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Despite the widespread effectiveness of pneumococcal conjugate vaccines on the overall incidence of invasive pneumococcal disease, the global epidemiological landscape continues to be transformed by residual disease from non-vaccine serotypes, thus highlighting the need for vaccines with expanded disease coverage. To address these needs, we have developed V116,an investigational 21-valent non-adjuvanted pneumococcal conjugate vaccine (PCV),containingpneumococcal polysaccharides (PnPs) 3, 6A, 7F, 8, 9N, 10A, 11A,12F, 15A, 16F, 17F, 19A, 20, 22F, 23A, 23B, 24F, 31, 33F, 35B, anda de-O-acetylated 15B(deOAc15B) individually conjugated to the nontoxic diphtheria toxoid CRM197 carrier protein. Preclinical studies evaluated the immunogenicity of V116 inadult monkeys, rabbits, and mice. Following one dose, V116 was found to be immunogenic in preclinical animal species and induced functional antibodies for all serotypes included in the vaccine, in addition to cross-reactive functional antibodies to serotypes 6C and 15B. In these preclinical animal studies, the increased valency of V116 did not result in serotype-specific antibody suppression when compared to lower valent vaccines V114 or PCV13. In addition, when compared with naïve controls, splenocytes from V116 to immunized animals demonstrated significant induction of CRM197-specific T cells in both IFN-γ and IL-4 ELISPOT assays, as well as Th1 and Th2 cytokine induction through in vitro stimulation assays, thus suggesting the ability of V116 to engage T cell dependent immune response pathways to aid in development of memory B cells. V116 also demonstrated significant protection in mice from intratracheal challenge with serotype 24F, a novel serotype not contained in any currently licensed vaccine.

We use photocatalytic reduction to synthesize mono and bimetallic nanoparticles. This approach reveals a new formation pathway involving continuous nucleation and allows the reaction to be turned on and off without impacting particle outcomes.

Aims: Process analytical technology (PAT) is increasingly being adopted within the pharmaceutical industry to build quality into a process. Development of PAT that provides real-time in situ analysis of critical quality attributes are highly desirable for rapid, improved process development. Conjugation of CRM-197 with pneumococcal polysaccharides to produce a desired pneumococcal conjugate vaccine is a significantly intricate process that can tremendously benefit from real-time process monitoring. Methods: In this work, a fluorescence-based PAT methodology is described to elucidate CRM-197-polysacharide conjugation kinetics in real time. Results & conclusion: In this work, a fluorescence-based PAT methodology is described to elucidate CRM-197-polysacharide conjugation kinetics in real time.

Ecclesiastics on both sides of the Anglo-Scottish border have often been forgotten in discussions of allegiance and political identity during the Scottish Wars of Independence. This article explores the careers and loyalties of English clergymen working in Scotland, their relationship to their Scottish counterparts, and their influence on the political landscape of the Anglo-Scottish border. It argues that the lives of these men can offer unique insights into the English administration of Scotland between 1332 and 1357, and challenges claims that the English sought to incorporate the regions of Berwickshire and Roxburghshire into the kingdom of England.

The use of intraoperative transesophageal echocardiography (TEE) has become the standard of care for most cardiac surgical procedures. There are guidelines established for training, practice, and quality improvement in perioperative TEE by the joint efforts of the American Society of Echocardiography and Society of Cardiovascular Anesthesiologists. Cardiac point-of-care ultrasound (POCUS) increasingly is being incorporated into anesthesiologists’ training and practice. While a special “certification in Critical Care Echocardiography” was created by the National Board of Echocardiography in 2019, there currently exist no guidelines for training, certification, and practice of perioperative TTE by anesthesiologists. In this review, the authors describe the categories, indications and applications of perioperative TTE and provide a recommended sequence for performing an examination tailored to the evaluation of perioperative patients. Although the authors describe a protocol utilized at their institution, there are no standards described in the literature for PTTE. Cardiac anesthesiologists and cardiac anesthesia societies (Society of Cardiovascular Anesthesiologists, European Association of Cardiothoracic Anesthesiologists) must come forward to establish standards working in collaboration with echocardiography societies (American Society of Echocardiography, European Society of Cardiology).

OBJECTIVE Obsessive-compulsive disorder (OCD) is among the most debilitating and medically refractory psychiatric disorders. While cingulotomy is an anatomically targeted neurosurgical treatment that has shown significant promise in treating OCD-related symptoms, the precise underlying neuroanatomical basis for its beneficial effects has remained poorly understood. Therefore, the authors sought to determine whether lesion location is related to responder status following cingulotomy. METHODS The authors reviewed the records of 18 patients who had undergone cingulotomy. Responders were defined as patients who had at least a 35% improvement in the Yale-Brown Obsessive Compulsive Scale (YBOCS) score. The authors traced the lesion sites on T1-weighted MRI scans and used an anatomical registration matrix generated by the imaging software FreeSurfer to superimpose these lesions onto a template brain. Lesion placement was compared between responders and nonresponders. The placement of lesions relative to various anatomical regions was also compared. RESULTS A decrease in postoperative YBOCS score was significantly correlated with more superiorly placed lesions (decrease −0.52, p = 0.0012). While all lesions were centered within 6 mm of the cingulate sulcus, responder lesions were placed more superiorly and posteriorly along the cingulate sulcus (1-way ANOVA, p = 0.003). The proportions of the cingulum bundle, cingulate gyrus, and paracingulate cortex affected by the lesions were the same between responders and nonresponders. However, all responders had lesions covering a larger subregion of Brodmann area (BA) 32. In particular, responder lesions covered a significantly greater proportion of the posterior BA32 (1-way ANOVA, p = 0.0064). CONCLUSIONS Lesions in patients responsive to cingulotomy tended to be located more superiorly and posteriorly and share greater coverage of a posterior subregion of BA32 than lesions in patients not responsive to this treatment.

Improved biomarkers are needed to guide the optimal use of autologous stem cell transplantation (ASCT) for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We hypothesized that minimal residual disease (MRD) identified using immunoglobulin high-throughput sequencing in apheresis stem cell (ASC) samples or post-ASCT peripheral blood mononuclear cell (PBMC) and plasma samples could predict relapse. We studied 159 patients with R/R DLBCL who underwent ASCT, of whom 98 had an ASC sample and 60 had post-ASCT surveillance samples. After a median post-ASCT follow-up of 60 months, the 5-year progression-free survival (PFS) was 48%. MRD was detected in 23/98 (23%) ASC samples and was associated with very poor PFS (5-year PFS 13% vs 53%, p

Tailored interventions have been shown to be effective and tailoring is a popular process with intuitive appeal for researchers and practitioners. However, the concept and process are ill-defined in implementation science. Descriptions of how tailoring has been applied in practice are often absent or insufficient in detail. This lack of transparency makes it difficult to synthesize and replicate efforts. It also hides the trade-offs for researchers and practitioners that are inherent in the process. In this article we juxtapose the growing prominence of tailoring with four key questions surrounding the process. Specifically, we ask: (1) what constitutes tailoring and when does it begin and end?; (2) how is it expected to work?; (3) who and what does the tailoring process involve?; and (4) how should tailoring be evaluated? We discuss these questions as a call to action for better reporting and further research to bring clarity, consistency, and coherence to tailoring, a key process in implementation science.

Axially chiral atropisomers have energetic barriers to rotation, Δ

Background: The implementation of models of integrated care for chronic conditions is not well understood. We conducted a realist evaluation to determine how and why the implementation of the National Diabetes Programme in Ireland worked (or not).Methods: Documentary analysis and qualitative interviews with a purposive sample of national stakeholders (n = 19), were used to develop an initial theory on expected programme delivery. We refined this theory using semi-structured interviews (n = 38) with professionals from different clinical disciplines involved in programme implementation.Results: Locally important contexts facilitating implementation included staff experience of delivering diabetes care, capacity, and familiarity with the intended purpose of new clinical posts. The extent to which integrated care was adopted and implemented depended on judgements made by professionals working in these contexts; specifically, judging the relative advantage of the programme and whether to engage in negotiations to legitimize their new roles in diabetes care.Conclusions: Our results highlight the need for adequate preparatory work to raise awareness of and support new roles to implement integrated care, clarification on the core components of new care models, and the development of local service infrastructures to support integrated care.

Background Neonicotinoid insecticide seed treatments were withdrawn from use on cereal crops in the European Union (EU) in 2018 exposing the crops to yellow dwarf viruses transmitted by cereal aphids. To reduce prophylactic pyrethroid sprays there is a need for easier, field-specific monitoring techniques given that pest incidence is spatially and temporally highly sporadic. A field-specific monitoring method based on the use of yellow sticky traps mounted horizontally just above the crop was developed and evaluated to determine: (i) predictive capabilities of the sticky trap system, (ii) practicalities of use by farmers and agronomists, and (iii) whether landscape composition, boundary type and type of tillage affect immigration of aphid vectors. Results Yellow sticky traps effectively sampled winged cereal aphids and identified spatial differences in immigration patterns within- and between fields. Farmers and agronomist's aphid identification skills need improving, although they could detect aphid trends with minimal training. At least three times more cereal aphids were captured in crop headlands, especially next to taller field boundaries indicating that wind currents determined aphid immigration patterns within fields. Considerable between field aphid immigration was detected (24% of fields had no aphid immigration) even on the same farm. Levels of immigrating grain aphids were positively related to the proportion of grassland in the landscape. Tillage type had no impact on levels of immigrating aphids. Conclusion Field-based monitoring and different management of headland areas could be used to reduce insecticide usage when controlling of cereal/barley yellow dwarf virus.

Background: The Cork and Kerry Diabetes and Heart Disease Study was established to investigate the prevalence of diabetes and cardiovascular disease among middle-aged adults in Ireland. The Mitchelstown cohort was recruited from a single large primary care centre between 2010–2011. A rescreen of this cohort was conducted in 2015. Methods: Data were collected on cardiovascular health and associated risk factors. In addition, the rescreen incorporated new measures which included information on cognition and frailty, medication adherence, dietary factors and the collection of stool samples with RNA sequencing of the gut microbiome. Results: Of 2047 participants in the original cohort, 237 (11.6%) were deceased, too ill to participate or were lost to follow-up. Of the remaining 1810 baseline study participants, 1378 men and women aged 51–77 years agreed to take part in the rescreen (response rate of 76.1%). The prevalence of hypertension was high, ranging from 50% to 64% depending on the measurement method. An investigation of the association of gut microbiota with metabolic syndrome and obesity indicated greater microbiome diversity in metabolically healthy non-obese individuals relative to their unhealthy counterparts. Analysis of prescribing data over time demonstrated a high prevalence of potentially inappropriate prescribing among older-aged people in primary care which increased as they progressed to more advanced old age. Conclusions: The rescreen has provided new insights into cardiovascular health. In addition, this study is embedded in a single primary care centre, enabling passive follow-up of study participants through electronic health records. All data collected at baseline and rescreen are maintained and stored at the School of Public Health, University College Cork and specific proposals for future collaborations are welcome.

Congenital anomalies of the kidney and urinary tract (CAKUTs) represent the leading cause of chronic kidney disease and end-stage kidney disease in children. Increasing evidence points to critical roles for the urothelium in the developing urinary tract and in the genesis of CAKUTs. The involvement of the urothelium in patterning the urinary tract is supported by evidence that CAKUTs can arise as a result of abnormal urothelial development. Emerging evidence indicates that congenital urinary tract obstruction triggers urothelial remodelling that stabilizes the obstructed kidney and limits renal injury. Finally, the diagnostic potential of radiological findings and urinary biomarkers derived from the urothelium of patients with CAKUTs might aid their contribution to clinical care.

Ion mobility spectrometry (IMS)-based instruments have historically been accurate to, at best, ±2% of the reduced ion mobility (K0) value of the chemical of interest. Fielded IMS-based detectors th...

It is widely recognized that landscape factors affect the biological control of weed seeds and insect pests in arable crops, but landscape effects have been found to be inconsistent between studies. Here, we compare six different types of sentinels (surrogate prey that was either live insects or seeds) to measure the effects of semi-natural habitats at field to landscape scales on levels of biological control in winter wheat in the UK. Sentinels were located in fields adjacent to three boundary types: grassy margin, hedgerows or woodland to study the local scale effects and in landscapes of varying heterogeneity in study areas of 1-km radius. Overall, mean levels of predation were higher for most insect prey (60.8%) located on the ground compared to the crop (12.2%) and was lower for seeds (5.8%). Predation of sentinels on the ground was attributed to generalist predators. Semi-natural habitats had both positive and negative effects at field and landscape scales, but the response varied with the sentinel type. Herbaceous linear semi-natural habitats had positive effects at local scales for Calliphora vomitoria and Sitobion avenae sentinels and provide evidence that farmers can introduce linear herbaceous features to benefit biological control. In contrast, our distance-weighted kernel models identified a positive relationship between woody habitats and the predation of C. vomitoria and Chenopodium album. Natural aphid infestations were lower in landscapes with more semi-natural habitat. Synthesis and applications. Sentinels may be sensitive enough to detect variation in levels of biological control influenced by semi-natural habitats, but this study confirms that landscape effects differ for different types of sentinel prey. This implies that it may not be possible to categorize landscapes as pest suppressive using a single sentinel type. Future studies should therefore consider using multiple sentinels to give a better perspective on predation intensity. The resulting recommendations for farm management include planting woodland adjacent wheat fields infested with seed predators and positioning herbaceous linear habitats adjacent wheat fields infested with Sitobion avenae, particularly if fields are bordered by woody liner habitats due to their association with decreased S. avenae predation.

Although there are effective evidence-based interventions (EBIs) to prevent, treat and coordinate care for chronic conditions they may not be adopted widely and when adopted, implementation challenges can limit their impact. Implementation strategies are “methods or techniques used to enhance the adoption, implementation, and sustainment of a clinical program or practice”. There is some evidence to suggest that to be more effective, strategies should be tailored; that is, selected and designed to address specific determinants which may influence implementation in a given context. Despite the growing popularity of tailoring the concept is ill-defined, and the way in which tailoring is applied can vary across studies or lack detail when reported. There has been less focus on the part of tailoring where stakeholders prioritise determinants and select strategies, and the way in which theory, evidence and stakeholders’ perspectives should be combined to make decisions during the process. Typically, tailoring is evaluated based on the effectiveness of the tailored strategy, we do not have a clear sense of the mechanisms through which tailoring works, or how to measure the “success” of the tailoring process. We lack an understanding of how stakeholders can be involved effectively in tailoring and the influence of different approaches on the outcome of tailoring. Our research programme, CUSTOMISE (Comparing and Understanding Tailoring Methods for Implementation Strategies in healthcare) will address some of these outstanding questions and generate evidence on the feasibility, acceptability, and efficiency of different tailoring approaches, and build capacity in implementation science in Ireland, developing and delivering training and supports for, and network of, researchers and implementation practitioners. The evidence generated across the studies conducted as part of CUSTOMISE will bring greater clarity, consistency, coherence, and transparency to tailoring, a key process in implementation science.

Background: While models of integrated care for people with chronic conditions have demonstrated promising results, there are still knowledge gaps about how these models are implemented in different contexts and which strategies may best support implementation. We aimed to evaluate the implementation of a multidisciplinary diabetes Community Specialist Team (CST) to support delivery of integrated type 2 diabetes care during COVID-19 in two health networks. Methods: A mixed methods approach was used. Quantitative data included administrative data on CST activity and caseload, and questionnaires with GPs, practice nurses (PN) and people with type 2 diabetes. Qualitative data were collected using semi-structured interviews and focus groups about the service from CST members, GPs, PNs and people with type 2 diabetes. We used the Consolidated Framework for Implementation Research framework to explain what influences implementation and to integrate different stakeholder perspectives. Results: Over a 6-month period (Dec 2020-May 2021), 516 patients were seen by podiatrists, 435 by dieticians, and 545 by CNS. Of patients who had their first CST appointment within the previous 6 months (n=29), 69% (n=20) waited less than 4 weeks to see the HCP. During initial implementation, CST members used virtual meetings to build ‘rapport’ with general practice staff, supporting ‘upskilling’ and referrals to the CST. Leadership from the local project team and change manager provided guidance on how to work as a team and ‘iron out’ issues. Where available, shared space enhanced networking between CST members and facilitated joint appointments. Lack of administrative support for the CST impacted on clinical time. Conclusions: This study illustrates how the CST benefited from shared space, enhanced networking, and leadership. When developing strategies to support implementation of integrated care, the need for administrative support, the practicalities of co-location to facilitate joint appointments, and relative advantages of different delivery models should be considered.

HeartMate III is an emerging, small-sized centrifugal ventricular assist device. Its lower pump thrombosis and stroke rates make it favorable for use in pediatrics. We report the use of HeartMate III as a bridge to transplantation in an adolescent with failed Fontan circulation. (Level of Difficulty: Advanced.), Graphical abstract, HeartMate III is an emerging, small-sized centrifugal ventricular assist device. Its lower pump thrombosis and stroke rates make it favorable for use…

BackgroundA National Clinical Programme for the Management of Hospital-Presenting Self-Harm (NCP-SH) was introduced in Ireland in 2014. This involved the development of a model of care to standardise the management of self-harm in emergency departments, to be delivered by dedicated clinical nurse specialists. The core components of the programme were to: ensure an empathic and timely response, conduct a biopsychosocial assessment, involve family members in assessment and discharge planning, and provide a bridge to next care. The overall aim of the programme was to reduce the rate of repeat self-harm. This multistage study will evaluate the impact of the NCP-SH on hospital-presenting self-harm and to identify determinants influencing its implementation.MethodsEmploying a sequential mixed methods design, the first stage will use data from the National Self-Harm Registry Ireland to examine the impact of the NCP-SH on self-harm repetition, along with other aspects of care, including provision of psychosocial assessments and changes in admissions and postdischarge referrals. A cost-effectiveness analysis will assess the cost per repeat self-harm attendance avoided as a result of the NCP-SH. The second stage will identify the influences of implementation fidelity—adherence to the programme’s core components—using a combination of document analysis and semistructured interviews with staff of the programme, guided by the Consolidated Framework for Implementation Research.Ethics and disseminationThis study has received full ethical approval and will run until August 2023. This study is novel in that it will identify important factors influencing successful implementation of complex programmes. It is expected that the findings will provide important learnings for the integration of mental health services in general hospital settings and will be disseminated via peer-review publications along with reports for clinicians and policy-makers.

The search for suitable ion mobility spectrometry (IMS) calibrant compounds is ongoing and necessitates the use of highly accurate reduced ion mobility (K0) values across a range of instrumental conditions. Such values will be used in calibrating devices to shift the ion mobility scales and alarm windows for chemicals of interest to their proper locations based on the instrumental conditions present during calibration and sampling. Many positive ion mode calibrants have been investigated, whereas investigations for a negative ion detection mode calibrant have been more limited. Isoflurane (IsoF) is a strong candidate as a negative ion mode calibrant. This report documents the accurately measured K0 values for IsoF product ions as a function of multiple instrumental parameters. K0 values were measured in two instrumentation modes as a function of drift gas temperature, water concentration, and dopant concentration. This report culminates with our evaluation of the suitability of IsoF as a negative ion mode calibrant for IMS applications.

Pneumococcal conjugate vaccines (PCVs) are formed by bioconjugation of a carrier protein to the purified capsular polysaccharide (Ps) from multiple serological strains of Streptococcus pneumoniae. The associated bioconjugation chemistry relies on initial selective modifications to the Ps backbone structure. Among these modifications, removal of a ketal functional group, termed deketalization, is one that is important for pharmaceutical PCV production. Herein, we report a process monitoring investigation into the deketalization of a polysaccharide relevant to PCV process development. We have applied process analytical technology (PAT) for in situ process monitoring to study the deketalization reaction in real time. We find that in situ FTIR spectroscopy elucidates multiple classes of reaction kinetics, one of which correlates strongly with the deketalization reaction of interest. This PAT approach to real time reaction monitoring offers the possibility of improved process monitoring in the pharmaceutical production of PCVs. To our knowledge, this report represents the first PAT investigation into Ps deketalization. Our findings suggest that broader application of PAT to the chemical modifications associated with PCV bioconjugation, as well as other pharmaceutically relevant bioconjugation processes, carries the power to enhance process understanding, control, and efficiency through real time process monitoring.

Background : Autologous stem cell transplantation (ASCT) is a standard of care for patients with chemosensitive, relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL). While the clinical benefit of ASCT has traditionally been attributed solely to cytoreduction from intensive chemotherapy, ASCT has important immunogenic effects which may contribute to its anti-tumor efficacy and could provide a favorable immune environment for post-ASCT immune-based maintenance treatments. We previously reported clinical results of a phase II trial (NCT02362997) testing 8 doses of pembrolizumab maintenance therapy after ASCT for patients with R/R cHL or DLBCL. To clarify the impact of pembrolizumab on immune reconstitution, we compared the kinetics of peripheral blood immune cell recovery after ASCT for trial patients receiving pembrolizumab maintenance to those of a contemporaneous control cohort of similar patients undergoing ASCT without pembrolizumab maintenance. Objective : To characterize the impact of post-ASCT pembrolizumab maintenance therapy on immune reconstitution for patients with R/R DLBCL and cHL and to identify candidate biomarkers of efficacy and immune-related adverse events (irAEs). Study design : Peripheral blood mononuclear cell (PBMC) samples were prospectively collected 1-18 months after ASCT and analyzed by flow cytometry using a panel of fluorophore-conjugated monoclonal antibodies to identify B cells, natural killer (NK) cells, and various dendritic cell (DC) and T cell subsets. Results : A median of 5 (range 1-8) post-ASCT PB samples were collected from 144 patients (59 pembrolizumab, 85 control). Clinical characteristics of the two cohorts were similar. Compared to cHL patients, DLBCL patients (who all received anti-CD20 monoclonal antibody therapy before ASCT) had delayed CD19+ cell reconstitution which persisted for at least 18-month after ASCT. No other differences in immune reconstitution were observed based on lymphoma subtype. Post-ASCT pembrolizumab maintenance therapy was associated with 1) an elevation in circulating DCs (driven by higher levels of plasmacytoid and immature DCs) which persisted for the duration of pembrolizumab treatment, and 2) a significant reduction in PD-1+ T cells which persisted for 6-12 months after completion of pembrolizumab therapy. Despite the key role of T cells in mediating the effects of PD-1 blockade, pembrolizumab maintenance did not affect recovery of any T cell subsets. In an exploratory analysis, a higher baseline CD4+ TEMRA cell count (defined as CD3+ CD4+ CD45RA+ CD62L-) was associated with inferior PFS, but only among patients who received pembrolizumab maintenance (p=0.003). As continuous variables, lower absolute levels of NK cells (p=0.009), PD-1+ CD4+ T cells (p=0.005), and PD-1+ CD8+ T cells (p=0.005) before pembrolizumab initiation were each associated with a higher risk of grade 2+ irAEs. Conclusion : Post-ACST pembrolizumab maintenance therapy is associated with a persistent elevation in circulating DCs, but its impact on the reconstitution of other immune cells in peripheral blood appears limited. Our study suggests that early features of post-ASCT immune reconstitution could be associated with PFS and risk of irAE and warrant additional investigation.

“Synthetic recombinant” populations have emerged as a useful tool for dissecting the genetics of complex traits. They can be used to derive inbred lines for fine QTL mapping, or the populations themselves can be sampled for experimental evolution. In the latter application, investigators generally value maximizing genetic variation in constructed populations. This is because in evolution experiments initiated from such populations, adaptation is primarily fueled by standing genetic variation. Despite this reality, little has been done to systematically evaluate how different methods of constructing synthetic populations shape initial patterns of variation. Here we seek to address this issue by comparing outcomes in synthetic recombinant Saccharomyces cerevisiae populations created using one of two strategies: pairwise crossing of isogenic strains or simple mixing of strains in equal proportion. We also explore the impact of the varying the number of parental strains. We find that more genetic variation is initially present and maintained when population construction includes a round of pairwise crossing. As perhaps expected, we also observe that increasing the number of parental strains typically increases genetic diversity. In summary, we suggest that when constructing populations for use in evolution experiments, simply mixing founder strains in equal proportion may limit the adaptive potential.