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.
One of the most important novels of the eighteenth-century, Sir Charles Grandison  shaped the English courtship novel, and was loved and admired by both Jane Austen and George Eliot. The book follows the life of Sir Charles, a man parallel in virtue with Richardson's female paragons Clarissa and Pamela; and a response to the fallible protagonist Tom Jones in Fielding's popular satire of moralising novels. Forming part of the first full scholarly edition of Richardson's complete works, comprehensive general and textual introductions significantly revise and advance understanding of the composition and printing history of Richardson's final novel, and reveal the central place of Sir Charles in the literature of the period. Including Richardson's Historical Index for the first time in any edition, extensive annotations and expansive notes also give readers crucial context, and provides scholars with paths to follow for future research.
Type 2 diabetes results mainly from weight gain in adult life and affects one in twelve people worldwide. In the Diabetes REmission Clinical Trial (DiRECT), the primary care-led Counterweight-Plus weight management program achieved remission of type 2 diabetes (for up to six years) for forty-six percent of patients after one year and thirty-six percent after two years. The objective of this study was to estimate the implementation costs of the program, as well as its two-year within-trial cost effectiveness and lifetime cost effectiveness.
Within-trial cost effectiveness included the Counterweight-Plus costs (including training, practitioner appointments, and low-energy diet), medications, and all routine healthcare contacts, combined with achieved remission rates. Lifetime cost per quality-adjusted life-year (QALY) was estimated according to projected durations of remissions, assuming continued relapse rates as seen in year two of DiRECT and the consequent life expectancy, quality of life and healthcare costs.
The two-year intervention cost was EUR 1,580 per participant, with over eighty percent of the costs incurred in year one. Compared with the control group, medication savings were EUR 259 (95% confidence interval [CI]: 166–352) for anti-diabetes drugs and EUR 29 (95% CI: 12–47) for anti-hypertensive medications. The intervention was modeled with a lifetime horizon to achieve a mean 0.06 (95% CI: 0.04–0.09) gain in QALYs for the DiRECT population and a mean total lifetime cost saving per participant of EUR 1,497 (95% CI: 755–2,331), with the intervention becoming cost-saving within six years.
The intensive weight loss and maintenance program reduced the cost of anti-diabetes drugs through improved metabolic control, achieved diabetes remission in over one-third of participants, and reduced total healthcare contacts and costs over two years. A substantial lifetime healthcare cost saving is anticipated from periods of diabetes remission and delaying complications. Healthcare resources could be shifted cost effectively to establish diabetes remission services, using the existing DiRECT intervention, even if remissions are only maintained for limited durations. However, more research investment is needed to further improve weight-loss maintenance and extend remissions.
To compare sensitivity of specimens for COVID-19 diagnosis, we tested 151 nasopharyngeal/midturbinate swab pairs from 117 COVID-19 inpatients using reverse-transcriptase polymerase chain reaction (RT-PCR). Sensitivity was 94% for nasopharyngeal and 75% for midturbinate swabs (P = .0001). In 88 nasopharyngeal/midturbinate pairs with matched saliva, sensitivity was 86% for nasopharyngeal swabs and 88% for combined midturbinate swabs/saliva.
A Canadian outbreak investigation into a cluster of Escherichia coli O121 was initiated in late 2016. When initial interviews using a closed-ended hypothesis-generating questionnaire did not point to a common source, cases were centrally re-interviewed using an open-ended approach. The open-ended interviews led cases to describe exposures with greater specificity, as well as food preparation activities. Data collected supported hypothesis generation, particularly with respect to flour exposures. In March 2017, an open sample of Brand X flour from a case home, and a closed sample collected at retail of the same brand and production date, tested positive for the outbreak strain of E. coli O121. In total, 76% (16/21) of cases reported that they used or probably used Brand X flour or that it was used or probably was used in the home during their exposure period. Crucial hypothesis-generating techniques used during the course of the investigation included a centralised open-ended interviewing approach and product sampling from case homes. This was the first outbreak investigation in Canada to identify flour as the source of infection.
To estimate the prevalence of unmet needs for assistance among middle-aged and older adults with subjective cognitive decline (SCD) in the US and to evaluate whether unmet needs were associated with health-related quality of life (HRQOL).
US – 50 states, District of Columbia, and Puerto Rico
Community-dwelling adults aged 45 years and older who completed the Cognitive Decline module on the 2015-–2018 Behavioral Risk Factor Surveillance System reported experiencing SCD and always, usually, or sometimes needed assistance with day-to-day activities because of SCD (n = 6,568).
We defined SCD as confusion or memory loss that was happening more often or getting worse over the past 12 months. Respondents with SCD were considered to have an unmet need for assistance if they sometimes, rarely, or never got the help they needed with day-to-day activities. We measured three domains of HRQOL: (1) mental (frequent mental distress, ≥14 days of poor mental health in the past 30 days), (2) physical (frequent physical distress, ≥14 days of poor physical health in the past 30 days), and (3) social (SCD always, usually, or sometimes interfered with the ability to work, volunteer, or engage in social activities outside the home). We used log-binomial regression models to estimate prevalence ratios (PRs). All estimates were weighted.
In total, 40.2% of people who needed SCD-related assistance reported an unmet need. Among respondents without depression, an unmet need was associated with a higher prevalence of frequent mental distress (PR = 1.55, 95% CI: 1.12–2.13, p = 0.007). Frequent physical distress and social limitations did not differ between people with met and unmet needs.
Middle-aged and older adults with SCD-related needs for assistance frequently did not have those needs met, which could negatively impact their mental health. Interventions to identify and meet the unmet needs among people with SCD may improve HRQOL.
Liquid phase (or liquid cell) transmission electron microscopy (LP-TEM) has been established as a powerful tool for observing dynamic processes in liquids at nanometer to atomic length scales. However, the simple act of observation using electrons irreversibly alters the nature of the sample. A clear understanding of electron-beam-driven processes during LP-TEM is required to interpret in situ observations and utilize the electron beam as a stimulus to drive nanoscale dynamic processes. In this article, we discuss recent advances toward understanding, quantifying, mitigating, and harnessing electron-beam-driven chemical processes occurring during LP-TEM. We highlight progress in several research areas, including modeling electron-beam-induced radiolysis near interfaces, electron-beam-induced nanocrystal formation, and radiation damage of soft materials and biomolecules.
Compulsory admission procedures of patients with mental disorders vary between countries in Europe. The Ethics Committee of the European Psychiatric Association (EPA) launched a survey on involuntary admission procedures of patients with mental disorders in 40 countries to gather information from all National Psychiatric Associations that are members of the EPA to develop recommendations for improving involuntary admission processes and promote voluntary care.
The survey focused on legislation of involuntary admissions and key actors involved in the admission procedure as well as most common reasons for involuntary admissions.
We analyzed the survey categorical data in themes, which highlight that both medical and legal actors are involved in involuntary admission procedures.
We conclude that legal reasons for compulsory admission should be reworded in order to remove stigmatization of the patient, that raising awareness about involuntary admission procedures and patient rights with both patients and family advocacy groups is paramount, that communication about procedures should be widely available in lay-language for the general population, and that training sessions and guidance should be available for legal and medical practitioners. Finally, people working in the field need to be constantly aware about the ethical challenges surrounding compulsory admissions.
The coronavirus disease 2019 pandemic has necessitated almost exclusive National Health Service focus on emergency work and cancer care. There are concerns that increased hospital and community pressures will lead to decreased referrals and worse outcomes for head and neck cancer patients.
This is a retrospective review of all cases referred for suspected head and neck cancer to our institution in January and April 2020.
There was a 55 per cent decrease in referrals but diagnostic yield rose from 2.9 per cent in January to 8.06 per cent in April. In both months, 100 per cent of patients met the 31- and 62-day targets, with similar 14-day wait time success (97.83 per cent for January vs 98.33 per cent for April). Referrals for laryngopharyngeal reflux rose from 27.5 per cent to 41.9 per cent. Referrals for those aged over 60 years fell from 42 per cent to 26 per cent.
It is suggested that further research be conducted into the reasons why fewer patients were referred, particularly elderly patients, and why laryngopharyngeal reflux is so prevalent in fast-track referrals.
Maternal obesity is an established risk factor for poor infant neurodevelopmental outcomes; however, the link between maternal weight and fetal development in utero is unknown. We investigated whether maternal obesity negatively influences fetal autonomic nervous system (ANS) development. Fetal heart rate variability (HRV) is an index of the ANS that is associated with neurodevelopmental outcomes in the infant. Maternal–fetal magnetocardiograms were recorded using a fetal biomagnetometer at 36 weeks (n = 46). Fetal HRV was represented by the standard deviation of sinus beat-to-beat intervals (SDNN). Maternal weight was measured at enrollment (12–20 weeks) and 36 weeks. The relationships between fetal HRV and maternal weight at both time points were modeled using adjusted ordinary least squares regression models. Higher maternal weight at enrollment and 36 weeks were associated with lower fetal HRV, an indicator of poorer ANS development. Further study is needed to better understand how maternal obesity influences fetal autonomic development and long-term neurodevelopmental outcomes.
Clozapine is uniquely effective in treatment-resistant psychosis but remains underutilised, partly owing to psychotic symptoms leading to non-adherence to oral medication. An intramuscular formulation is available in the UK but outcomes remain unexplored.
This was a retrospective clinical effectiveness study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis over a 3-year period.
Successful initiation of oral clozapine after intramuscular prescription was the primary outcome. Secondary outcomes included all-cause clozapine discontinuation 2 years following initiation, and 1 year after discharge. Discontinuation rates were compared with a cohort prescribed only oral clozapine. Propensity scores were used to address confounding by indication.
Among 39 patients prescribed intramuscular clozapine, 19 received at least one injection, whereas 20 accepted oral clozapine when given an enforced choice between the two. Thirty-six (92%) patients successfully initiated oral clozapine after intramuscular prescription; three never transitioned to oral. Eight discontinued oral clozapine during the 2-year follow-up, compared with 83 out of 162 in the comparator group (discontinuation rates of 24% and 50%, respectively). Discontinuation rates at 1-year post-discharge were 21%, compared with 44% in the comparison group. Intramuscular clozapine prescription was associated with a non-significantly lower hazard of discontinuation 2 years after initiation (hazard ratio 0.39, 95% CI 0.14–1.06) and 1 year after discharge (hazard ratio 0.37, 95% CI 0.11–1.24). The only reported adverse event specific to the intramuscular formulation was injection site pain and swelling.
Intramuscular clozapine prescription allowed transition to oral maintenance in an initially non-adherent cohort. Discontinuation rates were similar to patients only prescribed oral clozapine and comparable to existing literature.
Clusters of Salmonella Enteritidis cases were identified by the Minnesota Department of Health using both pulsed-field gel electrophoresis (PFGE) and whole genome sequencing (WGS) single nucleotide polymorphism analysis from 1 January 2015 through 31 December 2017. The median turnaround time for obtaining WGS results was 11 days longer than for PFGE (12 vs. 1 day). WGS analysis more than doubled the number of clusters compared to PFGE analysis, but reduced the total number of cases included in clusters by 34%. The median cluster size was two cases for WGS compared to four for PFGE, and the median duration of WGS clusters was 27 days shorter than PFGE clusters. While the percentage of PFGE clusters with a confirmed source (46%) was higher than WGS clusters (32%), a higher percentage of cases in clusters that were confirmed as outbreaks reported the vehicle or exposure of interest for WGS (78%) than PFGE (46%). WGS cluster size was a significant predictor of an outbreak source being confirmed. WGS data have enhanced S. Enteritidis cluster investigations in Minnesota by improving the specificity of cluster case definitions and has become an integral part of the S. Enteritidis surveillance process.
Results of in situ U–Pb dating of calcite spherulites, cone-in-cone (CIC) calcite and calcite fibres from a calcareous concretion of the upper Ediacaran of Finnmark, Arctic Norway, are reported. Calcite spherulites from the innermost layers of the concretion yielded a lower intercept age of 563 ± 70 Ma, which, although imprecise, is within uncertainty of the age of sedimentation based on fossil assemblages. Non-deformed CIC calcite from the bottom part of the concretion yielded an age of 475 ± 25 Ma, which is interpreted as the age of CIC calcite formation during a period of fluid overpressure induced during burial of the sediments. Deformed CIC calcite from the top part of the concretion yielded an age of 418 ± 23 Ma, which overlaps with a known Caledonian tectono-metamorphic event, and indicates a potential post-depositional overprint at this time. Calcite fibres that grew in small fissures along spherulite rims, which are interpreted as a recrystallization feature during deformation and formation of a cleavage, gave an imprecise age of 486 ± 161 Ma. Our results show that U–Pb dating of calcite can provide age constraints for ancient carbonates and syn- to post-depositional processes that operated during burial and metamorphic overprinting.
Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population.
The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials.
The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner.
Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.
This article examines provincial policy influence on long-term care (LTC) professionals’ advice-seeking networks in Canada’s Maritime provinces. The effects of facility ownership, geography, and region-specific political landscapes on LTC best-practice dissemination are examined. We used sociometric statistics and network sociograms, calculated from surveys with 169 senior leaders in LTC facilities, to identify advice-seeking network structures and to select 11 follow-up interview participants. Network structures were distinguished by density, sub-group number, opinion leader, and boundary spanner distribution. Network structure was affected by ownership model in Nova Scotia and Prince Edward Island, and by regional geography in New Brunswick. Political instability within each province’s LTC system negatively affected network actors’ capabilities to enact innovation. Moreover, provincial policy variations influence advice-seeking network structures, facilitating and constraining relationship development and networking. Consequently, local policy context is essential to informing dissemination strategy design or implementation.
Mild cognitive impairment (MCI) may gradually worsen to dementia, but often remains stable for extended periods of time. Little is known about the predictors of decline to help explain this variation. We aimed to explore whether this heterogeneous course of MCI may be predicted by the presence of Lewy body (LB) symptoms in a prospectively-recruited longitudinal cohort of MCI with Lewy bodies (MCI-LB) and Alzheimer's disease (MCI-AD).
A prospective cohort (n = 76) aged ⩾60 years underwent detailed assessment after recent MCI diagnosis, and were followed up annually with repeated neuropsychological testing and clinical review of cognitive status and LB symptoms. Latent class mixture modelling identified data-driven sub-groups with distinct trajectories of global cognitive function.
Three distinct trajectories were identified in the full cohort: slow/stable progression (46%), intermediate progressive decline (41%) and a small group with a much faster decline (13%). The presence of LB symptomology, and visual hallucinations in particular, predicted decline v. a stable cognitive trajectory. With time zeroed on study end (death, dementia or withdrawal) where available (n = 39), the same subgroups were identified. Adjustment for baseline functioning obscured the presence of any latent classes, suggesting that baseline function is an important parameter in prospective decline.
These results highlight some potential signals for impending decline in MCI; poorer baseline function and the presence of probable LB symptoms – particularly visual hallucinations. Identifying people with a rapid decline is important but our findings are preliminary given the modest cohort size.
New information on acritarchs from the Duolbagáisá Formation, Digermulen Peninsula, Arctic Norway, enable recognition of the three Cambrian Series 2 acritarch-based zones: the Skiagia ornata–Fimbriaglomerella membranacea, Heliosphaeridium dissimilare–Skiagia ciliosa and Volkovia dentifera–Liepaina plana Assemblage zones. Acritarchs of the Skiagia ornata–Fimbriaglomerella membranacea Zone (Cambrian Stage 3) appear near the base of the unit, close to an undetermined trilobite. In the Upper Member of the Duolbagáisá Formation, in levels with Kjerulfia n. sp. and Elliptocephala n. sp., appears an assemblage with abundant Skiagia ciliosa, indicative of the Heliosphaeridium dissimilare–Skiagia ciliosa Zone. A few metres higher appear Liepaina plana, Heliosphaeridium notatum and Retisphaeridium dichamerum, which indicate the Volkovia dentifera–Liepaina plana Zone (Cambrian Stage 4). The transition between the Duolbagáisá Formation and the overlying Kistedalen Formation is marked by the appearance of Comasphaeridium longispinosum, Multiplicisphaeridium llynense and Eliasum llaniscum, diagnostic of the Miaolingian Series. This coincides with the disappearance of Skiagia; occurrences of Skiagia in Miaolingian strata consist of reworked material related to the Hawke Bay regression at the Cambrian Stage 4–Wuliuan transition. The absence of Skiagia in higher levels of the Duolbagáisá Formation and Kistedalen Formation suggests that no unconformity formed during the Hawke Bay regression in this area. The chronostratigraphical significance of the Skiagia ornata–Fimbriaglomerella membranacea, Heliosphaeridium dissimilare–Skiagia ciliosa and Volkovia dentifera–Liepaina plana zones is critically analysed. Correlation of the Duolbagáisá Formation with peri-Gondwanan terrains of Avalonia and Iberia is established. The Digermulen Peninsula has great potential as a reference section for establishing a Cambrian chronostratigraphy based on acritarchs.
In foodborne outbreak investigations, case-control and cohort studies are used to test hypotheses and identify a source, but these studies are resource-intensive and may have challenges of representativeness, temporality or accessibility. We used online surveys to collect population control data for two foodborne outbreaks and compared the data collected to our cases and existing population exposure data. Online survey population controls were comparable to cases based on age and sex. Exposure data collected through online surveys were more precise than existing control data, represented the disease-specific exposure period and could be easily modified. In one outbreak the online control exposure data differed from established population data. In both outbreaks, the information from the online population control survey supported the hypothesis of the investigation. Our findings demonstrate that online surveys were a rapid and representative way to collect responses from controls during outbreak investigations.