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Several changes occur in both the cartilage's material properties and anatomical structure as osteoarthritis progresses. Unlike most numerical studies that solely consider individual changes, our study aimed to understand the impact on cartilage mechanics by considering the combined effect of material properties and cartilage thickness varied with osteoarthritis progression. In total, 3 three-dimensional finite element models, representing the intact, early, and late osteoarthritis conditions, were developed to simulate a load-bearing area in the knee. The articular cartilage was modelled as fluid-saturated linear biphasic poroelastic to incorporate solid-fluid interaction. All models underwent prolonged creep (50 N) and relaxation (0.3 mm) analyses for 600 s. In the early stage of osteoarthritis, the tibial cartilage demonstrated an overall stiffer behaviour attributed to cartilage swelling despite decreased stiffness at the material level. On the other hand, in the late stage of osteoarthritis, the decrease in cartilage thickness led to increased knee deformation. Additionally, increased permeability resulted in accelerated fluid exudation across all osteoarthritis models, and the elevation in void ratio further intensified fluid pressure within the cartilage to a higher magnitude. Furthermore, these changes collectively influenced both the magnitude and distribution of the outcomes. A holistic understanding of the material properties altered in osteoarthritis may contribute to a better understanding of the mechanical performance of cartilage during disease progression. [ABSTRACT FROM AUTHOR]

Abstract Lung cancer is the malignant tumor with the highest morbidity and mortality in China, and nonsmall cell lung cancer is a common form of lung cancer. After undergoing chemotherapy and molecular targeted therapy, the treatment of lung cancer has now fully entered the era of immunotherapy. Immunotherapy‐based treatment has become one of the standard treatments for lung cancer. Immunotherapy has also gradually moved from the back line to the front line, from advanced to early patients. This article focuses on the latest developments in perioperative and advanced lung cancer immunotherapy, discusses the problems and challenges at the current stage, and explores new directions for future development.

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Purpose: To investigate the clinical efficacy of anti-programmed cell death-1 (PD-1) immunotherapy in combination with chemotherapy in patients suffering from locally advanced non-small cell lung cancer (NSCLC). Methods: A total of 110 NSCLC patients admitted in The Second Affiliated Hospital of Hainan Medical University, Haikou, China were randomly divided into two groups using envelope method. The control group was administered pemetrexed and cisplatin, and the study group was further treated with nivolumab. Each treatment cycle lasted for 21 days, and a total of 6 cycles were administered for the duration of therapy. The short-term objective response rate, adverse reactions, programmed cell death-5 (PDCD-5), tumor necrosis factor-α (TNF-α), tumor necrosis factor-β1 (TGF-β1), and immune status indices were determined. Results: The objective remission rate in study group was 79.25 % (42/53), which was higher than that in control group (61.40 %, 35/57; p < 0.05). After treatment, both groups showed higher levels of PDCD-5 and TNF-α compared to their pre-treatment values, while demonstrating lower levels of TGF-β1. Furthermore, PDCD-5 and TNF-α in study group were higher than those in control group, while TGF-β1 was lower than that in control group (p < 0.05). In control group, the values of clusters of differentiation 3+(CD3+), 4+(CD4+), and 8+(CD8+) decreased after treatment, while the values of CD8+ increased after treatment. The CD3+, CD4+, and CD4+/CD8+ in study group were higher than those in control group, while CD8+ was lower than those in control group (p < 0.05). Conclusion: Anti-PD-1 immunotherapy combination with chemotherapy in the treatment of local NSCLC stabilizes the immune system and improves the short-term efficacy of patients with advanced NSCLC. Further clinical trials are, however, required prior to application of this combination clinical practice. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) presents clinical heterogeneity in late-stage patients who show a varied responsivity to subthalamic nucleus deep brain stimulation (STN-DBS) on motor symptoms. To explore the heterogeneity of STN-DBS effect on motor symptoms in late-stage PD patients and to categorize the patients, basic characteristics, preoperative motor symptoms, and motor symptoms one month and one year after the operation of 28 late-stage PD patients were collected and analyzed with agglomerative hierarchical clustering. Preoperative motor complications, non-motor symptoms, and late-stage related manifestations were also collected and compared among the clusters. The analysis revealed three patient clusters with different motor features: 1) high response; 2) low response, and 3) moderate response with fast progression. Clinical characteristics showed significant differences in disease duration, postoperative UPDRS-III, decrease in UPDRS-III, and index of progression. Patterns of the six major motor symptoms can clearly differentiate the three clusters. Preoperative dyskinesia, memory decline, and visual hallucination were also found to differ in the three clusters. The current study identified three clusters of late-stage PD patients showing distinct responses to STN-DBS on motor symptoms. These clustering patterns may relate with diverse dopaminergic/non-dopaminergic impairments and hopefully help to categorize late-stage PD patients and to select adequate STN-DBS candidates.

Objectives: Quality of life (QOL) is a valuable prognostic indicator of survival in cancer patients. It further aids the health-care professionals to cater to patient needs. This study aimed to estimate longitudinally the changes in the QOL of oral cancer patients in early and late stages and receiving chemotherapy treatment. Materials and Methods: This was a prospective observational study conducted with 400 oral cancer patients receiving chemotherapy treatment at a government tertiary care cancer hospital in Jaipur city. QOL for each patient was measured before treatment, after 6 months, and 1 year posttreatment using the instrument Functional Assessment of Cancer Therapy-Head and Neck version 4. Statistical analysis was conducted with IBM Statistical Package for the Social Sciences for Windows version 17.0 software (IBM Corp., Armonk, NY, USA). For all the analyses, P < 0.05 was considered statistically significant. Results: A statistically significant difference in the mean score for physical (P < 0.0001), social (P < 0.0001), and functional (P = 0.001) well-being was recorded for early- and late-stage cancer patients at baseline. Only emotional (0.03) and social (0.04) well-being showed a significant improvement for late-stage cancer patients in contrast to early-stage patients where all QOL subscores improved longitudinally. Conclusion: Early-stage disease is associated with better QOL. Chemotherapy treatment could improve only emotional and social well-being parameters in late-stage disease patients. QOL studies can be fruitful clinical endpoint and should be inculcated in the framework of various tertiary care centers.

ObjectiveThe Hungarian Undiagnosed Lung Cancer (HULC) study aimed to explore the potential reasons for missed LC (lung cancer) diagnosis by comparing healthcare and socio-economic data among patients with post-mortem diagnosed LC with those who were diagnosed with LC during their lives.MethodsThis nationwide, retrospective study used the databases of the Hungarian Central Statistical Office (HCSO) and National Health Insurance Fund (NHIF) to identify patients who died between January 1, 2019 and December 31, 2019 and were diagnosed with lung cancer post-mortem (population A) or during their lifetime (population B). Patient characteristics, socio-economic factors, and healthcare resource utilization (HCRU) data were compared between the diagnosed and undiagnosed patient population.ResultsDuring the study period, 8,435 patients were identified from the HCSO database with LC as the cause of death, of whom 1,203 (14.24%) had no LC-related ICD (International Classification of Diseases) code records in the NHIF database during their lives (post-mortem diagnosed LC population). Post-mortem diagnosed LC patients were significantly older than patients diagnosed while still alive (mean age 71.20 vs. 68.69 years, p

Purpose: The aim of this study was to elucidate the electro-clinical features and management of the late stage of Lafora disease (LD). Methods: We investigated the electro-clinical data andmedical complications of three LD patients withmutations in EPM2A and two in NHLRC1 genes during the LD late stage. Results: The late stage emerged after a mean period of 7 ± 1.41 years from the onset of the disease. All patients developed gait ataxia becoming bedbound with severe dementia. Pluri-monthly and drug-resistant myoclonic seizures, and myoclonic absence and tonic-clonic seizures were associated with daily/pluri-daily myoclonus, while the EEG/polygraphic findings showed diffusely slow activity with epileptiform abnormalities, often correlated with myoclonic jerks. Seizure emergencies with motor cluster/status epilepticus and medical complications dominated the clinical picture. In particular, video-EEG/polygraphic recordings disclosed status epilepticus with prominent motor symptoms of different subtypes refractory to IV new anti-seizure medications and responsive in 75% of cases to IV phenytoin. The main complications were dysphagia, aspiration pneumonia, acute respiratory failure, sepsis, immobility, and spasticity with bedsores. A coordinated and multidisciplinary management of the three patients with EPM2A mutations has demonstrated a reduction in seizure emergencies, medical complications and days of hospitalization, and a prolongation of the years of disease compared to the two patients with NHLRC1 mutations. Conclusion: Status epilepticus with prominent motor symptoms of different subtypes, often responsive to IV phenytoin, and multiple medical complications characterize the LD late stage. An effective management requires a multidisciplinary medical and nursing team, coordinated by an epileptologist with the aim of reducing seizure emergencies and medical complications. [ABSTRACT FROM AUTHOR]

PurposeThe aim of this study was to elucidate the electro-clinical features and management of the late stage of Lafora disease (LD).MethodsWe investigated the electro-clinical data and medical complications of three LD patients with mutations in EPM2A and two in NHLRC1 genes during the LD late stage.ResultsThe late stage emerged after a mean period of 7 ± 1.41 years from the onset of the disease. All patients developed gait ataxia becoming bedbound with severe dementia. Pluri-monthly and drug-resistant myoclonic seizures, and myoclonic absence and tonic–clonic seizures were associated with daily/pluri-daily myoclonus, while the EEG/polygraphic findings showed diffusely slow activity with epileptiform abnormalities, often correlated with myoclonic jerks. Seizure emergencies with motor cluster/status epilepticus and medical complications dominated the clinical picture. In particular, video-EEG/polygraphic recordings disclosed status epilepticus with prominent motor symptoms of different subtypes refractory to IV new anti-seizure medications and responsive in 75% of cases to IV phenytoin. The main complications were dysphagia, aspiration pneumonia, acute respiratory failure, sepsis, immobility, and spasticity with bedsores. A coordinated and multidisciplinary management of the three patients with EPM2A mutations has demonstrated a reduction in seizure emergencies, medical complications and days of hospitalization, and a prolongation of the years of disease compared to the two patients with NHLRC1 mutations.ConclusionStatus epilepticus with prominent motor symptoms of different subtypes, often responsive to IV phenytoin, and multiple medical complications characterize the LD late stage. An effective management requires a multidisciplinary medical and nursing team, coordinated by an epileptologist with the aim of reducing seizure emergencies and medical complications.

Cancer is a serious disease that affects the lives of millions around the globe. During COVID-19 pandemic, cancer patients were neglected and due to their miss management in hospitals, they presented in advanced stages of their primary disease specifically due to the suspension of elective services. The current study aimed to determine the impact of the COVID-19 pandemic on cancer patients. The current study was designed at the department of surgery in Khyber Teaching Hospital (KTH) Peshawar from 1st April 2020 to 30th March 2021 in Khyber Teaching Hospital, Peshawar. A total of 160-cancer patients were divided equally into 2 groups i.e. Group-A (pre-COVID-19 era patients) and Group-B (COVID-19 era patients). These two groups were selected on basis of non-probability consecutive sampling technique. Different statistic tools like SPSS and Origin 2018 soft ware were used for means, standard deviation and percentages. Results: During April and December a total of 160 cancer patients were studied in both years i.e. 2019 (pre-COVID-19 period) and 2020 (COVID-19 period). The mean age of presentation for patients in 2019 was 46.11 and in 2020 it was 50.38. Patients who were hospitalized to surgical wards during the COVID-19 tenure had comparatively longer mean duration of hospital stay with around 8 days (CI 2.49-13.39) hence showing significance with a p-value of 0.011. Breast cancer (n=32 [40% in 2019], n=17 [21.2% in 2020]) and rectal cancer (n=11 [13.8% in 2019], n=18 [22.5% in 2020]) were the two most common entities observed. Most importantly, study sample was analyzed and results showed that 57.5% (n=46) of the patients presented to surgical wards with less aggressive tumors in 2019 as opposed to 2020 where 67.5% (n=54) of patients came to the hospital with advanced stage malignancies; this indicates a significant p-value of 0.001. Conclusion: We are of the opinion that the pandemic is not over yet. Problems such as the global spread of cancer due to COVID-19 and its long term effects on the quality of life of patients worldwide is still being investigated. It is stipulated that the long-term consequences of decreased cancer screening, delayed hospital visits as well as the rise in elective surgery waiting times on cancer stage progression and outcomes, are anticipated to be significant. [ABSTRACT FROM AUTHOR]

Objectives: Quality of life (QOL) is a valuable prognostic indicator of survival in cancer patients. It further aids the health-care professionals to cater to patient needs. This study aimed to estimate longitudinally the changes in the QOL of oral cancer patients in early and late stages and receiving chemotherapy treatment. Materials and Methods: This was a prospective observational study conducted with 400 oral cancer patients receiving chemotherapy treatment at a government tertiary care cancer hospital in Jaipur city. QOL for each patient was measured before treatment, after 6 months, and 1 year posttreatment using the instrument Functional Assessment of Cancer Therapy-Head and Neck version 4. Statistical analysis was conducted with IBM Statistical Package for the Social Sciences for Windows version 17.0 software (IBM Corp., Armonk, NY, USA). For all the analyses, P < 0.05 was considered statistically significant. Results: A statistically significant difference in the mean score for physical (P < 0.0001), social (P < 0.0001), and functional (P = 0.001) well-being was recorded for early- and late-stage cancer patients at baseline. Only emotional (0.03) and social (0.04) well-being showed a significant improvement for late-stage cancer patients in contrast to early-stage patients where all QOL subscores improved longitudinally. Conclusion: Early-stage disease is associated with better QOL. Chemotherapy treatment could improve only emotional and social well-being parameters in late-stage disease patients. QOL studies can be fruitful clinical endpoint and should be inculcated in the framework of various tertiary care centers. [ABSTRACT FROM AUTHOR]

Late-stage Parkinson's disease (LSPD) patients are highly dependent on activities of daily living and require significant medical needs. In LSPD, there is a significant caregiver burden and greater health economic impact compared to earlier PD stages. The clinical presentation in LSPD is dominated by motor and non-motor symptoms (NMS) that most of the time have a sub-optimal to no response to dopaminergic treatment, especially when dementia is present. Non-pharmacological interventions, including physiotherapy, cognitive stimulation, speech, occupational therapy, and a specialized PD nurse, assume a key role in LSPD to mitigate the impact of disease milestones or prevent acute clinical worsening and optimize the management of troublesome NMS. However, the feasibility of these approaches is limited by patients' cognitive impairment and the difficulty in delivering care at home. The present care challenge for LSPD is the ability to offer a person-centered, home-delivered palliative care model based on Advanced Care Planning. An ongoing European multicentric project, PD_Pal, aims to address this challenge. [ABSTRACT FROM AUTHOR]

Where venture capitalists have traditionally focused on early-stage innovative firms, increasingly venture capitalists are investing in late-stage firms, especially in Asia. The performance consequences of this novel phenomenon of late-stage venture capital remain unexplored. This paper provides novel insight into this phenomenon by examining the impact of late-stage venture capital on two key dimensions of firm performance in the venture capital literature: innovation and financial performance. We link VC investment events to financial indicators of Chinese listed firms to account for the timing of VC entry and identify the firm performance impacts. Utilizing a matching and difference-in-differences procedure to account for selection biases, our results show that late-stage venture capital improves investee firms' financial performance but reduces their innovation performance. Our findings advance understanding about the emergence of late-stage venture capital and its performance consequences, especially in emerging economies. Our work has implications for entrepreneurs and policymakers. [ABSTRACT FROM AUTHOR]

Background: Oral squamous cell carcinoma (OSCC) is a type of malignancy characterized by high relapse and recurrence rates in the late stage despite optimal surgical intervention and postoperative chemoradiotherapy. Because the management of relapse following definitive treatment is challenging, accurate risk stratification is of clinical significance to improve treatment outcomes. Circular RNAs (circRNAs) are noncoding RNAs featured with cell-type specificity and high stability, owing to their circular structure, making these molecules excellent biomarkers for a variety of diseases. Methods: The levels of hsa_circ_0000190 and 0001649 in plasma samples from 30 healthy controls and 66 OSCC patients were determined by droplet digital polymerase chain reaction. The same primer sets were used with PCR to examine the expression of these two circRNAs in cancerous and adjacent normal tissues. A receiver operating characteristics curve was generated to evaluate the diagnostic value. The Kaplan-Meier method with a log-rank test was used for survival analysis. Results: We identified two circRNAs as potential biomarkers for OSCC, showing that the plasma level of hsa_circ_0000190 was significantly decreased in the late stage and marginally correlated with the development of second primary OSCC. We also found that the decreased plasma hsa_circ_0001649 was correlated with the recurrence and poor prognosis of patients. Additionally, we found that high plasma hsa_circ_0000190, but not hsa_circ_0001649, possibly predicted a better response of patients to induction chemotherapy. Conclusion: Our study demonstrated the potential of biomarkers in plasma to inform not just the tumor but the entire oral cavity, thereby offering a prediction for early recurrence and second primary OSCC. The plasma circRNAs remain valuable for OSCC, albeit the easy accessibility to the oral cavity. [ABSTRACT FROM AUTHOR]

Background: Little is known about how factors combine to influence progression of squamous cell carcinoma of the head and neck (HNSCC). We aimed to evaluate multidimensional influences of factors associated with HNSCC stage by race. Methods: Using retrospective data, patients with similar socioeconomic status (SES), access to care (travel time/distance), and behavioral risk factors (tobacco/alcohol use and dental care) were grouped by latent class analysis. Relative frequency differences (RFD) were calculated to evaluate latent classes by stage, race, and p16 status. Results: We identified three latent classes. Advanced T‐stage was higher for black (RFD = +20.2%; 95% CI: −4.6 to 44.9) than white patients (RFD = +10.7%; 95% CI: 2.1–19.3) in the low‐SES/high‐access/high‐behavioral risk class and higher for both black (RFD = +29.6%; 95% CI: 4.7–54.5) and white patients (RFD = +23.9%; 95% CI: 15.2–32.6) in the low‐SES/low‐access/high‐behavioral risk class. Conclusion: Results suggest that SES, access to care, and behavioral risk factors combine to underly the association with advanced T‐stage. Additionally, differences by race warrant further investigation. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate the driver's neck movement and injuries in the late stage of frontal collision. Firstly, the simulation model of the driver restraint system was developed and validated. Secondly, the design parameters of airbag and safety belt were optimized globally in the early stage of frontal collision. Finally, the driver's neck movement state and the effects of the design parameters of driver seat on the neck injuries in the late stage of frontal collision were studied. The movement state of the driver's upper and lower neck could be divided into three phases, and the peak extension bending moments of the upper and lower neck all occur in the second phase. By reducing the headrest stiffness and the upper seatback stiffness of driver seat, the rotational stiffness of the seatback recliner of driver seat, the upper and lower neck injuries can be decreased significantly.

Late-stage Parkinson’s disease (LSPD) patients are highly dependent on activities of daily living and require significant medical needs. In LSPD, there is a significant caregiver burden and greater health economic impact compared to earlier PD stages. The clinical presentation in LSPD is dominated by motor and non-motor symptoms (NMS) that most of the time have a sub-optimal to no response to dopaminergic treatment, especially when dementia is present. Non-pharmacological interventions, including physiotherapy, cognitive stimulation, speech, occupational therapy, and a specialized PD nurse, assume a key role in LSPD to mitigate the impact of disease milestones or prevent acute clinical worsening and optimize the management of troublesome NMS. However, the feasibility of these approaches is limited by patients’ cognitive impairment and the difficulty in delivering care at home. The present care challenge for LSPD is the ability to offer a person-centered, home-delivered palliative care model based on Advanced Care Planning. An ongoing European multicentric project, PD_Pal, aims to address this challenge.

Introduction: The burden of non-motor symptoms (NMS) is a major determinant of health-related quality of life in Parkinson's disease (PD), particularly at its late stage. Areas covered: The late stage is usually defined as the period from unstable advanced to the palliative stage, characterized by a combination of emerging treatment-resistant axial motor symptoms (freezing of gait, postural instability, falls and dysphagia), as well as both non-dopaminergic and dopaminergic NMS: cognitive decline, neuropsychiatric symptoms, aspects of dysautonomia, pain and sleep disturbances (insomnia and excessive day-time sleepiness). Here, the authors summarize the current knowledge on NMS dominating the late stage of PD and propose a pragmatic and clinically focused approach for their recognition and treatment. Expert opinion: The NMS progression pattern is complex and remains under-researched. While dopamine-dependent NMS may improve with dopamine replacement therapy, non-dopamine dependent NMS worsen progressively and culminate at the late stages of PD. Furthermore, some PD specific features could interact negatively with other comorbidities, multiple medication use and frailty – the evaluation of these aspects is important in the creation of personalized management plans in the late stage of PD. [ABSTRACT FROM AUTHOR]

The convenient cross‐coupling of sp2 or sp3 carbons with a specific boron vertex on carborane cage represents significant synthetic values and insurmountable challenges. In this work, we report an Rh‐catalyzed reaction between o‐carborane and N‐acyl‐glutarimides to construct various Bcage−C bonds. Under the optimized condition, the removable imine directing group (DG) leads to B(3)− or B(3,6)−C couplings, while the pyridyl DG leads to B(3,5)−Ar coupling. In particular, an unexpected rearrangement of amide reagent is observed in pyridyl directed B(4)−C(sp3) formation. This scalable protocol has many advantages, including easy access, the use of cheap and widely available coupling agents, no requirement of an external ligand, base or oxidant, high efficiency, and a broad substrate scope. Leveraging the RhI dimer and twisted amides, this method enables straightforward access to diversely substituted and therapeutically important carborane derivatives at boron site, and provides a highly valuable vista for carborane‐based drug screening. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is a chronic, progressive, neurodegenerative disease involving both motor and non-motor symptoms (NMS). In the late stage of the disease, Hoehn and Yahr (HY) stages IV-V, the symptomatology is often severe and patients become increasingly dependent on help in their daily life, resulting in an increased burden for the informal caregivers. To assess the implications of the caregiver burden, caregiver quality of life (QoL) was assessed in 74 informal caregivers to patients in late stage PD, by the Alzheimer’s Patient Partners Life Impact Questionnaire (APPLIQue), which has been found useful also in PD. The majority of caregivers were the spouse/partner. Individual items provided information on which aspects of caregiver burden were the most common, i.e., items: “feel guilty if not there” (71% affirmed), “situation wears me down” (65% affirmed) and “always on my mind” (61% affirmed). In simple linear regression analyses, female patient gender (p = 0.007), better cognition (p = 0.004), lower NMS burden (p = 0.012) and not being the partner (p = 0.022) were associated with better caregiver QoL. Multivariable linear regression analyses identified better cognition (p = 0.004) and female patient gender (p = 0.035) as independently associated with better informal caregiver QoL. Identifying and treating NMS as well as recognizing and alleviating caregiver burden seem essential to enhance QoL for both patients and caregivers in late stage PD.

Abstract Realistic illness understanding is essential to an advanced cancer patient's ability to make informed medical decisions at the end of life. This study sought to determine whether advanced cancer patients better understood the late stage of their cancer if an oncologist, compared to other members of the care team, was present to discuss their scan results. Data were derived from a multi‐institutional, longitudinal cohort study of patients recruited between 2010 and 2015. Patients (n = 209) with late‐stage cancers (metastatic cancers that progressed after at least one chemotherapy regimen) were interviewed before and after clinic visits in which scan results were discussed. Patients reported pre‐ and postvisit if their cancer was at a late stage. Postvisit, patients reported if they discussed scan results with an oncologist or another oncology provider (i.e., oncology fellow, oncology resident, nurse practitioner, nurse, physician's assistant, or other). Logistic regression analysis was used to determine if the presence of an oncologist during scan results discussions differentially predicted the patients' likelihood of postvisit late‐stage illness understanding (LSIU). Propensity weighting was used to correct for sociodemographic imbalances between groups, and previsit LSIU and the presence of multiple providers were controlled for in the logistic regression analyses. After propensity‐weighted adjustment and controlling for previsit LSIU and the presence of multiple providers, patients were 2.6 times more likely (AOR = 2.6; 95% CI = 1.2, 6.0; P = 0.021) to report that their disease was late stage if an oncologist was present for the scan results discussion compared to if an oncologist was absent. The presence of an oncologist during scan results discussions was associated with a higher likelihood of patients acknowledging being in a late stage of their disease. These results suggest that oncologist involvement in scan results discussions is associated with advanced cancer patients having better prognostic understanding.

Background: Major adverse cardiovascular events (MACE) are the leading cause of deathin chronic kidney disease (CKD) patients. The relationship between the initiation of peritoneal dialysis (PD) and MACE is unclear. Objective: This study compared the incidence of MACE in PD patients when the estimated- glomerular filtration rate (eGFR) is calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI) equation with the Thai eGFR equation. Method: The study was conducted among 684 end-stage CKD patients in a referral hospital in Thailand between 2011-2018. The first occurrence of cardiovascular events related MACE was defined as dependent variable. Logistic regression was used to identify the relationship. Results: The incidence of MACE was different between CKD-EPI group (10.9%) and Thai eGFR group (12.4%). After adjusting for other factors, the PD initiation using eGFR calculated by CKD-EPI equation did not affect the incidence of MACE when compared to those from Thai eGFR equation (Ajd.OR: 1.11; 95%CI: 0.68-1.82, P-value = 0.685). Conclusion: There was no effect on incidence of MACE when PD was initiated based on eGFR calculated using the CKD-EPI equation compared with the Thai eGFR equation. [ABSTRACT FROM AUTHOR]

Background: Subthalamic deep brain stimulation (STN-DBS) effects may decrease with Parkinson's disease (PD) progression. There is no indication if, when, and how to consider the interruption of DBS treatment in late-stage PD. The objective of the current study was to investigate the percentage of "poor stimulation responders" among late-stage PD patients for elaborating an algorithm to decide whether and when DBS discontinuation may be considered.Methods: Late-stage PD patients (Hoehn Yahr stage ≥4 and Schwab and England Scale <50 in medication on/stimulation on condition) treated with STN-DBS for at least 5 years underwent a crossover, double-blind, randomized evaluation of acute effects of stimulation. Physicians, caregivers, and patients were blinded to stimulation conditions. Poor stimulation responders (MDS-UPDRS part III change <10% between stimulation on/medication off and stimulation off/medication off) maintained the stimulation off/medication on condition for 1 month for open-label assessment.Results: Thirty-six patients were included. The acute effect of stimulation was significant (17% MDS-UPDRS part III), with 80% of patients classified as "good responders." Seven patients were classified as "poor stimulation responders," and the stimulation was switched off, but in 4 cases the stimulation was switched back "on" because of worsening of parkinsonism and dysphagia with a variable time delay (up to 10 days). No serious adverse effects occurred.Conclusions: The vast majority of late-stage PD patients (92%) show a meaningful response to STN-DBS. Effects of stimulation may take days to disappear after its discontinuation. We present a safe and effective decisional algorithm that could guide physicians and caregivers in making challenging therapeutic decisions in late-stage PD. © 2020 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common cancer worldwide and is a fundamental health problem in the UK. Mortality rates are much higher in the UK than other European countries, with overall 5-year survival rates in England and Wales currently as low as 7%. Reducing diagnostic delays may increase the proportion of early stage lung cancer and improve survival, yet the literature surrounding these issues suggests that many people continue to wait a considerable time before presenting symptoms to a clinician. To gain an in-depth understanding into the factors that may influence this delay, this review aims to explore some of the social and psychological barriers that patients face in seeking medical attention for lung cancer symptoms. Likewise, with the majority of lung cancer cases strongly linked to tobacco use, the impact of smoking status and whether it has an effect on an individual’s pathway to diagnosis is imperative to this review. The evidence found suggests that delays in symptom reporting are attributed to low perceptions of risk and a difficulty in recognising lung cancer symptoms early, especially when other comorbidities are present. Additionally, the de-normalisation of smoking appears to have confused understanding regarding risk and reinforced blame and stigma, which ultimately hinders help-seeking behaviours. Future research is thus required to develop strategies and interventions that raise awareness of lung cancer symptoms and empower people to engage in help-seeking behaviours.

Purpose: To report a case of rhegmatogenous retinal detachment in the late stage, despite the fact that it had previously been halted after intravitreal injection of an antimicrobial agent against endogenous bacterial endophthalmitis (EBE). Case: This study involved a 62-year-old male who had previously been diagnosed with septicemia due to liver abscess and the detection of Klebsiella pneumoniae in a culture of his liver abscess, and who underwent ophthalmic examination after his conjunctival hyperemia had failed to improve. Visual acuity could not be measured due to his general condition being poor and his declining level of consciousness. Slit lamp examination revealed bilateral iritis and cataracts, and the fundus was invisible due to vitreous opacity. Ultrasonic B-mode examination showed subretinal abscess and exudative retinal detachment, leading to the diagnosis of EBE. Vitreous injections of antibiotics were administered to both of his eyes. His right eye became affected by phthisis bulbi, but the condition in his left eye subsided, leaving a scarred lesion near the macula. However, complete retinal detachment occurred in his left eye approximately 10 months after the vitreous injection. During vitreous surgery, proliferative membrane formation was observed in the posterior pole area, and an irregular retinal break was detected in the scar margin caused by the traction of the proliferative membrane. After vitreous surgery, the retina was reattached under silicone oil. Conclusion: In cases of EBE, even if the inflammation has previously subsided, strict follow-up examinations are necessary, since complications such as rhegmatogenous retinal detachment may occur at a late stage.

Background: Few data exist on the rate of clinical progression for Parkinson's disease (PD) patients who have entered a late stage of the disease.Objective: Study the clinical progression of a late-stage PD (LSPD) population over one year follow-up.Methods: 50 LSPD patients (Schwab and England ADL Scale <50 or Hoehn Yahr Stage >3 in MED ON) underwent an extensive clinical assessment at baseline and after one year and an acute levodopa test at baseline.Results: Mean age of LSPD patients (female 46%) was 77.5 ± 5.9 years and mean disease duration was 15.5 ± 6.5 years. At baseline, 76% had levodopa-induced motor complications (MC), usually non-troublesome, 68% were demented, 54% had psychosis and 68% depression. Caregiver distress was high. l-dopa responsiveness was mild (18% ± 12 of improvement on MDS-UPDRS-III). After one-year, 20% of the patients were dead, institutionalized or HY 5. MDS-UPDRS-motor mean score worsened 7.2 ± 10.3 points although there was heterogeneity between patients, and there was a global worsening of non-motor symptoms, mostly in cognition/mood, urinary and gastrointestinal domains. Nevertheless, MC improved despite similar levodopa equivalent dose. Functional independence and quality of life worsened. Dysphagia severity at baseline predicted a poor outcome (death, institutionalization or HY 5) (Hazard ratio 2.3, 95% CI 1.12-4.4; p = 0.01), whereas magnitude of l-dopa response of LSPD patients did not.Conclusions: LSPD patients still present a significant, although heterogeneous, motor and non-motor progression over 1 year. Dysphagia severity predicts the occurrence of additional disease severity milestones and its management must be prioritized. [ABSTRACT FROM AUTHOR]

Objectives: To measure disease-free, disease-specific, and overall survival among patients with T4aN0M0 mandibular gingival squamous cell carcinoma who were treated with surgery alone.Study Design: Case series with chart review.Setting: Tertiary care center.Subjects and Methods: A retrospective chart review was performed of all adult patients treated surgically with an oral cavity composite resection between January 2005 and March 2017. Among other data, patient preoperative characteristics were recorded (eg, age, sex, smoking history, alcohol use, and clinical stage); operative notes were reviewed to determine tumor subsite involvement, reconstruction method, and intraoperative surgical complications; and pathology reports were evaluated for various pathologic findings. Survival outcomes were determined with Kaplan-Meier analysis.Results: The mean follow-up was 18.5 months (range, 0.1-100). The 1- and 5-year disease-free survival rates were 90.5% and 84.5%, respectively, while the 1- and 5-year disease-specific survival rates were 87.8% and 81.9%. The 1- and 5-year overall survival rates were 86.4% and 80.6%.Conclusions: Patients with T4aN0M0 squamous cell carcinoma of the mandibular gingiva treated with surgery alone have a 5-year overall survival of 80.6%. Treatment with surgery alone obviates morbidities associated with adjuvant therapy while upholding survival outcomes. [ABSTRACT FROM AUTHOR]

Background: Cervical and breast cancers are the most common cancers among women in developing countries contributing to high morbidity and mortality. Even though both these cancers have a better prognosis if caught early; however, studies conducted in Nigeria still show a large incidence of late tumor stage presentation. Objectives: This study aimed at identifying the patient and disease characteristics of women with breast and cervical cancers presenting at a tertiary medical facility in Nigeria, with emphasis on the prevalence of late-stage presentation and reasons for late-stage presentation. Patients and Methods: This cross-sectional study recruited women at Lagos University Teaching Hospital (LUTH) with breast and cervical cancers from April to June 2016; an interviewer-based questionnaire was administered to 105 patients who seen to elicit information needed to achieve the set objectives. Results: The mean age of patients was 51.09 (±11.70) years; majority had no known family history and no health insurance. Most cervical cancer patients were unaware of their human papillomavirus status. About 72.81% of all patients presented late, surprisingly 87.6% of patients presented in an appropriate health-care facility as place of the first contact, but still presented in LUTH at late stages of their disease mostly due to misdiagnosis. Reasons for late presentation included fear, misconceptions, misdiagnosis, ignorance, and prolonged investigation time. Conclusion: As late-stage presentation was associated with both poor health-seeking behavior and health system delays; interventions should not only include increased awareness for the early detection and diagnosis but also measures to ensure improvements in health service delivery to ensure timely diagnosis and the management of breast and cervical cancers. [ABSTRACT FROM AUTHOR]

The impact of the new International Association for the Study of Lung Cancer pathology committee grading system for advanced lung adenocarcinoma (LADC) on survival is unclear, especially in Asian populations. In this study, we reviewed the prognostic outcomes of patients with late-stage disease according to the new grading system. We reviewed 136 LADC cases who underwent a small biopsy from 2007 to 2018. Tumors were classified according to the new grading system for LADC. Baseline characteristics (age, sex, smoking status, body mass index, and driver gene mutations) were analyzed. Kaplan–Meier and Cox regression analyses were used to determine correlations with the new grading system and prognosis. Patients with poorly differentiated adenocarcinoma were significantly correlated with a poor progression-free survival (PFS) (p = 0.013) but not overall survival (OS) (p = 0.154). Subgroup analysis showed that wild-type EGFR patients with poorly differentiated adenocarcinoma treated with chemotherapy had significantly worse PFS (p = 0.011). There was no significant difference in survival among the patients with epidermal growth factor receptor mutations who were treated with tyrosine kinase inhibitors. Patients aged >70 years and those with a BMI ≤ 25 kg/m2 and wild-type patients had significantly worse OS in both univariate (HR = 1.822, p = 0.006; HR = 2.250, p = 0.004; HR = 1.537, p = 0.046, respectively) and multivariate analyses (HR = 1.984, p = 0.002; HR = 2.383, p = 0.002; HR = 1.632, p = 0.028, respectively). Despite therapy, patients with poorly differentiated tumors still fared worse than those with better differentiated tumors. No differences were found among the EGFR mutations treated with TKI. Our findings highlight that the therapeutic regimen should be adjusted for EGFR Wild-type patients with poorly differentiated adenocarcinoma treated with chemotherapy to provide better outcomes.

We detected Zika virus in breast milk of a woman in Brazil infected with the virus during the 36th week of pregnancy. Virus was detected 33 days after onset of signs and symptoms and 9 days after delivery. No abnormalities were found during fetal assessment or after birth of the infant.

Background: We sought to characterize the clinical, neuropsychological, electrophysiological, and neuroimaging features of Parkinson’s disease (PD) after over 35 years since the onset of motor symptoms.Methods: Five consecutively consenting PD patients treated with subthalamic nucleus deep brain stimulation (STN-DBS) were recruited in a cross-sectional study of motor (Unified PD Rating Scale section-III), non-motor (Non-Motor Symptoms Scale), autonomic (Scale for Outcome in PD-Autonomic), and neuropsychological features associated with the very advanced phase of PD. In addition, patients underwent neurophysiological (autonomic tests and nerve conduction studies) and neuroimaging (brain MRI, 123I-FP-CIT SPECT, and 123I-MIBG myocardial scintigraphy) studies, as well as a genetic analysis of 34 genes and single nucleotide polymorphisms associated with PD.Results: There was a sustained motor response to L-dopa (range 14.4-35.6%), STN-DBS (23.3-38.4%), and L-dopa plus STN-DBS (37.8-63.0%). There were mild-to-moderate non-motor symptoms (range 19-83 on a scale of 0 to 360) and autonomic dysfunction (8-28 on a scale of 0-69). Two patients were demented, one had mild cognitive impairment, and two were cognitively preserved. Three patients had a sensory-axonal peripheral neuropathy and two a moderate-to-severe autonomic neuropathy. All cases showed a complete nigro-striatal dopaminergic denervation and a severe cardiovascular noradrenergic denervation. The brain MRI revealed only moderate frontal atrophy. The genetic tests were unremarkable.Conclusions: Even after more than 35 years of disease, L-dopa  and STN-DBS remain effective on PD cardinal symptoms. Although axial, autonomic, and neuropsychological features may become key determinants of disability, some patients maintain a satisfactory quality of life, without significant motor and non-motor impairment. [ABSTRACT FROM AUTHOR]

Background: Non-motor symptoms (NMS) are common in late stage Parkinson’s disease (PD), as the frequency and severity of most of these symptoms increase with advancing disease. Objective: To assess effect of dopaminergic therapy on NMS in late stage PD and to investigate relationships between dopaminergic effect on NMS and on motor function. Method: Thirty PD patients in Hoehn and Yahr (HY) stages IV and V in “on” were included. Dopaminergic effect on non-motor symptomatology was assessed by the modified version of the Non-Motor Symptoms Scale (NMSS) in the “off” and the “on” state during a standardized L-dopa test, in parallel also assessing motor function. Results: NMS were common and many of the symptoms occurred in >80% of the individuals. The highest NMSS scores were seen within the NMSS domains 3: mood/apathy and 7: urinary in both the “off” and the “on” state. There was a statistically significant (p < 0.001) improvement in the modified NMSS total score (median) from 79 in “off” to 64 in “on”. There were statistically significant differences between the “off” and the “on” state for domains 2: sleep/fatigue, 3: mood/apathy, 5: attention/memory, 6: gastrointestinal and 7: urinary. The differences in the NMSS score between the “off” and the “on” state were in general larger for motor responders than for motor non-responders. In motor non-responders, differences of the NMSS score between the “off” and the “on” state were found for the total score, domain 3: mood/apathy and its item 11-flat moods. Conclusion: There is an effect of dopaminergic medication on NMS in late stage PD, to some extent also for those with a non-significant response on motor function during L-dopa test. It is therefore of importance to optimize dopaminergic therapy in order to give the most effective symptomatic treatment possible. [ABSTRACT FROM AUTHOR]

Abstract: Realistic illness understanding is essential to an advanced cancer patient's ability to make informed medical decisions at the end of life. This study sought to determine whether advanced cancer patients better understood the late stage of their cancer if an oncologist, compared to other members of the care team, was present to discuss their scan results. Data were derived from a multi‐institutional, longitudinal cohort study of patients recruited between 2010 and 2015. Patients (n = 209) with late‐stage cancers (metastatic cancers that progressed after at least one chemotherapy regimen) were interviewed before and after clinic visits in which scan results were discussed. Patients reported pre‐ and postvisit if their cancer was at a late stage. Postvisit, patients reported if they discussed scan results with an oncologist or another oncology provider (i.e., oncology fellow, oncology resident, nurse practitioner, nurse, physician's assistant, or other). Logistic regression analysis was used to determine if the presence of an oncologist during scan results discussions differentially predicted the patients' likelihood of postvisit late‐stage illness understanding (LSIU). Propensity weighting was used to correct for sociodemographic imbalances between groups, and previsit LSIU and the presence of multiple providers were controlled for in the logistic regression analyses. After propensity‐weighted adjustment and controlling for previsit LSIU and the presence of multiple providers, patients were 2.6 times more likely (AOR = 2.6; 95% CI = 1.2, 6.0; P = 0.021) to report that their disease was late stage if an oncologist was present for the scan results discussion compared to if an oncologist was absent. The presence of an oncologist during scan results discussions was associated with a higher likelihood of patients acknowledging being in a late stage of their disease. These results suggest that oncologist involvement in scan results discussions is associated with advanced cancer patients having better prognostic understanding. [ABSTRACT FROM AUTHOR]

Herpes simplex virus type 2 (HSV-2) is the causative pathogen of genital herpes and is closely associated with the occurrence of cervical cancer and human immunodeficiency virus (HIV) infection. The absence of an effective vaccine and the emergence of drug resistance to commonly used nucleoside analogs emphasize the urgent need for alternative antivirals against HSV-2. Recently, ABMA [1-adamantyl (5-bromo-2-methoxybenzyl) amine] has been demonstrated to be an inhibitor of several pathogens exploiting host-vesicle transport, which also participates in the HSV-2 lifecycle. Here, we showed that ABMA inhibited HSV-2-induced cytopathic effects and plaque formation with 50% effective concentrations of 1.66 and 1.08 μM, respectively. We also preliminarily demonstrated in a time of compound addition assay that ABMA exerted a dual antiviral mechanism by impairing virus entry, as well as the late stages of the HSV-2 lifecycle. Furthermore, in vivo studies showed that ABMA protected BALB/c mice from intravaginal HSV-2 challenge with an improved survival rate of 50% at 5 mg/kg (8.33% for the untreated virus infected control). Consequently, our study has identified ABMA as an effective inhibitor of HSV-2, both in vitro and in vivo, for the first time and presents an alternative to nucleoside analogs for HSV-2 infection treatment. [ABSTRACT FROM AUTHOR]

Background and purpose: Biomarker changes in cognitively impaired patients with small vessel disease are largely unknown. The rate of amyloid/lacune progression, cortical thinning and cognitive decline were evaluated in subcortical vascular mild cognitive impairment (svMCI) patients. Methods: Seventy‐two svMCI patients were divided into early stage (ES‐svMCI, n = 39) and late stage (LS‐svMCI, n = 33) according to their Clinical Dementia Rating Sum of Boxes score. Patients were annually followed up with neuropsychological tests and brain magnetic resonance imaging for 3 years, and underwent a second [11C] Pittsburgh compound B (PiB) positron emission tomography scan within a mean interval of 32.4 months. Results: There was no difference in the rate of increase in PiB uptake or lacune number between the ES‐svMCI and LS‐svMCI. However, LS‐svMCI showed more rapid cortical thinning and cognitive decline than did the ES‐svMCI. Conclusions: We suggest that, whilst the rate of change in pathological burden did not differ between ES‐svMCI and LS‐svMCI, cortical thinning and cognitive decline progressed more rapidly in the LS‐svMCI. [ABSTRACT FROM AUTHOR]

Background: It is unclear to which degree Levodopa (L-dopa) remains effective also in the late stage of Parkinson's disease (PD) and to which degree motor fluctuations and dyskinesias remain a problem. Objective: To assess responsiveness of motor symptomatology to L-dopa in a group of patients with late stage PD. Moreover, to investigate the extent to which motor fluctuations and dyskinesias occur. Methods: Thirty PD patients in Hoehn and Yahr (HY) stages IV and V in “on" were included. L-dopa responsiveness was assessed with a standardized L-dopa test in the defined “off" and defined “on" states. Motor function was assessed by the Unified PD Rating Scale (UPDRS) III and timed tests. Motor fluctuations and dyskinesias were assessed by the UPDRS IV. The participants were further monitored for 10 days with a mobile movement-analyses-system, the Parkinson's Kinetigraph (PKG). The median (q1–q3) L-dopa equivalent daily dose (LEDD) was 799 (536–973) mg. Results: The UPDRS III score improved with ≥15% in 15 (50%) and with ≥30% in six (20%) participants during the L-dopa test. The median (q1–q3) UPDRS III score in “off" was 46 (37–53) and in “on" 36 (28–46). Twenty-one (70%) of the participants reported either predictable or unpredictable “off" fluctuations (items 36–37). The prevalence of dyskinesias (item 32, duration of dyskinesias ≥1) was 47%. The PKG indicated that dyskinesias primarily were mild and that a majority had a pronounced “off" symptomatology, spending a large proportion of the day either asleep or very inactive. Conclusions: Half of a group of patients with late stage PD had an L-dopa response of ≥15% on the UPDRS III. According to the UPDRS IV, a majority of the patients had motor fluctuations and about half had dyskinesias, although the PKG results suggested that these were not very severe. [ABSTRACT FROM AUTHOR]

BackgroundParkinson’s disease (PD) patients are affected by hypokinetic dysarthria, characterized by hypophonia and dysprosody, which worsens with disease progression. Levodopa’s (l-dopa) effect on quality of speech is inconclusive; no data are currently available for late-stage PD (LSPD).ObjectiveTo assess the modifications of speech and voice in LSPD following an acute l-dopa challenge.MethodLSPD patients [Schwab and England score 3 (MED ON)] performed several vocal tasks before and after an acute l-dopa challenge. The following was assessed: respiratory support for speech, voice quality, stability and variability, speech rate, and motor performance (MDS-UPDRS-III). All voice samples were recorded and analyzed by a speech and language therapist blinded to patients’ therapeutic condition using Praat 5.1 software.Results24/27 (14 men) LSPD patients succeeded in performing voice tasks. Median age and disease duration of patients were 79 [IQR: 71.5–81.7] and 14.5 [IQR: 11–15.7] years, respectively. In MED OFF, respiratory breath support and pitch break time of LSPD patients were worse than the normative values of non-parkinsonian. A correlation was found between disease duration and voice quality (R = 0.51; p = 0.013) and speech rate (R = −0.55; p = 0.008). l-Dopa significantly improved MDS-UPDRS-III score (20%), with no effect on speech as assessed by clinical rating scales and automated analysis.ConclusionSpeech is severely affected in LSPD. Although l-dopa had some effect on motor performance, including axial signs, speech and voice did not improve. The applicability and efficacy of non-pharmacological treatment for speech impairment should be considered for speech disorder management in PD.

Background: Parkinson's disease (PD) patients are affected by hypokinetic dysarthria, characterized by hypophonia and dysprosody, which worsens with disease progression. Levodopa's (L-dopa) effect on quality of speech is inconclusive; no data are currently available for late-stage PD (LSPD). Objective: To assess the modifications of speech and voice in LSPD following an acute L-dopa challenge. Method: LSPD patients [Schwab and England score <50/Hoehn and Yahr stage >3 (MED ON)] performed several vocal tasks before and after an acute l-dopa challenge. The following was assessed: respiratory support for speech, voice quality, stability and variability, speech rate, and motor performance (MDS-UPDRS-III). All voice samples were recorded and analyzed by a speech and language therapist blinded to patients' therapeutic condition using Praat 5.1 software. Results: 24/27 (14 men) LSPD patients succeeded in performing voice tasks. Median age and disease duration of patients were 79 [IQR: 71.5-81.7] and 14.5 [IQR: 11-15.7] years, respectively. In MED OFF, respiratory breath support and pitch break time of LSPD patients were worse than the normative values of non-parkinsonian. A correlation was found between disease duration and voice quality (R = 0.51; p = 0.013) and speech rate (R = -0.55; p = 0.008). L-Dopa significantly improved MDS-UPDRS-III score (20%), with no effect on speech as assessed by clinical rating scales and automated analysis. Conclusion: Speech is severely affected in LSPD. Although l-dopa had some effect on motor performance, including axial signs, speech and voice did not improve. The applicability and efficacy of non-pharmacological treatment for speech impairment should be considered for speech disorder management in PD. [ABSTRACT FROM AUTHOR]

Purpose: To report a case of rhegmatogenous retinal detachment in the late stage, despite the fact that it had previously been halted after intravitreal injection of an antimicrobial agent against endogenous bacterial endophthalmitis (EBE). Case: This study involved a 62-year-old male who had previously been diagnosed with septicemia due to liver abscess and the detection of Klebsiella pneumoniae in a culture of his liver abscess, and who underwent ophthalmic examination after his conjunctival hyperemia had failed to improve. Visual acuity could not be measured due to his general condition being poor and his declining level of consciousness. Slit lamp examination revealed bilateral iritis and cataracts, and the fundus was invisible due to vitreous opacity. Ultrasonic B-mode examination showed subretinal abscess and exudative retinal detachment, leading to the diagnosis of EBE. Vitreous injections of antibiotics were administered to both of his eyes. His right eye became affected by phthisis bulbi, but the condition in his left eye subsided, leaving a scarred lesion near the macula. However, complete retinal detachment occurred in his left eye approximately 10 months after the vitreous injection. During vitreous surgery, proliferative membrane formation was observed in the posterior pole area, and an irregular retinal break was detected in the scar margin caused by the traction of the proliferative membrane. After vitreous surgery, the retina was reattached under silicone oil. Conclusion: In cases of EBE, even if the inflammation has previously subsided, strict follow-up examinations are necessary, since complications such as rhegmatogenous retinal detachment may occur at a late stage. [ABSTRACT FROM AUTHOR]

Herpes simplex virus type 2 (HSV-2) is the causative pathogen of genital herpes and is closely associated with the occurrence of cervical cancer and human immunodeficiency virus (HIV) infection. The absence of an effective vaccine and the emergence of drug resistance to commonly used nucleoside analogs emphasize the urgent need for alternative antivirals against HSV-2. Recently, ABMA [1-adamantyl (5-bromo-2-methoxybenzyl) amine] has been demonstrated to be an inhibitor of several pathogens exploiting host-vesicle transport, which also participates in the HSV-2 lifecycle. Here, we showed that ABMA inhibited HSV-2-induced cytopathic effects and plaque formation with 50% effective concentrations of 1.66 and 1.08 μM, respectively. We also preliminarily demonstrated in a time of compound addition assay that ABMA exerted a dual antiviral mechanism by impairing virus entry, as well as the late stages of the HSV-2 lifecycle. Furthermore, in vivo studies showed that ABMA protected BALB/c mice from intravaginal HSV-2 challenge with an improved survival rate of 50% at 5 mg/kg (8.33% for the untreated virus infected control). Consequently, our study has identified ABMA as an effective inhibitor of HSV-2, both in vitro and in vivo, for the first time and presents an alternative to nucleoside analogs for HSV-2 infection treatment.

Background: We determined whether the current SEER registries are representative of the nation's cancer cases or the socio-demographic characteristics.Methods: We used breast cancer (BC) and colorectal cancer (CRC) cases diagnosed 2004-2009 from the US Cancer Statistics (USCS) database. Cases were classified into groups residing in SEER coverage areas and the other areas. We compared difference between SEER and non-SEER areas in: age-race-specific proportions of late-stage BC or CRC, area demographics and socioeconomic factors, and data quality.Results: For late-stage CRC diagnosis, SEER areas contained lower proportions of people with other race and higher proportions of Asian and Hispanic females aged <40, than non-SEER areas. For late-stage BC diagnosis, SEER and non-SEER estimates were comparable. SEER areas had lower percentages of whites and higher percentages of young people, were more urban, and had higher percentage of poor, lower educational attainment, and higher unemployment. SEER areas also tended to have a higher percentage of case completeness than non-SEER areas.Conclusion: Overall, SEER registries were not significantly different from non-SEER areas in terms of average age-race-specific proportions of late-stage BC or CRC, except for estimates of late-stage CRC for other race and young Asian and Hispanic women. Although case completeness was better in SEER areas than non-SEER areas, SEER areas had greater economic disadvantage and greater minority diversity among the population. This study demonstrated a need for caution in using SEER data and discussed advantages of using the more complete USCS database. [ABSTRACT FROM AUTHOR]

Background: Late-stage Parkinson' disease (PD) is dominated by loss of autonomy due to motor and non-motor symptoms which can be marginally corrected by medications adjustments. However, controversy exists on the mechanisms underlying the apparent decrease of benefit from levodopa.Objective: To study the response to levodopa in late-stage PD (LSPD).Methods: 20 LSPD patients (Schwab and England ADL Scale <50 or Hoehn Yahr Stage >3 in MED ON) and 22 PD patients treated with subthalamic deep brain stimulation (DBS) underwent an acute levodopa challenge test. MDS-UPDRS-III and the modified Abnormal Involuntary Movement Scale were evaluated in off and after administration of a supra-maximal levodopa dose.Results: LSPD patients had a median age of 78.8 (IQR: 73.5-82) and median disease duration of 14 years (IQR: 10-19.75). DBS patients had a median age of 66 (IQR: 61-72) and median disease duration of 18 years (IQR: 15-22). LSPD and DBS patients' MDS-UPDRS-III score improved 11.3% and 37% after levodopa, respectively. Rest tremor showed the largest improvement, while axial signs did not improve in LSPD. However, the magnitude of levodopa response significantly correlated with dyskinesias severity in LSPD patients. One third of LSPD and 9% of DBS patients reported moderate drowsiness.Conclusions: LSPD patients show a slight response to a supra-maximal levodopa dose, which is greater if dyskinesia are present, but it is frequently associated with adverse effects. A decrease in levodopa response is a potential marker of disease progression in LSPD. [ABSTRACT FROM AUTHOR]

Becker muscular dystrophy (BMD) represents an X-linked genetic disease (Xp21 locus) resulting in dystrophin production defect. Dystrophin is an essential protein in skeletal muscles and myocardium that reduces cell membrane stress during muscle contractions. The insufficient production of dystrophin in patients with Becker muscular dystrophy results in slow and progressive muscle weakness that affects predominantly proximal pelvic muscles. There is no correlation between cardiac involvement and the severity of myopathy. The onset of cardiac involvement is usually in the third decade of life (28,7 ± 7.1 years) and is the main cause of death in these patients. As soon as the diagnosis of BMD is established, a comprehensive cardiac examination should be performed. Because cardiac involvement in BMD is progressive and adequate therapy is available, cardiac investigations need to be regularly repeated. If cardiac involvement in BMD is recognized early, appropriate therapy may be applied early, resulting in more favorable outcome. We present the case of 37-year-old male with BMD, dilative cardiomyopathy and LV thrombus, diagnosed at late stage of the disease progression. [ABSTRACT FROM AUTHOR]

The aim of this paper is to evaluate relationships between decomposition rates of Scots pine ( Pinus sylvestris ) and lodgepole pine ( Pinus contorta var. contorta) needle litter in the late stage of decomposition (>30% accumulated mass loss), and the progressively changing concentrations of manganese (Mn), nitrogen (N), and acid unhydrolyzable residue (AUR), as well as mean annual temperature (MAT) and mean annual precipitation (MAP). Using available long-term decomposition studies on pine needle litter in a climate gradient in Sweden, we calculated annual mass loss and related to concentrations of Mn, N, and AUR at the start of each one-year period as well as to MAT and MAP. We investigated these relationships for (i) all data on annual mass loss combined and (ii) annual mass loss for five different decomposition categories as defined by accumulated mass loss. We found highly significant, negative, and dominant relationships between annual mass loss and N ( R 2 = 0.39) and AUR ( R 2 = 0.39), a slight but significant positive relationship to Mn ( R 2 = 0.08) and a significant negative relationship to MAT ( R 2 = 0.06). The relationships were dynamic, and changed with accumulated mass loss. The rate-dampening effect of N decreased to be a rate-enhancing effect at c. 60–80% accumulated mass loss. A similar trend was found for AUR, becoming rate-enhancing at 70–80% accumulated mass loss. For Scots pine needle litter the effect of MAT on mass loss decreased with increasing accumulated mass loss and changed to a rate-dampening effect at c. 50–70% accumulated mass loss. Mn showed a stimulating effect on mass loss rate in all categories whereas MAP showed no effect in this mainly boreal climatic gradient. The current approach indicates a method for detailed studies of rate-regulating factors for litter decomposition. [ABSTRACT FROM AUTHOR]

Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuro-protective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the human RPGR transgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy of RPGR gene augmentation and substantially broaden the therapeutic window for intervention in patients with RPGR-XLRP. [ABSTRACT FROM AUTHOR]

Background: Late stage of cancer at diagnosis is an important predictor of cancer mortality. In many areas worldwide, cancer registry systems, available data and mapping technologies can provide information about late stage cancer by geographical regions, offering valuable opportunities to identify areas where further investigation and interventions are needed. The current study examined geographical variation in late stage breast cancer incidence across eight states in the United States with the objective to identify areas that might benefit from targeted interventions. Methods: Data from the Surveillance Epidemiology and End Results Program on late stage breast cancer incidence was used as dependent variable in regression analysis and certain factors known to contribute to high rates of late stage cancer (socioeconomic characteristics, health insurance characteristics, and the availability and utilization of cancer screening) as covariates. Geographic information systems were used to map and highlight areas that have any combination of high late stage breast cancer incidence and significantly associated risk factors. Results: The differences in mean rates of late stage breast cancer between eight states considered in this analysis are statistically significant. Factors that have statistically negative association with late stage breast cancer incidence across the eight states include: density of mammography facilities, percent population with Bachelor's degree and English literacy while percent black population has statistically significant positive association with late stage breast cancer incidence. Conclusions: This study describes geographic disparities in late stage breast cancer incidence and identifies areas that might benefit from targeted interventions. The results suggest that in the eight US states examined, higher rates of late stage breast cancer are more common in areas with predominantly black population, where English literacy, percentage of population with college degree and screening availability are low. The approach described in this work may be utilized both within and outside US, wherever cancer registry systems and technologies offer the same opportunity to identify places where further investigation and interventions for reducing cancer burden are needed. [ABSTRACT FROM AUTHOR]

Introduction. We investigated incidence and staging patterns of prostate, female breast, lung, and colorectal cancer among American Indians/Alaska Natives (AI/ANs) and non-Hispanic Whites (NHWs) in the Northern Plains. Methods. Cancer registry data (2002-2009) from Nebraska, North Dakota, and South Dakota were analyzed. Incidence rates were calculated and multivariate logistic regression analyses identified factors associated with unstaged versus staged and late-stage cancer cases versus early. Results. The incidence rate was higher among AI/ANs than NHWs for lung cancer (92.2 vs. 60.6 per 100,000). Compared with NHWs, AI/ANs were 2.0 times more likely to receive an unstaged diagnosis and 1.2 times more likely to receive a late-stage diagnosis. AI/ANs were significantly more likely than NHWs to receive an unstaged diagnosis. Discussion. Increased efforts are needed to reduce unstaged and late-stage diagnoses among Northern Plains AIs. Efforts to promote early detection of cancer should target younger AI/ANs. [ABSTRACT FROM AUTHOR]

Background In this study we report on the outcome including overall and cause-specific mortality of Parkinson's disease (PD) patients subsequent to 38 years of surveillance. This is an extension study of our previous report on mortality. Methods Two hundred thirty-seven patients with a symptom onset between 1974 and 1984 were followed until the date of December 31, 2012 or death, representing a follow-up period of up to 38 years. Overall and cause-specific standardized mortality ratios (SMRs) were calculated, and predictors for survival at disease onset were estimated. Results and Conclusion Two hundred thirty patients had died by December 31, 2012; a total of 3,489 person-years were available for observation. The SMR at 38 years of follow-up was 2.02 (1.76-2.29). Employing Cox's proportional hazard modeling, male sex, gait disorder, absence of classical rest tremor, and absence of asymmetry predicted poor survival in this cohort. Increased cause-specific SMRs were found for pneumonia and cerebrovascular and cardiovascular diseases. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background and purpose Handicap has not been explored as a patient-centred outcome measure in Parkinson's disease ( PD). The clinical features and medication use in late stages of PD ( LS- PD) were reported previously. Methods Handicap, medical conditions, use of healthcare resources and the impact of LS- PD upon caregivers were characterized in a cross-sectional study of LS- PD stages 4 or 5 of Hoehn and Yahr (H&Y). Handicap was measured using the London Handicap Scale ( LHS: 0, maximal handicap; 1, no handicap). Results The mean LHS score in 50 patients was 0.33 ( SD ±0.15). The presence of dementia, the Unified Parkinson's Disease Rating Scale part I score and the H&Y stage in 'off' independently predicted the LHS score (adjusted R2 = 0.62; P = 0.000). Comorbidities and past medical conditions were frequent. Thirty-five patients lived at their house. Forty-five received unpaid care. Mean visits to the family doctor in the preceding 6 months were 2.2 ( SD ±3.0) and to a neurologist 1.7 ( SD ±1.0). Use of other health resources was low. Unpaid caregivers spent much time with patients and reported a high burden. Conclusion Handicap could be measured in LS- PD and the LHS was easily completed by patients and caregivers. The high handicap in our cohort was mostly driven by the presence of dementia, behavioural complaints and the severity of non-dopaminergic motor features. Patients visited doctors infrequently and made low use of health resources, whilst unpaid caregivers reported a high burden. [ABSTRACT FROM AUTHOR]