The Reliability of Alcohol Abusers’ Self-Reports Of Drinking and Life Events That Occurred In the Distant Past

This study investigated the test-retest reliability of 69 alcohol abusers\u27 current reports about their past (approximately 8 years prior to interview) drinking behavior and life events. Drinking behavior was assessed by the Lifetime Drinking History (LDH) questionnaire and life events were assessed using the Recent Life Changes Questionnaire (RLCQ). Reliability coefficients for LDH variables were generally moderate to high (r = .52 to .81). Using empirical criteria, the diagnostic power of the two LDH interviews to classify correctly subjects as either having had or not having had a drinking problem was quite high. The reliability coefficient for the RLCQ was r = .85 and 91.7% of the identified events were reported in both interviews. Similarly high test-retest reliabilities and individual event agreement rates were obtained for the six homogeneous subscales of the RLCQ. Subjects were also asked why they had given inconsistent answers to life events questions in the two interviews. Inconsistencies often resulted from errors in the temporal placement of events or from misunderstanding items, rather than from failure to recall an event; this suggests that some sources of error in recalling life events can be reduced. It is concluded that alcohol abusers\u27 reports of drinking and life events occurring many years prior to the date of interview are generally reliable. This finding is consistent with previous studies showing high test-retest reliabilities for reports of recent drinking and related events

A cylindrical silicon-on-insulator microdosimeter: charge collection characteristics

A novel silicon-on-insulator microdosimeter for estimating the radiobiolgical effectiveness (RBE) of a mixed radiation field is presented. An ion beam induced charge collection study has confirmed the microdosimeter possesses well defined micron sized 3D cylindrical sensitive volumes. An array of these SVs has the capabilitiy of studying the track structure of high energy heavy ions typical of a deep space environment

3D silicon microdosimetry and RBE study using C-12 ion of different energies

This paper presents a new version of the 3D mesa "bridge" microdosimeter comprised of an array of 4248 silicon cells fabricated on 10 µm thick silicon-on-insulator substrate. This microdosimeter has been designed to overcome limitations existing in previous generation silicon microdosimeters and it provides well-defined sensitive volumes and high spatial resolution. The charge collection characteristics of the new 3D mesa microdosimeter were investigated using the ANSTO heavy ion microprobe, utilizing 5.5 MeV He2+ ions. Measurement of microdosimetric quantities allowed for the determination of the Relative Biological Effectiveness of 290 MeV/u and 350 MeV/u 12C heavy ion therapy beams at the Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan. The microdosimetric RBE obtained showed good agreement with the tissue-equivalent proportional counter. Utilizing the high spatial resolution of the SOI microdosimeter, the LET spectra for 70 MeV 12C+6 ions, like those present at the distal edge of 290 and 350 MeV/u beams, were obtained as the ions passed through thin layers of polyethylene film. This microdosimeter can provide useful information about the lineal energy transfer (LET) spectra downstream of the protective layers used for shielding of electronic devices for single event upset prediction

Thin Silicon Microdosimeter utilizing 3D MEMS Fabrication Technology: Charge Collection Study and its application in mixed radiation fields

New 10-μm-thick silicon microdosimeters utilizing 3-D technology have been developed and investigated in this paper. The TCAD simulations were carried out to understand the electrical properties of the microdosimeters\u27 design. A charge collection study of the devices was performed using 5.5-MeV He2+ ions which were raster scanned over the surface of the detectors and the charge collection median energy maps were obtained and the detection yield was also evaluated. The devices were tested in a 290 MeV/u carbon ion beam at the Heavy Ion Medical Accelerator in Chiba (HIMAC) in Japan. Based on the microdosimetric measurements, the quality factor and dose equivalent out of field were obtained in a mixed radiation field mimicking the radiation environment for spacecraft in deep space

Variation in the plasma membrane monoamine transporter (PMAT) (encoded by SLC29A4) and organic cation transporter 1 (OCT1) (encoded by SLC22A1) and gastrointestinal intolerance to metformin in type 2 diabetes:An IMI direct study

OBJECTIVE Gastrointestinal adverse effects occur in 20–30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5–10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects. RESEARCH DESIGN AND METHODS The study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in the SLC29A4 and SLC22A1 genes on odds of intolerance. RESULTS Women (P < 0.001) and older people (P < 0.001) were more likely to develop metformin intolerance. Concomitant use of transporter-inhibiting drugs increased the odds of intolerance (odds ratio [OR] 1.72, P < 0.001). In an adjusted logistic regression model, the G allele at rs3889348 (SLC29A4) was associated with gastrointestinal intolerance (OR 1.34, P = 0.005). rs3889348 is the top cis-expression quantitative trait locus for SLC29A4 in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with transporter-inhibiting drugs had more than three times higher odds of intolerance compared with carriers of no G allele and not treated with inhibiting drugs (OR 3.23, P < 0.001). Use of a genetic risk score derived from rs3889348 and SLC22A1 variants found that the odds of intolerance were more than twice as high in individuals who carry three or more risk alleles compared with those carrying none (OR 2.15, P = 0.01). CONCLUSIONS These results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin

Comparative Genomic Characterization of Francisella tularensis Strains Belonging to Low and High Virulence Subspecies

Tularemia is a geographically widespread, severely debilitating, and occasionally lethal disease in humans. It is caused by infection by a gram-negative bacterium, Francisella tularensis. In order to better understand its potency as an etiological agent as well as its potential as a biological weapon, we have completed draft assemblies and report the first complete genomic characterization of five strains belonging to the following different Francisella subspecies (subsp.): the F. tularensis subsp. tularensis FSC033, F. tularensis subsp. holarctica FSC257 and FSC022, and F. tularensis subsp. novicida GA99-3548 and GA99-3549 strains. Here, we report the sequencing of these strains and comparative genomic analysis with recently available public Francisella sequences, including the rare F. tularensis subsp. mediasiatica FSC147 strain isolate from the Central Asian Region. We report evidence for the occurrence of large-scale rearrangement events in strains of the holarctica subspecies, supporting previous proposals that further phylogenetic subdivisions of the Type B clade are likely. We also find a significant enrichment of disrupted or absent ORFs proximal to predicted breakpoints in the FSC022 strain, including a genetic component of the Type I restriction-modification defense system. Many of the pseudogenes identified are also disrupted in the closely related rarely human pathogenic F. tularensis subsp. mediasiatica FSC147 strain, including modulator of drug activity B (mdaB) (FTT0961), which encodes a known NADPH quinone reductase involved in oxidative stress resistance. We have also identified genes exhibiting sequence similarity to effectors of the Type III (T3SS) and components of the Type IV secretion systems (T4SS). One of the genes, msrA2 (FTT1797c), is disrupted in F. tularensis subsp. mediasiatica and has recently been shown to mediate bacterial pathogen survival in host organisms. Our findings suggest that in addition to the duplication of the Francisella Pathogenicity Island, and acquisition of individual loci, adaptation by gene loss in the more recently emerged tularensis, holarctica, and mediasiatica subspecies occurred and was distinct from evolutionary events that differentiated these subspecies, and the novicida subspecies, from a common ancestor. Our findings are applicable to future studies focused on variations in Francisella subspecies pathogenesis, and of broader interest to studies of genomic pathoadaptation in bacteria

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy