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Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1C variants were reviewed. Results: Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including one individual with clear TCS features. Several cases did not exhibit all the typical radiologic characteristics of POLR3-HLD. A total of 29 different pathogenic variants in POLR1C were identified, including 13 new disease-causing variants. Conclusions: Based on the largest cohort of patients to date, these results suggest novel characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.
Mental health and wellbeing, including addressing impacts of historical trauma and substance use among young people, has been identified as a key priority by Indigenous communities and leaders across Canada and globally. Yet, research to understand mental health among young Indigenous people who have used drugs is limited.
To examine longitudinal risk and strengths-based factors associated with psychological distress among young Indigenous people who use drugs.
The Cedar Project is an ongoing cohort study involving young Indigenous people who use drugs in Vancouver, Prince George, and Chase, British Columbia, Canada. This study included participants who completed the Symptom Checklist-90-Revised, returned for follow-up between 2010 and 2012, and completed the Childhood Trauma Questionnaire. Adjusted linear mixed-effects models estimated effects of study variables on changes in area T-scores of psychological distress.
Of 202 eligible participants, 53% were women and the mean age was 28 years. Among men, childhood maltreatment (emotional abuse, physical abuse, sexual abuse, physical neglect), any drug use, blackouts from drinking, and sex work were associated with increased distress. Among women, childhood maltreatment (emotional abuse, physical abuse, physical neglect), blackouts from drinking, and sexual assault were associated with increased distress, while having attempted to quit using drugs was associated with reduced distress. Marginal associations were observed between speaking their traditional language and living by traditional culture with lower distress among men.
Culturally safe mental wellness interventions are urgently needed to address childhood trauma and harmful coping strategies that exacerbate distress among young Indigenous people who use drugs.
Agriculture in the Central Himalayan Region depends on the availability of suitable germplasm as well as natural conditions. Due to extreme weather conditions, food and nutrition security is a major issue for communities inhabiting these remote and inaccessible areas. Millets are common crops grown in these areas. Foxtail millet (Setaria italica (L.) P. Beauv) is an important crop and forms a considerable part of the diet in this region. The aim of the present study was to explore, collect, conserve and evaluate the untapped genetic diversity of foxtail millet at the molecular level and discover variability in their nutritional traits. A total of 30 accessions having unique traits of agronomic importance were collected and molecular profiling was performed. A total of 63 alleles were generated with an average of 2.52 alleles per locus and average expected heterozygosity of 0.37 ± 0.231. Significant genetic variability was revealed through the genetic differentiation (Fst) and gene flow (Nm) values. Structure-based analysis divided whole germplasm into three sub-groups. Rich variability was found in nutritional traits such as dietary fibre in husked grains, carbohydrate, protein, lysine and thiamine content. The collected germplasm may be useful for developing nutritionally rich and agronomically beneficial varieties of foxtail millet and also designing strategies for utilization of unexploited genetic diversity for food and nutrition security in this and other similar agro-ecological regions.
The 98 min eclipsing cataclysmic variable EX Hya possesses a strong 67 min modulation in its light. This has led to a discussion of EX Hya in the context of intermediate polar variables. The observed P/Ṗ of the 67 min modulation provides a useful constraint on EX Hya models. Here we report additional timing data obtained over the interval 1982 to 1985 which bears on this matter.
In low- and middle-income countries, mental health training often includes sending few generalist clinicians to specialist-led programs for several weeks. Our objective is to develop and test a video-assisted training model addressing the shortcomings of traditional programs that affect scalability: failing to train all clinicians, disrupting clinical services, and depending on specialists.
We implemented the program -video lectures and on-site skills training- for all clinicians at a rural Nepali hospital. We used Wilcoxon signed-rank tests to evaluate pre- and post-test change in knowledge (diagnostic criteria, differential diagnosis, and appropriate treatment). We used a series of ‘Yes’ or ‘No’ questions to assess attitudes about mental illness, and utilized exact McNemar's test to analyze the proportions of participants who held a specific belief before and after the training. We assessed acceptability and feasibility through key informant interviews and structured feedback.
For each topic except depression, there was a statistically significant increase (Δ) in median scores on knowledge questionnaires: Acute Stress Reaction (Δ = 20, p = 0.03), Depression (Δ = 11, p = 0.12), Grief (Δ = 40, p < 0.01), Psychosis (Δ = 22, p = 0.01), and post-traumatic stress disorder (Δ = 20, p = 0.01). The training received high ratings; key informants shared examples and views about the training's positive impact and complementary nature of the program's components.
Video lectures and on-site skills training can address the limitations of a conventional training model while being acceptable, feasible, and impactful toward improving knowledge and attitudes of the participants.
Many medications administered to patients with schizophrenia possess anticholinergic properties. When aggregated, pharmacological treatments may result in a considerable anticholinergic burden. The extent to which anticholinergic burden has a deleterious effect on cognition and impairs ability to participate in and benefit from psychosocial treatments is unknown.
Seventy patients were followed for approximately 3 years. The MATRICS consensus cognitive battery (MCCB) was administered at baseline. Anticholinergic burden was measured with the Anticholinergic Cognitive Burden (ACB) scale. Ability to benefit from psychosocial programmes was measured using the DUNDRUM-3 Programme Completion Scale (D-3) at baseline and follow-up. Psychiatric symptoms were measured using the PANSS. Total antipsychotic dose was measured using chlorpromazine equivalents. Functioning was measured using the Social and Occupational Functioning Assessment Scale (SOFAS).
Mediation analysis found that the influence of anticholinergic burden on ability to participate and benefit from psychosocial programmes was completely mediated by the MCCB. For every 1-unit increase on the ACB scale, change scores for DUNDRUM-3 decreased by −0.27 points. This relationship appears specific to anticholinergic burden and not total antipsychotic dose. Moreover, mediation appears to be specific to cognition and not psychopathology. Baseline functioning also acted as mediator but only when MCCB was not controlled for.
Anticholinergic burden has a significant impact on patients’ ability to participate in and benefit from psychosocial treatment programmes. Physicians need to be mindful of the cumulative effect that medications can have on patient cognition, functional capacity and ability to benefit from psychosocial treatments.
This study aimed to assess the utility of onlay pectoralis major myofascial flap in preventing pharyngocutaneous fistula following salvage total laryngectomy.
A retrospective analysis was performed of 172 patients who underwent salvage laryngectomy for recurrent carcinoma of the larynx or hypopharynx between 1999 and 2014. One hundred and ten patients underwent primary closure and 62 patients had pectoralis major myofascial flap onlay.
The overall pharyngocutaneous fistula rate was 43 per cent, and was similar in both groups (primary closure group, 43.6 per cent; onlay flap group, 41.9 per cent; p = 0.8). Fistulae in the onlay flap group healed faster: the median and mean fistula duration were 37 and 55 days, respectively, in the primary closure group and 20 and 25 days, respectively, in the onlay flap group (p = 0.008).
Use of an onlay pectoralis major myofascial flap did not decrease the pharyngocutaneous fistula rate, although fistula duration was shortened. A well-designed randomised-controlled trial is needed to establish parameters for its routine use in clinical practice.
This study was carried out to determine time controls of erosion and sedimentation in the catchment area and lakes of the Naini Tal district in the Kumaon Himalayas. We present here our preliminary data from five lakes, Beon Tal, Garud Tal, Sukha Tal, Bhim Tal and Kamal Tal (Naukuchia Tal). A number of 14C dates are now available to estimate the sedimentation rate of the five lakes and magnetic susceptibility (xL; xfd) variation to determine the signature of sediment source. High xfd values indicate a higher proportion of soil component generally characterized by a slower rate of deposition, and low xfd values with a higher rate of sedimentation indicate rock-debris-derived sediment. A 14C chronology enables us to estimate the mean sedimentation rate whereas rock magnetic properties help us to characterize the type of source responsible for sedimentation.
We have measured 14C, 210Pb and 137Cs profiles in two representative cores from Manasbal Lake, Kashmir, India. The sedimentation rate derived from 210Pb and 137Cs in the upper part of the core is in the range of 3.4 to 5.5 mm yr−1. In contrast, 14C ages show an inversion at depths >20 cm. These results are attributed to the erosion of the ubiquitous 10–20-m-thick loess mantle, based on the similarity of 14C ages of the inversion layer in the sediments and the paleosols present in the catchment area. Frequency-dependent mineral magnetic susceptibility (χfd), carbon to nitrogen ratios and pigment concentrations in the profile show a significant amount of allochthonous component in the lake deposits and support the conclusion that the 14C dates do not reflect the chronology of the in-situ lake sedimentation but episodic deposition of the surrounding loess. Thus, 14C serves as a useful tracer to understand source components of the sediments.
Sedimentological, mineral magnetic and carbon isotopic studies on cores from Mansar Lake in the Jammu area provide paleomonsoonal history dating back to 580 bc. From ca. 580 bc to ad 300, the region experienced precipitation similar to the present, whereas from ad 300 to 1400, the monsoon was relatively subdued. A small excursion ca. ad 1100 suggests an effect of medieval warming. Studies in the Kumaon region did not provide a proper precipitation record, as anthropogenic activity interfered with sedimentation. Manasbal Lake in Kashmir gave an inversion of 14C chronology due to younger paleosols in the drainage basin. Further, the episodic nature of sedimentation in Manasbal Lake hampered the reconstruction of precipitation history in the area.
The binary X-ray source GX 1 + 4 was observed during a balloon flight in 1986, November. The source was in a relatively high intensity state. Time analysis of the data shows that the pulsation period was 111.8 ± 1.0 s indicating that one or more episodes of spin-down occurred between 1980 and 1986. Folded pulse profiles are very broad with an indication of a notch at the peak. Evidence has been found for a correlation between hard X-ray intensity and phase of the proposed 304 day orbital period. The time averaged intensity since 1980 is an order of magnitude lower than during the 1970’s. A survey of the post 1980 data shows that several reversals of the period derivative have occurred. Spin-up at the rates typical of the 1970’s has been followed by a dramatic spin-down episode with dP/dt>2.4 × 10−7 s/s.
To assess the efficacy of endoscopic-guided botulinum toxin injection into the cricopharyngeus muscle and evaluate the duration of its effects.
A 3-year prospective study of 12 patients undergoing injection of botulinum toxin was conducted, with a telephone survey to assess dysphagia pre-operatively, and at 1, 3 and 6 months post-treatment, using the MD Anderson Dysphagia Inventory.
Median age was 66.2 years. Causes of cricopharyngeal dysphagia included idiopathic cricopharyngeal hypertrophy (67 per cent), previous cerebrovascular accident (17 per cent), cranial nerve palsy (8 per cent) and previous chemoradiotherapy to the neck (8 per cent). There were no complications. Two patients had repeat injections after six months. There was significant improvement in MD Anderson Dysphagia Inventory scores at one and three months versus pre-operative scores (73.1 ± 14.9 vs 46.9 ± 7.6, p = 0.0001, and 65.1 ± 11.5 vs 46.9 ± 7.6, p = 0.0001), but not at six months (51.0 ± 11.0 vs 46.9 ± 7.6, p = 0.14).
Endoscopic-guided injection of botulinum toxin into the cricopharyngeus muscle is a safe and effective method for treating cricopharyngeal muscle dysfunction, lasting up to six months.
There is increasing evidence that Mars may have once been a habitable environment. Gypsum is targeted in the search for Martian biosignatures because it can host extensive cryptoendolithic communities in extreme terrestrial environments and is widespread on Mars. In this study the viability of using different spectroscopy-based techniques to identify the presence of gypsum endolithic communities was investigated by analysing various cryptoendoliths collected from the Lake St. Martin impact crater (LSM), a Mars analogue site found in Manitoba, Canada. Concurrently, the cryptoendolithic microbial community structure present was also analysed to aid in assigning spectroscopic features to microbial community members. Two main morphologies of endolithic communities were collected from gypsum deposits at LSM: true cryptoendolithic communities and annular deposits on partially buried boulders and cobbles <1 cm below the soil surface. Endolithic communities were found to be visibly present only in gypsum with a high degree of translucency and could occur as deep as 3 cm below the exterior surface. The bacterial community was dominated by a phylum (Chloroflexi) that has not been previously observed in gypsum endoliths. The exterior surfaces of gypsum boulders and cobbles are devoid of spectroscopic features attributable to organic molecules and detectable by reflectance, Raman, or ultraviolet-induced fluorescence spectroscopies. However, exposed interior surfaces show unique endolithic signatures detectable by each spectroscopic technique. This indicates that cryptoendolithic communities can be detected via spectroscopy-based techniques, provided they are either partially or fully exposed and enough photon–target interactions occur to enable detection.
We report on the fabrication of device-quality AlN heterostructures grown on SiC for high-temperature electronic devices. The AlN films were grown by pulsed laser deposition (PLD) at substrate temperatures ranging from 25 °C (room temperature) to 1000 °C. The as-grown films were investigated using x-ray diffraction, Rutherford backscattering specttroscopy, ion channeling, atomic force microscopy, and transmission electron microscopy. The AlN films grown above 700 °C were highly c-axis oriented with rocking curve FWHM of 5 to 6 arc-min. The ion channeling minimum yields near the surface region for the AlN films were ∼2 to 4%, indicating their high degree of crystallinity. TEM studies indicated that AlN films were epitaxial and single crystalline in nature with a large number of stacking faults as a results of lattice mismatch and growth induced defects. The surface roughness for the films was about 0.5 nm, which is close to the unit cell height of the AlN. Epitaxial TiN ohmic contacts were also developed on SiC, GaN, and AlN by in-situ PLD. Epitaxial TiN/AlN/SiC MIS capacitors with gate areas of 4 * 10−4 cm2 were fabricated, and high-temperature current-voltage (I-V) characteristics were studied up to 450 °C. We have measured leakage current densities of low 10−8 A/cm2 at room temperature, and have mid 10−3 A/cm2 at 450°C under a field of 2 MV/cm.