Joint patient and clinician priority setting to identify 10 key research questions regarding the long-term sequelae of COVID-19.

Given the large numbers of people infected and high rates of ongoing morbidity, research is clearly required to address the needs of adult survivors of COVID-19 living with ongoing symptoms (long COVID). To help direct resource and research efforts, we completed a research prioritisation process incorporating views from adults with ongoing symptoms of COVID-19, carers, clinicians and clinical researchers. The final top 10 research questions were agreed at an independently mediated workshop and included: identifying underlying mechanisms of long COVID, establishing diagnostic tools, understanding trajectory of recovery and evaluating the role of interventions both during the acute and persistent phases of the illness.

Declining oral intake towards the end of life: how to talk about it? A qualitative study.

BACKGROUND: Decreasing oral intake is common towards the end of life and a potential source of distress and concern for patients, relatives, whanau and clinicians. This paper provides insight to inform practice regarding clinicians' perceptions, practices, responses and communication with patients and their companions regarding declining oral intake towards the end of life. METHODS: In this qualitative study ten specialist palliative care staff participated in semi-structured interviews. Qualitative thematic analysis was used to analyse the data. FINDINGS: Three themes were identified: declining oral intake was a natural part of the dying process; responding empathetically; and clinicians described specific aims and ways regarding communication. CONCLUSION: Insight into clinicians' endeavours to manage declining oral intake and support the wellbeing of patients, families, and whanau can inform practice. However the perspectives of family, whanau and health professionals continue to show significant variation regarding the communication given and received around declining oral intake towards the end of life.

Improving patients' readiness for coronary artery bypass graft surgery.

BACKGROUND: Preoperative interventions improve outcomes for patients after coronary artery bypass surgery (CABG). OBJECTIVE: To reduce mortality for patients undergoing urgent CABG. METHODS: Eight centers implemented preoperative aspirin and statin, preinduction heart rate less than 80/min, hematocrit greater than 30%, blood sugar less than 150 mg/dL (8.3 mmol/L), and delayed surgery at least 3 days after a myocardial infarction. Data were collected on the last 150 isolated, urgent CABGs at each center (n=1200). A "bundle" score of 0 to 100 was calculated for each patient to represent the percentage of interventions used. RESULTS: Scores ranged from 33 to 100. About 56% of patients had a perfect score. Crude mortality and composite rates were lower in patients with higher scores, but once adjusted for patient and disease characteristics, the difference in scores was not significant. Higher scores were associated with shorter intubation: 6.0 hours (score 100), 8.0 hours (score 80-99), 8.4 hours (score<80) (log-rank P<.001). Median length of stay was shorter for patients with higher scores: 5 days (score 100), 6 days (scores 80-99), and 6 days (scores <80) (log-rank P<.001). CONCLUSION: Implementation of interventions to optimize patients' "readiness for surgery" is associated with shorter intubation times and shorter hospital stays after CABG.

Bereaved relatives' perspectives of the patient's oral intake towards the end of life: a qualitative study.

BACKGROUND: Patients approaching death often have a decreasing oral intake, which can be distressing for relatives. Little is known about the relatives' experiences with and perceptions of oral intake at the end of life. AIM: This study aims to contribute to a more thorough understanding of relatives' concerns regarding decreased oral intake of the patient at the end of life. DESIGN: Qualitative interview study: semi-structured interviews were transcribed verbatim and analysed using qualitative content analysis. SETTING/PARTICIPANTS: Twenty-three bereaved relatives of patients who had been referred to a New Zealand palliative care service were interviewed. RESULTS: All relatives experienced significant changes in patients' oral intake at the end of life. Oral intake towards the end of life was considered important and is perceived as meaningful by relatives in different ways, such as nutritional value, enjoyment, social time, daily routine and a way of caring. Relatives responded differently to decreasing oral intake; some accepted it as inherent to the dying process, others continued efforts to support the patient's oral intake. Some relatives perceived decreasing oral intake as the patient's choice, and some viewed maintaining oral intake as part of the battle against the disease. Relatives recalled limited communication with health-care professionals concerning oral intake at the end of life. CONCLUSIONS: This study revealed the complexity of meaning relatives' experiences with dying patients' decreasing oral intake. Their perceptions and concerns were related to their awareness of the imminent death. These findings can guide staff involved in care delivery to better support relatives.

International palliative care experts' view on phenomena indicating the last hours and days of life.

BACKGROUND: Providing the highest quality care for dying patients should be a core clinical proficiency and an integral part of comprehensive management, as fundamental as diagnosis and treatment. The aim of this study was to provide expert consensus on phenomena for identification and prediction of the last hours or days of a patient's life. This study is part of the OPCARE9 project, funded by the European Commission's Seventh Framework Programme. METHOD: The phenomena associated with approaching death were generated using Delphi technique. The Delphi process was set up in three cycles to collate a set of useful and relevant phenomena that identify and predict the last hours and days of life. Each cycle included: (1) development of the questionnaire, (2) distribution of the Delphi questionnaire and (3) review and synthesis of findings. RESULTS: The first Delphi cycle of 252 participants (health care professionals, volunteers, public) generated 194 different phenomena, perceptions and observations. In the second cycle, these phenomena were checked for their specific ability to diagnose the last hours/days of life. Fifty-eight phenomena achieved more than 80% expert consensus and were grouped into nine categories. In the third cycle, these 58 phenomena were ranked by a group of palliative care experts (78 professionals, including physicians, nurses, psycho-social-spiritual support; response rate 72%, see Table 1) in terms of clinical relevance to the prediction that a person will die within the next few hours/days. Twenty-one phenomena were determined to have "high relevance" by more than 50% of the experts. Based on these findings, the changes in the following categories (each consisting of up to three phenomena) were considered highly relevant to clinicians in identifying and predicting a patient's last hours/days of life: "breathing", "general deterioration", "consciousness/cognition", "skin", "intake of fluid, food, others", "emotional state" and "non-observations/expressed opinions/other". CONCLUSION: Experts from different professional backgrounds identified a set of categories describing a structure within which clinical phenomena can be clinically assessed, in order to more accurately predict whether someone will die within the next days or hours. However, these phenomena need further specification for clinical use.

Staff perceptions of the impact of the Liverpool Care Pathway in aged residential care in New Zealand.

AIM: To determine staff perceptions of the impact of the Liverpool Care Pathway for the dying patient (LCP) in three aged residential care facilities in New Zealand. METHODS: A mixed methodology approach was adopted, including the use of a survey, focus groups, and individual interviews. FINDINGS: Fifteen of 194 staff participated in the focus groups (five nurses and nine health-care assistants). The interviewees included three GPs, one registered nurse, and one manager. The post-implementation survey response rate of 13% was poorer than the 32% response rate to a pre-implementation survey reported elsewhere. Nevertheless, there was congruence across the data sources. The participating staff perceived multiple benefits to residents, family, whãnau, and staff following implementation of the LCP. CONCLUSION: As a tool the LCP was effective in supporting, guiding, and prompting care delivery. However, challenges remained, particularly regarding environmental factors.

Staff perceptions of end-of-life care following implementation of the liverpool care pathway for the dying patient in the acute care setting: a New Zealand perspective.

BACKGROUND AND METHODS: Ensuring appropriate palliative and end-of-life (EOL) care in the acute environment is complex and challenging. The Liverpool Care Pathway (LCP) aims to support staff to provide holistic EOL care utilizing a structured framework to prompt and guide care. We report on the post-implementation findings of a mixed methodology (survey and focus group [FG] forums) study into staff perceptions of EOL care following the pilot implementation of the LCP into two acute wards. RESULTS AND CONCLUSIONS: Study results suggest that within acute settings staff perceive that the LCP improves EOL care overall, assists interdisciplinary communication around death and dying, and that is a useful tool to positively influence decision making and care delivery. Further research into aspects of staff communication, diagnosing dying, changing direction of care, and the physical environment is warranted.

Complexity in non-pharmacological caregiving activities at the end of life: an international qualitative study.

BACKGROUND: In late-stage palliative cancer care, relief of distress and optimized well-being become primary treatment goals. Great strides have been made in improving and researching pharmacological treatments for symptom relief; however, little systematic knowledge exists about the range of non-pharmacological caregiving activities (NPCAs) staff use in the last days of a patient's life. METHODS AND FINDINGS: Within a European Commission Seventh Framework Programme project to optimize research and clinical care in the last days of life for patients with cancer, OPCARE9, we used a free-listing technique to identify the variety of NPCAs performed in the last days of life. Palliative care staff at 16 units in nine countries listed in detail NPCAs they performed over several weeks. In total, 914 statements were analyzed in relation to (a) the character of the statement and (b) the recipient of the NPCA. A substantial portion of NPCAs addressed bodily care and contact with patients and family members, with refraining from bodily care also described as a purposeful caregiving activity. Several forms for communication were described; information and advice was at one end of a continuum, and communicating through nonverbal presence and bodily contact at the other. Rituals surrounding death and dying included not only spiritual/religious issues, but also more subtle existential, legal, and professional rituals. An unexpected and hitherto under-researched area of focus was on creating an aesthetic, safe, and pleasing environment, both at home and in institutional care settings. CONCLUSIONS: Based on these data, we argue that palliative care in the last days of life is multifaceted, with physical, psychological, social, spiritual, and existential care interwoven in caregiving activities. Providing for fundamental human needs close to death appears complex and sophisticated; it is necessary to better distinguish nuances in such caregiving to acknowledge, respect, and further develop end-of-life care.

Issues and needs in end-of-life decision making: an international modified Delphi study.

BACKGROUND: end-of-life decision making is an important aspect of end-of-life care that can have a significant impact on the process of dying and patients' comfort in the last days of life. AIM: the aim of our study was to identify issues and considerations in end-of-life decision making, and needs for more evidence among palliative care experts, across countries and professions. PARTICIPANTS: 90 palliative care experts from nine countries participated in a modified Delphi study. Participants were asked to identify important issues and considerations in end-of-life decision making and to rate the need for more evidence. RESULTS: experts mentioned 219 issues in end-of-life decision making related to the medical domain, 122 issues related to the patient wishes and 92 related to relatives' wishes, regardless of profession or country (p > 0.05). In accordance, more than 90% of the experts rated the comfort and wishes of the patient and the potential futility of treatment as important considerations in end-of-life decision making, although some variation was present. When asked about issues that are in need of more evidence, 87% mentioned appropriate indications for using sedatives and effects of artificial hydration at the end of life. A total of 83% mentioned adequate communication approaches. CONCLUSIONS: palliative care experts from different professions in different countries encounter similar issues in end-of-life decision making. Adequate communication about these issues is universally experienced as a challenge, which might benefit from increased knowledge. This shared experience enables and emphasizes the need for more international research.

Staff perceptions of end-of-life care in the acute care setting: a New Zealand perspective.

BACKGROUND: Understanding current end of life (EOL) care delivery in acute care is an important prerequisite to positively influencing practice, and published New Zealand (NZ) and international data are limited. Therefore, staff perceptions of EOL care in the hospital setting were investigated via survey. This article presents key findings. METHOD AND RESULTS: A total of 610 staff members in a 194-bed regional hospital were surveyed regarding their perceptions of EOL care, which yielded a response rate of 29% with 179 surveys returned. Respondents were from medical, nursing, and allied health staff working in medical, surgical, elder health, and a regional cancer treatment service. Responses to Likert scale statements regarding the Care of the dying, Communication, Teamwork, Documentation, Attitudes to death and dying in the workplace, and Barriers to the care of patients, their whanau (a NZ Maori word that refers to extended family or family group), and families frequently contrasted with additional and explanatory comments. The thematic analysis of written text identified five themes: The reality of care, The team dynamic, The direction of care, Knowledge and education, and Environmental and organizational factors. CONCLUSION: The quality and timeliness of EOL care was significantly influenced by the elements informing the themes and the pervasive nature and importance of communication. Meeting the needs of dying patients in acute care was complex but a significant priority for staff.

Staff perceptions of end-of-life care in aged residential care: a New Zealand perspective.

BACKGROUND: Increasingly, aged residential care (ARC) facilities are places where the lives of older people with complex care needs end. Hence, end-of-life (EOL) care is a significant component of work for ARC staff. In the absence of New Zealand research, staff perceptions of EOL care were sought at three aged-care facilities in a New Zealand District Health Board region. The research provided valuable data regarding care delivery and can be used to inform the introduction of an integrated care pathway (ICP). EOL care pathways are not commonly used in New Zealand ARC facilities and the influence of ICPs, such as the Liverpool Care Pathway (LCP) for the dying patient has not been investigated. Additionally, most international studies report on the introduction of the LCP without baseline preimplementation data. DESIGN: In the present study, staff (n = 195) involved in caring for residents, their families, and whanau at EOL were surveyed to obtain demographic data and staff perceptions of EOL care via Likert scale and open ended questions. RESULTS: A response rate of 32% was obtained. Respondents indicated a relatively high level of confidence regarding their care of the dying, including aspects of communication, teamwork and use of documentation. However, this was often contradicted by their written responses. Written comments were analyzed thematically and six themes identified: the naturalness of dying; the character of care; care relationships; emotional response; knowledge; and the organizational environment. Data analysis provided a rich and informative description of staff perceptions of EOL and issues influencing care.

Rationalising the treatment of anaemia in cardiac surgery: short and mid-term results from a local quality improvement initiative.

BACKGROUND: Transfusion of red blood cells, while often used for treating blood loss or haemodilution, is also associated with higher infection rates and mortality. The authors implemented an initiative to reduce variation in the number of perioperative transfusions associated with cardiac surgery. METHODS: The authors examined patients undergoing non-emergent cardiac surgery at a single centre from the third quarter 2004 to the second quarter 2007. Phase I focused on understanding the current process of managing and treating perioperative anaemia. Phase II focused on (1) quality-improvement project dissemination to staff, (2) developing and implementing new protocols, and (3) assessing the effect of subsequent interventions. Data reports were updated monthly and posted in the clinical units. Phase III determined whether reductions in transfusion rates persisted. RESULTS: Indications for transfusions were investigated during Phase II. More than half (59%) of intraoperative transfusions were for low haematocrit (Hct), and 31% for predicted low Hct during cardiopulmonary bypass. 43% of postoperative transfusions were for low Hct, with an additional 16% for failure to diurese. The last Hct value prior to transfusion was noted (Hct 25-23, p=0.14), suggestive of a higher tolerance for a lower Hct by staff surgeons. Intraoperative transfusions diminished across phases: 33% in Phase I, 25.8% in Phase II and 23.4% in Phase III (p<0.001). Relative to Phase I, postoperative transfusions diminished significantly over Phase II and III. CONCLUSIONS: We report results from a focused quality-improvement initiative to rationalise treatment of perioperative anaemia. Transfusion rates declined significantly across each phase of the project.

Conditional deletion of Abca3 in alveolar type II cells alters surfactant homeostasis in newborn and adult mice.

ATP-binding cassette A3 (ABCA3) is a lipid transport protein required for synthesis and storage of pulmonary surfactant in type II cells in the alveoli. Abca3 was conditionally deleted in respiratory epithelial cells (Abca3(Δ/Δ)) in vivo. The majority of mice in which Abca3 was deleted in alveolar type II cells died shortly after birth from respiratory distress related to surfactant deficiency. Approximately 30% of the Abca3(Δ/Δ) mice survived after birth. Surviving Abca3(Δ/Δ) mice developed emphysema in the absence of significant pulmonary inflammation. Staining of lung tissue and mRNA isolated from alveolar type II cells demonstrated that ∼50% of alveolar type II cells lacked ABCA3. Phospholipid content and composition were altered in lung tissue, lamellar bodies, and bronchoalveolar lavage fluid from adult Abca3(Δ/Δ) mice. In adult Abca3(Δ/Δ) mice, cells lacking ABCA3 had decreased expression of mRNAs associated with lipid synthesis and transport. FOXA2 and CCAAT enhancer-binding protein-α, transcription factors known to regulate genes regulating lung lipid metabolism, were markedly decreased in cells lacking ABCA3. Deletion of Abca3 disrupted surfactant lipid synthesis in a cell-autonomous manner. Compensatory surfactant synthesis was initiated in ABCA3-sufficient type II cells, indicating that surfactant homeostasis is a highly regulated process that includes sensing and coregulation among alveolar type II cells.

STAT3 regulates ABCA3 expression and influences lamellar body formation in alveolar type II cells.

ATP-Binding Cassette A3 (ABCA3) is a lamellar body associated lipid transport protein required for normal synthesis and storage of pulmonary surfactant in type II cells in the alveoli. In this study, we demonstrate that STAT3, activated by IL-6, regulates ABCA3 expression in vivo and in vitro. ABCA3 mRNA and immunostaining were decreased in adult mouse lungs in which STAT3 was deleted from the respiratory epithelium (Stat3(Delta/Delta) mice). Consistent with the role of STAT3, intratracheal IL-6 induced ABCA3 expression in vivo. Decreased ABCA3 and abnormalities in the formation of lamellar bodies, the intracellular site of surfactant lipid storage, were observed in Stat3(Delta/Delta) mice. Expression of SREBP1a and 1c, SCAP, ABCA3, and AKT mRNAs was inhibited by deletion of Stat3 in type II cells isolated from Stat3(Delta/Delta) mice. The activities of PI3K and AKT were required for normal Abca3 gene expression in vitro. AKT activation induced SREBP expression and increased the activity of the Abca3 promoter in vitro, consistent with the role of STAT3 signaling, at least in part via SREBP, in the regulation of ABCA3. ABCA3 expression is regulated by IL-6 in a pathway that includes STAT3, PI3K, AKT, SCAP, and SREBP. Activation of STAT3 after exposure to IL-6 enhances ABCA3 expression, which, in turn, influences pulmonary surfactant homeostasis.

Functional genomic responses to cystic fibrosis transmembrane conductance regulator (CFTR) and CFTR(delta508) in the lung.

Cystic fibrosis (CF), a common lethal pulmonary disorder in Caucasians, is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) that disturbs fluid homeostasis and host defense in target organs. The effects of CFTR and delta508-CFTR were assessed in transgenic mice that 1) lack CFTR expression (Cftr-/-); 2) express the human delta508 CFTR (CFTR(delta508)); 3) overexpress the normal human CFTR (CFTR(tg)) in respiratory epithelial cells. Genes were selected from Affymetrix Murine Gene-Chips analysis and subjected to functional classification, k-means clustering, promoter cis-elements/modules searching, literature mining, and pathway exploring. Genomic responses to Cftr-/- were not corrected by expression of CFTR(delta508). Genes regulating host defense, inflammation, fluid and electrolyte transport were similarly altered in Cftr-/- and CFTR(delta508) mice. CFTR(delta508) induced a primary disturbance in expression of genes regulating redox and antioxidant systems. Genomic responses to CFTR(tg) were modest and were not associated with lung pathology. CFTR(tg) and CFTR(delta508) induced genes encoding heat shock proteins and other chaperones but did not activate the endoplasmic reticulum-associated degradation pathway. RNAs encoding proteins that directly interact with CFTR were identified in each of the CFTR mouse models, supporting the hypothesis that CFTR functions within a multiprotein complex whose members interact at the level of protein-protein interactions and gene expression. Promoters of genes influenced by CFTR shared common regulatory elements, suggesting that their co-expression may be mediated by shared regulatory mechanisms. Genes and pathways involved in the response to CFTR may be of interest as modifiers of CF.

Role of Sonic hedgehog in patterning of tracheal-bronchial cartilage and the peripheral lung.

Sonic hedgehog (Shh) was conditionally deleted in respiratory epithelial cells of the embryonic lung in vivo. Deletion of Shh before embryonic day (E) 13.5 resulted in respiratory failure at birth. While lobulation was not perturbed, the lungs were hypoplastic, with reduced branching of peripheral lung tubules, evident from E13.5. Smooth muscle and endothelial cells were absent or reduced, the latter in relationship to the loss of peripheral lung parenchyma. Tracheal-bronchial ring abnormalities occurred when Shh was deleted between E8.5 and E12.5. Deletion of Shh later in gestation (after E13.5) caused mild abrogation of peripheral branching morphogenesis but did not disrupt tracheal-bronchial development. Defects in branching morphogenesis and vascularization seen in Shh null mutant (Shh(-/-)) mice were substantially corrected when SHH was ectopically expressed in the respiratory epithelium; however, peripheral expression of SHH failed to correct cartilage abnormalities in the trachea and bronchi, indicating a spatial requirement for SHH expression near sites of cartilage formation. Expression of SHH by the respiratory epithelium plays an important role in the patterning of tracheal-bronchial mesenchyme required for formation of cartilage rings in conducting airways. SHH regulates branching morphogenesis and influences differentiation of the peripheral lung mesenchyme required for formation of bronchial and vascular smooth muscle.

Foxf1 haploinsufficiency reduces Notch-2 signaling during mouse lung development.

The forkhead box (Fox) f1 transcription factor is expressed in the mouse splanchnic (visceral) mesoderm, which contributes to development of the liver, gallbladder, lung, and intestinal tract. Pulmonary hemorrhage and peripheral microvascular defects were found in approximately half of the newborn Foxf1(+/-) mice, which expressed low levels of lung Foxf1 mRNA [low-Foxf1(+/-) mice]. Microvascular development was normal in the surviving newborn high-Foxf1(+/-) mice, which compensated for pulmonary Foxf1 haploinsufficiency and expressed wild-type Foxf1 levels. To identify expression of genes regulated by Foxf1, we used Affymetrix microarrays to determine embryonic lung RNAs influenced by Foxf1 haploinsufficiency. Embryonic Foxf1(+/-) lungs exhibited diminished expression of hepatocyte growth factor receptor c-Met, myosin VI, the transcription factors SP-3, BMI-1, ATF-2, and glucocorticoid receptor, and cell cycle inhibitors p53, p21(Cip1), retinoblastoma, and p107. Furthermore, Notch-2 signaling was decreased in embryonic Foxf1(+/-) lungs, as evidenced by significantly reduced levels of the Notch-2 receptor and the Notch-2 downstream target hairy enhancer of split-1. The severity of the Notch-2-signaling defect in 18-day postcoitus Foxf1(+/-) lungs correlated with Foxf1 mRNA levels. Disruption of pulmonary Notch-2 signaling continued in newborn low-Foxf1(+/-) mice, which died of lung hemorrhage and failed to compensate for Foxf1 haploinsufficiency. In contrast, in newborn high-Foxf1(+/-) lungs, Notch-2 signaling was restored to the level found in wild-type mice, which was associated with normal microvascular formation and survival. Foxf1 haploinsufficiency disrupted pulmonary expression of genes in the Notch-2-signaling pathway and resulted in abnormal development of lung microvasculature.

TTF-1 phosphorylation is required for peripheral lung morphogenesis, perinatal survival, and tissue-specific gene expression.

Thyroid transcription factor-1 (TTF-1) is a 43-kDa, phosphorylated member of the Nkx2 family of homeodomain-containing proteins expressed selectively in lung, thyroid, and the central nervous system. To assess the role of TTF-1 and its phosphorylation during lung morphogenesis, mice bearing a mutant allele, in which seven serine phosphorylation sites were mutated, Titf1PM/PM, were generated by homologous recombination. Although heterozygous Titf1PM/+ mice were unaffected, homozygous Titf1PM/PM mice died immediately following birth. In contrast to Titf1 null mutant mice, which lack peripheral lung tissues, bronchiolar and peripheral acinar components of the lung were present in the Titf1PM/PM mice. Although lobulation and early branching morphogenesis were maintained in the mutant mice, abnormalities in acinar tubules and pulmonary hypoplasia indicated defects in lung morphogenesis later in development. Although TTF-1PM protein was readily detected within the nuclei of pulmonary epithelial cells at sites and abundance consistent with that of endogenous TTF-1, expression of a number of known TTF-1 target genes, including surfactant proteins and secretoglobulin 1A, was variably decreased in the mutant mice. Vascular endothelial growth factor mRNA was decreased in association with decreased formation of peripheral pulmonary blood vessels. Genes mediating surfactant homeostasis, vasculogenesis, host defense, fluid homeostasis, and inflammation were highly represented among those regulated by TTF-1. Thus, in contrast to the null Titf1 mutation, the Titf1PM/PM mutant substantially restored lung morphogenesis. Direct and indirect transcriptional targets of TTF-1 were identified that are likely to play important roles in lung formation and function.