To send content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about sending content to .
To send content items to your Kindle, first ensure firstname.lastname@example.org
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about sending to your Kindle.
Note you can select to send to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: SUNFISH (NCT02908685) is an ongoing multicenter, double-blind, placebo-controlled, operationally seamless study (randomized 2:1, risdiplam:placebo) in patients aged 2–25 years, with Type 2/3 SMA. Part 1 (n=51) assesses safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Pivotal Part 2 (n=180) assesses safety and efficacy of the risdiplam dose level selected based on Part 1 results. Results: Part 1 results showed a sustained, >2-fold increase in median SMN protein versus baseline following 1 year of treatment. Adverse events were mostly mild, resolved despite ongoing treatment and reflected underlying disease. No drug-related safety findings have led to withdrawal (data-cut 06/17/18). SUNFISH Part 1 exploratory endpoint results and Part 2 study design will also be presented. Conclusions: To date, no drug-related safety findings have led to withdrawal. Risdiplam led to sustained increases in SMN protein levels.
Whereas genetic susceptibility increases the risk for major depressive disorder (MDD), non-genetic protective factors may mitigate this risk. In a large-scale prospective study of US Army soldiers, we examined whether trait resilience and/or unit cohesion could protect against the onset of MDD following combat deployment, even in soldiers at high polygenic risk.
Data were analyzed from 3079 soldiers of European ancestry assessed before and after their deployment to Afghanistan. Incident MDD was defined as no MDD episode at pre-deployment, followed by a MDD episode following deployment. Polygenic risk scores were constructed from a large-scale genome-wide association study of major depression. We first examined the main effects of the MDD PRS and each protective factor on incident MDD. We then tested the effects of each protective factor on incident MDD across strata of polygenic risk.
Polygenic risk showed a dose–response relationship to depression, such that soldiers at high polygenic risk had greatest odds for incident MDD. Both unit cohesion and trait resilience were prospectively associated with reduced risk for incident MDD. Notably, the protective effect of unit cohesion persisted even in soldiers at highest polygenic risk.
Polygenic risk was associated with new-onset MDD in deployed soldiers. However, unit cohesion – an index of perceived support and morale – was protective against incident MDD even among those at highest genetic risk, and may represent a potent target for promoting resilience in vulnerable soldiers. Findings illustrate the value of combining genomic and environmental data in a prospective design to identify robust protective factors for mental health.
In product design engineering (PDE), ideation involves the generation of technical behaviours and physical structures to address specific functional requirements. This differs from generic creative ideation tasks, which emphasise functional and technical considerations less. To advance knowledge about the neural basis of PDE ideation, we present the first fMRI study on professional product design engineers practising in industry. We aimed to explore brain activation during ideation, and compare activation in open-ended and constrained tasks. Imagery manipulation tasks were contrasted with ideation tasks in a sample of 29 PDE professionals. The key findings were: (1) PDE ideation is associated with greater activity in left cingulate gyrus; (2) there were no significant differences between open-ended and constrained tasks; and (3) a preliminary association with activity in the right superior temporal gyrus was also observed. The results are consistent with existing fMRI work on generic creative ideation, suggesting that PDE ideation may share a number of similarities at the neural level. Future work includes: functional connectivity analysis of open-ended and constrained ideation to further investigate potential differences; investigating the effects of aspects of design expertise/training on processing; and the use of novelty measures directly linked to the designer’s internal processing in fMRI analysis.
Infants with prenatally diagnosed CHD are at high risk for adverse outcomes owing to multiple physiologic and psychosocial factors. Lack of immediate physical postnatal contact because of rapid initiation of medical therapy impairs maternal–infant bonding. On the basis of expected physiology, maternal–infant bonding may be safe for select cardiac diagnoses.
This is a single-centre study to assess safety of maternal–infant bonding in prenatal CHD.
In total, 157 fetuses with prenatally diagnosed CHD were reviewed. On the basis of cardiac diagnosis, 91 fetuses (58%) were prenatally approved for bonding and successfully bonded, 38 fetuses (24%) were prenatally approved but deemed not suitable for bonding at delivery, and 28 (18%) were not prenatally approved to bond. There were no complications attributable to bonding. Those who successfully bonded were larger in weight (3.26 versus 2.6 kg, p<0.001) and at later gestation (39 versus 38 weeks, p<0.001). Those unsuccessful at bonding were more likely to have been delivered via Caesarean section (74 versus 49%, p=0.011) and have additional non-cardiac diagnoses (53 versus 29%, p=0.014). There was no significant difference regarding the need for cardiac intervention before hospital discharge. Infants who bonded had shorter hospital (7 versus 26 days, p=0.02) and ICU lengths of stay (5 versus 23 days, p=0.002) and higher survival (98 versus 76%, p<0.001).
Fetal echocardiography combined with a structured bonding programme can permit mothers and infants with select types of CHD to successfully bond before ICU admission and intervention.
Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease. In June 2017, Health Canada approved Nusinersen, currently the only available drug for SMA. Since 2016, patients in Ontario have been treated clinically with Nusinersen through different access programs. Methods: Retrospective case series of patients with SMA treated clinically with Nusinersen in Ontario, describing clinical characteristics and logistics of intrathecal Nusinersen administration. Results: Twenty patients have been treated across four centres. To date, we have reviewed 8 cases at one centre (seven SMA Type I, one SMA Type II). Age at first dose ranged from 3-156 months and disease duration 9-166 months. Patients had received 4-7 doses at last evaluation. Three patients with scoliosis (2 with spinal rods) required fluoroscopy-guided radiologist administration, and 4 required general anesthesia. No complications/adverse events were reported. At last follow up, 5/8 families reported improved daily activities. Of 5 patients with baseline and follow up motor function testing, 3 demonstrated improved scores. One patient died due to respiratory decline at age 9 months, despite improved motor outcome scores. Conclusions: We describe the first Canadian post-marketing experience with Nusinersen. Timely dissemination of this information is needed to guide clinicians, hospital administrators, and policy-makers.
The effect of transportation and lairage on the faecal shedding and post-slaughter contamination of carcasses with Escherichia coli O157 and O26 in young calves (4–7-day-old) was assessed in a cohort study at a regional calf-processing plant in the North Island of New Zealand, following 60 calves as cohorts from six dairy farms to slaughter. Multiple samples from each animal at pre-slaughter (recto-anal mucosal swab) and carcass at post-slaughter (sponge swab) were collected and screened using real-time PCR and culture isolation methods for the presence of E. coli O157 and O26 (Shiga toxin-producing E. coli (STEC) and non-STEC). Genotype analysis of E. coli O157 and O26 isolates provided little evidence of faecal–oral transmission of infection between calves during transportation and lairage. Increased cross-contamination of hides and carcasses with E. coli O157 and O26 between co-transported calves was confirmed at pre-hide removal and post-evisceration stages but not at pre-boning (at the end of dressing prior to chilling), indicating that good hygiene practices and application of an approved intervention effectively controlled carcass contamination. This study was the first of its kind to assess the impact of transportation and lairage on the faecal carriage and post-harvest contamination of carcasses with E. coli O157 and O26 in very young calves.
To investigate an outbreak of Burkholderia cepacia complex and describe the measures that revealed the source.
A 629-bed, tertiary-care, pediatric hospital in Houston, Texas.
Pediatric patients without cystic fibrosis (CF) hospitalized in the pediatric and cardiovascular intensive care units.
We investigated an outbreak of B. cepacia complex from February through July 2016. Isolates were evaluated for molecular relatedness with repetitive extragenic palindromic polymerase chain reaction (rep-PCR); specific species identification and genotyping were performed at an independent laboratory. The investigation included a detailed review of all cases, direct observation of clinical practices, and respiratory surveillance cultures. Environmental and product cultures were performed at an accredited reference environmental microbiology laboratory.
Overall, 18 respiratory tract cultures, 5 blood cultures, 4 urine cultures, and 3 stool cultures were positive in 24 patients. Among the 24 patients, 17 had symptomatic infections and 7 were colonized. The median age of the patients was 22.5 months (range, 2–148 months). Rep-PCR typing showed that 21 of 24 cases represented the same strain, which was identified as a novel species within the B. cepacia complex. Product cultures of liquid docusate were positive with an identical strain of B. cepacia complex. Local and state health departments, as well as the CDC and FDA, were notified, prompting a multistate investigation.
Our investigation revealed an outbreak of a unique strain of B. cepacia complex isolated in clinical specimens from non-CF pediatric patients and from liquid docusate. This resulted in a national alert and voluntary recall by the manufacturer.
Pertussis is a vaccine-preventable respiratory infection caused by Bordetella pertussis which can be fatal in infants. Although high vaccine coverage led to prolonged disease control in England, a national outbreak of pertussis in 2011 led to the largest increase in over two decades, including a marked increase in cases aged ⩾15 years. A case-control study in four regions of England was undertaken to investigate risk factors for pertussis in adolescents and adults, specifically employment type and professional and household contact with children. Pertussis cases were laboratory-confirmed and aged ⩾15 years. Controls were recruited through general practitioner nomination. Demographic and risk factor information were collected using an online survey. Multivariable logistic regression was used to estimate independent associations with outcome. Two hundred and thirty-one cases and 190 controls were recruited. None of the four employment variables (social care, education, health sector, patient contact) were significantly associated with pertussis. Professional contact with children aged < 1 year was associated with a significantly reduced odds of pertussis [odds ratio (OR) 0·25, 95% confidence interval (CI) 0·08–0·78, P = 0·017]. Household contact with ⩾1 child aged 10–14 years was associated with significantly increased odds of pertussis (OR 2·61, 95% CI 1·47–4·64, P = 0·001). Occupational contact with very young children was associated with reduced odds of pertussis, probably due to immune boosting by low-level exposures to B. pertussis. Sharing a household with a young adolescent was a significant risk factor for pertussis in adults and older teenagers. The primary focus of the childhood pertussis vaccination programmes is to prevent infant disease. Although evidence is emerging that adolescent vaccination does not provide indirect protection to infants, our results highlight the importance of children aged 10–14 years in pertussis transmission to older adolescents and adults.
The present study investigated alteration of brain resting-state activity induced by antidepressant treatment and attempted to investigate whether treatment efficacy can be predicted at an early stage of pharmacological treatment.
Forty-eight first-episode medication-free patients diagnosed with major depression received treatment with escitalopram. Resting-state functional magnetic resonance imaging was administered prior to treatment, 5 h after the first dose, during the course of pharmacological treatment (week 4) and at endpoint (week 8). Resting-state activity was evaluated in the course of the 8-week treatment and in relation to clinical improvement.
Escitalopram dynamically modified resting-state activity in depression during the treatment. After 5 h the antidepressant induced a significant decrease in the signal in the occipital cortex and an increase in the dorsolateral and dorsomedial prefrontal cortices and middle cingulate cortex. Furthermore, while remitters demonstrated more obvious changes following treatment, these were more modest in non-responders suggesting possible tonic and dynamic differences in the serotonergic system. Changes after 5 h in the caudate, occipital and temporal cortices were the best predictor of clinical remission at endpoint.
This study revealed the possibility of using the measurement of resting-state neural changes a few hours after acute administration of antidepressant to identify individuals likely to remit after a few weeks of treatment.
The cat flea, Ctenocephalides felis, is a major pest species on companion animals thus of significant importance to the animal health industry. The aim of this study was to develop sampling and storage protocols and identify stable reference genes for gene expression studies to fully utilize the growing body of molecular knowledge of C. felis. RNA integrity was assessed in adult and larvae samples, which were either pierced or not pierced and stored in RNAlater at ambient temperature. RNA quality was maintained best in pierced samples, with negligible degradation evident after 10 days. RNA quality from non-pierced samples was poor within 3 days. Ten candidate reference genes were evaluated for their stability across four group comparisons (developmental stages, genders, feeding statuses and insecticide-treatment statuses). Glyceraldehyde 3 phosphate dehydrogenase (GAPDH), 60S ribosomal protein L19 (RPL19) and elongation factor-1α (Ef) were ranked highly in all stability comparisons, thus are recommended as reference genes under similar conditions. Employing just two of these three stable reference genes was sufficient for accurate normalization. Our results make a significant contribution to the future of gene expression studies in C. felis, describing validated sample preparation procedures and reference genes for use in this common pest.
Detrital zircon U–Pb ages in 37 sandstones from late Early – Late Cretaceous marine and non-marine successions across southern Zealandia indicate a provenance from local basement within present-day Zealandia. Samples from Taranaki Basin were derived from Median and Karamea batholith granitoids with transport directions from west to east. Samples from West Coast, Western Southland and Great South basins contain components derived more locally and more variably from Median Batholith and Rahu Suite granitoids and/or the Palaeozoic Buller Terrane. West Coast Basin samples have more plutonic contributions and Great South Basin localities have more Albian-aged (c. 110–100 Ma) zircons. Samples from Canterbury Basin were sourced from Torlesse Composite Terrane basement. The provenance variations are present in both marine and non-marine sandstones and suggest localized watersheds. This fits an interpretation of Late Cretaceous deposition in rift-controlled basins across southern Zealandia during pre-Gondwana break-up regional extension. More speculatively, some additional source areas may have been created at the rifted margins of Zealandia during this break-up.
Introduction: Acute upper gastrointestinal (UGI) bleeding is a relatively common emergency resulting in death in 6 to 8% of cases. UGI endoscopy is the intervention of choice which requires procedural sedation and analgesia (PSA). The Halifax Infirmary emergency department (ED) performs 1000 PSAs annually, performed by advanced care paramedics (ACPs). This has been shown safe for other indications for PSA, such as orthopedic procedures. Considering that UGI endoscopy involves upper airway manipulation, and patients are at an increased risk of massive bleeding, this procedure would be expected to be more complex and have an increased risk of adverse events (AEs). This study aims to compare PSA for UGI endoscopy performed by ACPs to that for orthopedic procedures for AEs, airway intervention and medication use. Methods: This study is a retrospective review of an ACP-performed ED PSA quality control database. A dataset was built matching 64 UGI endoscopy PSAs to 192 orthopedic PSAs by propensity scores calculated using age, gender and ASA classification. Outcomes assessed were hypotension (SBP < 100, or 15% decrease from baseline), hypoxia (SaO2 < 90), apnea (> 30sec), vomiting, arrhythmias and death in the ED. The need for airway intervention and medication use was assessed. Results: The UGI endoscopy group was 4.60 times more likely to suffer hypotension than the orthopedic group (OR=4.6, CI:2.2-9.6), and a fifth as likely to require airway repositioning (OR=0.2, CI:0.1-0.5). One endoscopy patient required endotracheal intubation. No patient died in either group. Compared to the orthopedic group, the UGI endoscopy group was one-third as likely to receive fentanyl (OR=0.3, CI:0.2-0.6). When fentanyl was administered, endoscopy patients received an average 26.7 mcg less than orthopedic patients. The endoscopy group was 15.4 times more likely to receive ketamine (OR=15.4, CI:4.7-66.5), and received 34.4 mg less on average. Four endoscopy patients received phenylephrine compared to none in the orthopedic group. There were no other differences. Conclusion: ED PSA for UGI endoscopy appears to differ significantly from that performed for orthopedic procedures. It was associated with more frequent hypotension and increased use of ketamine as a sedative. Patients undergoing UGI endoscopy were less likely to receive fentanyl and require airway repositioning. Only patients in the endoscopy group required intubation or a vasopressor agent.
As part of the activities of the Collaborative Research Centre ‘SFB 350’, measurements of geodetic and geodynamic changes in the area of the Lower Rhine Embayment and the Rhenish Shield are being performed at different scales in space and time. Continuous borehole tilt measurements and repeated microgravimetric surveys yield information on the local stability of the ground and changes in horizontal gravity gradients that are both dominated by seasonal fluctuations. Results of more than seven years of regular GPS campaigns are discussed in terms of vertical and horizontal point motions. The most prominent motions are man-induced effects occurring in or near the browncoal mining areas, where groundwater withdrawal produces subsidence of up to 2.2 cm/y in the area under investigation. Horizontal and vertical motions at other GPS points are smaller by one order of magnitude and in most cases are only marginally detectable. The eastward motion of two points in the Bergisches Land and the westward motion of two points in the Eifel near the Belgian border may be interpreted as a result of the ongoing extension of the Cenozoic rift system in the western part of the Eurasian plate.
Introduction: HNPP presentation in childhood is rare and diverse and most of the published literature is based on case reports. Materials and Methods: we analyzed the data of 11 children with deletion in PMP22 gene, reviewed the published reports of HNPP in children and compared our data with the reports from the literature review. Results: Peroneal palsy was the most common presentation (50%) followed by the brachial plexus palsy in 30% of cases. The trigger of the demyelinating event was identified only in 27%. 72% of our cohort developed only one acute episode of nerve palsy. Nerve conduction studies were always suggestive of the diagnosis demonstrating 60% of cases a polyneuropathy, 50% of cases conduction block but 100% of bilateral or unilateral electrophysiologic entrapment of the median nerve at the carpal tunnel. Conclusion: The clinical presentation of HNPP in childhood is heterogeneous and EMG findings are abnormal. Any unexplained mononeuropathy or multifocal neuropathy should lead to PMP22 gene testing to look for the deletion. Early diagnosis is important for the genetic counselling but also for the appropriate care of these patients.