Abstract
Recent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and ethanol and nicotine abuse in humans. However, their hallucinogenic side-effects ...often preclude their clinical use. Lysergic acid diethylamide (LSD) is a prototypical hallucinogen and its psychedelic actions are exerted through the 5-HT
2A
serotonin receptor (5-HT2AR). 5-HT2AR activation stimulates Gq- and β-arrestin- (βArr) mediated signaling. To separate these signaling modalities, we have used βArr1 and βArr2 mice. We find that LSD stimulates motor activities to similar extents in WT and βArr1-KO mice, without effects in βArr2-KOs. LSD robustly stimulates many surrogates of psychedelic drug actions including head twitches, grooming, retrograde walking, and nose-poking in WT and βArr1-KO animals. By contrast, in βArr2-KO mice head twitch responses are low with LSD and this psychedelic is without effects on other surrogates. The 5-HT2AR antagonist MDL100907 (MDL) blocks the LSD effects. LSD also disrupts prepulse inhibition (PPI) in WT and βArr1-KOs, but not in βArr2-KOs. MDL restores LSD-mediated disruption of PPI in WT mice; haloperidol is required for normalization of PPI in βArr1-KOs. Collectively, these results reveal that LSD’s psychedelic drug-like actions appear to require βArr2.
Sleep disruption is a prevalent symptom reported by survivors of childhood cancer. However, there is no validated instrument for assessing this symptom in this population group. To bridge the ...literature gap, this study translated and adapted the Pittsburgh Sleep Quality Index (PSQI) for Hong Kong Chinese cancer survivors and examined its psychometric properties and factor structure. A convenience sample of 402 Hong Kong Chinese childhood cancer survivors aged 6-18 years were asked to complete the Chinese version of the PSQI, Center for Epidemiologic Studies Depression Scale for Children (CES-DC), Fatigue Scale-Child (FS-C)/Fatigue Scale-Adolescent (FS-A), and Pediatric Quality of Life Inventory (PedsQL). To assess known-group validity, 50 pediatric cancer patients and 50 healthy counterparts were recruited. A sample of 40 children were invited to respond by phone to the PSQI 2 weeks later to assess test-retest reliability. A cutoff score for the translated PSQI used with the survivors was determined using receiver operating characteristic analysis. The Chinese version of the PSQI had a Cronbach alpha of 0.71, with an intraclass correlation coefficient of 0.90. Childhood cancer survivors showed significantly lower mean PSQI scores than children with cancer, and significantly higher mean scores than healthy counterparts. This reflected that childhood cancer survivors had a better sleep quality than children with cancer, but a poorer sleep quality than healthy counterparts. We observed positive correlations between PSQI and CES-DC scores and between PSQI and FS-A/FS-C scores, but a negative correlation between PSQI and PedsQL scores. The results supported that the Chinese version of the PSQI showed convergent validity. Confirmatory factor analysis showed that the translated PSQI data best fit a three-factor model. The best cutoff score to detect insomnia was 5, with a sensitivity of 0.81 and specificity of 0.70. The Chinese version of the PSQI is a reliable and valid instrument to assess subjective sleep quality among Hong Kong Chinese childhood cancer survivors. The validated PSQI could be used in clinical settings to provide early assessments for sleep disruption. Appropriate interventions can therefore be provided to minimize its associated long-term healthcare cost.
Abstract
Tungsten ditelluride (WTe
2
) is an atomically layered transition metal dichalcogenide whose physical properties change systematically from monolayer to bilayer and few-layer versions. In ...this report, we use apertureless scattering-type near-field optical microscopy operating at Terahertz (THz) frequencies and cryogenic temperatures to study the distinct THz range electromagnetic responses of mono-, bi- and trilayer WTe
2
in the same multi-terraced micro-crystal. THz nano-images of monolayer terraces uncovered weakly insulating behavior that is consistent with transport measurements. The near-field signal on bilayer regions shows moderate metallicity with negligible temperature dependence. Subdiffractional THz imaging data together with theoretical calculations involving thermally activated carriers favor the semimetal scenario with
$$\Delta \approx -10\,{{{\rm{meV}}}$$
Δ
≈
−
10
meV
over the semiconductor scenario for bilayer WTe
2
. Also, we observed clear metallic behavior of the near-field signal on trilayer regions. Our data are consistent with the existence of surface plasmon polaritons in the THz range confined to trilayer terraces in our specimens. Finally, data for microcrystals up to 12 layers thick reveal how the response of a few-layer WTe
2
asymptotically approaches the bulk limit.
Abstract
T-cell-redirecting bispecific antibodies have emerged as a new class of therapeutic agents designed to simultaneously bind to T cells via CD3 and to tumor cells via tumor-cell-specific ...antigens (TSA), inducing T-cell-mediated killing of tumor cells. The promising preclinical and clinical efficacy of TSAxCD3 antibodies is often accompanied by toxicities such as cytokine release syndrome due to T-cell activation. How the efficacy and toxicity profile of the TSAxCD3 bispecific antibodies depends on the binding affinity to CD3 remains unclear. Here, we evaluate bispecific antibodies that were engineered to have a range of CD3 affinities, while retaining the same binding affinity for the selected tumor antigen. These agents were tested for their ability to kill tumor cells in vitro, and their biodistribution, serum half-life, and anti-tumor activity in vivo. Remarkably, by altering the binding affinity for CD3 alone, we can generate bispecific antibodies that maintain potent killing of TSA + tumor cells but display differential patterns of cytokine release, pharmacokinetics, and biodistribution. Therefore, tuning CD3 affinity is a promising method to improve the therapeutic index of T-cell-engaging bispecific antibodies.
Extremity arterial injury after penetrating trauma is common in military conflict or urban trauma centers. Most peripheral arterial injuries occur in the femoral and popliteal vessels of the lower ...extremity. The Eastern Association for the Surgery of Trauma first published practice management guidelines for the evaluation and treatment of penetrating lower extremity arterial trauma in 2002. Since that time, there have been advancements in the management of penetrating lower extremity arterial trauma. As a result, the Practice Management Guidelines Committee set out to develop updated guidelines.
A MEDLINE computer search was performed using PubMed (www.pubmed.gov). The search retrieved English language articles regarding penetrating lower extremity trauma from 1998 to 2011. References of these articles were also used to locate articles not identified through the MEDLINE search. Letters to the editor, case reports, book chapters, and review articles were excluded. The topics investigated were prehospital management, diagnostic evaluation, use of imaging technology, the role of temporary intravascular shunts, use of tourniquets, and the role of endovascular intervention.
Forty-three articles were identified. From this group, 20 articles were selected to construct the guidelines.
There have been changes in practice since the publication of the previous guidelines in 2002. Expedited triage of patients is possible with physical examination and/or the measurement of ankle-brachial indices. Computed tomographic angiography has become the diagnostic study of choice when imaging is required. Tourniquets and intravascular shunts have emerged as adjuncts in the treatment of penetrating lower extremity arterial trauma. The role of endovascular intervention warrants further investigation.
Within the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework, we performed a systematic review and developed evidence-based recommendations to answer the following ...PICO (Population, Intervention, Comparator, Outcomes) question: should patients who present pulseless after critical injuries (with and without signs of life after penetrating thoracic, extrathoracic, or blunt injuries) undergo emergency department thoracotomy (EDT) (vs. resuscitation without EDT) to improve survival and neurologically intact survival?
All patients who underwent EDT were included while those involving either prehospital resuscitative thoracotomy or operating room thoracotomy were excluded. Quantitative synthesis via meta-analysis was not possible because no comparison or control group (i.e., survival or neurologically intact survival data for similar patients who did not undergo EDT) was available for the PICO questions of interest.
The 72 included studies provided 10,238 patients who underwent EDT. Patients presenting pulseless after penetrating thoracic injury had the most favorable EDT outcomes both with (survival, 182 21.3% of 853; neurologically intact survival, 53 11.7% of 454) and without (survival, 76 8.3% of 920; neurologically intact survival, 25 3.9% of 641) signs of life. In patients presenting pulseless after penetrating extrathoracic injury, EDT outcomes were more favorable with signs of life (survival, 25 15.6% of 160; neurologically intact survival, 14 16.5% of 85) than without (survival, 4 2.9% of 139; neurologically intact survival, 3 5.0% of 60). Outcomes after EDT in pulseless blunt injury patients were limited with signs of life (survival, 21 4.6% of 454; neurologically intact survival, 7 2.4% of 298) and dismal without signs of life (survival, 7 0.7% of 995; neurologically intact survival, 1 0.1% of 825).
We strongly recommend that patients who present pulseless with signs of life after penetrating thoracic injury undergo EDT. We conditionally recommend EDT for patients who present pulseless and have absent signs of life after penetrating thoracic injury, present or absent signs of life after penetrating extrathoracic injury, or present signs of life after blunt injury. Lastly, we conditionally recommend against EDT for pulseless patients without signs of life after blunt injury.
Systematic review/guideline, level III.
Corticostriatal atrophy is a cardinal manifestation of Huntington’s disease (HD). However, the mechanism(s) by which mutant huntingtin (mHTT) protein contributes to the degeneration of the ...corticostriatal circuit is not well understood. We recreated the corticostriatal circuit in microfluidic chambers, pairing cortical and striatal neurons from the BACHD model of HD and its WT control. There were reduced synaptic connectivity and atrophy of striatal neurons in cultures in which BACHD cortical and striatal neurons were paired. However, these changes were prevented if WT cortical neurons were paired with BACHD striatal neurons; synthesis and release of brain-derived neurotrophic factor (BDNF) from WT cortical axons were responsible. Consistent with these findings, there was a marked reduction in anterograde transport of BDNF in BACHD cortical neurons. Subunits of the cytosolic chaperonin T-complex 1 (TCP-1) ring complex (TRiC or CCT for chaperonin containing TCP-1) have been shown to reduce mHTT levels. Both CCT3 and the apical domain of CCT1 (ApiCCT1) decreased the level of mHTT in BACHD cortical neurons. In cortical axons, they normalized anterograde BDNF transport, restored retrograde BDNF transport, and normalized lysosomal transport. Importantly, treating BACHD cortical neurons with ApiCCT1 prevented BACHD striatal neuronal atrophy by enhancing release of BDNF that subsequently acts through tyrosine receptor kinase B (TrkB) receptor on striatal neurons. Our findings are evidence that TRiC reagent-mediated reductions in mHTT enhanced BDNF delivery to restore the trophic status of BACHD striatal neurons.
To develop a clinical practice guideline for red blood cell transfusion in adult trauma and critical care.
Meetings, teleconferences and electronic-based communication to achieve grading of the ...published evidence, discussion and consensus among the entire committee members.
This practice management guideline was developed by a joint taskforce of EAST (Eastern Association for Surgery of Trauma) and the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM). We performed a comprehensive literature review of the topic and graded the evidence using scientific assessment methods employed by the Canadian and U.S. Preventive Task Force (Grading of Evidence, Class I, II, III; Grading of Recommendations, Level I, II, III). A list of guideline recommendations was compiled by the members of the guidelines committees for the two societies. Following an extensive review process by external reviewers, the final guideline manuscript was reviewed and approved by the EAST Board of Directors, the Board of Regents of the ACCM and the Council of SCCM.
Key recommendations are listed by category, including (A) Indications for RBC transfusion in the general critically ill patient; (B) RBC transfusion in sepsis; (C) RBC transfusion in patients at risk for or with acute lung injury and acute respiratory distress syndrome; (D) RBC transfusion in patients with neurologic injury and diseases; (E) RBC transfusion risks; (F) Alternatives to RBC transfusion; and (G) Strategies to reduce RBC transfusion.
Evidence-based recommendations regarding the use of RBC transfusion in adult trauma and critical care will provide important information to critical care practitioners.
Background Recent trials have shown that low‐density lipoprotein cholesterol (LDL‐C) <1.80 mmol/L (<70 mg/dL) is associated with a reduced risk of major adverse cardiovascular events in White ...patients with ischemic stroke with atherosclerosis. However, it remains uncertain whether the findings can be generalized to Asian patients, or that similar LDL‐C targets should be adopted in patients with stroke without significant atherosclerosis. Methods and Results We performed a prospective cohort study and recruited consecutive Chinese patients with ischemic stroke with magnetic resonance angiography of the intra‐ and cervicocranial arteries performed at the University of Hong Kong between 2008 and 2014. Serial postevent LDL‐C measurements were obtained. Risk of major adverse cardiovascular events in patients with mean postevent LDL‐C <1.80 versus ≥1.80 mmol/L, stratified by presence or absence of significant (≥50%) large‐artery disease (LAD) and by ischemic stroke subtypes, were compared. Nine hundred four patients (mean age, 69±12 years; 60% men) were followed up for a mean 6.5±2.4 years (mean, 9±5 LDL‐C readings per patient). Regardless of LAD status, patients with a mean postevent LDL‐C <1.80 mmol/L were associated with a lower risk of major adverse cardiovascular events (with significant LAD: multivariable‐adjusted subdistribution hazard ratio, 0.65; 95% CI, 0.42–0.99; without significant LAD: subdistribution hazard ratio, 0.53; 95% CI, 0.32–0.88) (both P <0.05). Similar findings were noted in patients with ischemic stroke attributable to large‐artery atherosclerosis (subdistribution hazard ratio, 0.48; 95% CI, 0.28–0.84) and in patients with other ischemic stroke subtypes (subdistribution hazard ratio, 0.64; 95% CI, 0.43–0.95) (both P <0.05). Conclusions A mean LDL‐C <1.80 mmol/L was associated with a lower risk of major adverse cardiovascular events in Chinese patients with ischemic stroke with and without significant LAD. Further randomized trials to determine the optimal LDL‐C cutoff in stroke patients without significant atherosclerosis are warranted.
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