median follow-up duration, 4.5 years). Anti-IFN-γ autoantibody levels were measured in plasma samples. RESULTS: Ninety-one percent of US patients were of Southeast Asian descent; there was a stronger female predominance (91%) in US than Thai (64%) patients. Mycobacterium abscessus (34%) and Mycobacterium avium complex (83%) were the most common nontuberculous mycobacteria in Thailand and the United States, respectively. Skin infections were more common in Thailand (P = .001), whereas bone (P < .0001), lung (P = .002), and central nervous system (P = .03) infections were more common in the United States. Twenty-four percent of Thai patients died, most from infections. None of the 19 US patients with follow-up data died. Anti-IFN-γ autoantibody levels decreased over time in Thailand (P < .001) and the United States (P = .017), with either cyclophosphamide (P = .01) or rituximab therapy (P = .001). CONCLUSIONS: Patients with anti-IFN-γ autoantibodies in Thailand and the United States had distinct demographic and clinical features. While titers generally decreased with time, anti-IFN-γ autoantibody disease had a chronic clinical course with persistent infections and death. Close long-term surveillance for new infections is recommended.

Cardiovascular effects of the post-COVID-19 condition.

Throughout the COVID-19 pandemic, the new clinical entity of the post-COVID-19 condition, defined as a multisystemic condition of persistent symptoms following resolution of an acute severe acute respiratory syndrome coronavirus 2 infection, has emerged as an important area of clinical focus. While this syndrome spans multiple organ systems, cardiovascular complications are often the most prominent features. These include, but are not limited to, myocardial injury, heart failure, arrhythmias, vascular injury/thrombosis and dysautonomia. As the number of individuals with the post-COVID-19 condition continues to climb and overwhelm medical systems, summarizing existing information and knowledge gaps in the complex cardiovascular effects of the post-COVID-19 condition has become critical for patient care. In this Review, we explore the current state of knowledge of the post-COVID-19 condition and identify areas where additional research is warranted. This will provide a framework for better understanding the cardiovascular manifestations of the post-COVID-19 condition with a focus on pathophysiology, diagnosis and management.

The Evolving Role of Echocardiography During the Coronavirus Disease 2019 Pandemic.

Coronavirus disease 2019 (COVID-19) has been associated with a wide spectrum of cardiovascular manifestations. Since the beginning of the pandemic, echocardiography has served as a valuable tool for triaging, diagnosing and managing patients with COVID-19. More recently, speckle-tracking echocardiography has been shown to be effective in demonstrating subclinical myocardial dysfunction that is often not detected in standard echocardiography. Echocardiographic findings in COVID-19 patients include left or right ventricular dysfunction, including abnormal longitudinal strain and focal wall motion abnormalities, valvular dysfunction and pericardial effusion. Additionally, some of these echocardiographic abnormalities have been shown to correlate with biomarkers and adverse clinical outcomes, suggesting an additional prognostic value of echocardiography. With increasing evidence of cardiac sequelae of COVID-19, the use of echocardiography has expanded to patients with cardiopulmonary symptoms after recovery from initial infection. This article aims to highlight the available echocardiographic tools and to summarize the echocardiographic findings across the full spectrum of COVID-19 disease and their correlations with biomarkers and mortality.

Disease Relapse After Drug-Free Remission in Ocular Mucous Membrane Pemphigoid.

PURPOSE: To quantitate the risk of relapse of ocular and extraocular disease among patients with mucous membrane pemphigoid (MMP) who had undergone drug-free remission. DESIGN: Retrospective, comparative, interventional case series. METHODS: There were 167 patients with biopsy-proven MMP who were seen at the Wilmer Eye Institute between November 1984 and December 2019. Among the 167 patients, 119 patients had ocular involvement and 103 of those patients received systemic treatment for MMP. The main outcome measures were the incidence of ocular remission, incidence rate of disease relapse after remission, and risk factors for disease relapse. RESULTS: Over a median follow-up time of 7 years, 74 of 103 treated patients (71.8%) experienced drug-free remission (incidence rate = 0.28/person-year [PY], 95% confidence interval [CI] 0.22-0.35/PY). Most patients (80/103, 77.7%) received cyclophosphamide therapy. Thirteen of the 74 patients (17.6%) had disease relapse after remission: 4 with ocular disease only, 4 with extraocular disease only, and 5 with both. The rate relapse of ocular MMP was 0.020/PY (95% CI 0.009-0.038/PY), and the rate of relapse of MMP at any site (ocular or extraocular site) was 0.029/PY (95% CI 0.015-0.050/PY). The use of cyclophosphamide was associated with a greater chance of remission (hazard ratio [HR] = 3.84, P < .0001) and a lower risk of relapse (HR = 0.32, P = .05) compared with other immunosuppressive drugs except for rituximab. Five patients experienced drug-free remission after rituximab therapy and none of them had relapse (median follow-up after remission = 3.6 years). When use of cyclophosphamide or rituximab was compared with all other treatments, the risk of MMP relapse at any site (HR = 0.17, P = .02) and of ocular MMP (HR = 0.11, P = .007) were significantly lower. CONCLUSIONS: Rates of relapse of MMP after drug-free remission are low but not zero; therefore, monitoring of patients remains necessary. Relapses were not observed among those patients treated with rituximab who had remission; however, follow-up duration in those patients was shorter than the whole MMP cohort and the sample size was small.

Bortezomib treatment for refractory nontuberculous mycobacterial infection in the setting of interferon gamma autoantibodies.

Interferon-γ autoantibodies increase the risk of disseminated nontuberculous mycobacterial infections. Addition of rituximab to antibiotics accelerates and improves outcomes, but refractory infections can occur due to persistent production of autoantibodies. We combined bortezomib with rituximab to reduce autoantibodies leading to clinical and radiographic improvement in infection.

Incidence and Clinical Characteristics of Ocular Involvement in Mucous Membrane Pemphigoid.

Purpose: To describe the risk of developing ocular mucous membrane pemphigoid (MMP) or a new extraocular site of MMP, and to identify risk factors for new involvement. Methods: Retrospective chart review of 162 biopsy-proven MMP patients. Results: At presentation, 109 of 162 MMP patients (67.3%) had ocular involvement and 53 patients did not. Of the 53 patients without ocular involvement at presentation followed up to 22 years, the risk of developing ocular MMP was 0.014 per person-year (PY, 95% confidence interval [CI]: 0.005/PY, 0.034/PY). The risk of developing any new location of extraocular MMP was 0.020/PY (95% CI: 0.007/PY, 0.043/PY). Smoking was a risk factor for developing an additional extraocular MMP location (hazard ratio [HR] = 4.09, p = 0.04). Conclusions: Patients presenting with extraocular MMP are at risk for developing ocular MMP, and all MMP patients are at risk for developing secondary extraocular MMP locations, although the rates were low.

Comparison of Access to Eye Care Appointments Between Patients With Medicaid and Those With Private Health Care Insurance.

Importance: Although low-income populations have more eye problems, whether they face greater difficulty obtaining eye care appointments is unknown. Objective: To compare rates of obtaining eye care appointments and appointment wait times for those with Medicaid vs those with private insurance. Design, Setting, and Participants: In this prospective, cohort study conducted from January 1, 2017, to July 1, 2017, researchers made telephone calls to a randomly selected sample of vision care professionals in Michigan and Maryland stratified by neighborhood (urban vs rural) and professional type (ophthalmologist vs optometrist) to request the first available appointment. Appointments were sought for an adult needing a diabetic eye examination and a child requesting a routine eye examination for a failed vision screening. Researchers called each practice twice, once requesting an appointment for a patient with Medicaid and the other time for a patient with Blue Cross Blue Shield (BCBS) insurance, and asked whether the insurance was accepted and, if so, when the earliest available appointment could be scheduled. Main Outcomes and Measures: Rate of successfully made appointments and mean wait time for the first available appointment. Results: A total of 603 telephone calls were made to 330 eye care professionals (414 calls [68.7%] to male and 189 calls [31.3%] to female eye care professionals). The sample consisted of ophthalmologists (303 [50.2%]) and optometrists (300 [49.8%]) located in Maryland (322 [53.4%]) and Michigan (281 [46.6%]). The rates of successfully obtaining appointments among callers were 61.5% (95% CI, 56.0%-67.0%) for adults with Medicaid and 79.3% (95% CI, 74.7%-83.9%) for adults with BCBS (P < .001) and 45.4% (95% CI, 39.8%-51.0%) for children with Medicaid and 62.5% (95% CI, 57.1%-68.0%) for children with BCBS (P < .001). Mean wait time did not vary significantly between the BCBS and Medicaid groups for both adults and children. Adults with Medicaid had significantly decreased odds of receiving an appointment compared with those with BCBS (odds ratio [OR], 0.41; 95% CI, 0.28-0.59; P < .001) but had increased odds of obtaining an appointment if they were located in Michigan vs Maryland (OR, 2.40; 95% CI, 1.49-3.87; P < .001) or with an optometrist vs an ophthalmologist (OR, 1.91; 95% CI, 1.31-2.79; P < .001). Children with Medicaid had significantly decreased odds of receiving an appointment compared with those with BCBS (OR, 0.41; 95% CI, 0.28-0.60; P < .001) but had increased odds of obtaining an appointment if they were located in Michigan vs Maryland (OR, 1.68; 95% CI, 1.04-2.73; P = .03) or with an optometrist vs an ophthalmologist (OR, 8.00; 95% CI, 5.37-11.90; P < .001). Conclusions and Relevance: Callers were less successful in trying to obtain eye care appointments with Medicaid than with BCBS, suggesting a disparity in access to eye care based on insurance status, although confounding factors may have contributed to this finding. Improving access to eye care professionals for those with Medicaid may improve health outcomes and decrease health care spending in the long term.

Near-infrared lipophilic fluorophores for tracing tissue growth.

Longitudinal monitoring of cell migration, division and differentiation is of paramount importance in cell-based medical treatment. However, currently available optical techniques for tracing cell growth and tissue development are limited in applications due to genetic modification, toxicity and inaccurate detection when utilizing the visible spectrum. We have developed lipophilic near-infrared (NIR) fluorophores with high optical properties and a low background signal that allows longitudinal monitoring of cell proliferation and differentiation. Intracellular labeling efficacy was highly dependent on the physicochemical properties of fluorophores such as lipophilicity, charge, polar surface area and rotational bonds. Among the series of NIR cyanine fluorophores, ESNF 13 showed high solubility in aqueous buffer, high membrane penetration, low cytotoxicity and a long-term signal maintainability with a high signal intensity. This study will guide tissue engineers in designing long-term cell trafficking agents with better physicochemical and optical properties.

Highly charged cyanine fluorophores for trafficking scaffold degradation.

Biodegradable scaffolds have been extensively used in the field of tissue engineering and regenerative medicine. However, noninvasive monitoring of in vivo scaffold degradation is still lacking. In order to develop a real-time trafficking technique, a series of meso-brominated near-infrared (NIR) fluorophores were synthesized and conjugated to biodegradable gelatin scaffolds. Since the pentamethine cyanine core is highly lipophilic, the side chain of each fluorophore was modified with either quaternary ammonium salts or sulfonate groups. The physicochemical properties such as lipophilicity and net charge of fluorophores played a key role in the fate of NIR-conjugated scaffolds in vivo after biodegradation. The positively charged fluorophore-conjugated scaffold fragments were found in salivary glands, lymph nodes, and most of the hepatobiliary excretion route. However, halogenated fluorophores intensively accumulated into lymph nodes and the liver. Interestingly, balanced-charged gelatin scaffolds were degraded into urine in a short period of time. These results demonstrate that the noninvasive optical imaging using NIR fluorophores can be useful for the translation of biodegradable scaffolds into the clinic.

Design considerations for targeted optical contrast agents.

Optical fluorescence imaging with the right combination of imaging modality and targeted contrast agents offers tremendous improvement in intraoperative imaging and clinical output (i.e., image-guided cancer surgery). Therefore, it is of paramount importance to gain an in-depth knowledge in the design of targeted contrast agents to meet clinical requirements. Currently, there are several clinically approved contrast agents available; however, none perform optimally in vivo by providing optimum sensitivity, stability, specificity, and safety for target imaging, diagnosis, and therapy. In this review, we discuss basic design considerations for targeted contrast agents in terms of optical and physicochemical properties, biological and physiological interactions, and biodistribution and targeting.