Location-Specific Hematoma Volume Cutoff and Clinical Outcomes in Intracerebral Hemorrhage.

BACKGROUND: Major intracerebral hemorrhage (ICH) trials have largely been unable to demonstrate therapeutic benefit in improving functional outcomes. This may be partly due to the heterogeneity of ICH outcomes based on their location, where a small strategic ICH could be debilitating, thus confounding therapeutic effects. We aimed to determine the ideal hematoma volume cutoff for different ICH locations in predicting ICH outcomes. METHODS: We retrospectively analyzed consecutive ICH patients enrolled in the University of Hong Kong prospective stroke registry from January 2011 to December 2018. Patients with premorbid modified Rankin Scale score >2 or who underwent neurosurgical intervention were excluded. ICH volume cutoff, sensitivity, and specificity in predicting respective 6-month neurological outcomes (good [modified Rankin Scale score 0-2], poor [modified Rankin Scale score 4-6], and mortality) for specific ICH locations were determined using receiver operating characteristic curves. Separate multivariate logistic regression models were also conducted for each location-specific volume cutoff to determine whether these cutoffs were independently associated with respective outcomes. RESULTS: Among 533 ICHs, the volume cutoff for good outcome according to ICH location was 40.5 mL for lobar, 32.5 mL for putamen/external capsule, 5.5 mL for internal capsule/globus pallidus, 6.5 mL for thalamus, 17 mL for cerebellum, and 3 mL for brainstem. ICH smaller than the cutoff for all supratentorial sites had higher odds of good outcomes (all P<0.05). Volumes exceeding 48 mL for lobar, 41 mL for putamen/external capsule, 6 mL for internal capsule/globus pallidus, 9.5 mL for thalamus, 22 mL for cerebellum, and 7.5 mL for brainstem were at greater risk of poor outcomes (all P<0.05). Mortality risks were significantly higher for volumes that exceeded 89.5 mL for lobar, 42 mL for putamen/external capsule, and 21 mL for internal capsule/globus pallidus (all P<0.001). All receiver operating characteristic models for location-specific cutoffs had good discriminant values (area under the curve >0.8), except in predicting good outcome for cerebellum. CONCLUSIONS: ICH outcomes differed with location-specific hematoma size. Location-specific volume cutoff should be considered in patient selection for ICH trials.

Comparison of the 12-month impact of COVID-19 and SARS on physiological capacity and health-related quality of life.

BACKGROUND: Little is known about the differences in medium to long-term recovery on spirometry, 6-minute walking distance (6MWD) and health-related quality of life (HRQoL) between COVID-19 and SARS. METHODS: We performed a 12-month prospective study on COVID-19 survivors. The changes in dynamic lung volumes at spirometry (%predicted FEV1, %predicted FVC), 6MWD and HRQoL at 1-3, 6 to 12 months were compared against a historical cohort of SARS survivors using the same study protocol. The residual radiological changes in HRCT in COVID-19 survivors were correlated with their functional capacity. RESULTS: 108 COVID-19 survivors of various disease severity (asymptomatic 2.9%, mild 33.3%, moderate 47.2%, severe 8.3%, critical 8.3%) were recruited. When compared with 97 SARS survivors, 108 COVID-19 survivors were older (48.1 ± 16.4 vs. 36.1 ± 9.5 years, p < 0.001) and required less additional support during hospitalization; with lower dynamic lung volumes, shorter 6MWD and better physical component score. Both groups of survivors had comparable changes in these parameters at subsequent follow-ups. Both COVID-19 and SARS survivors had similar mental component score (MCS) at 6 and 12 months. COVID-19 survivors initially experienced less (between-group difference, -3.1, 95% confidence interval [CI] -5.5 to -0.7, p = 0.012) and then more improvement (between-group difference 2.9, 95%, CI 0.8 to 5.1, p = 0.007) than SARS survivors in the MCS at 1-3 to 6 months and 6 to 12 months respectively. Forty (44.0%) out of 91 COVID-19 survivors had residual abnormalities on HRCT at 12 months, with a negative correlation between the severity scores of parenchymal changes and 6MWD (r=-0.239, p < 0.05). CONCLUSIONS: COVID-19 survivors demonstrated a similar recovery speed in dynamic lung volumes and exercise capacity, but different paces of psychological recovery as SARS survivors in the convalescent phase. The severity of parenchymal changes in HRCT is negatively correlated with the 6MWD of COVID-19 survivors. TRIAL REGISTRATION: This prospective study was registered at ClinicalTrials.gov on 2 November 2020 (Identifier: NCT04611243).

Use of Berlin questionnaire in comparison to polysomnography and home sleep study in patients with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a common disorder with significant morbidity and mortality. We aimed to evaluate the predictive accuracy of the Berlin questionnaire in patients with suspected OSAS undergoing PSG in the sleep laboratory setting against those going through the Embletta™ portable diagnostic system (Embletta PDS) at home. METHODS: Patients with suspected OSAS were recruited from respiratory clinics to complete Berlin questionnaire and Epworth Sleepiness Score (ESS). Patients were randomized to undergo either home-based sleep test (group A) or hospital-based polysomnography (PSG) (group B). RESULTS: Three hundreds and sixteen subjects with newly referred suspected OSAS were recruited and randomized into group A (n = 157) and group B (n = 159). The prevalence of moderate to severe OSAS defined as apnea-hypopnea index (AHI) ≥ 15/h was 54%. The Berlin questionnaire identified 69.7% (n = 99) of subjects as high risk in group A and 77.5% (n = 100) in group B. The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the questionnaire to predict an AHI ≥ 15/h as diagnosed by PSG was 78, 23, 67 and 35%. When compared with Embletta PDS, the specificity and NPV increased to 48 and 63%. The area under the Receiver Operator Curve (ROC) based on PSG (AUC = 0.539, 95%CI 0.417, 0.661) and based on home Embletta (AUC = 0.712, 95%CI 0.617, 0.907). CONCLUSIONS: The questionnaire was not reliable in predicting OSAS through PSG AHI whereas there was some predictive ability in discriminating patients with OSAS from normal subjects based on home Embletta sleep test. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (Identifier: NCT01828216) on 10 April 2013.

Continuous positive airway pressure for obstructive sleep apnoea does not improve asthma control.

BACKGROUND AND OBJECTIVE: Unrecognized obstructive sleep apnoea syndrome (OSAS) may lead to poor asthma control despite optimal therapy. We assessed asthma control, airway responsiveness, daytime sleepiness and health status at baseline and 3 months after continuous positive airway pressure (CPAP) treatment among asthma patients with nocturnal symptoms and OSAS. METHODS: Patients with nocturnal asthma symptoms despite receiving at least moderate-dose inhaled corticosteroid and long-acting bronchodilators underwent a home sleep study using 'Embletta' portable diagnostic system. Patients with significant OSAS (apnoea-hypopnoea index (AHI) ≥10/h) were randomized to receive either CPAP or conservative treatment for 3 months. RESULTS: Among 145 patients recruited, 122 underwent sleep study with 41 (33.6%) having AHI ≥10/h. Patients with significant OSAS had higher BMI (27.4 (5.1) vs 25.1 (4.5) kg/m2 , P = 0.016), bigger neck circumference (36.6 (3.1) vs 34.8 (3.6) cm, P = 0.006) and lower minimum SaO2 (80.7 (6.6) vs 87.2 (3.9) %, P < 0.001). Using intention-to-treat analysis among 37 patients with AHI ≥10/h (CPAP group (n = 17) vs control group (n = 20)), there was no significant difference in Asthma Control Test score (CPAP 3.2 (2.7) vs control 2.4 (5.7), P = 0.568) but the CPAP group had a greater improvement in Epworth Sleepiness Scale (-3.0 (4.5) vs 0.5(3.8), P = 0.014), Asthma Quality of Life Questionnaire (0.6 (0.8) vs 0.02 (0.7), P = 0.022) and vitality domain in the SF-36 questionnaire (14.7 (16.8) vs 0.3 (16.2), P = 0.012) after 3 months. Data are presented as mean (SD) unless otherwise stated. CONCLUSION: A high prevalence of OSAS was found among patients with asthma and snoring. CPAP therapy for 3 months did not enhance asthma control but improved daytime sleepiness, quality of life and vitality.

Digital Image Comparison of Cellular Yield in Bronchial Brushing: Pre- and Post-Biopsy Lavage Cytology.

INTRODUCTION: Bronchoscopy is a useful diagnostic tool capable of performing core biopsy, forceps biopsy, bronchoalveolar lavage, and bronchial brushing. This study compares the cellularity of bronchial cytology including pre- and post-biopsy lavage by digital image analysis, aiming to increase diagnostic and tumor yield by optimizing the sequence and combination of bronchial biopsy and cytology. METHODS: Alveolar macrophage, bronchial epithelium, and tumor cell cellularity from liquid-based cytology preparations of bronchial brushing and pre-biopsy and post-biopsy bronchoalveolar lavage were annotated on digitized whole-slide images and compared. Secondary analysis on the relationship of tumor cell and non-lesional cell yield was performed. RESULTS: Overall, 118 cytology specimens from 43 patients were retrieved in total. Bronchial epithelium count was higher in pre-biopsy than post-biopsy lavage (p < 0.01) but not for alveolar macrophages nor tumor cell (p > 0.05). Tumor cell count was higher for bronchial brushing cytology samples than lavage (p = 0.018). The alveolar macrophage count was higher in post-biopsy lavage than bronchial brushing (p = 0.033); otherwise, brushing showed consistently higher bronchial epithelium and tumor cell counts. There were 33 false negative (tumor cell absent) specimens, and the combination of bronchial brushing and pre-biopsy lavage yielded the lowest false negative cases. Correlation between bronchial epithelium and alveolar macrophage counts with tumor cell count was weak (correlation coefficient = -0.168-0.203) except for post-biopsy lavage (correlation coefficient = 0.412-0.479, p < 0.05). CONCLUSION: Bronchial brushing yields a greater amount of tumor cell than lavage, and timing lavage before or after core biopsy does not affect tumor cell yield. Combining bronchial brushing and pre-biopsy lavage results in the lowest false negative rate.

Large increases in methane emissions expected from North America's largest wetland complex.

Natural methane (CH4) emissions from aquatic ecosystems may rise because of human-induced climate warming, although the magnitude of increase is highly uncertain. Using an exceptionally large CH4 flux dataset (~19,000 chamber measurements) and remotely sensed information, we modeled plot- and landscape-scale wetland CH4 emissions from the Prairie Pothole Region (PPR), North America's largest wetland complex. Plot-scale CH4 emissions were driven by hydrology, temperature, vegetation, and wetland size. Historically, landscape-scale PPR wetland CH4 emissions were largely dependent on total wetland extent. However, regardless of future wetland extent, PPR CH4 emissions are predicted to increase by two- or threefold by 2100 under moderate or severe warming scenarios, respectively. Our findings suggest that international efforts to decrease atmospheric CH4 concentrations should jointly account for anthropogenic and natural emissions to maintain climate mitigation targets to the end of the century.

1-Year Prospective Study of the Relationship of Serial Exhaled Nitric Oxide Level and Asthma Control.

Background and Objective: Previous studies found that the fractional nitric oxide concentration in exhaled breath (FeNO) levels in healthy Chinese adults was higher than in White adults. More understanding of serial changes of FeNO levels with asthma control in a real-life clinical setting would be important to explore the utility of this biomarker in routine asthma management. This study assessed the FeNO levels of Chinese asthma subjects with different levels of asthma control and the serial changes with respect to the changes in asthma control over 1 year. Methods: A 12-month prospective study (subjects recruited between November 2019 and January 2021) with serial measurement of FeNO levels at baseline, 4, 8 and 12 months. Asthma control was assessed by the Global Initiative for Asthma classification, Asthma Control Test (ACT) and Asthma Control Questionnaire (ACQ). Results: Altogether, 136 subjects (mean age 51.51±15.09 years, 46[33.8%] male) had successful baseline FeNO measurements. At baseline, the FeNO levels did not show a statistically significant difference for controlled, partly controlled and uncontrolled asthma according to GINA classification, ACT and ACQ. FeNO levels decreased with improving asthma control and stayed at similar levels with unchanged or worsening asthma control for all subjects. For subjects with baseline blood eosinophil levels ≥300 cells/µL(n=59), FeNO levels decreased with improving asthma control, stayed similar without change for asthma control and increased with worsening asthma control. Receiver operating characteristic (ROC) analysis with the highest area under curve (AUC) for changes in FeNO levels for improving asthma control was between ≤ -10 to -25 ppb at various time points in the 12-month study. Conclusion: Changes in FeNO levels over time were associated with changes in clinical asthma control, particularly in those with higher blood eosinophil count and are likely more useful than a single time point measurement in managing asthma.

LRRK2, GBA and their interaction in the regulation of autophagy: implications on therapeutics in Parkinson's disease.

Mutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA) represent two most common genetic causes of Parkinson's disease (PD). Both genes are important in the autophagic-lysosomal pathway (ALP), defects of which are associated with α-synuclein (α-syn) accumulation. LRRK2 regulates macroautophagy via activation of the mitogen activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) kinase (MEK) and the calcium-dependent adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathways. Phosphorylation of Rab GTPases by LRRK2 regulates lysosomal homeostasis and endosomal trafficking. Mutant LRRK2 impairs chaperone-mediated autophagy, resulting in α-syn binding and oligomerization on lysosomal membranes. Mutations in GBA reduce glucocerebrosidase (GCase) activity, leading to glucosylceramide accumulation, α-syn aggregation and broad autophagic abnormalities. LRRK2 and GBA influence each other: GCase activity is reduced in LRRK2 mutant cells, and LRRK2 kinase inhibition can alter GCase activity in GBA mutant cells. Clinically, LRRK2 G2019S mutation seems to modify the effects of GBA mutation, resulting in milder symptoms than those resulting from GBA mutation alone. However, dual mutation carriers have an increased risk of PD and earlier age of onset compared with single mutation carriers, suggesting an additive deleterious effect on the initiation of PD pathogenic processes. Crosstalk between LRRK2 and GBA in PD exists, but its exact mechanism is unclear. Drugs that inhibit LRRK2 kinase or activate GCase are showing efficacy in pre-clinical models. Since LRRK2 kinase and GCase activities are also altered in idiopathic PD (iPD), it remains to be seen if these drugs will be useful in disease modification of iPD.

Assessing Patient Preferences in Rare Diseases: Direct Preference Elicitation in the Rare Chronic Kidney Disease, Immunoglobulin A Nephropathy.

BACKGROUND: Patient preference information is increasingly being used to inform decision making; however, further work is required to support the collection of preference information in rare diseases. This study illustrates the use of direct preference elicitation methods to collect preference data from small samples in the context of early decision making to inform the development of a product for the treatment of immunoglobulin A nephropathy. METHOD: An interview-based swing weighting approach was used to elicit preferences from 40 patients in the US and China. Attributes were identified through a background review, expert engagement and patient focus groups. Participants completed a series of tasks that involved ranking, rating and scoring improvements in the attributes to obtain attribute swing weights and partial value functions. The preference results were then incorporated into a benefit-risk assessment simulation tool. RESULTS: Participants placed the greatest value on avoiding end-stage renal/kidney disease. Similar weight was given to short-term quality-of-life improvements and avoiding infections. Treatment burden (number of vaccinations) received the least weight. Heterogeneity in preferences was also observed. Consistency tests did not identify statistically significant variation in preferences, and qualitative data suggested that the elicitation exercise was sensitive to participants' interpretation of attributes and that participants were able to express their preferences. CONCLUSION: Direct preference elicitation methods can be used to collect preference data from small samples. Further work should continue to test the validity of the estimate generated by such methods.

A Systematic Review of Discrete Choice Experiments in Oncology Treatments.

BACKGROUND: As the number and type of cancer treatments available rises and patients live with the consequences of their disease and treatments for longer, understanding preferences for cancer care can help inform decisions about optimal treatment development, access, and care provision. Discrete choice experiments (DCEs) are commonly used as a tool to elicit stakeholder preferences; however, their implementation in oncology may be challenging if burdensome trade-offs (e.g. length of life versus quality of life) are involved and/or target populations are small. OBJECTIVES: The aim of this review was to characterise DCEs relating to cancer treatments that were conducted between 1990 and March 2020. DATA SOURCES: EMBASE, MEDLINE, and the Cochrane Database of Systematic Reviews were searched for relevant studies. STUDY ELIGIBILITY CRITERIA: Studies were included if they implemented a DCE and reported outcomes of interest (i.e. quantitative outputs on participants' preferences for cancer treatments), but were excluded if they were not focused on pharmacological, radiological or surgical treatments (e.g. cancer screening or counselling services), were non-English, or were a secondary analysis of an included study. ANALYSIS METHODS: Analysis followed a narrative synthesis, and quantitative data were summarised using descriptive statistics, including rankings of attribute importance. RESULT: Seventy-nine studies were included in the review. The number of published DCEs relating to oncology grew over the review period. Studies were conducted in a range of indications (n = 19), most commonly breast (n =10, 13%) and prostate (n = 9, 11%) cancer, and most studies elicited preferences of patients (n = 59, 75%). Across reviewed studies, survival attributes were commonly ranked as most important, with overall survival (OS) and progression-free survival (PFS) ranked most important in 58% and 28% of models, respectively. Preferences varied between stakeholder groups, with patients and clinicians placing greater importance on survival outcomes, and general population samples valuing health-related quality of life (HRQoL). Despite the emphasis of guidelines on the importance of using qualitative research to inform attribute selection and DCE designs, reporting on instrument development was mixed. LIMITATIONS: No formal assessment of bias was conducted, with the scope of the paper instead providing a descriptive characterisation. The review only included DCEs relating to cancer treatments, and no insight is provided into other health technologies such as cancer screening. Only DCEs were included. CONCLUSIONS AND IMPLICATIONS: Although there was variation in attribute importance between responder types, survival attributes were consistently ranked as important by both patients and clinicians. Observed challenges included the risk of attribute dominance for survival outcomes, limited sample sizes in some indications, and a lack of reporting about instrument development processes. PROTOCOL REGISTRATION: PROSPERO 2020 CRD42020184232.

Region-specific blood-brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer's disease.

BACKGROUND: Research into amisulpride use in Alzheimer's disease (AD) implicates blood-brain barrier (BBB) dysfunction in antipsychotic sensitivity. Research into BBB transporters has been mainly directed towards the ABC superfamily, however, solute carrier (SLC) function in AD has not been widely studied. This study tests the hypothesis that transporters for organic cations contribute to the BBB delivery of the antipsychotics (amisulpride and haloperidol) and is disrupted in AD. METHODS: The accumulation of [3H]amisulpride (3.7-7.7 nM) and [3H]haloperidol (10 nM) in human (hCMEC/D3) and mouse (bEnd.3) brain endothelial cell lines was explored. Computational approaches examined molecular level interactions of both drugs with the SLC transporters [organic cation transporter 1 (OCT1), plasma membrane monoamine transporter (PMAT) and multi-drug and toxic compound extrusion proteins (MATE1)] and amisulpride with the ABC transporter (P-glycoprotein). The distribution of [3H]amisulpride in wildtype and 3×transgenic AD mice was examined using in situ brain perfusion experiments. Western blots determined transporter expression in mouse and human brain capillaries . RESULTS: In vitro BBB and in silico transporter studies indicated that [3H]amisulpride and [3H]haloperidol were transported by the influx transporter, OCT1, and efflux transporters MATE1 and PMAT. Amisulpride did not have a strong interaction with OCTN1, OCTN2, P-gp, BCRP or MRP and could not be described as a substrate for these transporters. Amisulpride brain uptake was increased in AD mice compared to wildtype mice, but vascular space was unaffected. There were no measurable changes in the expression of MATE1, MATE2, PMAT OCT1, OCT2, OCT3, OCTN1, OCTN2 and P-gp in capillaries isolated from whole brain homogenates from the AD mice compared to wildtype mice. Although, PMAT and MATE1 expression was reduced in capillaries obtained from specific human brain regions (i.e. putamen and caudate) from AD cases (Braak stage V-VI) compared to age matched controls (Braak stage 0-II). CONCLUSIONS: Together our research indicates that the increased sensitivity of individuals with Alzheimer's to amisulpride is related to previously unreported changes in function and expression of SLC transporters at the BBB (in particular PMAT and MATE1). Dose adjustments may be required for drugs that are substrates of these transporters when prescribing for individuals with AD.