Elimination of Chlamydia muridarum from the female reproductive tract is IL-12p40 dependent, but independent of Th1 and Th2 cells.

Chlamydia vaccine approaches aspire to induce Th1 cells for optimal protection, despite the fact that there is no direct evidence demonstrating Th1-mediated Chlamydia clearance from the female reproductive tract (FRT). We recently reported that T-bet-deficient mice can resolve primary Chlamydia infection normally, undermining the potentially protective role of Th1 cells in Chlamydia immunity. Here, we show that T-bet-deficient mice develop robust Th17 responses and that mice deficient in Th17 cells exhibit delayed bacterial clearance, demonstrating that Chlamydia-specific Th17 cells represent an underappreciated protective population. Additionally, Th2-deficient mice competently clear cervicovaginal infection. Furthermore, we show that sensing of IFN-γ by non-hematopoietic cells is essential for Chlamydia immunity, yet bacterial clearance in the FRT does not require IFN-γ secretion by CD4 T cells. Despite the fact that Th1 cells are not necessary for Chlamydia clearance, protective immunity to Chlamydia is still dependent on MHC class-II-restricted CD4 T cells and IL-12p40. Together, these data point to IL-12p40-dependent CD4 effector maturation as essential for Chlamydia immunity, and Th17 cells to a lesser extent, yet neither Th1 nor Th2 cell development is critical. Future Chlamydia vaccination efforts will be more effective if they focus on induction of this protective CD4 T cell population.

Vascular Proteome Responses Precede Organ Dysfunction in a Murine Model of Staphylococcus aureus Bacteremia.

Vascular dysfunction and organ failure are two distinct, albeit highly interconnected, clinical outcomes linked to morbidity and mortality in human sepsis. The mechanisms driving vascular and parenchymal damage are dynamic and display significant molecular cross talk between organs and tissues. Therefore, assessing their individual contribution to disease progression is technically challenging. Here, we hypothesize that dysregulated vascular responses predispose the organism to organ failure. To address this hypothesis, we have evaluated four major organs in a murine model of Staphylococcus aureus sepsis by combining in vivo labeling of the endothelial cell surface proteome, data-independent acquisition (DIA) mass spectrometry, and an integrative computational pipeline. The data reveal, with unprecedented depth and throughput, that a septic insult evokes organ-specific proteome responses that are highly compartmentalized, synchronously coordinated, and significantly correlated with the progression of the disease. These responses include abundant vascular shedding, dysregulation of the intrinsic pathway of coagulation, compartmentalization of the acute phase response, and abundant upregulation of glycocalyx components. Vascular cell surface proteome changes were also found to precede bacterial invasion and leukocyte infiltration into the organs, as well as to precede changes in various well-established cellular and biochemical correlates of systemic coagulopathy and tissue dysfunction. Importantly, our data suggest a potential role for the vascular proteome as a determinant of the susceptibility of the organs to undergo failure during sepsis. IMPORTANCE Sepsis is a life-threatening response to infection that results in immune dysregulation, vascular dysfunction, and organ failure. New methods are needed for the identification of diagnostic and therapeutic targets. Here, we took a systems-wide approach using data-independent acquisition (DIA) mass spectrometry to track the progression of bacterial sepsis in the vasculature leading to organ failure. Using a murine model of S. aureus sepsis, we were able to quantify thousands of proteins across the plasma and parenchymal and vascular compartments of multiple organs in a time-resolved fashion. We showcase the profound proteome remodeling triggered by sepsis over time and across these compartments. Importantly, many vascular proteome alterations precede changes in traditional correlates of organ dysfunction, opening a molecular window for the discovery of early markers of sepsis progression.

Advancing Global Palliative Care Over Two Decades: Health System Integration, Access to Essential Medicines, and Pediatrics.

CONTEXT: Between 2000 and 2020 Open Society Foundations was one of very few funders that supported global palliative care development and advocacy. OBJECTIVES: To describe progress made in three priority areas-the integration of palliative care into public health systems, access to controlled medicines, and pediatric palliative care-during those 20 years. METHODS: Activities and developments between 2000 and 2020 on global integration of palliative care into health systems, access to and availability of controlled medicines, and pediatric palliative care are described and analyzed. RESULTS: Major progress has been made in each area. Whereas in 2000, integration of palliative care into public healthcare systems was on the agenda in just a few pioneering countries, by 2020 a global consensus had emerged that palliative care should be integral to all health systems including in universal health coverage and countries were increasingly taking steps to integrate it into national health systems. While limited availability of these medicines was barely recognized as a public health or drug control issue in 2000, it had become an important priority in global drug policy debates by 2020 and numerous countries had taken steps to improve access to these medicines. Pediatric palliative care, available mostly in a small number of wealthy countries in the 1990s, has seen rapid growth, especially in low- and middle-income countries, and now has a solid foothold in all world regions. CONCLUSION: Despite this progress, significant challenges remain as funding for palliative care advocacy is limited, the overdose crisis in the US has recently had a chilling effect on efforts to improve availability of opioid analgesics, and economic crises related to the COVID-19 pandemic create uncertainty over the future of universal health coverage.

Planning implementation and scale-up of physical activity interventions for people with walking difficulties: study protocol for the process evaluation of the ComeBACK trial.

BACKGROUND: There is currently little evidence of planning for real-world implementation of physical activity interventions. We are undertaking the ComeBACK (Coaching and Exercise for Better Walking) study, a 3-arm hybrid Type 1 randomised controlled trial evaluating a health coaching intervention and a text messaging intervention. We used an implementation planning framework, the PRACTical planning for Implementation and Scale-up (PRACTIS), to guide the process evaluation for the trial. The aim of this paper is to describe the protocol for the process evaluation of the ComeBACK trial using the framework of the PRACTIS guide. METHODS: A mixed methods process evaluation protocol was developed informed by the Medical Research Council (MRC) guidance on process evaluations for complex interventions and the PRACTIS guide. Quantitative data, including participant questionnaires, health coach and administrative logbooks, and website and text message usage data, is being collected over the trial period. Semi-structured interviews and focus groups with trial participants, health coaches and health service stakeholders will explore expectations, factors influencing the delivery of the ComeBACK interventions and potential scalability within existing health services. These data will be mapped against the steps of the PRACTIS guide, with reporting at the level of the individual, provider, organisational and community/systems. Quantitative and qualitative data will elicit potential contextual barriers and facilitators to implementation and scale-up. Quantitative data will be reported descriptively, and qualitative data analysed thematically. DISCUSSION: This process evaluation integrates an evaluation of prospective implementation and scale-up. It is envisaged this will inform barriers and enablers to future delivery, implementation and scale-up of physical activity interventions. To our knowledge, this is the first paper to describe the application of PRACTIS to guide the process evaluation of physical activity interventions. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ( ANZCTR ) Registration date: 10/12/2018.

Palliative care and catastrophic costs in Malawi after a diagnosis of advanced cancer: a prospective cohort study.

BACKGROUND: Inclusive universal health coverage requires access to quality health care without financial barriers. Receipt of palliative care after advanced cancer diagnosis might reduce household poverty, but evidence from low-income and middle-income settings is sparse. METHODS: In this prospective study, the primary objective was to investigate total household costs of cancer-related health care after a diagnosis of advanced cancer, with and without the receipt of palliative care. Households comprising patients and their unpaid family caregiver were recruited into a cohort study at Queen Elizabeth Central Hospital in Malawi, between Jan 16 and July 31, 2019. Costs of cancer-related health-care use (including palliative care) and health-related quality-of-life were recorded over 6 months. Regression analysis explored associations between receipt of palliative care and total household costs on health care as a proportion of household income. Catastrophic costs, defined as 20% or more of total household income, sale of assets and loans taken out (dissaving), and their association with palliative care were computed. FINDINGS: We recruited 150 households. At 6 months, data from 89 (59%) of 150 households were available, comprising 89 patients (median age 50 years, 79% female) and 64 caregivers (median age 40 years, 73% female). Patients in 55 (37%) of the 150 households died and six (4%) were lost to follow-up. 19 (21%) of 89 households received palliative care. Catastrophic costs were experienced by nine (47%) of 19 households who received palliative care versus 48 (69%) of 70 households who did not (relative risk 0·69, 95% CI 0·42 to 1·14, p=0·109). Palliative care was associated with substantially reduced dissaving (median US$11, IQR 0 to 30 vs $34, 14 to 75; p=0·005). The mean difference in total household costs on cancer-related health care with receipt of palliative care was -36% (95% CI -94 to 594; p=0·707). INTERPRETATION: Vulnerable households in low-income countries are subject to catastrophic health-related costs following a diagnosis of advanced cancer. Palliative care might result in reduced dissaving in these households. Further consideration of the economic benefits of palliative care is justified. FUNDING: Wellcome Trust; National Institute for Health Research; and EMMS International.

Endothelial Heparan Sulfate Mediates Hepatic Neutrophil Trafficking and Injury during Staphylococcus aureus Sepsis.

Hepatic failure is an important risk factor for poor outcome in septic patients. Using a chemical tagging workflow and high-resolution mass spectrometry, we demonstrate that rapid proteome remodeling of the vascular surfaces precedes hepatic damage in a murine model of Staphylococcus aureus sepsis. These early changes include vascular deposition of neutrophil-derived proteins, shedding of vascular receptors, and altered levels of heparin/heparan sulfate-binding factors. Modification of endothelial heparan sulfate, a major component of the vascular glycocalyx, diminishes neutrophil trafficking to the liver and reduces hepatic coagulopathy and organ damage during the systemic inflammatory response to infection. Modifying endothelial heparan sulfate likewise reduces neutrophil trafficking in sterile hepatic injury, reflecting a more general role of heparan sulfate contribution to the modulation of leukocyte behavior during inflammation. IMPORTANCE Vascular glycocalyx remodeling is critical to sepsis pathology, but the glycocalyx components that contribute to this process remain poorly characterized. This article shows that during Staphylococcus aureus sepsis, the liver vascular glycocalyx undergoes dramatic changes in protein composition associated with neutrophilic activity and heparin/heparan sulfate binding, all before organ damage is detectable by standard circulating liver damage markers or histology. Targeted manipulation of endothelial heparan sulfate modulates S. aureus sepsis-induced hepatotoxicity by controlling the magnitude of neutrophilic infiltration into the liver in both nonsterile and sterile injury. These data identify an important vascular glycocalyx component that impacts hepatic failure during nonsterile and sterile injury.

Clinician Perspectives of an Avatar-Directed Scheduling and Memory App.

BACKGROUND AND AIMS: Effective strategies are needed to address the need for scheduling support in the unique setting of a home rehabilitation service, providing home based therapy, as well as telerehabilitation. One approach is an electronic avatar-directed scheduling and memory aid in the form of an app. The aim of this study is to investigate clinician perspectives on the use of this type of technology. METHODS: In this mixed method study a total of sixteen clinicians from various disciplines based at a metropolitan hospital in Adelaide (SA, Australia) participated in 2 semi-structured focus groups aimed to explore experiences and attitudes towards scheduling support in the form of an avatar-directed app, perceptions on the usefulness of the app, as well as acceptability. Thematic analysis was undertaken on focus groups' transcripts. Self-reported technology proficiency, perceived usefulness (PU), and perceived ease of use (PEOU) were assessed quantitatively. Summary statistics were used to analyse the quantitative data and Spearman's correlation was used to explore the relationship between participant characteristics and individual and mean scores for PU and PEOU. RESULTS: Four themes emerged from the focus groups: effectiveness versus efficiency, patient empowerment, practicality and ease of use, and likability of the avatar. Clinicians experienced time constraints, and welcomed technology that could assist with reliable scheduling of appointments and therapy sessions. They liked the concept of the avatar and found the app interesting, novel and fun. However, although the app was reasonably easy to use, the setting up was problematic and time consuming. Clinicians did not see the app as beneficial to their patients, and felt that the technology did not add value to the delivery of care. The older, more experienced, clinicians found the app more difficult to use, but neither the level of technological competency, nor gender, was found to be associated with PU or PEOU. DISCUSSION: Although clinicians appreciated the concept of an avatar-directed scheduling and memory app, they did not see it as a useful tool in the provision of scheduling assistance in this particular setting providing short-term rehabilitation services. Clinicians felt time-poor and emphasized the importance of a time-efficient solution. Perceived lack of usefulness in this context and poor likeability of the avatar highlight the need for clinician involvement in the design process before an app can be successfully implemented in a clinical setting.

'Well, if the kids can do it, I can do it': older rehabilitation patients' experiences of telerehabilitation.

BACKGROUND AND OBJECTIVE: Although trials continue to emerge supporting the role of telerehabilitation, implementation has been slow. Key users include older people living with disabilities who are frequent users of hospital rehabilitation services but whose voices are rarely heard. It is unclear whether the use of technologies and reduced face-to-face contact is acceptable to these people. We report on a qualitative study of community dwelling participants who had received a home telerehabilitation programme as an alternative to conventional rehabilitation. DESIGN: Thirteen older participants, three spouses and one carer were interviewed. All had participated in an individualized therapy programme, using a combination of face-to-face and video consults with therapists. The programme used 'off-the-shelf' technologies including iPads for videoconferencing and electronic FitBitR devices. Interviews were recorded, transcribed verbatim and analysed using NVivo software. RESULTS: Thematic analysis resulted in five emergent themes: (i) telerehabilitation is convenient; (ii) telerehabilitation promotes motivation and self-awareness; (iii) telerehabilitation fosters positive therapeutic relationships; (iv) mastering technologies used by younger relatives is a valued aspect of telerehabilitation; and (v) Telerehabilitation does not replace traditional face-to-face rehabilitation therapies. CONCLUSIONS: Participants found telerehabilitation convenient and motivating, coped well with the technology and developed positive therapeutic relationships. The learning and practice aspects sat well in the context of a rehabilitation programme. The use of commercially available technologies may have contributed to respondents' high levels of acceptability. The perception of telerehabilitation as complementary to in-person care and the expectation of technological support have implications for the implementation and delivery of telerehabilitation services to older people.

Student life - Hello, how are you? What can I do to help?

As a nursing student, approaching a patient for the first time can be nerve-racking. Not only will you be conscious of the need to be professional, you will be aware of your status as a student and your lack of experience when communicating with patients.

Telerehabilitation for older people using off-the-shelf applications: acceptability and feasibility.

We investigated the feasibility of providing telerehabilitation in the home as an alternative to conventional ambulatory rehabilitation. Two groups of patients were accepted for telerehabilitation. The first group were community patients who needed rehabilitation, e.g. following a stroke, a fracture or prolonged hospital admission. The second group was from two rural nursing homes where residents were identified with a recent injury, fall or hospitalisation. Telerehabilitation employed a coaching model, with fewer therapist home visits, more feedback and "homework" for the patient. Patients had a tablet computer loaded with a videoconferencing app to connect with therapists and relevant therapeutic apps. Multidisciplinary care was provided for up to 8 weeks. The majority (86%) of eligible patients consented to receive telerehabilitation in their own home (n = 61) or in the country nursing home where they lived (n = 17). Most services were delivered using the 3G and 4G wireless networks with few technical problems. On average participants felt that they had achieved 75% of the goals set at the beginning of the programme. High levels of satisfaction were recorded. There was a 50% reduction in home visits by staff, or 10 visits per patient. Speech therapists were able to double occasions of service and direct patient contact time, whilst halving their travel time. Previous experience with technology and age were not barriers to this method of delivery but did affect recruitment. Telerehabilitation using off-the-shelf technology is feasible for post-acute treatment.

Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.

The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.

A global update on the development of palliative care services.

On World Hospice and Palliative Care Day-8 October 2011-the Worldwide Palliative Care Alliance (WPCA) launched a global update highlighting the progress that has been made in hospice and palliative care over the past 5 years (Lynch et al, 2011; WPCA 2011). Encouragingly, the study shows that there has been a marked increase in the number of countries providing one or more hospice and palliative care services-from 49% of countries in 2006 to 58% in 2011. Here we explore some of the key factors behind this progress, focusing particularly on advocacy and policy.

Oxidative cyclization reactions of trienes and dienynes: total synthesis of membrarollin.

Trienes and dienynes containing one electron-deficient double bond were shown to undergo regio- and stereoselective oxidative cyclization in the presence of permanganate ion to afford 2,5-bis-hydroxyalkyltetrahydrofurans (THF diols). The THF diols produced retained either alkene or alkyne functionalities, which provided convenient handles for the metal oxo-mediated introduction of an adjacent THF ring with overall control of relative and absolute stereochemistry. Adjacent bis-THFs possessing threo-cis-threo-trans-erythro, threo-cis-threo-trans-threo, threo-cis-threo-cis-erythro, threo-cis-erythro-cis-threo, or threo-cis-erythro-trans-threo relationships were synthesized by appropriate selection of alkene geometry and methodology for the closure of the second ring. The threo-cis-threo-cis-erythro stereochemical arrangement is embodied within the bis-THF core units of a number of Annonaceous acetogenins including membrarollin, while trilobacin has a threo-cis-erythro-trans-threo configured core. As an application of the selective oxidative cyclization approach, a total synthesis of membrarollin was completed in 17 linear steps from dodecyne. The C21,C22 double epimer of membrarollin was also synthesized in 15 linear steps and without recourse to the use of hydroxyl group protection.