Management of childbearing with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders: A scoping review and expert co-creation of evidence-based clinical guidelines.

OBJECTIVE: To co-create expert guidelines for the management of pregnancy, birth, and postpartum recovery in the context of hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). DESIGN: Scoping Review and Expert Co-creation. SETTING: United Kingdom, United States of America, Canada, France, Sweden, Luxembourg, Germany, Italy, and the Netherlands. SAMPLE: Co-creators (n = 15) included expertise from patients and clinicians from the International Consortium on the Ehlers-Danlos syndromes and Hypermobility Spectrum Disorders, facilitated by the Ehlers-Danlos Society. METHODS: A scoping review using Embase, Medline, the Cochrane Central Register of Controlled Trials and CINHAL was conducted from May 2022 to September 2023. Articles were included if they reported primary research findings in relation to childbearing with hEDS/HSD, including case reports. No language limitations were placed on our search, and our team had the ability to translate and screen articles retrieved in English, French, Spanish, Italian, Russian, Swedish, Norwegian, Dutch, Danish, German, and Portuguese. The Mixed Methods Appraisal Tool was used to assess bias and quality appraise articles selected. The co-creation of guidelines was based on descriptive evidence synthesis along with practical and clinical experience supported by patient and public involvement activities. RESULTS: Primary research studies (n = 14) and case studies (n = 21) including a total of 1,260,317 participants informed the co-creation of guidelines in four overarching categories: 1) Preconceptual: conception and screening, 2) Antenatal: risk assessment, management of miscarriage and termination of pregnancy, gastrointestinal issues and mobility, 3) Intrapartum: risk assessment, birth choices (mode of birth and intended place of birth), mobility in labor and anesthesia, and 4) Postpartum: wound healing, pelvic health, care of the newborn and infant feeding. Guidelines were also included in relation to pain management, mental health, nutrition and the common co-morbidities of postural orthostatic tachycardia syndrome, other forms of dysautonomia, and mast cell diseases. CONCLUSIONS: There is limited high quality evidence available. Individualized strategies are proposed for the management of childbearing people with hEDS/HSD throughout pregnancy, birth, and the postpartum period. A multidisciplinary approach is advised to address frequently seen issues in this population such as tissue fragility, joint hypermobility, and pain, as well as common comorbidities, including dysautonomia and mast cell diseases.

A Physiotherapy-Led Transition to Home Intervention for Older Adults Following Emergency Department Discharge: A Pilot Feasibility Randomised Controlled Trial (ED PLUS).

Background: Older adults frequently attend the emergency department (ED) and experience high rates of subsequent adverse outcomes including functional decline, ED re-presentation and unplanned hospital admission. The development of effective interventions to prevent such outcomes is a key priority for research and service provision. Our aim was to evaluate the feasibility of a physiotherapy-led integrated care intervention for older adults discharged from the ED (ED PLUS). Patients and Methods: Older adults presenting to the ED of a university teaching hospital with undifferentiated medical complaints and discharged within 72 hours were computer randomised in a ratio of 1:1:1 to deliver usual care, Comprehensive Geriatric Assessment (CGA) in the ED, or ED PLUS. ED PLUS is an evidence-based and stakeholder-informed intervention to bridge the care transition between the ED and community by initiating a CGA in the ED and implementing a six-week, multi-component, self-management programme in the patient's home. Feasibility and acceptability were assessed quantitatively and qualitatively. All clinical and process outcomes were assessed by a research nurse blinded to group allocation. Data analyses were primarily descriptive. Results: Twenty-nine participants were recruited indicating a 67% recruitment rate. At 6 months, there was 100% retention in the usual care group, 88% in the CGA group and 90% in the ED PLUS group. ED PLUS participants expressed positive feedback, and there was a trend towards improved function and quality of life and less ED revisits and unscheduled hospitalisations in the ED PLUS group. Conclusion: ED PLUS bridges the transition of care between the index visit to the ED and the community and is feasible using systematic recruitment strategies. Despite recruitment challenges in the context of COVID-19, the intervention was successfully delivered and well received by participants. There was a lower incidence of functional decline and improved quality of life in the ED PLUS group. Trial Registration: The trial was registered in Clinical Trials Protocols and Results System as of 21st July 2021, with registration number NCT04983602.

A physiotherapy-led transition to home intervention for older adults following Emergency Department discharge: a pilot feasibility randomised controlled trial.

INTRODUCTION: Older adults frequently attend the emergency department (ED) and experience high rates of adverse outcomes following ED presentation including functional decline, ED re-presentation and unplanned hospital admission. Our aim was to evaluate the feasibility of a physiotherapy-led integrated care intervention for older adults discharged from the ED (ED-PLUS). METHODS: Older adults presenting to the ED with undifferentiated medical complaints and discharged within 72 hours were computer randomised in a ratio of 1:1:1 to deliver usual care, Comprehensive Geriatric Assessment (CGA) in the ED, or ED-PLUS (trial registration: NCT04983602). ED-PLUS is an evidence-based and stakeholder-informed intervention to bridge the care transition between the ED and community by initiating a CGA in the ED and implementing a 6-week, multi-component, self-management programme in the patient's own home. Feasibility (recruitment and retention rates) and acceptability of the programme were assessed quantitatively and qualitatively. Functional decline was examined post-intervention using the Barthel Index. All outcomes were assessed by a research nurse blinded to group allocation. RESULTS: Twenty-nine participants were recruited, indicating 97% of our recruitment target; 90% of participants completed the ED-PLUS intervention. All participants expressed positive feedback about the intervention. The incidence of functional decline at 6 weeks was 10% in the ED-PLUS group versus 70%-89% in the usual care and CGA-only groups. DISCUSSION: High adherence and retention rates were observed among participants and preliminary findings indicate a lower incidence of functional decline in the ED-PLUS group. Recruitment challenges existed in the context of COVID-19. Data collection is ongoing for 6-month outcomes.

What is the level of nutrition care provided to older adults attending emergency departments? A scoping review protocol.

Introduction: Nutrition status among older adults is an important factor in health and clinical outcomes but malnutrition goes unrecognised in routine health care.  Older adults often present to emergency departments (ED) and are subsequently discharged without hospital admission.  Discharge is a transitionary time of care when nutritional vulnerability could be mitigated with the instigation of targeted nutrition care pathways. This protocol outlines a scoping review to identify the level of nutrition care provided to older adults attending emergency departments. Methods: This scoping review will be conducted using the framework proposed by the Joanna Briggs Institute. The Preferred Reporting Items for Systematic Reviews and Meta-analysis extension for scoping reviews (PRISMA-ScR) will be used to guide the reporting. Two researchers will search electronic databases (Medline, CINAHL Complete, EMBASE, Cochrane Library and Scopus), grey literature sources (DART-Europe E-theses portal, Open Grey, and Trip Medical database) and website searches (Google, Google Scholar, Pubmed, NICE and LENUS) to identify appropriate data for inclusion within the last 10 years. Key information will be categorised and classified to generate a table charting the level of nutrition and dietetic care initiated for older adults in the ED according to the Nutrition Care Process Model. A narrative synthesis will be conducted. Conclusions: This scoping review will be used to inform a foundational concept of nutrition care in an ED setting and allow the future examination of nutrition care pathways, practice, policy, and research within models of integrated care for older persons.

CD40mAb adjuvant induces a rapid antibody response that may be beneficial in post-exposure prophylaxis.

Active vaccination can be effective as a post-exposure prophylaxis, but the rapidity of the immune response induced, relative to the incubation time of the pathogen, is critical. We show here that CD40mAb conjugated to antigen induces a more rapid specific antibody response than currently used immunological adjuvants, alum and monophosphoryl lipid A.

Investigation of non-linear adaptive responses and split dose recovery induced by ionizing radiation in three human epithelial derived cell lines.

Two almost completely exclusive fields in radiobiology deal with splitting doses of radiation and comparing the effect to a similar total dose given in one exposure. In radiotherapy, dose "fractionation" is used to "spare" normal tissue and in the low dose field, the adaptive response is well documented as a phenomenon where a small "priming" dose administered before the larger "challenge" dose reduces the effect of the large dose. There have been very few studies where these fields overlap, thus it is not possible to ascertain whether common or distinct mechanisms underlie both phenomena but this is certainly an interesting question and relevant to our understanding of high and low dose radiobiology. This paper presents data for three human cell lines with varying p53 status and radiation responses, treated at a range of times between first and second dose and for 3 different first doses (0.1, 0.5 and 2Gy). The data show that time between doses is critical. Protective (adaptive) effects were seen in each cell line but most prominently in the malignant HT 29 cell line. Surprisingly none of the cell lines showed pronounced split dose recovery. This suggests different mechanisms may underlie the two phenomena.

Radiation-induced adaptive response is not seen in cell lines showing a bystander effect but is seen in lines showing HRS/IRR response.

PURPOSE: A previous study comparing the bystander effect and low-dose hypersensitivity found that they were inversely correlated. In the current study seven cell lines with established bystander effect and hyper-radiosensitivity/increased radioresistance (HRS/IRR) were further screened for the presence of an adaptive response. MATERIALS AND METHODS: Cell survival after exposure to direct radiation with or without a 0.1 Gy priming dose, was determined using the colony forming assay for seven human cell lines (HaCAT, HPV-G, SW48, T98G, U373, HGL21 and HT29). Furthermore, the impact of the bystander effect on cell survival after exposure to irradiated cell culture medium was measured concurrently. RESULTS: An adaptive response was induced in four cell lines (U373, T98G, HGL21 and HT29) causing increased cell survival. In agreement with previous publications, a bystander effect was induced in three cell lines (HPV-G, HaCAT and SW48); while no bystander effect was seen in U373, T98G, HGL21 and HT29. An adaptive response was detected in cell lines known to produce hypersensitive response, and was inversely correlated with the bystander effect. CONCLUSIONS: These results suggest that for the cell lines tested the ability to induce an adaptive response may be mutually exclusive to the bystander effect.

Dilution of irradiated cell conditioned medium and the bystander effect.

While nontargeted and low-dose effects such as the bystander effect are now accepted, the mechanisms underlying the response have yet to be elucidated. It has been shown that the transfer of irradiated cell conditioned medium (ICCM) can kill cells that are not directly irradiated; however, to date the effect of ICCM concentration on cell killing has not been reported. The occurrence of a bystander effect was determined by measuring cell survival after exposure to various ICCM dilutions, using the colony-forming assay, in cells of six human cell lines with varied bystander responses and tumor/ p53 status. Autologous ICCM transfer for these cell lines induced a bystander effect as reported previously. ICCM from these cell lines was transferred to cells of a common reporter cell line (HPV-G) to investigate whether the lack of an induced bystander effect was due to their inability to generate or to respond to a bystander signal(s). ICCM from cells of four cell lines induced a bystander effect in HPV-G reporter cells, confirming that signal production is a critical factor. A saturation response was observed when ICCM was diluted. Survival was found to increase linearly until a plateau was reached and the bystander effect was abolished at 2x dilution. The effect of ICCM from the different cell lines reached a plateau at different dilutions, which were found to correlate with the cell line's radiosensitivity.

Radiation-induced adaptive response in fish cell lines.

There is considerable interest at present in low-dose radiation effects in non-human species. In this study gamma radiation-induced adaptive response, a low-dose radiation effect, was examined in three fish cell lines, (CHSE-214 (Chinook salmon), RTG-2 (rainbow trout) and ZEB-2J (zebrafish)). Cell survival after exposure to direct radiation with or without a 0.1 Gy priming dose, was determined using the colony forming assay for each cell line. Additionally, the occurrence of a bystander effect was examined by measuring the effect of irradiated cell culture medium from the fish cell lines on unexposed reporter cells. A non-linear dose response was observed for all cell lines. ZEB-2J cells were very sensitive to low doses and a hyper-radiosensitive (HRS) response was observed for doses <0.5 Gy. A typical protective adaptive response was not detected in any of the three fish cell lines tested. Rather, it was found that pre-exposure of these cells to 0.1 Gy radiation sensitized the cells to subsequent high doses. In CHSE-214 cells, increased sensitivity to subsequent high doses of radiation was observed when the priming and challenge doses were separated by 4 h; however, this sensitizing effect was no longer present when the interval between doses was greater than 8 h. Additionally, a "protective" bystander response was observed in these cell lines; exposure to irradiated medium from fish cells caused increased cloning efficiency in unirradiated reporter cells. The data confirm previous conclusions for mammalian cells that the adaptive response and bystander effect are inversely correlated and contrary to expectations probably have different underlying mechanisms.

A new strategy for the preparation of peptide-targeted radiopharmaceuticals based on an fmoc-lysine-derived single amino acid chelate (SAAC). automated solid-phase synthesis, NMR characterization, and in vitro screening of fMLF(SAAC)G and fMLF[(SAAC-Re(CO)3)+]G.

A tridentate single amino acid chelate (SAAC) derived from N-alpha-Fmoc-l-lysine was incorporated within a short peptide sequence using an automated peptide synthesizer. Novel derivatives of the chemotactic peptide fMLF were prepared such that the SAAC and its Re complex were selectively placed between a terminal glycine amino acid and the targeting fMLF sequence. The products, which were synthesized in parallel, were characterized by mass spectrometry and multi-NMR spectroscopy. The latter technique demonstrated that the structures of the targeting portions of the peptides are the same in the SAAC and Re-SAAC derivatives. The affinities of the reported compounds for the formyl peptide receptor were subsequently determined using flow cytometry and were found to be comparable to that of the parent peptide. The results of this work demonstrate the feasibility and numerous benefits of using the SAAC system to prepare peptide-targeted Tc(I) and Re(I) radiopharmaceuticals.