Spontaneous Activity of Cochlear Hair Cells Triggered by Fluid Secretion Mechanism in Adjacent Support Cells.

Spontaneous electrical activity of neurons in developing sensory systems promotes their maturation and proper connectivity. In the auditory system, spontaneous activity of cochlear inner hair cells (IHCs) is initiated by the release of ATP from glia-like inner supporting cells (ISCs), facilitating maturation of central pathways before hearing onset. Here, we find that ATP stimulates purinergic autoreceptors in ISCs, triggering Cl(-) efflux and osmotic cell shrinkage by opening TMEM16A Ca(2+)-activated Cl(-) channels. Release of Cl(-) from ISCs also forces K(+) efflux, causing transient depolarization of IHCs near ATP release sites. Genetic deletion of TMEM16A markedly reduces the spontaneous activity of IHCs and spiral ganglion neurons in the developing cochlea and prevents ATP-dependent shrinkage of supporting cells. These results indicate that supporting cells in the developing cochlea have adapted a pathway used for fluid secretion in other organs to induce periodic excitation of hair cells.

CD39 Is Expressed on Functional Effector and Tissue-resident Memory CD8+ T Cells.

The ecto-ATPase CD39 is expressed on exhausted CD8+ T cells in chronic viral infection and has been proposed as a marker of tumor-specific CD8+ T cells in cancer, but the role of CD39 in an effector and memory T cell response has not been clearly defined. We report that CD39 is expressed on Ag-specific CD8+ short-lived effector cells, while it's co-ectoenzyme, CD73, is found on memory precursor effector cells (MPECs) in vivo. Inhibition of CD39 enzymatic activity during in vitro T cell priming enhances MPEC differentiation in vivo after transfer and infection. The enriched MPEC phenotype is associated with enhanced tissue resident memory T cell (TRM cell) establishment in the brain and salivary gland following an acute intranasal viral infection, suggesting that CD39 ATPase activity plays a role in memory CD8+ T cell differentiation. We also show that CD39 is expressed on human and murine TRM cells across several nonlymphoid tissues and melanoma, whereas CD73 is expressed on both circulating and resident memory subsets in mice. In contrast to exhausted CD39+ T cells in chronic infection, CD39+ TRM cells are fully functional when stimulated ex vivo with cognate Ag, further expanding the identity of CD39 beyond a T cell exhaustion marker.

Cancer treatment and survivorship statistics, 2016.

The number of cancer survivors continues to increase because of both advances in early detection and treatment and the aging and growth of the population. For the public health community to better serve these survivors, the American Cancer Society and the National Cancer Institute collaborate to estimate the number of current and future cancer survivors using data from the Surveillance, Epidemiology, and End Results cancer registries. In addition, current treatment patterns for the most prevalent cancer types are presented based on information in the National Cancer Data Base and treatment-related side effects are briefly described. More than 15.5 million Americans with a history of cancer were alive on January 1, 2016, and this number is projected to reach more than 20 million by January 1, 2026. The 3 most prevalent cancers are prostate (3,306,760), colon and rectum (724,690), and melanoma (614,460) among males and breast (3,560,570), uterine corpus (757,190), and colon and rectum (727,350) among females. More than one-half (56%) of survivors were diagnosed within the past 10 years, and almost one-half (47%) are aged 70 years or older. People with a history of cancer have unique medical and psychosocial needs that require proactive assessment and management by primary care providers. Although there are a growing number of tools that can assist patients, caregivers, and clinicians in navigating the various phases of cancer survivorship, further evidence-based resources are needed to optimize care. CA Cancer J Clin 2016;66:271-289. © 2016 American Cancer Society.

Suppression of Experimental Autoimmune Encephalomyelitis by ILT3.Fc.

Multiple sclerosis (MS) is a chronic autoimmune disease of the CNS that is characterized by demyelination, axonal loss, gliosis, and inflammation. The murine model of MS is the experimental autoimmune encephalopathy (EAE) induced by immunization of mice with myelin oligodendrocyte glycoprotein (MOG)35-55 Ig-like transcript 3 (ILT3) is an inhibitory cell surface receptor expressed by tolerogenic human dendritic cells. In this study, we show that the recombinant human ILT3.Fc protein binds to murine immune cells and inhibits the release of proinflammatory cytokines that cause the neuroinflammatory process that result in paralysis. Administration of ILT3.Fc prevents the rapid evolution of the disease in C57BL/6 mice and is associated with a profound reduction of proliferation of MOG35-55-specific Th1 and Th17 cells. Inhibition of IFN-γ and IL-17A in mice treated with ILT3.Fc is associated with delayed time of onset of the disease and its evolution to a peak clinical score. Neuropathological analysis shows a reduction in inflammatory infiltrates and demyelinated areas in the brains and spinal cords of treated mice. These results indicate that inhibition of Th1 and Th17 development provides effective suppression of EAE and suggests the feasibility of a clinical approach based on the use of ILT3.Fc for treatment of MS. Furthermore, our results open the way to further studies on the effect of the human ILT3.Fc protein in murine experimental models of autoimmunity and cancer.

A Validated Method to Identify Neuro-Ophthalmologists in a Large Administrative Claims Database.

BACKGROUND: Validated methods to identify neuro-ophthalmologists in administrative data do not exist. The development of such method will facilitate research on the quality of neuro-ophthalmic care and health care utilization for patients with neuro-ophthalmic conditions in the United States. METHODS: Using nationally representative, 20% sample from Medicare carrier files from 2018, we identified all neurologists and ophthalmologists billing at least 1 office-based evaluation and management (E/M) outpatient visit claim in 2018. To isolate neuro-ophthalmologists, the National Provider Identifier numbers of neuro-ophthalmologists in the North American Neuro-Ophthalmology Society (NANOS) directory were collected and linked to Medicare files. The proportion of E/M visits with International Classification of Diseases-10 diagnosis codes that best distinguished neuro-ophthalmic care ("neuro-ophthalmology-specific codes" or NSC) was calculated for each physician. Multiple logistic regression models assessed predictors of neuro-ophthalmology specialty designation after accounting for proportion of ophthalmology, neurology, and NSC claims and primary specialty designation. Sensitivity, specificity, and positive predictive value (PPV) for varying proportions of E/M visits with NSC were calculated. RESULTS: We identified 32,293 neurologists and ophthalmologists who billed at least 1 outpatient E/M visit claim in 2018 in Medicare. Of the 472 NANOS members with a valid individual National Provider Identifier, 399 (84.5%) had a Medicare outpatient E/M visit in 2018. The model containing only the proportion of E/M visits with NSC best predicted neuro-ophthalmology specialty designation (odds ratio 1.05 [95% confidence interval 1.04, 1.05]; P < 0.001; area under the receiver operating characteristic [AUROC] = 0.91). Model predictiveness for neuro-ophthalmology designation was maximized when 6% of all billed claims were for NSC (AUROC = 0.89; sensitivity: 84.0%; specificity: 93.9%), but PPV was low (14.9%). The threshold was unchanged when limited only to neurologists billing ≥1% ophthalmology claims or ophthalmologists billing ≥1% neurology claims, but PPV increased (33.3%). CONCLUSIONS: Our study provides a validated method to identify neuro-ophthalmologists who can be further adapted for use in other administrative databases to facilitate future research of neuro-ophthalmic care delivery in the United States.

Sociodemographic and Geographic Variation in Access to Neuro-Ophthalmologists in the United States.

BACKGROUND: Neuro-ophthalmologists have expertise in rare and complex disorders, but the ability of patients to access neuro-ophthalmic care has not been examined at a nationwide level. METHODS: Using the 2020 directory of all 502 members of the North American Neuro-Ophthalmology Society as a reference, we found the practice locations of 461 confirmed practicing members and converted each street address to latitude and longitude coordinates. We calculated the travel distance and time from each census tract to the nearest practice location and calculated population-weighted averages by state, region, and other prespecified factors. Choropleth maps were used to visualize the distribution of travel distances and times across the United States. RESULTS: California had the most practicing neuro-ophthalmologists out of any state (50), whereas 4 states (DE, MT, SD, and WY) had none. Washington, DC and MA had the most neuro-ophthalmologists per capita. The average travel distance and time to the nearest neuro-ophthalmologists were found to be 40.90 miles and 46.50 minutes, respectively, although a large portion of western plains and mountain regions had travel times of over 120 minutes. Patients in rural areas had longer travel times than those in urban areas, and Native American patients had the longest travel times of any racial or ethnic group. CONCLUSION: The travel time to see a neuro-ophthalmologist varies widely by state, region, and rurality, with Native American patients and rural patients being disproportionately affected. By identifying the areas with the greatest travel burdens, future policies can work to alleviate these potential barriers to care.

Mutational Landscape and Outcomes of Conjunctival Melanoma in 101 Patients.

PURPOSE: To evaluate targetable mutations and molecular genetic pathways in conjunctival melanoma with clinical correlation. DESIGN: Observational case series. PARTICIPANTS: Patients with conjunctival melanoma. MAIN OUTCOME MEASURES: Mutational profile of the tumor by next-generation sequencing (NGS), alternative lengthening of telomeres (ALT) by fluorescence in situ hybridization (FISH), and ATRX immunohistochemistry. Outcomes at 2 years and 5 years of tumor-related metastasis and death were recorded. RESULTS: Of the 101 patients, mean age at presentation was 60 years, 52% were male, and 88% were White. The NGS panels initially targeted BRAF only (n = 6, 6%), BRAF/NRAS (n = 17, 17%), and BRAF/NRAS/NF1 (n = 10, 10%). Sixty-eight tumors were tested with the expanded 592-gene panel. Next-generation sequencing identified high-frequency mutations in NF1 (29/74, 39%), BRAF (31/101, 31%), NRAS (25/95, 26%), and ATRX (17/68, 25%). Of those with an ATRX mutation, 12 (71%) had an additional NF1 mutation. A subset analysis of 21 melanomas showed that the ATRX mutation was associated with loss of ATRX protein expression and ALT. Loss of ATRX expression and ALT were present in both intraepithelial and invasive tumors, suggesting that an ATRX mutation is an early event in conjunctival melanoma progression. The NF1 and ATRX mutations were associated with tarsal (vs. nontarsal) tumors (NF1: 28% vs. 9%, P = 0.035, ATRX: 41% vs. 14%, P = 0.021) and orbital (vs. nonorbital) tumors (ATRX: 24% vs. 2%, P = 0.007). ATRXMUT (vs. ATRXWT) tumors were associated with a lower 2-year rate of metastasis (0% vs. 24%, P = 0.005). NRASMUT (vs. NRASWT) tumors were associated with a greater 2-year rate of metastasis (28% vs. 14%, P = 0.07) and death (16% vs. 4%, P = 0.04), with a 5-fold increased risk of death (relative risk, 5.45 [95% confidence interval, 1.11-26.71], P = 0.039). CONCLUSIONS: This study confirms the high frequency of previously documented BRAF and NRAS mutations and recently reported ATRX and NF1 mutations in conjunctival melanoma. An NRAS mutation implied increased risk for metastasis and death. Loss of ATRX and ALT may be early events in conjunctival melanoma development.

The utility of the bilateral temporal artery biopsy for diagnosis of giant cell arteritis.

OBJECTIVE: A surgical temporal artery biopsy (TAB) is the gold standard for diagnosis of giant cell arteritis (GCA). The necessity of performing a bilateral biopsy remains under debate. The primary objective of this study was to assess the rate of discordance between pathology results in patients who underwent bilateral TAB for suspected GCA. METHODS: We performed a retrospective review of patients who underwent bilateral TAB for the diagnosis of GCA between 2011 and 2020. The primary end point was the rate of discordance between specimens for patients with pathology positive GCA. Secondary end points included assessments of the sensitivity of preoperative temporal artery duplex and the effects of specimen length and specialty of referring provider on the diagnostic yield of the biopsy. RESULTS: During the study period, 310 patients underwent bilateral TAB for the diagnosis of GCA. These patients were primarily female (73.9%), elderly (mean age, 70.8 years), and Caucasian (95.8%). Preoperative symptoms for patients were typically bilateral (59%) and included headache (81%), vision changes (45.2%), and temporal tenderness (32.6%). Most patients (85.2%) were on preoperative steroid therapy at the time of surgical biopsy with a mean preoperative duration of steroid therapy of 15.1 days. Overall, 91 patients (29.4%) had a positive pathologic diagnosis after bilateral TAB. Of these patients, 11 had a positive pathology result in only a single specimen, resulting in a discordance rate of 12.1%. Preoperative temporal artery duplex demonstrated a low sensitivity (27.3%) for identifying patients with pathologic positive disease. There were no significant differences between the pathology-positive and -negative patients in terms of mean surgical specimen length (1.67 cm vs 1.64 cm; P = .67) or the specialty of the referring provider (P = .73). CONCLUSIONS: At our institution, we observed a 12.1% discordance rate between pathology results in patients who underwent bilateral TAB for diagnosis of GCA. A preoperative temporal artery duplex provided little value in identifying patients with biopsy-proven GCA.

Community Intent to Activate Emergency Medical Services May Be Associated with Regional tPA Treatment.

INTRODUCTION: Acute stroke treatments are underutilized in the USA. Enhancing stroke preparedness, the recognition of stroke symptoms, and intent to call emergency medical services (EMS) could reduce delay in hospital arrival thereby increasing eligibility for time-sensitive stroke treatments. Whether higher stroke preparedness is associated with higher tissue plasminogen activator (tPA) treatment rates is however uncertain. We therefore set out to determine the contribution of stroke preparedness to regional variation in tPA treatment. METHODS: The region was defined by hospital service area (HSA). Stroke preparedness was determined by using Behavioral Risk Factor Surveillance System survey questions assessing stroke symptom recognition and intent to call 911 in response to a stroke. We used Medicare data to determine the percentage of tPA-treated hospitalized stroke patients in 2007, 2009, and 2011, adjusting for number of stroke hospitalizations in each HSA (primary outcome). We performed multivariate linear regression to estimate the association of regional stroke preparedness on log-transformed tPA treatment rates controlling for demographic, EMS, and hospital characteristics. RESULTS: The adjusted percentage of stroke patients receiving tPA ranged from 1.4% (MIN) to 11.3% (MAX) of stroke/TIA hospitalizations. Across HSAs, a median (IQR) of 86% (81-90%) of responses to a witnessed stroke indicated intent to call 911, and a median (IQR) of 4.4 (4.2-4.6) out of 6 stroke symptoms was recognized. Every 1% increase in an HSA's intent to call 911 was associated with a 0.44% increase in adjusted tPA treatment rate (p = 0.05). Lower accuracy of recognition of stroke symptoms was associated with higher adjusted tPA treatment rates (p = 0.05). CONCLUSIONS: There was little regional variation in intent to call EMS and stroke symptom recognition. Intent to call EMS and stroke symptom recognition are modest contributors to regional variation in tPA treatment.

Cancer statistics: Breast cancer in situ.

An estimated 60,290 new cases of breast carcinoma in situ are expected to be diagnosed in 2015, and approximately 1 in 33 women is likely to receive an in situ breast cancer diagnosis in her lifetime. Although in situ breast cancers are relatively common, their clinical significance and optimal treatment are topics of uncertainty and concern for both patients and clinicians. In this article, the American Cancer Society provides information about occurrence and treatment patterns for the 2 major subtypes of in situ breast cancer in the United States-ductal carcinoma in situ and lobular carcinoma in situ-using data from the North American Association of Central Cancer Registries and the 13 oldest Surveillance, Epidemiology, and End Results registries. The authors also present an overview of in situ breast cancer detection, treatment, risk factors, and prevention and discuss research needs and initiatives.

COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital.

Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical centre. The mean age was 74 years (38-97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit. Hospital-associated complications were common, including eight patients (20%) with deep vein thrombosis/pulmonary embolism, seven (17%) with acute kidney injury requiring dialysis and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 h of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20-30 areas from each brain revealed hypoxic/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, although none showed evidence of vasculitis. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases, which was not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR, RNAscope® and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleocapsid regions. The PCR analysis revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in the nasal epithelia. RNAscope® and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in coronavirus disease 2019 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischaemia. Further studies are needed to define whether these pathologies, if present in patients who survive coronavirus disease 2019, might contribute to chronic neurological problems.

Cancer treatment and survivorship statistics, 2014.

The number of cancer survivors continues to increase due to the aging and growth of the population and improvements in early detection and treatment. In order for the public health community to better serve these survivors, the American Cancer Society and the National Cancer Institute collaborated to estimate the number of current and future cancer survivors using data from the Surveillance, Epidemiology, and End Results (SEER) program registries. In addition, current treatment patterns for the most common cancer types are described based on information in the National Cancer Data Base and the SEER and SEER-Medicare linked databases; treatment-related side effects are also briefly described. Nearly 14.5 million Americans with a history of cancer were alive on January 1, 2014; by January 1, 2024, that number will increase to nearly 19 million. The 3 most common prevalent cancers among males are prostate cancer (43%), colorectal cancer (9%), and melanoma (8%), and those among females are cancers of the breast (41%), uterine corpus (8%), and colon and rectum (8%). The age distribution of survivors varies substantially by cancer type. For example, the majority of prostate cancer survivors (62%) are aged 70 years or older, whereas less than one-third (32%) of melanoma survivors are in this older age group. It is important for clinicians to understand the unique medical and psychosocial needs of cancer survivors and to proactively assess and manage these issues. There are a growing number of resources that can assist patients, caregivers, and health care providers in navigating the various phases of cancer survivorship.

The impact of the Patient Protection and Affordable Care Act on insurance coverage and cancer-directed treatment in HIV-infected patients with cancer in the United States.

BACKGROUND: To the authors' knowledge, little is known regarding the impact of the Patient Protection and Affordable Care Act (ACA) on people living with HIV and cancer (PLWHC), who have lower cancer treatment rates and worse cancer outcomes. To investigate this research gap, the authors examined the effects of the ACA on insurance coverage and receipt of cancer treatment among PLWHC in the United States. METHODS: HIV-infected individuals aged 18 to 64 years old with cancer diagnosed between 2011 and 2015 were identified in the National Cancer Data Base. Health insurance coverage and cancer treatment receipt were compared before and after implementation of the ACA in non-Medicaid expansion and Medicaid expansion states using difference-in-differences analysis. RESULTS: Of the 4794 PLWHC analyzed, approximately 49% resided in nonexpansion states and were more often uninsured (16.7% vs 4.2%), nonwhite (65.2% vs 60.2%), and of low income (36.3% vs 26.9%) compared with those in Medicaid expansion states. After 2014, the percentage of uninsured individuals decreased in expansion states (from 4.9% to 3%; P = .01) and nonexpansion states (from 17.6% to 14.6%; P = .06), possibly due to increased Medicaid coverage in expansion states (from 36.9% to 39.2%) and increased private insurance coverage in nonexpansion states (from 29.5% to 34.7%). There was no significant difference in cancer treatment receipt noted between Medicaid expansion and nonexpansion states. However, the percentage of PLWHC treated at academic facilities increased significantly only in expansion states (from 40.2% to 46.7% [P < .0001]; difference-in-differences analysis: 7.2 percentage points [P = .02]). CONCLUSIONS: The implementation of the ACA was associated with improved insurance coverage among PLWHC. Lack of insurance still is common in non-Medicaid expansion states. Patients with minority or low socioeconomic status more often resided in nonexpansion states, thereby highlighting the need for further insurance expansion.

Advanced stage at diagnosis and elevated mortality among US patients with cancer infected with HIV in the National Cancer Data Base.

BACKGROUND: People living with HIV (PLWH) are at an increased risk of developing several cancers, but to the authors' knowledge less is known regarding how HIV impacts the rate of progression to advanced cancer or death. METHODS: The authors compared stage of disease at the time of presentation and mortality after diagnosis between 14,453 PLWH and 6,368,126 HIV-uninfected patients diagnosed with cancers of the oral cavity, stomach, colorectum, anus, liver, pancreas, lung, female breast, cervix, prostate, bladder, kidney, and thyroid and melanoma using data from the National Cancer Data Base (2004-2014). Polytomous logistic regression and Cox proportional hazards regression were used to evaluate the association between HIV, cancer stage, and stage-adjusted mortality after diagnosis, respectively. Regression models accounted for the type of health facility at which cancer treatment was administered and the type of individual health insurance. RESULTS: HIV-infected patients with cancer were found to be more likely to be uninsured (HIV-infected: 5.0% vs HIV-uninfected: 3.3%; P < .0001) and were less likely to have private health insurance (25.4% vs 44.7%; P < .0001). Compared with those not infected with HIV, the odds of being diagnosed at an advanced stage of disease were significantly elevated in PLWH for melanoma and cancers of the oral cavity, liver, female breast, prostate, and thyroid (odds ratio for stage IV vs stage I range, 1.24-2.06). PLWH who were diagnosed with stage I to stage III disease experienced elevated mortality after diagnosis across 13 of the 14 cancer sites evaluated, with hazard ratios ranging from 1.20 (95% CI, 1.14-1.26) for lung cancer to 1.85 (95% CI, 1.68-2.04), 1.85 (95% CI, 1.51-2.27), and 2.93 (95% CI, 2.08-4.13), respectively, for cancers of the female breast, cervix, and thyroid. CONCLUSIONS: PLWH were more likely to be diagnosed with advanced-stage cancers and to experience elevated mortality after a cancer diagnosis, even after accounting for health care-related factors.

Aqueous-Phase Synthesis of Size-Tunable PbSe Nanocubes at Room Temperature for Optical Property Characterization.

A simple aqueous-phase synthesis of PbSe nanocubes with tunable sizes has been developed by first preparing a Na2 SeSO3 stock solution through dissolution of selenium powder in a solution of Na2 SO3 at 90-100 °C for 30 min, and adding part of this solution to a mixture of lead acetate and acetic acid at room temperature with stirring for only 5-8 min to complete the nanocrystal growth. Adjusting the volume of acetic acid and Na2 SeSO3 solution added enabled the size of the nanocrystals to be tuned, with average edge lengths of 13 to 121 nm attained. Changes in solution color revealed very different crystal growth rates for the 13 and 121 nm nanocubes. The PbSe cubes exhibit size-dependent absorption bands in the ultraviolet and visible-light region; the band positions show progressive redshifts with increasing particle size. Slight photocatalytic activity upon 532 nm laser irradiation of the nanocubes suggests the presence of higher energy levels in the band structure of PbSe. The synthetic conditions can be easily scaled up to obtain a large quantity of PbSe nanocubes for applications.

Increased risk of sleep apnoea among primary headache disorders: a nationwide population-based longitudinal study.

BACKGROUND: Primary headache disorders (PHDs) are associated with sleep problems. It is suggested that headache and sleep disorder share anatomical and physiological characteristics. We hypothesised that patients with PHDs were exposed to a great risk for developing sleep apnoea (SA). METHODS: In this retrospective longitudinal study, the data obtained from the Longitudinal Health Insurance Database in Taiwan were analysed. The study included 1346 patients with PHDs who were initially diagnosed and 5348 patients who were randomly selected and age/sex matched with the study group as controls. PHDs, SA, comorbidities and other confounding factors were defined based on International Classification of Diseases, Ninth Revision, Clinical Modification. Cox proportional hazards regressions were employed to examine adjusted HRs after adjusting with confounding factors. RESULTS: Our data revealed that patients with PHDs had a higher risk (HR 2.17, 95% CI 1.259 to 3.739, p<0.05) to develop SA compared with matched cohorts, whereas patients with migraine exhibited a high risk (HR 2.553, 95% CI 1.460 to 4.395, p<0.01). The results showed that patients with PHDs aged 18-44 exhibited highest risk of developing SA. In addition, males with PHDs exhibited an HR 3.159 (95% CI 1.479 to 6.749, p<0.01) for developing SA, respectively. The impact of PHDs on SA risk was progressively increased by various follow-up time intervals. CONCLUSION: Our results suggest that PHDs are linked to an increased risk for SA with sex-dependent and time-dependent characteristics.

Increased risk of non-multiple sclerosis demyelinating syndromes in patients with preexisting septicaemia: a nationwide retrospective cohort study.

BACKGROUND: Growing evidence shows links between septicaemia and non-multiple sclerosis demyelinating syndromes (NMSDS); nevertheless, epidemiological data are still very limited. This study aimed to explore the relationship between septicaemia and NMSDS in a general population. METHODS: The study included 482 781 individuals diagnosed with septicaemia and 1 892 825 age/sex-matched non-septicaemia patients for the comparison. Data were drawn from a population-based nationwide National Health Insurance Research Database Taiwan, from 1 January 2002 to 31 December 2011. The two cohorts of patients with and without septicaemia were followed up for the occurrence of NMSDS. The Cox-proportional hazard regression model was performed to estimate adjusted HR after multivariate adjustment. RESULTS: Individuals with septicaemia had a 4.17-fold (95% CI 3.21 to 5.4, p < 0.001) higher risk to develop NMSDS compared with those without septicaemia. Patients aged <65 years had a greater NMSDS risk (<45 years: HR = 6.41, 95% CI 3.65 to 11.3, p < 0.001; 45-64 years: HR = 6.66, 95% CI 3.98 to 11.2, p < 0.001). Furthermore, females with septicaemia and individuals with higher severity of septicaemia were associated with increased risks of developing NMSDS. CONCLUSIONS: Our results indicated that patients with septicaemia were likely to develop NMSDS. A possible contributing role of septicaemia in increasing the hazard of NMSDS is proposed, based on the outcome that individuals with higher severity of septicaemia carried elevated threat of encountering NMSDS.

Patterns of axillary evaluation in older patients with breast cancer and associations with adjuvant therapy receipt.

PURPOSE: Although axillary lymph node status has traditionally been a key factor in informing adjuvant breast cancer therapy recommendations, this information may be less relevant as our focus shifts more towards tumor biology, particularly in older patients where comorbidity influences treatment decisions and nodal staging and/or surgery may not improve outcomes. We examined patterns of axillary surgery and associations between axillary surgery and receipt of adjuvant treatment in older breast cancer patients. METHODS: Women aged ≥ 65 years with clinically node-negative, stage I-II breast cancer treated between 2012 and 2013 were identified using the National Cancer Data Base. Using multivariable logistic regression, we examined associations between axillary surgery and age, adjusting for patient, clinical, and facility factors. We also examined receipt of adjuvant treatment by nodal surgery. RESULTS: Among 68,205 women, 40.1% were aged 65-70, 24.5% were 71-75, 17.4% were 76-80, and 18.0% were > 80. Overall, 91.2% had axillary surgery (67.8% sentinel lymph node biopsy, 11.7% axillary lymph node dissection, 11.7% unspecified/unknown axillary surgery); 88.0% of those aged ≥ 70 with lower risk, hormone receptor-positive tumors underwent axillary surgery. In adjusted analyses, compared to patients aged 65-70, increasing age was associated with lower odds of any axillary surgery (ages 71-75: OR 0.64, 95% CI 0.57-0.71; ages 76-80: OR 0.33, 95% CI 0.30-0.37; age > 80: OR 0.08, 95% CI 0.07-0.08). Axillary surgery was associated with higher odds of receipt of radiation after breast conservation and receipt of chemotherapy in human epidermal growth factor 2-positive disease. CONCLUSIONS: In a large nationwide dataset, the vast majority of older women with clinically node-negative breast cancer underwent axillary staging despite uncertainty about its impact on survival, particularly for those with lower-risk disease. Further study on how to tailor node assessment in older patients is warranted.

Most Gleason 8 Biopsies are Downgraded at Prostatectomy-Does 4 + 4 = 7?

PURPOSE: Nonrepresentative biopsy sampling of prostate cancers with a biopsy Gleason score of 8 can adversely influence decisions regarding androgen deprivation in men receiving primary radiation therapy. The frequency of and factors associated with downgrading Gleason 8 biopsies at prostatectomy are not well known. MATERIALS AND METHODS: We used records from NCDB (National Cancer Database), a hospital based registry in the United States, of 72,556 men with prostate cancer diagnosed from 2010 to 2013, including 5,474 with Gleason 8 biopsies and no other high progression risk criteria according to NCCN (National Comprehensive Cancer Network®) Guidelines®. The prevalence of Gleason 8 downgrading was calculated. Generalized estimating equation multivariable regression models were used to estimate the prevalence ratios and 95% CIs of downgrading by demographic and clinical factors, and evaluate the association of Gleason 8 downgrading with cT (clinical T) to pathological T category up staging. RESULTS: Of 5,474 Gleason 8 biopsies in men lacking other high progression risk criteria 3,263 (60%) were downgraded, changing the progression risk category from high to intermediate. A higher prevalence of Gleason 8 downgrading was significantly and independently associated with decreasing age, African American race, lower cT category, lower prostate specific antigen quartile and certain combinations of primary and secondary Gleason grades (3 + 5 greater than 4 + 4 greater than 5 + 3). Gleason 8 downgrading in cases of cT less than 3 was independently and significantly associated with a lower prevalence of up staging (prevalence ratio = 0.65, 95% CI 0.61-0.69). CONCLUSIONS: Downgrading Gleason 8 biopsies is common. Patient evaluation based on Gleason 8 biopsies often results in overestimating progression risk and disease extent, which may lead to overtreatment.