Choroid Plexus Calcification Correlates with Cortical Microglial Activation in Humans: A Multimodal PET, CT, MRI Study.

BACKGROUND AND PURPOSE: The choroid plexus (CP) within the brain ventricles is well-known to produce cerebrospinal fluid (CSF). Recently, the CP has been recognized as critical in modulating inflammation. MRI-measured CP enlargement has been reported in neuroinflammatory disorders like MS as well as with aging and neurodegeneration. The basis of MRI-measured CP enlargement is unknown. On the basis of tissue studies demonstrating CP calcification as a common pathology associated with aging and disease, we hypothesized that previously unmeasured CP calcification contributes to MRI-measured CP volume and may be more specifically associated with neuroinflammation. MATERIALS AND METHODS: We analyzed 60 subjects (43 healthy controls and 17 subjects with Parkinson's disease) who underwent PET/CT using 11C-PK11195, a radiotracer sensitive to the translocator protein expressed by activated microglia. Cortical inflammation was quantified as nondisplaceable binding potential. Choroid plexus calcium was measured via manual tracing on low-dose CT acquired with PET and automatically using a new CT/MRI method. Linear regression assessed the contribution of choroid plexus calcium, age, diagnosis, sex, overall volume of the choroid plexus, and ventricle volume to cortical inflammation. RESULTS: Fully automated choroid plexus calcium quantification was accurate (intraclass correlation coefficient with manual tracing = .98). Subject age and choroid plexus calcium were the only significant predictors of neuroinflammation. CONCLUSIONS: Choroid plexus calcification can be accurately and automatically quantified using low-dose CT and MRI. Choroid plexus calcification-but not choroid plexus volume-predicted cortical inflammation. Previously unmeasured choroid plexus calcium may explain recent reports of choroid plexus enlargement in human inflammatory and other diseases. Choroid plexus calcification may be a specific and relatively easily acquired biomarker for neuroinflammation and choroid plexus pathology in humans.

Metacognitive-Focused Occupational Therapy for Substance Abuse in Medical-Social Service Collaboration: a Case Report.

We describe a 26-year-old man who underwent Metacognitive-Focused Occupational Therapy for his substance abuse problems.

Radiation segmentectomy of hepatic metastases with Y-90 glass microspheres.

PURPOSE: To evaluate safety and efficacy of radiation segmentectomy (RS) with 90Y glass microspheres in patients with limited metastatic liver disease not amenable to resection or percutaneous ablation. METHODS: Patients with ≤ 3 tumors treated with RS from 6/2015 to 12/2017 were included. Target tumor radiation dose was > 190 Gy based on medical internal radiation dose (MIRD) dosimetry. Tumor response, local tumor progression (LTP), LTP-free survival (LTPFS) and disease progression rate in the treated segment were defined using Choi and RECIST 1.1 criteria. Toxicities were evaluated using modified SIR criteria. RESULTS: Ten patients with 14 tumors underwent 12 RS. Median tumor size was 3 cm (range 1.4-5.6). Median follow-up was 17.8 months (range 1.6-37.3). Response rates per Choi and RECIST 1.1 criteria were 8/8 (100%) and 4/9 (44%), respectively. Overall LTP rate was 3/14 (21%) during the study period. One-, two- and three-year LTPFS was 83%, 83% and 69%, respectively. Median LTPFS was not reached. Disease progression rate in the treated segment was 6/18 (33%). Median overall survival was 41.5 months (IQR 16.7-41.5). Median delivered tumor radiation dose was 293 Gy (range 163-1303). One major complication was recorded in a patient post-Whipple procedure who suffered anaphylactic reaction to prophylactic cefotetan and liver abscess in RS region 6.5 months post-RS. All patients were alive on last follow-up. CONCLUSION: RS of ≤ 3 hepatic segments can safely provide a 2-year local tumor control rate of 83% in selected patients with limited metastatic liver disease and limited treatment options. Optimal dosimetry methodology requires further investigation.

Voltage-Induced Single-Molecule Junction Planarization.

Probing structural changes of a molecule induced by charge transfer is important for understanding the physicochemical properties of molecules and developing new electronic devices. Here, we interrogate the structural changes of a single diketopyrrolopyrrole (DPP) molecule induced by charge transport at a high bias using scanning tunneling microscope break junction (STM-BJ) techniques. Specifically, we demonstrate that application of a high bias increases the average nonresonant conductance of single Au-DPP-Au junctions. We infer from the increased conductance that resonant charge transport induces planarization of the molecular backbone. We further show that this conformational planarization is assisted by thermally activated junction reorganization. The planarization only occurs under specific electronic conditions, which we rationalize by ab initio calculations. These results emphasize the need for a comprehensive view of single-molecule junctions which includes both the electronic properties and structure of the molecules and the electrodes when designing electrically driven single-molecule motors.

Too Cool for Blackbody Radiation: Overbias Photon Emission in Ambient STM Due to Multielectron Processes.

Light emission from tunnel junctions are a potential photon source for nanophotonic applications. Surprisingly, the photons emitted can have energies exceeding the energy supplied to the electrons by the bias. Three mechanisms for generating these so-called overbias photons have been proposed, but the relationship between these mechanisms has not been clarified. In this work, we argue that multielectron processes provide the best framework for understanding overbias light emission in tunnel junctions. Experimentally, we demonstrate for the first time that the superlinear dependence of emission on conductance predicted by this theory is robust to the temperature of the tunnel junction, indicating that tunnel junctions are a promising candidate for electrically driven broadband photon sources.

Update to the Hong Kong Epilepsy Guideline: evidence-based recommendations for clinical management of women with epilepsy throughout the reproductive cycle.

Since the publication of the Hong Kong Epilepsy Guideline in 2009, there has been significant progress in antiepileptic drug development. New AEDs have emerged, and data about their uses have been published. Women require special attention in epilepsy care. Drug teratogenicity, pregnancy, breastfeeding, contraception, reproduction technology, menopause, and catamenial epilepsy are major topics. Antiepileptic drugs should be chosen individually for patients who are pregnant or may become pregnant with consideration of their teratogenicity and seizure control properties. Folate is commonly prescribed for women of childbearing age who are taking antiepileptic drugs. Spontaneous vaginal delivery and breastfeeding are not contra-indicated in most cases but need to be considered individually based on the patient's medical condition and wishes. Serum drug level monitoring of certain antiepileptic drugs during pregnancy and puerperium can guide dosage adjustment. For catamenial epilepsy, intermittent benzodiazepines such as clobazam during the susceptible phase of the menstrual cycle could be a treatment option.

Mechanically Tunable Quantum Interference in Ferrocene-Based Single-Molecule Junctions.

Ferrocenes are ubiquitous organometallic building blocks that comprise a Fe atom sandwiched between two cyclopentadienyl (Cp) rings that rotate freely at room temperature. Of widespread interest in fundamental studies and real-world applications, they have also attracted some interest as functional elements of molecular-scale devices. Here we investigate the impact of the configurational degrees of freedom of a ferrocene derivative on its single-molecule junction conductance. Measurements indicate that the conductance of the ferrocene derivative, which is suppressed by 2 orders of magnitude as compared to a fully conjugated analogue, can be modulated by altering the junction configuration. Ab initio transport calculations show that the low conductance is a consequence of destructive quantum interference effects of the Fano type that arise from the hybridization of localized metal-based d-orbitals and the delocalized ligand-based π-system. By rotation of the Cp rings, the hybridization, and thus the quantum interference, can be mechanically controlled, resulting in a conductance modulation that is seen experimentally.

Cardiac Manifestations of Sarcopenia.

OBJECTIVES: Screening questions for sarcopenia used in the community (SARC-F) may be regarded as indicators of exercise tolerance. DESIGN: Observational study. SETTING: We tested the hypothesis that community-living older people who are screened positive for sarcopenia using the SARC-F tool but without a history of heart failure (HF) have a higher prevalence of cardiac abnormalities compared with those who are SARC-F negative. PARTICIPANTS: Participants were recruited from a territory-wide primary care needs assessment for older people based in community centres, and from non-acute hospitals in the same region as the study centre. MEASUREMENTS: Participants with a total score of >=4 and who did not have any history of HF were invited to attend for further cardiac assessment. Grip strength, walking speed, and the 6-minute walk test and echocardiography were carried out. Patients with frailty and at least Grade II diastolic dysfunction were considered to have heart failure with preserved ejection fraction (HFpEF) if they also had concomitant elevated N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) of at least 300 pg/ml. RESULTS: Diastolic dysfunction (DD) was significantly associated with SARC-F score >=4 and higher circulating NT-proBNP levels. ROC curves evaluating the predictive values of SARC-F, HGS and gait speed for DD showed that a combination of SARC-F and HGS or gait speed provided significant incremental value in predicting DD. CONCLUSIONS: Community living older people with sarcopenia detected using a simple questionnaire have a higher prevalence of DD accompanied by elevated NT proBNP. Addition of hand grip strength or walking speed improve the magnitude of the association. SARC-F may be used as a tool to detect early cardiac dysfunction in the community.

Utility of the FRAIL Questionnaire in Detecting Heart Failure with Preserved Ejection Fraction.

OBJECTIVE: To test the utility of the FRAIL questionnaire as a screening tool for heart failure. DESIGN: Cross sectional study. SETTING: Chinese older people in Hong Kong. PARTICIPANTS: Participants aged 60 years and over were recruited from a territory-wide primary care needs assessment for older people based in community centers as well as two nonacute hospitals. MEASUREMENTS: Questionnaire administered included the five-item FRAIL scale, and information regarding sociodemographic data, smoking and alcohol use, history of cardiovascular disease and diabetes, and heart failure symptoms. Handgrip strength, walking speed and 6 minute walk distance were recorded. Cardiac assessment included electrocardiogram, echocardiography, and blood assay for N-terminal prohormone of B-type natriuretic peptide (NT-proBNP). RESULTS: The prevalence of diastolic dysfunction was high, being 52% in the robust group, increasing to 65% in the pre-frail and 85% in the frail group. This finding is accompanied by a corresponding increase in NT-proBNP from 64.18 pg/ml in the robust group, to 118.57 pg/ml in the pre-frail and 167.98 pg/ml in the frail group. Three of the five components of the FRAIL scale, fatigue, resistance and ambulation, were associated with increased odds ratios of diastolic dysfunction among those aged 75 years and older, while resistance alone was associated with increased odds ratio among those less than 75 years old. CONCLUSION: Frailty is associated with heart failure with preserved ejection fraction (HFpEF), and frailty screening may be used to detect undiagnosed HFpEF. The findings support the proposal that HFpEF be considered a geriatric syndrome.

Breaking Down Resonance: Nonlinear Transport and the Breakdown of Coherent Tunneling Models in Single Molecule Junctions.

The promise of the field of single-molecule electronics is to reveal a new class of quantum devices that leverages the strong electronic interactions inherent to subnanometer scale systems. Here, we form Au-molecule-Au junctions using a custom scanning tunneling microscope and explore charge transport through current-voltage measurements. We focus on the resonant tunneling regime of two molecules, one that is primarily an electron conductor and one that conducts primarily holes. We find that in the high bias regime, junctions that do not rupture demonstrate reproducible and pronounced negative differential resistance (NDR)-like features followed by hysteresis with peak-to-valley ratios exceeding 100 in some cases. Furthermore, we show that both junction rupture and NDR are induced by charging of the molecular orbital dominating transport and find that the charging is reversible at lower bias and with time with kinetic time scales on the order of hundreds of milliseconds. We argue that these results cannot be explained by existing models of charge transport and likely require theoretical advances describing the transition from coherent to sequential tunneling. Our work also suggests new rules for operating single-molecule devices at high bias to obtain highly nonlinear behavior.

Resonant Transport in Single Diketopyrrolopyrrole Junctions.

We study the single-molecule transport properties of small bandgap diketopyrrolopyrrole oligomers (DPP n, n = 1-4) with lengths varying from 1 to 5 nm. At a low bias voltage, the conductance decays exponentially as a function of length indicative of nonresonant transport. However, at a high bias voltage, we observe a remarkably high conductance close to 10-2 G0 with currents reaching over 0.1 µA across all four oligomers. These unique transport properties, together with density functional theory-based transport calculations, suggest a mechanism of resonant transport across the highly delocalized DPP backbones in the high bias regime. This study thus demonstrates the unique properties of diketopyrrolopyrrole derivatives in achieving highly efficient long-range charge transport in single-molecule devices.

An update of the Hong Kong Epilepsy Guideline: consensus statement on the use of antiepileptic drugs in Hong Kong.

OBJECTIVE: New information about antiepileptic drugs has arisen since the publication of the Hong Kong Epilepsy Guideline in 2009. This article set out to fill the knowledge gap between 2007 and 2016 on the use of antiepileptic drugs in Hong Kong. PARTICIPANTS: Between May 2014 and April 2016, four consensus meetings were held in Hong Kong, where a group comprising 15 professionals (neurologists, paediatricians, neurosurgeons, radiologists, and clinical psychologists) from both public and private sectors aimed to review the best available evidence and update all practising physicians on a range of clinical issues including drug-related matters. All participants were council members of The Hong Kong Epilepsy Society. EVIDENCE: A literature review of the clinical use of antiepileptic drugs as monotherapy suggested Level A evidence for levetiracetam and Level B evidence for lacosamide. No change in the level of evidence was found for oxcarbazepine (Level A evidence) or pregabalin (undesignated), and no evidence was found for perampanel. A literature review on the clinical use of antiepileptic drugs as adjunctive therapy suggested Level A evidence for both lacosamide and perampanel. No change to the level of evidence was found for levetiracetam (Level A evidence), oxcarbazepine (Level A evidence), or pregabalin (Level A evidence). A literature search on the use of generic antiepileptic drugs suggested Level A evidence for the use of lamotrigine in generic substitution. CONSENSUS PROCESS: Three lead authors of the Subcommittee drafted the manuscript that consisted of two parts-part A: evidence on new antiepileptic drugs, and part B: generic drugs. The recommendations on monotherapy/adjunctive therapy were presented during the meetings. The pros and cons for our health care system of generic substitution were discussed. The recommendations represent the 'general consensus' of the participants in keeping with the evidence found in the literature. CONCLUSIONS: Recommendations for the use of levetiracetam, lacosamide, oxcarbazepine, pregabalin, and perampanel were made. The consensus statements may provide a reference to physicians in their daily practice. Controversy exists over the use of generic products among patients who are currently taking brand medications. In this regard, approvals from prescriber and patient are pivotal. Good communication between doctors and patients is essential, as well as enlisting the assistance of doctors, nurses, and pharmacists, therapeutic blood monitoring if available, and the option of brand antiepileptic drug as a self-financed item. The physical appearance of generic drugs should be considered as it may hamper drug compliance. Support from medical services is recommended. In the longer term, the benefit of flexibility and the options to have a balance between the generic and brand drug market may need to be addressed by institutions and regulatory bodies.

Review and update of the Hong Kong Epilepsy Guideline on status epilepticus.

Convulsive status epilepticus is the most extreme form of seizure. It is a medical and neurological emergency that requires prompt and appropriate treatment. Treatment of convulsive status epilepticus is usually divided into stages/steps. The International League Against Epilepsy has released a new definition of status epilepticus that may help to unify the definition in future studies. Over the last few years new information has become available regarding its management. The Rapid Anticonvulsant Medication Prior to Arrival Trial demonstrated non-inferiority of intramuscular midazolam in early status epilepticus compared with intravenous lorazepam. Valproate and levetiracetam have also emerged as possible alternatives to phenytoin in established status epilepticus. The potential role of lacosamide in this stage of status epilepticus remains to be defined. The ongoing Established Status Epilepticus Treatment Trial may help to determine the most effective treatment for benzodiazepine-resistant status epilepticus. Management of refractory status epilepticus and super-refractory status epilepticus remains mostly non-evidence-based. Increasing recognition of a possible autoimmune aetiology has led to the use of immune-modulation in super-refractory status epilepticus. Ketamine is also increasingly used in this challenging condition. There are also reports of potential use of a ketogenic diet and magnesium.

Too Hot for Photon-Assisted Transport: Hot-Electrons Dominate Conductance Enhancement in Illuminated Single-Molecule Junctions.

We investigate light-induced conductance enhancement in single-molecule junctions via photon-assisted transport and hot-electron transport. Using 4,4'-bipyridine bound to Au electrodes as a prototypical single-molecule junction, we report a 20-40% enhancement in conductance under illumination with 980 nm wavelength radiation. We probe the effects of subtle changes in the transmission function on light-enhanced current and show that discrete variations in the binding geometry result in a 10% change in enhancement. Importantly, we prove theoretically that the steady-state behavior of photon-assisted transport and hot-electron transport is identical but that hot-electron transport is the dominant mechanism for optically induced conductance enhancement in single-molecule junctions when the wavelength used is absorbed by the electrodes and the hot-electron relaxation time is long. We confirm this experimentally by performing polarization-dependent conductance measurements of illuminated 4,4'-bipyridine junctions. Finally, we perform lock-in type measurements of optical current and conclude that currents due to laser-induced thermal expansion mask optical currents. This work provides a robust experimental framework for studying mechanisms of light-enhanced transport in single-molecule junctions and offers tools for tuning the performance of organic optoelectronic devices by analyzing detailed transport properties of the molecules involved.

Probing the Conductance of the σ-System of Bipyridine Using Destructive Interference.

Guidelines to predict trends in the electrical conductance of molecules have been developed for the π-system of conjugated systems. Little is known, however, about the conductance of the underlying σ-systems because the π-system usually dominates the transport. Here we study a family of bipyridine-based molecules using STM-break junction experiments and density functional theory transport calculations. We use different lengths and substitution patterns to probe the role of both the σ-system and the π-system in controlling conductance. By exploiting the destructive interference feature found in the π-system of the meta-coupled six-membered aromatic rings, we show that the conductance of the σ-system of a meta-coupled molecule can be probed directly and can even exceed that of its para-coupled analog. These results add to the understanding of the conductance through the chemically hidden σ-electrons.