Mutations in the human NBEAL2 gene cause gray platelet syndrome (GPS), a bleeding diathesis characterized by a lack of α granules in platelets. The functions of the NBEAL2 protein have not been ...explored outside platelet biology, but there are reports of increased frequency of infection and abnormal neutrophil morphology in patients with GPS. We therefore investigated the role of NBEAL2 in immunity by analyzing the phenotype of Nbeal2-deficient mice. We found profound abnormalities in the Nbeal2-deficient immune system, particularly in the function of neutrophils and NK cells. Phenotyping of Nbeal2-deficient neutrophils showed a severe reduction in granule contents across all granule subsets. Despite this, Nbeal2-deficient neutrophils had an enhanced phagocyte respiratory burst relative to Nbeal2-expressing neutrophils. This respiratory burst was associated with increased expression of cytosolic components of the NADPH oxidase complex. Nbeal2-deficient NK cells were also dysfunctional and showed reduced degranulation. These abnormalities were associated with increased susceptibility to both bacterial (Staphylococcus aureus) and viral (murine CMV) infection in vivo. These results define an essential role for NBEAL2 in mammalian immunity.
Background Pachyonychia congenita (PC), a rare autosomal-dominant keratin disorder caused by mutations in keratin genes KRT6A/B , KRT16 , or KRT17 , is characterized by painful plantar keratoderma ...and hypertrophic nail dystrophy. Available studies assessing oral retinoid treatment for PC are limited to a few case reports. Objective We sought to assess overall effectiveness, adverse effects, and patient perspective in patients with PC receiving oral retinoids. Methods In a questionnaire-based retrospective cross-sectional survey of 30 patient with PC assessing oral retinoids (10-50 mg/d for 1-240 months), we determined the clinical score, satisfaction score, visual analog pain scale, and adverse effects. Results In 50% of patients there was thinning of hyperkeratoses (average improvement 1.6 on a scale from –3 to +3) (95% confidence interval 1.2-1.9, P < .001). In all, 14% observed amelioration of their pachyonychia; 79% did not experience any nail change. The self-reported overall satisfaction score with oral retinoid treatment was 2 or greater in 50% of the patients (mean 4.5 on a scale of 1-10). Although 33% reported decreased and 27% increased plantar pain with treatment, 40% did not notice any pain change. All patients experienced adverse effects, and 83% reported to have discontinued medication. Risk/benefit analysis favored lower retinoid doses (≤25 mg/d) over a longer time period (>5 months), compared with higher doses (>25 mg/d) for a shorter time (≤5 months). Limitations The retrospective, cross-sectional study design is prone to a recall bias. Conclusion Oral retinoids are effective in some patients with PC. However, many patients discontinued medication because adverse effects outweighed the benefits. Careful dose titration is warranted in patients informed about potential adverse effects.
Aldehyde dehydrogenase (ALDH) 1A1 is an immunohistological biomarker of various solid tumours, but has not been successfully proved as a colorectal cancer (CRC) marker. We recently reported that ...ALDH1B1, which has functional roles in tumourigenesis, may be a better CRC marker than ALDH1A1.
Human CRC explants and cell lines were analysed to identify candidate CRC markers from eight ALDH isozymes including ALDH1A1 and ALDH1B1. A tissue microarray, including paired specimens of normal and tumour tissues, was subsequently analysed to determine if candidate ALDHs could distinguish CRC from normal tissue.
Based on mRNA analysis, ALDH1B1 and ALDH2 were selected as suitable candidates. These were strongly and regularly expressed in tumour tissue and cell lines, including highly tumourigenic cell populations (ALDH
CD44
cells), while other ALDHs, including ALDH1A1, showed differential or low expression. No genetic alteration of ALDH1B1 in CRC was suggested by the relationships between mRNA and protein levels/enzymatic activities, and cDNA sequences of CRC cell lines. Tissue microarray findings showed that ALDH1B1, but not ALDH2, could distinguish CRC from normal tissue. Furthermore, ratios of ALDH1B1 to ALDH1A1 or ALDH2 were found to be powerful CRC indicators.
These results suggest that ALDH1B1 is a novel human CRC biomarker.
Purpose
The combination of paclitaxel, ifosfamide, and cisplatin (TIP) is frequently used for the treatment of metastatic germ cell tumors. Due to complex supportive care and infusion requirements, ...TIP is typically given in the inpatient setting. This analysis describes the development and implementation of a protocol for complete outpatient administration of TIP chemotherapy.
Methods
From July 2020 to June 2021, adults receiving TIP for germ cell tumor at University of Michigan Rogel Cancer Center were evaluated for outpatient administration. The primary outcome was number of inpatient bed days saved by giving outpatient TIP chemotherapy, with the goal of giving 75% of TIP cycles outpatient. Patients receiving outpatient TIP were also assessed for chemotherapy dose reduction or delays and acute toxicities of kidney injury, encephalopathy, and hemorrhagic cystitis.
Results
From July 2020 to July 2021, three patients received 13 cycles of TIP. Ten cycles (77%) were administered in the outpatient setting, resulting in a savings of 50 inpatient bed days in one year. No patients required a dose reduction or delay in chemotherapy or experienced acute kidney injury, encephalopathy, or hemorrhagic cystitis during outpatient TIP treatment.
Conclusion
Despite logistic and supportive care challenges, TIP can be administered completely in the outpatient setting.
This exploratory analysis of the randomized controlled Aortic Surgery Cerebral Protection Evaluation CardioLink-3 trial sought to determine if cerebral oximetry desaturation during elective proximal ...arch repair is associated with detrimental postoperative neuroradiologic and neurofunctional outcomes.
Cerebral oximetry and pre- and postoperative brain magnetic resonance imaging data from 101 participants were analyzed. Oximetry data from the trial allocation groups were compared; the relationships between cerebral oximetry indices and new ischemic cerebral lesions on magnetic resonance imaging and neurologic outcomes were also evaluated.
Total cerebral desaturation events (>20% decrease from baseline) on the left (median interquartile range, 1 1-3 vs 1.5 0.5-3 with innominate and axillary cannulation; P = .80) were comparable to those on the right (1 1-3 vs 1 0-3; P = .75) as were the total area under the curve of desaturation (left, P = .61; right, P = .84). Seventy patients had new ischemic lesions, among whom 36 had new severe lesions. Total desaturation events and area under the curve of desaturation were similar in patients with and without new ischemic lesions or severe lesions. The nadir regional cerebral saturation was lower on the left (49% 41-56) than the right (53% 44-59); left desaturation episodes were associated with lower postoperative cognitive test scores (P = .004).
The innominate and axillary cannulation techniques for elective proximal arch repair with unilateral antegrade cerebral perfusion were associated with similar occurrences of cerebral oximetry desaturation and neither were associated with new ischemic lesions.
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Children and adolescents with early-onset psychosis (EOP) have more rare genetic variants than individuals with adult-onset forms of the illness, implying that fewer EOP participants are needed for ...genetic discovery. The Schizophrenia Exome Sequencing Meta-analysis (SCHEMA) study predicted that 10 genes with ultra-rare variation were linked to adult-onset schizophrenia. We hypothesized that rare variants predicted "High" and "Moderate" by the Variant Effect Predictor Algorithm (abbreviated as VEPHMI) in these 10 genes would be enriched in our EOP cohort.
We compared rare VEPHMI variants in individuals with EOP (N = 34) with race- and sex-matched controls (N = 34) using the sequence kernel association test (SKAT).
variants were significantly increased in the EOP cohort (
= 0.004), with seven individuals (20% of the EOP cohort) carrying a rare VEPHMI variant. The EOP cohort was then compared to three additional control cohorts.
variants were significantly increased in the EOP cohort for two of the additional control sets (
= 0.02 and
= 0.02), and trending towards significance for the third (
= 0.06).
Despite a small sample size,
VEPHMI variant burden was increased in a cohort of individuals with EOP in comparison to controls.
variants have been associated with a range of neuropsychiatric disorders including adult-onset psychotic spectrum disorder and childhood-onset schizophrenia. This study supports the role of
in EOP and emphasizes its role in neuropsychiatric disorders.
Biological sex is important. Male sex is associated with worse outcomes in most measures, including cerebrovascular disease, hospital admissions, and blood transfusions, but not survival. Females ...also appear to have a better response to hydroxyurea therapy, reduced markers of inflammation, and better liver function.
Avatars or agents are digitized self-representations of a player in mediated environments. While using agents to navigate through mediated environments, players form bonds with their self-agents or ...characters, a process referred to as identification. Identification can involve automatic, but temporary, self-concept “shifts in implicit self-perceptions” (Klimmt et al.,
2010
, p. 323) of the media user by adopting or emphasizing the action choices on behalf of the social expectation of the avatar in the mediated environment. In the current study, we test the possibility that users' identification with video game avatars–a bond built between avatars and players- would account for subsequent behavior changes. We did so by using 3-month longitudinal data involving a narratively-based serious game: Socially Optimized Learning in Virtual Environments (SOLVE), a 3D-interactive game designed to reduce risky sexual behaviors among young men who have sex with men (
n
= 444). Results show that video game identification predicts both the reduction of risky sexual behaviors over time, and reduction in the number of non-primary partners with whom risky sex occurs. And when players identify with the game character, they tend to make healthier choices, which significantly mediates the link between video game identification and reduction of risky behaviors.
Headache is a common condition with a substantial burden of disease worldwide. Concerns have been raised over the potential impact of long-term mobile phone use on headache due to radiofrequency ...electromagnetic fields (RF-EMFs). We explored prospectively the association between mobile phone use at baseline (2009–2012) and headache at follow-up (2015–2018) by analysing pooled data consisting of the Dutch and UK cohorts of the Cohort Study of Mobile Phone Use and Health (COSMOS) (N = 78,437). Frequency of headache, migraine, and information on mobile phone use, including use of hands-free devices and frequency of texting, were self-reported. We collected objective operator data to obtain regression calibrated estimates of voice call duration. In the model mutually adjusted for call-time and text messaging, participants in the high category of call-time showed an adjusted odds ratio (OR) of 1.04 (95 % CI: 0.94–1.15), with no clear trend of reporting headache with increasing call-time. However, we found an increased risk of weekly headache (OR = 1.40, 95 % CI: 1.25–1.56) in the high category of text messaging, with a clear increase in reporting headache with increasing texting. Due to the negligible exposure to RF-EMFs from texting, our results suggest that mechanisms other than RF-EMFs are responsible for the increased risk of headache that we found among mobile phone users.
•Prospective study exploring the relationship between mobile phone use and headache.•Mobile phone use, particularly texting, was associated with headache.•Associations with call-time were largely explained by texting.•Associations likely to reflect behavioural aspects of mobile phone use.
A Lancet Commission for COVID-19 task force is shaping recommendations to achieve vaccine and therapeutics access, justice, and equity. This includes ensuring safety and effectiveness harmonized ...through robust systems of global pharmacovigilance and surveillance. Global production requires expanding support for development, manufacture, testing, and distribution of vaccines and therapeutics to low- and middle-income countries (LMICs). Global intellectual property rules must not stand in the way of research, production, technology transfer, or equitable access to essential health tools, and in context of pandemics to achieve increased manufacturing without discouraging innovation. Global governance around product quality requires channelling widely distributed vaccines through WHO prequalification (PQ)/emergency use listing (EUL) mechanisms and greater use of national regulatory authorities. A World Health Assembly (WHA) resolution would facilitate improvements and consistency in quality control and assurances. Global health systems require implementing steps to strengthen national systems for controlling COVID-19 and for influenza vaccinations for adults including pregnant and lactating women. A collaborative research network should strive to establish open access databases for bioinformatic analyses, together with programs directed at human capacity utilization and strengthening. Combating anti-science recognizes the urgency for countermeasures to address a global-wide disinformation movement dominating the internet and infiltrating parliaments and local governments.
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