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Background The emergence of molecular targeted therapies (MTTs) has altered the treatment landscape of hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) metastatic breast cancer (MBC). The objective of this study was to describe treatment patterns, clinical outcomes, and safety profiles among patients with HR+/HER2- MBC treated with palbociclib, abemaciclib, or everolimus in a clinical practice setting. Methods Forty-five patients with HR+/HER2- MBC were enrolled; of these, 40 received molecular targeted therapy (MTT) in ≥3rd lines and 5 received treatment in the 1st/2nd line. The results were compared with clinical trials. Results Median progression-free survival (PFS) in all patients was 5.3 months (95% confidence interval [CI] 2.8-8.4), and a similar PFS was found for patients receiving 1st/2nd line (5.5 months, 95% CI 1.8- ) and ≥ 3rd line (5.1 months, 95% CI 2.8-9.4) treatments. Eleven patients continued with the same regimen for >1 year; treatment is ongoing for 15 patients. In 23 patients (51%), everolimus was administered prior to cyclin-dependent kinase (CDK) 4/6 inhibitors. The most frequent grade 3 or higher adverse event (AE) with CDK4/6 inhibitors was neutropenia, whereas AEs ≥ grade 3 with everolimus included Pneumocystis pneumonia, sepsis, and stomatitis. Conclusions Molecular targeted therapy (MTT) was mostly used in ≥ 3rd lines, and PFS of patients receiving 1st/2nd line and ≥ 3rd line treatments was similar; however, this study included heavily treated patients and a limited number of cases. Treatment options should take into consideration the maximal benefit to the patient based on the results of clinical trials.

Objective Poor sleep quality, such as nocturnal arousal and sleep inefficiency, is associated with frailty and sarcopenia. Herein, we evaluated the relationship between poor sleep quality and locomotive syndrome (LS), a motor organ dysfunction common among community-dwelling middle-aged and older women. Methods Participants comprised 2246 Japanese middle-aged and older women. LS was classified into stages LS-1, LS-2, and LS-3 (from least to most severe) according to the results of the stand-up test, two-step test, and 25-question Geriatric Locomotive Function Scale. Sleep quality was assessed using the Pittsburgh Sleep Quality Index. Results The Pittsburgh Sleep Quality Index scores were significantly higher in the LS group than that in the non-LS group (P Conclusions Poor sleep quality was independently associated with LS among community-dwelling middle-aged and older women. As the stage of LS progressed, the proportion of women with poor sleep quality increased significantly.

PURPOSE To compare the efficacy and safety of a combination therapy of prednisolone and cyclosporine and corticosteroid pulse therapy in Vogt-Koyanagi-Harada (VKH) disease. STUDY DESIGN A prospective, multicenter, randomized, non-inferiority trial. METHODS Patients of new-onset acute VKH disease at 11 centers in Japan between 2014 and 2018 were randomized to a combination (oral prednisolone 60 mg daily with gradual taper-off to 35 mg/day and cyclosporine 3 mg/kg/day) and corticosteroid (methylprednisolone 1000 mg for 3 days followed by oral prednisolone) groups, and were followed for 1 year. RESULTS Thirty-four were assigned to the combination and thirty-six patients to the corticosteroid group. Recurrence/worsening risk was 0.15 (95% confidence-interval [CI] 0.03-0.27) in the combination group and 0.25 (95% CI 0.11-0.39) in the corticosteroid group, with a risk difference of - 0.10 (90% CI - 0.27 to 0.06), demonstrating non-inferiority of the combination group with a non-inferiority margin of 0.20 (P = 0.0013). Serious adverse events occurred in three patients (two with hyponatremia and one with severe headaches) in the combination group and none in the corticosteroid group. Sunset glow fundus grades and cataract rates at 1 year were 0.57 (95% CI 0.42-71) and 4.3% in the combination group and 0.91 (95% CI 0.78-1.04) and 34.0% in the corticosteroid group, respectively. CONCLUSIONS Combination therapy was noninferior to corticosteroid therapy with respect to recurrence/worsening risk. Notably, the recurrence/worsening risk, sunset glow fundus grade, and cataract rate were lower in the combination group than in the corticosteroid group.

A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days post-virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC., After recovery from acute SARS-CoV-2 infection, mice exhibit chronic lung disease similar to some humans, allowing for testing of therapeutics.

Purpose Herpes simplex diffuse endotheliitis with accompanying feathery infiltration is difficult to diagnose due to corneal findings that are similar to fungal keratitis. This case series reports on the effectiveness of using real-time polymerase chain reaction (PCR) to diagnose herpes simplex diffuse endotheliitis that is similar in appearance to fungal keratitis. Methods After extracting corneal smear sample DNA, samples were then applied to two independent PCR assays, a qualitative multiplex 24-pathogen strip PCR assay, and a quantitative real-time PCR assay of herpes simplex virus type 1 (HSV-1). Results All 3 cases showed ciliary injection, feathery infiltration in the corneal stroma and hypopyon, which are corneal findings similar to that observed for fungal keratitis. Retrocorneal plaques, which showed clear boundaries between the corneal endothelial surfaces and retrocorneal plaques in anterior segment optical coherence tomography, were observed in 2 out of 3 cases. Corneal scraping was performed in all cases, followed by initiation of antifungal treatment. However, real-time PCR of the corneal scraping detected 6.0 × 106, 1.0 × 105 and 5.0 × 105 copies/μg glyceraldehyde 3-phosphate dehydrogenase (GAPDH) of HSV-1 DNA per each microgram of the samples. Fungi were not cultured in any of the cases. After switching the medication from antifungal to antiviral, the feathery corneal infiltration was cured with only mild scarring. Conclusions Real-time PCR was an effective tool in diagnosing HSV diffuse endotheliitis with feathery infiltration. Topical corticosteroids in conjunction with oral and topical antivirals were an effective treatment.

Purpose To determine distinguishing features of the clinical characteristics of anterior uveitis (AU) caused by herpes simplex virus (HSV), varicella-zoster virus (VZV), and cytomegalovirus (CMV). Design Retrospective, multicenter case series. Methods Consecutive patients with herpetic AU examined at 11 tertiary centers in Japan between January 2012 and December 2017 and who were followed for ≥3 months were evaluated. Diagnosis was made by polymerase chain reaction (PCR) for HSV, VZV, or CMV in the aqueous humor, or classical signs of herpes zoster ophthalmicus. Results This study enrolled 259 herpetic AU patients, including PCR-proven HSV-AU (30 patients), VZV-AU (50), and CMV-AU (147), and herpes zoster ophthalmicus (32). All HSV-AU and VZV-AU patients were unilateral, while 3% of CMV-AU patients were bilateral. Most HSV-AU and VZV-AU patients were sudden onset with an acute clinical course, while CMV-AU had a more insidious onset and chronic course. There were no significant differences for all surveyed symptoms, signs, and complications between HSV-AU and VZV-AU. However, significant differences were detected for many items between CMV-AU and the other two herpetic AU types. Ocular hyperemia and pain, blurring of vision, ciliary injection, medium-to-large keratic precipitates (KPs), cells and flare in the anterior chamber, and posterior synechia significantly more often occurred in HSV-AU and VZV-AU vs CMV-AU. In contrast, small KPs, coin-shaped KPs, diffuse iris atrophy, elevated intraocular pressure, and glaucoma surgery were significantly more frequent in CMV-AU vs HSV-AU and VZV-AU. Conclusion This multicenter, retrospective study identified distinguishing features of HSV-AU, VZV-AU, and CMV-AU.

Rationale: Identification of the specific cell types expressing CFTR (cystic fibrosis [CF] transmembrane conductance regulator) is required for precision medicine therapies for CF. However, a full ...

Purpose Current polymerase chain reaction (PCR) methods for the diagnosis of infections are time consuming and require large sample volume and skilled technicians. We developed a novel, easy-to-use, and rapid (processing time, 1 minute; total time, 33 minutes) multiplex real-time PCR test (Direct Strip PCR) that did not require DNA extraction to detect 9 pathogens that could cause uveitis in 20-μl samples. Design Multicenter prospective evaluation of a diagnostic PCR test. Participants A total of 511 participants (patients with infectious uveitis and controls) were examined at 18 institutes worldwide. Methods After validation, intraocular fluid samples were subjected to etiologic or exclusive diagnosis, including intraoperative rapid diagnosis. Main Outcome Measures The concordance and correlations between Direct Strip PCR and quantitative PCR (qPCR) results. Results Direct Strip PCR exhibited rapid detection, good repeatability and specificity, long storage stability, and detection ability equal to that of qPCR. It also showed low interinstitutional variability compared with qPCR, even when PCR beginners used various real-time PCR machines. The Direct Strip PCR for 9 pathogens exhibited high concordance against the qPCR (positive concordance rate, 98.8%–100%; negative concordance rate, 99.8%–100%; κ coefficient, 0.969–1.000; P Conclusions The Direct Strip PCR test may improve the prognosis of various infectious diseases because it facilitates rapid etiologic evaluation at the first hospital visit and can be used for intraoperative diagnosis.

Infectious uveitis is a vision-threatening condition that requires prompt clinical diagnosis and proper treatment. However, rapid and proper diagnosis in infectious uveitis remains challenging. Several examination tests, including polymerase chain reaction (PCR) tests, are transitioning from laboratory-based basic research-level tests to bedside clinical tests, and recently tests have changed to where they can be performed right next to clinicians. In this review, we introduce an updated overview of recent studies that are representative of the current trends in clinical microbiological techniques including PCR tests for infectious uveitis.

Purpose: The purpose of this study was to investigate the treatment outcomes of secondary glaucoma caused by cytomegalovirus (CMV)-anterior uveitis (AU) with continuous 0.5% ganciclovir eye drop. Study Design: Retrospective observational study. Place and Duration of Study: Department of Ophthalmology, Oita University Hospital, between January 2012 and December 2017. Methodology: Nineteen eyes of 19 patients with secondary glaucoma associated with CMV-AU diagnosed by a polymerase chain reaction analysis from human aqueous samples were enrolled. They were treated with continuous 4-times-daily topical 0.5% ganciclovir in addition to topical steroids and anti-glaucoma medications. We performed glaucoma surgery for patients with poorly medically controlled intraocular pressure (IOP). Results: Anterior chamber inflammation and IOP were controlled without systemic ganciclovir or glaucoma surgery during the follow-up period (mean: 59.2±27.0 months) in 9 (47%) eyes. Five (26%) eyes required systemic ganciclovir and ten (53%) eyes required glaucoma surgery. Patients were divided into two groups for the comparison: one group requiring glaucoma surgery and one treated with medication. The mean IOP and number of anti-glaucoma medications at the first visit were significantly higher in the surgery group than in the medication group. The mean number of IOP spikes per year (IOP >30 mmHg) was 1.4±0.9 in the surgery group and 0.4±0.5 in the medication group. The recurrence of anterior chamber inflammation was suppressed in both groups. The cumulative survival rate after glaucoma surgery was 80% at 12 months and 70% at 36 months. Conclusion: The anterior chamber inflammation and IOP were controlled with continuous 0.5% ganciclovir eye drop treatment in half of the patients with CNV-AU. A high IOP at the first visit and frequent IOP spikes were risk factors for additional glaucoma surgeries.Cytomegalovirus

COVID-19 survivors develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal samples. Mouse-adapted SARS-CoV-2 MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute disease through clinical recovery. At 15-120 days post-virus clearance, histologic evaluation identified subpleural lesions containing collagen, proliferative fibroblasts, and chronic inflammation with tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal upregulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.

BackgroundOcular toxoplasmosis is common across all regions of the world. Understanding of the epidemiology and approach to diagnosis and treatment have evolved recently. In November 2020, an international group of uveitis-specialised ophthalmologists formed the International Ocular Toxoplasmosis Study Group to define current practice.Methods192 Study Group members from 48 countries completed a 36-item survey on clinical features, use of investigations, indications for treatment, systemic and intravitreal treatment with antiparasitic drugs and corticosteroids, and approach to follow-up and preventive therapy.ResultsFor 77.1% of members, unilateral retinochoroiditis adjacent to a pigmented scar accounted for over 60% of presentations, but diverse atypical presentations were also reported. Common complications included persistent vitreous opacities, epiretinal membrane, cataract, and ocular hypertension or glaucoma. Most members used clinical examination with (56.8%) or without (35.9%) serology to diagnose typical disease but relied on intraocular fluid testing—usually PCR—in atypical cases (68.8%). 66.1% of members treated all non-pregnant patients, while 33.9% treated selected patients. Oral trimethoprim–sulfamethoxazole was first-line therapy for 66.7% of members, and 60.9% had experience using intravitreal clindamycin. Corticosteroid drugs were administered systemically by 97.4%; 24.7% also injected corticosteroid intravitreally, almost always in combination with an antimicrobial drug (72.3%). The majority of members followed up all (60.4%) or selected (35.9%) patients after resolution of acute disease, and prophylaxis against recurrence with trimethoprim–sulfamethoxazole was prescribed to selected patients by 69.8%.ConclusionOur report presents a current management approach for ocular toxoplasmosis, as practised by a large international group of uveitis-specialised ophthalmologists.

To estimate the prevalence of glaucoma and its risk factors in a Japanese community.This study included 3405 Japanese community dwellers who were ≥40 years of age and enrolled in the Hisayama Study. This population-based, cross-sectional study was conducted from 2017 to 2018. A glaucoma screening test was performed using stereo fundus images and swept-source optical coherence tomography. Glaucoma was defined based on the International Society of Geographical and Epidemiological Ophthalmology criteria.The prevalence of glaucoma was 7.6% (95% confidence interval [CI], 6.7-8.6) overall. The prevalence of primary open-angle glaucoma (POAG) was 5.8% (95% CI, 5.0-6.6); that of primary angle-closure glaucoma (PACG) was 0.7% (95% CI, 0.5-1.1); and that of exfoliation glaucoma was 1.1% (95% CI, 0.7-1.4). In addition to aging, lower estimated glomerular filtration rate (eGFR) (odds ratio [OR] = 1.15; 95% CI, 1.02-1.33), higher intraocular pressure (OR = 1.06; 95% CI, 1.01-1.12), longer axial length (OR = 1.44; 95% CI, 1.31-1.59), and thinner central corneal thickness (CCT) (OR = 1.09; 95% CI, 1.04-1.15) were significant risk factors for POAG. Diabetes (OR = 2.81; 95% CI, 1.19-6.62) was a significant risk factor for PACG, and diabetes (OR = 2.15; 95% CI, 1.03-4.47) and thinner CCT (OR = 1.14; 95% CI, 1.02-1.28) were significant risk factors for exfoliation glaucoma.The prevalence of glaucoma was approximately 8%, probably due to the increase in the Japanese aging population. Not only ocular factors but also lower eGFR for POAG and diabetes for PACG and exfoliation glaucoma were risk factors in a general Japanese population.Systemic factors such as eGFR and diabetes must also be considered when implementing preventive measures against glaucoma.

Carriers of functionally deficient mutations in the CYP39A1 gene have been recently reported to have a 2-fold increased risk of exfoliation syndrome (XFS). The aim of this study was to evaluate the risk of blindness and related clinical phenotypes of XFS patients carrying the loss-of-function CYP39A1 G204E mutation in comparison with XFS patients without any CYP39A1 mutation.Retrospective case study.A total of 35 patients diagnosed with XFS carrying the CYP39A1 G204E mutation and 150 XFS patients without any CYP39A1 mutation who were randomly selected from the Japanese XFS cohort.Two-sided Fisher exact test with an alpha level0.05 was used to estimate the significance of the calculated odds ratio (OR) for all categorical measures. Comparisons between groups of subjects were performed using linear mixed effect models with group as random effect and taking possible dependence between eyes within a subject into account.Primary analysis compared the incidence of blindness (defined as visual acuity [VA]0.05 decimal), prevalence of exfoliation glaucoma (XFG), history of glaucoma surgery, and indices of glaucoma severity such as visual field (VF) mean deviation (MD), intraocular pressure (IOP), and vertical cup-disc ratio (CDR) between CYP39A1 G204E carriers and those without any CYP39A1 mutation.The overall risk for blindness was significantly higher in XFS patients carrying the CYP39A1 G204E variant (10/35 [28.6%]) compared with XFS patients without any CYP39A1 mutations (8/150 [5.4%]; odds ratio [OR], 7.1; 95% confidence interval [CI], 2.7-20.2]; P0.001). A higher proportion of XFS patients with the CYP39A1 G204E mutation (23/35 [65.7%]) had evidence of XFG in at least 1 eye compared with the comparison group (41/150 [27.3%]; OR, 5.1; 95% CI, 2.4-11.4]; P0.0001). Significantly higher peak IOP, larger vertical CDR, and worse VF MD were also found in CYP39A1 G204E variant carriers (P0.001). Additionally, patients with the CYP39A1 G204E mutation (18/35 [51.4%]) required more laser or glaucoma surgical interventions compared with those without any CYP39A1 mutation (32/150 [21.3%], P0.001).Patients with XFS carrying the CYP39A1 G204E mutation had significantly increased risk of blindness, higher occurrence of XFG, and more severe glaucoma compared with patients with XFS without any CYP39A1 mutation.

Background Fulvestrant 500 mg has been an option for endocrine therapy for advanced or recurrent breast cancer after prior endocrine treatment since November 2011 in Japan. This study aimed to clarify the effectiveness and safety of fulvestrant 500 mg in clinical settings. Methods This was a multicenter, both prospective and retrospective, observational study of 132 postmenopausal women (median age 66) with locally advanced or metastatic breast cancer, who had been treated with fulvestrant. Information from medical records was retrospectively obtained from 9 hospitals (Saitama Breast Cancer Clinical Study Group: SBCCSG) in Saitama prefecture, Japan, from October 2012 to April 2014. The primary end point was time to treatment failure (TTF). The secondary end points were overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and adverse events (AE) (CTCAE ver. 4). The choice of subsequent therapy after fulvestrant was also evaluated. Results The median TTF was 6.1 months. Median OS was 28.5 months (the starting date was the first day of fulvestrant). ORR was 12.9% and CBR was 45.5%. The most common AEs were injection site reactions (9.1%). The rate of grade 3 AE was only 2.3% (3/132). The number of patients who underwent subsequent therapy after fulvestrant were 54 (55.7%) receiving chemotherapy, 42 (43.3%) receiving non-fulvestrant endocrine therapy, and 1 (1%) receiving mammalian target of rapamycin inhibitor (mTORi) + endocrine therapy (ET). Conclusion Fulvestrant 500 mg is an effective and safe treatment for patients with advanced or recurrent breast cancer after prior endocrine treatment.

Mapping the spatial distribution and molecular identity of constituent cells is essential for understanding tissue dynamics in health and disease. We lack a comprehensive map of human distal airways, including the terminal and respiratory bronchioles (TRBs), which are implicated in respiratory diseases1-4. Here, using spatial transcriptomics and single-cell profiling of microdissected distal airways, we identify molecularly distinct TRB cell types that have not-to our knowledge-been previously characterized. These include airway-associated LGR5+ fibroblasts and TRB-specific alveolar type-0 (AT0) cells and TRB secretory cells (TRB-SCs). Connectome maps and organoid-based co-cultures reveal that LGR5+ fibroblasts form a signalling hub in the airway niche. AT0 cells and TRB-SCs are conserved in primates and emerge dynamically during human lung development. Using a non-human primate model of lung injury, together with human organoids and tissue specimens, we show that alveolar type-2 cells in regenerating lungs transiently acquire an AT0 state from which they can differentiate into either alveolar type-1 cells or TRB-SCs. This differentiation programme is distinct from that identified in the mouse lung5-7. Our study also reveals mechanisms that drive the differentiation of the bipotent AT0 cell state into normal or pathological states. In sum, our findings revise human lung cell maps and lineage trajectories, and implicate an epithelial transitional state in primate lung regeneration and disease.

To compare the efficacy and safety of a combination therapy of prednisolone and cyclosporine and corticosteroid pulse therapy in Vogt-Koyanagi-Harada (VKH) disease.A prospective, multicenter, randomized, non-inferiority trial.Patients of new-onset acute VKH disease at 11 centers in Japan between 2014 and 2018 were randomized to a combination (oral prednisolone 60 mg daily with gradual taper-off to 35 mg/day and cyclosporine 3 mg/kg/day) and corticosteroid (methylprednisolone 1000 mg for 3 days followed by oral prednisolone) groups, and were followed for 1 year.Thirty-four were assigned to the combination and thirty-six patients to the corticosteroid group. Recurrence/worsening risk was 0.15 (95% confidence-interval [CI] 0.03-0.27) in the combination group and 0.25 (95% CI 0.11-0.39) in the corticosteroid group, with a risk difference of - 0.10 (90% CI - 0.27 to 0.06), demonstrating non-inferiority of the combination group with a non-inferiority margin of 0.20 (P = 0.0013). Serious adverse events occurred in three patients (two with hyponatremia and one with severe headaches) in the combination group and none in the corticosteroid group. Sunset glow fundus grades and cataract rates at 1 year were 0.57 (95% CI 0.42-71) and 4.3% in the combination group and 0.91 (95% CI 0.78-1.04) and 34.0% in the corticosteroid group, respectively.Combination therapy was noninferior to corticosteroid therapy with respect to recurrence/worsening risk. Notably, the recurrence/worsening risk, sunset glow fundus grade, and cataract rate were lower in the combination group than in the corticosteroid group.

Polymerase chain reaction (PCR) can be used to confirm or deny infectious ocular inflammation such as uveitis. The purpose of this article is to review the current practical use of PCR examination in ophthalmology, especially multiplex and broad-range PCR, and a novel PCR, termed Strip PCR. At first, in the Introduction, we show the development of the PCR examination in ophthalmology. We next show the clinical applications of multiplex PCR and broad-range PCR. These advances in PCR continue to contribute greatly to the ophthalmology field. We also show how the sample for PCR is collected. Recently, we established a novel examination, a multiplex real-time PCR (Strip PCR) prototype for detecting 24 pathogens responsible for ocular infectious diseases. Moreover, we developed the Direct Strip PCR method, which skips the DNA extraction step in the procedure. This PCR is anticipated to ease etiologic evaluation, increasing pathogen detection in the intraocular fluids of uveitis patients even by general ophthalmologists. We also describe the following: (1) representative cases in which PCR is useful, (2) representative cases in which PCR can exclude a diagnosis, (3) the current status of PCR in the diagnosis of infectious uveitis and advanced medical service, and (4) the prospects for clinical PCR in ophthalmology. We have established and developed the multiplex PCR, broad-range PCR, Strip PCR, and Direct Strip PCR methods and have reported the efficacy of such tests in multicenter studies. Our goal is “rapid and simple comprehensive PCR diagnosis anywhere and by anyone” for ocular infections.

Current polymerase chain reaction (PCR) methods for the diagnosis of infections are time consuming and require large sample volume and skilled technicians. We developed a novel, easy-to-use, and rapid (processing time, 1 minute; total time, 33 minutes) multiplex real-time PCR test (Direct Strip PCR) that did not require DNA extraction to detect 9 pathogens that could cause uveitis in 20-μl samples.Multicenter prospective evaluation of a diagnostic PCR test.A total of 511 participants (patients with infectious uveitis and controls) were examined at 18 institutes worldwide.After validation, intraocular fluid samples were subjected to etiologic or exclusive diagnosis, including intraoperative rapid diagnosis.The concordance and correlations between Direct Strip PCR and quantitative PCR (qPCR) results.Direct Strip PCR exhibited rapid detection, good repeatability and specificity, long storage stability, and detection ability equal to that of qPCR. It also showed low interinstitutional variability compared with qPCR, even when PCR beginners used various real-time PCR machines. The Direct Strip PCR for 9 pathogens exhibited high concordance against the qPCR (positive concordance rate, 98.8%-100%; negative concordance rate, 99.8%-100%; κ coefficient, 0.969-1.000; P0.001-0.031). Additionally, results obtained using Direct Strip PCR and qPCR were highly correlated (ρ = 0.748; P0.001). This assay was used for rapid intraoperative diagnosis.The Direct Strip PCR test may improve the prognosis of various infectious diseases because it facilitates rapid etiologic evaluation at the first hospital visit and can be used for intraoperative diagnosis.

The mode of acquisition and causes for the variable clinical spectrum of coronavirus disease 2019 (COVID-19) remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest angiotensin-converting enzyme 2 (ACE2) expres-sion in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) versus distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-in-fected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings high-light the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host in-teractions in protective immunity, host susceptibility, and virus pathogenesis.

Background Axillary staging is important for predicting prognosis, and for local control in early breast cancer. Sentinel lymph node biopsy (SLNB) is a widely accepted method to avoid unnecessary axillary lymph node dissection (ALND). Since the ACOSOG Z0011 trial was published, we have refrained from ALND for selected patients with positive SLNB results. However, some cases have shown regional lymph node recurrences after SLNB without axillary dissection. The purpose of this study is to identify risk factors for recurrences, to ensure a safe axillary surgery. Methods A retrospective review of 1011 patientswho underwent SLNB without ALND between June 2004 and March 2017 was performed. Since October 2012, we have not performed ALND in patients (a) with 1 or 2 positive sentinel lymph nodes (SLNs), (b) with positive SLNs that are unmatted or not gross extra nodal extension, (C) in whom clinical tumor size is Results Of the 1011 patients, 969 had negative and 42 had positive SLNs. The median age of patients was 59 years (range 21-88). The median invasive breast tumor size was 15 mm (range 0.05-85), with 1.9% tumors being pathological T3 lesions; 127 patients (12.3%) developed lymphatic vessel invasion. SLNs identification rate was 99.4%. The median number of SLNs removed per patient was 2 (range 1-7). After follow-up of a median 78.5 months, 10 patients (1.0%) had an axillary recurrence and all of them had negative SLN metastasis. The median time to axillary recurrence was 26 months (range 9-94). The hormone receptor (HR) status was significantly related to axillary recurrence (p=0.008). While triple negativity had a tendency to relate (p=0.06), human epidermal growth factor receptor 2 (HER2) status did not correlate with axillary recurrence (p=0.13). Tumor subtypes and axillary recurrence SLNB without ALND (n=1011)Axillary recurrenceP valueHR positive72650.009HR negative1615 HER2 positive12130.13HER2 negative7667 Triple Negative10030.06Not Triple Negative7877 DCIS1240 DCIS: Ductal carcinoma in situ Conclusions As reported previously, the axillary recurrence rate after SLNB was low. Our results show that HR negativity was a significant factor for axillary recurrence. Although the ACOSOG Z0011 trial criteria focused on ALNB positive cases, they do not mention the tumor subtypes. Our findings show that HR negative patients without ALND have to follow up carefully. Citation Format: Sekine C, Nakano S, Mibu A, Otsuka M, Oinuma T. Hormone receptor status is a predictive factor for axillary lymph node recurrence after sentinel lymph node biopsy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-22-15.

International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Purpose A novel multiplex polymerase chain reaction (PCR) test (Strip PCR) for 24 common ocular infectious disease pathogens was established. Solid-phase techniques provide stable, prompt, and accurate results while using less sample amount with lower cost than conventional quantitative real-time PCR (qPCR). Strip PCR for infectious uveitis was optimized and evaluated using intraocular samples. Design Evaluation of diagnostic testing. Methods We examined 722 samples at 14 institutions. Genomic DNA from aqueous humor and vitreous fluid was analyzed by qPCR and Strip PCR. Clinical diagnosis was determined based on symptoms, clinical findings, and laboratory tests. M ain O utcome M easures : The diagnostic parameters of the Strip PCR were based on qPCR results. Results Strip PCR showed low intra- and inter-institutional variability even when performed by technicians with various PCR skill levels. The targets of Strip PCR for infectious uveitis were optimized for 9 major pathogens (herpes simplex virus [HSV] 1, HSV2, varicella-zoster virus, human T-cell lymphotropic virus 1, human herpesvirus 6, Epstein-Barr virus, cytomegalovirus, Toxoplasma gondii, and Treponema pallidum) with 772 intraocular samples. The Strip PCR successfully detected pathogen DNA at concentrations ranging from 100 to 109 copies/mL in 252 of the 255 qPCR-positive samples. It yielded negative results for all the 191 qPCR-negative samples. Strip PCR had higher sensitivity (98.8%), specificity (98.5%), positive predictive value (98.8%), and negative predictive value (98.5%) than qPCR, with distinct primers. The Strip PCR results had strong correlation with that of the qPCR (r = 0.838) and they were consistent with the clinical diagnosis. Conclusions Easy-to-use Strip PCR is recommended for rapid diagnosis of infectious uveitis, as its results are equivalent to that of conventional qPCR.

IMPORTANCE Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. OBJECTIVE To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. DESIGN, SETTING, AND PARTICIPANTS A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. EXPOSURES Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. MAIN OUTCOMES AND MEASURES The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 x 10(-6). The secondary outcomes included biochemical enzymatic assays and gene expression analyses. RESULTS The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 x 10(-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4%[interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. CONCLUSIONS AND RELEVANCE In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings. National Research Foundation of SingaporeNational Research Foundation, Singapore [NRF-NRFI2018-01]; US National Eye Institute of the National Institutes of Health [R01 EY020928, P30 EY014104, UM1 CA186107, U01 CA167552, EY015473]; Glaucoma Research Foundation of Canada [X052, CIRG17may053]; National Medical Research Council of SingaporeNational Medical Research Council, Singapore The study was funded by grant NRF-NRFI2018-01 from the National Research Foundation of Singapore. Additional support was provided by grants R01 EY020928, P30 EY014104, UM1 CA186107, U01 CA167552, and EY015473 from the US National Eye Institute of the National Institutes of Health, funding from the Glaucoma Research Foundation of Canada, and grants X052 and CIRG17may053 from the National Medical Research Council of Singapore.

Highlights • Spontaneous cancer remission without treatment is a known phenomenon with various types of cancer. • Although spontaneous breast cancer remission has been thought to be a rare, this may occurs at a certain rate(not rare phenomenon). • When cancer was not detected in the pathological specimen and there were no known biological markers to provide information for the decision regarding adjuvant therapy, observation without further treatment can be option., Introduction Spontaneous breast cancer remission is a rare phenomenon. We report the disappearance from the remaining breast of a new primary carcinoma that had been confirmed through cytology of a pathological specimen, in a case that is strongly suspected to be spontaneous remission. Presentation of case A 44-year-old woman underwent breast-conserving surgery for a tumor located on the border between the upper-outer and lower-outer quadrants of the left breast (T2, N1, M0; Stage IIB). Eleven years after surgery, computed tomography indicated a mass in the upper-inner quadrant of the left breast. Excisional biopsy was initially planned for treatment following the definitive diagnosis because cytology revealed malignancy. The patient had noticed tumor regression one month after fine-needle aspiration and repeat ultrasonography performed the day before excisional biopsy confirmed the tumor reduction. On pathological examination, no tumor cells were observed in the mass. Discussion There was a discrepancy between FNA cytology and pathological diagnosis in our patient. The cytological findings indicated malignancy, but the pathological findings did not. When a tumor’s pathological diagnosis is not malignant even though its FNA cytology diagnosis was malignant, sampling error, cytological over-diagnosis or some other error may have occurred. In this case, however, these were not detected. Because fibrosis was visible on pathological examination, we believe that these events corresponded to spontaneous remission. Conclusion We report a rare case of spontaneous remission in which the cancer disappeared on pathological examination although the cytological diagnosis had been malignant.

Needle biopsy has replaced excisional biopsy as a definitive diagnostic technique for breast tumours, although excisional biopsy is still used for complete tumour removal for therapeutic and/or diagnostic purposes. Many vacuum-assisted breast biopsy (VAB) systems have been made available by several manufacturers since the release of the Mammotome (MMT) by Johnson & Johnson in 1995. Several recent discussions have been conducted to identify whether core needle biopsy (CNB) or VAB, is more appropriate. However, currently available VAB systems differ from the conventional system (i.e. articulate arm type 11-gauge(G) MMT), and the characteristics of both CNB and VAB have been improved. In CNB, a 14-G needle is frequently used to obtain a larger sample. By contrast, VAB is considered easier to perform because it uses a thinner needle and a lighter, non-tethered system. When differentiating CNB from VAB, the type of VAB should also be defined. In this review, we discuss the characteristics of ultrasonography-guided VAB and CNB with a focus on practical issues such as the number of samples and volume of tissue obtained during ultrasonography-guided needle biopsy.

Background Sedentary behavior increases the risks of obesity and cardiovascular disease in adults, but these relationships are uncertain in elementary and junior high school students. We investigated whether sedentary behavior is related to overweight status and obesity in high-risk children with lifestyle diseases. Method A cross-sectional study was performed in 115 children and primary caregivers who attended a lecture for preventing child lifestyle diseases in Ibaraki prefecture, Japan. The main outcome measure was excess weight (percent overweight). Factors associated with excess weight in children were evaluated using multiple regression analysis. Basic physical and demographic characteristics, biochemical data (total cholesterol [TC], low and high density lipoprotein cholesterol [LDL-C and HDL-C], alanine aminotransferase [ALT]), blood pressure, child and parental sedentary time, parental BMI, and family environment were evaluated. Results In total, 107 children were eligible for participation in the study. Excess weight in these children was 28.6 ± 18.4. Sedentary time was 337.2 ± 122.5 min/day in children and 347.0 ± 196.2 min/day in parents. Multiple regression analysis revealed that children's sedentary behavior (β = 0.02, (95%CI: 0.00 to 0.04)) and HDL-C (β = -0.59, (95%CI: -0.81 to -0.38)) as independent predictors of children's excess weight. Conclusion Study findings suggest that decreasing children's sedentary behavior in addition to greater physical activity is important for the prevention of overweight status and obesity in high-risk children with lifestyle diseases. Reduction of sedentary time, and engaging in regular exercise are all important for proper weight maintenance in children.

Purpose. To perform multivariate analysis for identifying independent predictors of elevated intraocular pressure (IOP) with neovascular glaucoma (NVG), including antivascular endothelial growth factor (VEGF) intravitreal injections.Methods. We retrospectively reviewed 142 NVG patients (181 eyes) with ischemic retinal diseases [proliferative diabetic retinopathy (PDR) in 134 eyes, retinal vein occlusion (RVO) in 29, and ocular ischemic syndrome in 18]. We analyzed age, gender, initial/final LogMAR VA, initial/final IOP, extent of iris and/or angle neovascularization, treatments, preexisting complications, concurrent medications, and follow-up duration.Results. The mean follow-up duration was 23.8 ± 18.8 months. At the final follow-up, 125 (72.3%) eyes had IOP ≤ 21 mmHg. NVG patients with RVO had a higher degree of angle closure and higher IOP. NVG with PDR had better IOP and LogMAR VA. Angle closure had the greatest impact on final IOP. Greater than 90% of patients treated with trabeculectomy with mitomycin C (LEC) had persistent declines in IOP (≤21 mmHg). Stand-alone and combination anti-VEGF therapies were not associated with improved long-term prognosis of IOP.Conclusions. Angle closure was found to have the greatest effect on NVG-IOP prognosis. When target IOP values are not obtained after adequate PRP with or without anti-VEGF, early LEC may improve the prognosis of IOP.