Prognostic Factors of Mortality in Nonchronic Obstructive Pulmonary Disease Chronic Lung Disease: A Scoping Review.

Introduction: Patients with chronic lung disease (CLD) experience a heavy symptom burden at the end of life, but their uptake of palliative care is notably low. Having an understanding of a patient's prognosis would facilitate shared decision making on treatment options and care planning between patients, families, and their clinicians, and complement clinicians' assessments of patients' unmet palliative needs. While literature on prognostication in patients with chronic obstructive pulmonary disease (COPD) has been established and summarized, information for other CLDs remains less consolidated. Summarizing the mortality risk factors for non-COPD CLDs would be a novel contribution to literature. Hence, we aimed to identify and summarize the prognostic factors associated with non-COPD CLDs from the literature. Methods: We conducted a scoping review following published guidelines. We searched MEDLINE, Embase, PubMed, CINAHL, Cochrane Library, and Web of Science for studies published between 2000 and 2020 that described non-COPD CLD populations with an all-cause mortality risk period of up to three years. Only primary studies which reported associations with mortality adjusted through multivariable analysis were included. Results: Fifty-five studies were reviewed, with 53 based on interstitial lung disease (ILD) or connective tissue disease-associated ILD populations and two in bronchiectasis populations. Prognostic factors were classified into 10 domains, with pulmonary function and disease being the largest. Older age, lower forced vital capacity, and lower carbon monoxide diffusing capacity were most commonly investigated and associated with statistically significant increases in mortality risks. Conclusions: This comprehensive overview of prognostic factors for patients with non-COPD CLDs would facilitate the identification and prioritization of candidate factors to predict short-term mortality, supporting tool development for decision making and to identify high-risk patients for palliative needs assessments. Literature focused on patients with ILDs, and more studies should be conducted on other CLDs to bridge the knowledge gap.

Protocol for a randomised controlled trial on impact of comprehensive geriatric and supportive assessment versus standard care in older adults with cancer undergoing curative treatment: The Geriatric Oncology SuPportive clinic for ELderly (GOSPEL) study.

Cancer affects older adults with varying levels of frailty, but cancer treatment is extrapolated from clinical trials involving predominantly young and robust subjects. Recent geriatric oncology randomised controlled trials (RCT) report that geriatric assessment leading to frailty-guided intervention reduces treatment-related toxicity whilst maintaining survival and improving quality of life (QoL). However, these positive results have not have been consistently reported in the literature. We postulate that the impact of geriatric interventions has been underestimated in these studies with the inclusion of subjects receiving palliative-intent chemotherapy in whom dose reduction is common. Integrating supportive care with current geriatric oncology models may improve the QoL of older adults undergoing treatment. However, no studies as yet have examined such integrated geriatric and supportive models of care. The Geriatric Oncology SuPportive clinic for Elderly (GOSPEL) study is a single-centre, open-label, analyst-blinded RCT evaluating the impact of comprehensive geriatric and supportive care on QoL of older adults with cancer undergoing curative treatment. Older adults aged above 65, with a Geriatric-8 score ≤ 14, with plans for high dose radiotherapy and/or curative chemotherapy will be recruited. The primary QoL outcome is measured using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-ELD14 mobility scale at 12 weeks. Secondary outcomes include overall and disease-free survival, treatment-related adverse events, and hospital admissions. We pre-powered this study to recruit 200 subjects based on the minimally clinically important difference for EORTC QLQ-ELD14 to achieve 80% statistical power (alpha 0.05), assuming 25% attrition. Outcomes will be analysed using intention-to-treat. Intervention consists of multi-domain comprehensive geriatric and supportive care assessments from a multidisciplinary team targeting unmet needs. These include functional decline, falls, incontinence, cognitive impairment, multi-morbidity, polypharmacy, and symptom relief, as well as social and psycho-spiritual concerns. Standard care entails routine oncological management with referral to geriatrics based on the discretion of the primary oncologist. Recruitment has been ongoing since August 2020. Results from the GOSPEL study will increase understanding of the impact of integrated geriatric and supportive care programs in older adults with cancer receiving curative treatment. Trial registration: This study is registered under ClinicalTrials.gov (ID NCT04513977).

Use of Phenobarbitone for Palliative Sedation in Dyspneic Crises Due to COVID-19 Pneumonia - A Case Series.

Patients who suffer from dyspnea while dying from COVID-19 are treated with opioids and benzodiazepines. In some instances, patients may experience refractory dyspnea at the end of life. Palliative sedation can be prescribed to alleviate such patients' suffering. We describe two patients being treated for severe COVID-19 pneumonia in a tertiary hospital. Both developed intractable dyspneic crises despite high-dose opioids and benzodiazepines. This led to their requirement of palliative sedation in the general ward using subcutaneous phenobarbitone (phenobarbital). We outline clinical considerations for the use of palliative sedation in COVID-19 related dyspnea. In particular, we discuss the evidence for, benefits and limitations of using phenobarbitone for palliative sedation in COVID-19 patients.

Impact of Palliative Care in End-of-Life of Fibrotic Interstitial Lung Disease Patients.

Background: Interstitial lung disease (ILD) is associated with poor quality of life (QoL) and high symptom burden. Studies evaluating the benefits of palliative care examined mainly idiopathic pulmonary fibrosis (IPF) patients. We aim to examine the impact of palliative care on a broader group of fibrotic ILD patients. Methods: Single center retrospective cohort study comparing deceased ILD patients who received outpatient palliative care services (palliative-intervention group) against a usual care group. Results: Of 63 subjects, 26 (41%) were in the palliative-intervention group and 37 (59%) in the usual care group. Median time to palliative care referral was 8.6 (IQR .3-21.2) months. Dyspnea-related disability was greater in the palliative-intervention group [mMRC dyspnea score 3.5(IQR 2-4) vs 2(IQR 2-4), P = .039], with more patients requiring long term oxygen therapy (70% vs 30%, P < .001). There was no difference in the median number of hospitalizations or length of stay in the last 6 months of life. Patients in the palliative-intervention group had a higher uptake of advance care planning (ACP) (39% vs 11%, P = .014), lower frequency of intensive care unit (ICU) admissions (5% vs 19%, P = .102) and were prescribed more opioids (96% vs 27%, P < .001) and benzodiazepines (39% vs 14%, P = .022). The palliative-intervention group experienced a longer median survival of 23.9 months (95% confidence interval [CI] 14.1-33.7) compared to the usual group (11.4 months [95% CI 5.4-17.3] (log-rank test: P = .023). Male gender was a strong predictor of 1-year mortality. Conclusions: The palliative-intervention group received earlier pharmacologic intervention for symptom relief. Healthcare utilization was not increased despite greater dyspnea-related disability.

Decrease of Pdzrn3 is required for heart maturation and protects against heart failure.

Heart failure is the final common stage of most cardiopathies. Cardiomyocytes (CM) connect with others via their extremities by intercalated disk protein complexes. This planar and directional organization of myocytes is crucial for mechanical coupling and anisotropic conduction of the electric signal in the heart. One of the hallmarks of heart failure is alterations in the contact sites between CM. Yet no factor on its own is known to coordinate CM polarized organization. We have previously shown that PDZRN3, an ubiquitine ligase E3 expressed in various tissues including the heart, mediates a branch of the Planar cell polarity (PCP) signaling involved in tissue patterning, instructing cell polarity and cell polar organization within a tissue. PDZRN3 is expressed in the embryonic mouse heart then its expression dropped significantly postnatally corresponding with heart maturation and CM polarized elongation. A moderate CM overexpression of Pdzrn3 (Pdzrn3 OE) during the first week of life, induced a severe eccentric hypertrophic phenotype with heart failure. In models of pressure-overload stress heart failure, CM-specific Pdzrn3 knockout showed complete protection against degradation of heart function. We reported that Pdzrn3 signaling induced PKC ζ expression, c-Jun nuclear translocation and a reduced nuclear ß catenin level, consistent markers of the planar non-canonical Wnt signaling in CM. We then show that subcellular localization (intercalated disk) of junction proteins as Cx43, ZO1 and Desmoglein 2 was altered in Pdzrn3 OE mice, which provides a molecular explanation for impaired CM polarization in these mice. Our results reveal a novel signaling pathway that controls a genetic program essential for heart maturation and maintenance of overall geometry, as well as the contractile function of CM, and implicates PDZRN3 as a potential therapeutic target for the prevention of human heart failure.

Health-related quality of life in a multiracial Asian interstitial lung disease cohort.

Background: Understanding health-related quality of life (HRQL) in patients with interstitial lung disease (ILD) provides insight into disease burden and treatment effects on patients' well-being. We examined HRQL in a multiracial Asian ILD cohort using the King's brief ILD (K-BILD) and EuroQol 5-dimension-3-level (EQ5D-3L) questionnaires and their associations with several clinical variables. Methods: This was a single-centre cross-sectional study of ILD patients in a university-affiliated tertiary public hospital in Singapore. All patients completed two self-administered HRQL questionnaires upon study entry, and their clinical information was retrieved from electronic medical records. Results: Ninety-nine patients (56% male, 75% Chinese) were included. The median (interquartile range) age was 63 (54-72) years. The most common ILD diagnosis was connective tissue disease-related ILD (n=51, 52%), followed by idiopathic pulmonary fibrosis (n=27, 27%). The mean (standard deviation) scores for the EQ5D-3L utility value, EQ5D Visual Analogue Scale (VAS) and K-BILD total were 0.806 (0.284), 75.1 (12.8) and 63.9 (14.3), respectively. A moderate correlation was found between the EQ5D-3L and K-BILD total and domain scores. The HRQL scores also correlate moderately with the modified Medical Research Council dyspnoea scale (mMRC) scores. There was a weak-to-moderate correlation between HRQL and forced vital capacity (FVC), carbon monoxide diffusing capacity (DLCO) and Charlson comorbidity index. Multiple linear regression showed a significant association of K-BILD total [beta coefficient 0.244, 95% confidence interval (CI): 0.075-0.414; P=0.005], K-BILD 'breathlessness and activities' (beta coefficient 0.448, 95% CI: 0.192-0.703; P=0.001), and the 'psychological' domain (beta coefficient 0.256, 95% CI: 0.024-0.488; P=0.031) with DLCO %pred after adjustment for age, sex, BMI, race, smoking history, comorbidities, FVC %pred and ILD diagnosis. Non-Chinese race was a predictor of better K-BILD 'psychological' domain (beta coefficient 8.680, 95% CI: 0.656-16.704; P=0.034) after adjustment. Conclusions: HRQL is significantly impaired in ILD patients, and low DLCO is a strong predictor of this impairment.

Palliative Rehabilitation Improves Health Care Utilization and Function in Frail Older Adults with Chronic Lung Diseases.

OBJECTIVES: The Integrated Care for Advanced REspiratory Disorders (ICARE) service is a stay-in, post-acute care program for hospitalized patients with chronic, nonmalignant lung diseases. It provides palliative rehabilitation-a novel model integrating functional rehabilitation with early palliative care. We compare reduction of health care utilization among ICARE participants vs matched controls receiving usual care. DESIGN: This is a prospective, propensity score-matched study. Primary outcomes were reduction in hospital readmissions and length of stay and emergency department (ED) visits, comparing the period 6 months before and after ICARE, or 6 months before and after hospital discharge (for controls). Secondary outcomes included 6-minute walking distance (6MWD) and Modified Barthel Index (MBI). SETTING: Participants were matched 1:1 to controls by age, respiratory diagnosis, socioeconomic strata, index hospitalization length of stay, frailty, and recent admissions into intensive care unit or noninvasive ventilation units. METHODS: Multidisciplinary interventions focused on symptom relief, functional rehabilitation, targeted comorbidity management, and postdischarge care coordination. RESULTS: One hundred pairs of patients were matched. Participants were older adults (mean age 73.9 ± 8.2 years) with prolonged index hospitalization (median 12.0 days; interquartile range 7-18). Overall, 57% had high Hospital Frailty Risk Scores and 71% had overlapping respiratory diagnoses, the most common commonest being COPD (89%), followed by interstitial lung disease (54%) and bronchiectasis (28%). Small reductions in health care utilization were observed among controls. ICARE was associated with a further 9.1 ± 19.9 days' reduction in hospitalization length of stay (P < .001), 0.8 ± 1.9 lesser admission (P < .001), and 0.6 ± 2.2 fewer ED visits (P < .02). Participants with longest index hospitalization were observed to have greatest reduction in length of stay. 6MWD and MBI scores improved by 41.0 ± 60.2 m and 12.3 ± 11.6 points, respectively (both P < .001). Greater improvement was observed in patients with lower baseline 6MWD and MBI scores. Prescription of slow-release opioids rose from 9% to 49%. Treatment for anxiety and depression rose from 5% to 19%. CONCLUSIONS AND IMPLICATIONS: Integrating palliative care with postexacerbation functional rehabilitation was associated with short-term reduction in health care utilization, improved functional capacity, and increased treatment of dyspnea, anxiety, and depression.

COVID 19: prioritise autonomy, beneficence and conversations before score-based triage.

At the start of the COVID-19 pandemic, mounting demand overwhelmed critical care surge capacities, triggering implementation of triage protocols to determine ventilator allocation. Relying on triage scores to ration care, while relieving clinicians from making morally distressing decisions under high situational pressure, distracts clinicians from what is essentially deeply humanistic issues entrenched in this protracted public health crisis. Such an approach will become increasingly untenable as countries flatten their epidemic curves. Decisions regarding intensive care unit admission are particularly challenging in older people, who are most likely to require critical care, but for whom benefits are most uncertain. Before applying score-based triage, physicians must first discern if older people will benefit from critical care (beneficence) and second, if he wants critical care (autonomy). When deliberating beneficence, physicians should steer away from solely using age-stratified survival probabilities from epidemiological data. Instead, decisions must be based on individualised risk-stratification that encompasses evidence-based predictors of adverse outcomes specific to older adults. Survival will also need to be weighed against burden of treatment, as well as longer term functional deficits and quality-of-life. By identifying the robust older people who may benefit from critical care, clinicians should proceed to elicit his values and preferences that would determine the treatment most aligned with his best interest. During these dialogues, physicians must truthfully convey the emergent clinical reality, discern the older person's therapeutic goals and discuss the feasibility of achieving them. Given that COVID-19 is here to stay, these conversations aimed at achieving goal-cordant care must become a new clinical norm.

The role of palliative medicine in ICU bed allocation in COVID-19: a joint position statement of the Singapore Hospice Council and the Chapter of Palliative Medicine Physicians.

Facing the possibility of a surge of COVID-19-infected patients requiring ventilatory support in Intensive Care Units (ICU), the Singapore Hospice Council and the Chapter of Palliative Medicine Physicians forward its position on the guiding principles that ought to drive the allocation of ICU beds and its role in care of these patients and their families.

"High-Risk" Clinical and Inflammatory Clusters in COPD of Chinese Descent.

BACKGROUND: COPD is a heterogeneous disease demonstrating inter-individual variation. A high COPD prevalence in Chinese populations is described, but little is known about disease clusters and prognostic outcomes in the Chinese population across Southeast Asia. We aim to determine if clusters of Chinese patients with COPD exist and their association with systemic inflammation and clinical outcomes. RESEARCH QUESTION: We aim to determine if clusters of Chinese patients with COPD exist and their association with clinical outcomes and inflammation. STUDY DESIGN AND METHODS: Chinese patients with stable COPD were prospectively recruited into two cohorts (derivation and validation) from six hospitals across three Southeast Asian countries (Singapore, Malaysia, and Hong Kong; n = 1,480). Each patient was followed more than 2 years. Clinical data (including co-morbidities) were employed in unsupervised hierarchical clustering (followed by validation) to determine the existence of patient clusters and their prognostic outcome. Accompanying systemic cytokine assessments were performed in a subset (n = 336) of patients with COPD to determine if inflammatory patterns and associated networks characterized the derived clusters. RESULTS: Five patient clusters were identified including: (1) ex-TB, (2) diabetic, (3) low comorbidity: low-risk, (4) low comorbidity: high-risk, and (5) cardiovascular. The cardiovascular and ex-TB clusters demonstrate highest mortality (independent of Global Initiative for Chronic Obstructive Lung Disease assessment) and illustrate diverse cytokine patterns with complex inflammatory networks. INTERPRETATION: We describe clusters of Chinese patients with COPD, two of which represent high-risk clusters. The cardiovascular and ex-TB patient clusters exhibit high mortality, significant inflammation, and complex cytokine networks. Clinical and inflammatory risk stratification of Chinese patients with COPD should be considered for targeted intervention to improve disease outcomes.

Higher rates of carbapenem-related seizures in older hospitalised adults.

Clinical experience suggests higher occurrence of carbapenem-associated seizures in the elderly than what is reported in the available literature (range between 0.2% and 0.7%). An audit of 1345 patients with age 60 years or older, who received imipenem, ertapenem or meropenem during their acute hospitalisation found 32 (2.4%) subjects developed seizures. Subjects with more than one central nervous system disorders were 11.6 times more likely to develop seizures (odds ratio 11.61, P < 0.001) and subjects with prior history of seizures is associated with four times greater risks (odds ratio 4.02, P = 0.005). Physicians should exercise caution when prescribing carbapenems in elderly, especially those with known epilepsy and a high number of intracranial pathologies.

From Bolam-Bolitho to Modified-Montgomery - A Paradigm Shift in the Legal Standard of Determining Medical Negligence in Singapore.

In a recent landmark litigation, the Singapore Court of Appeal introduced a new legal standard for determining medical negligence with regards to information disclosure - the Modified-Montgomery test. This new test fundamentally shifts the legal position concerning the standard of care expected of a doctor when he dispenses medical advice. Previously, a doctor is expected to disclose what a "reasonable physician" would tell his patient. Now, a doctor must disclose "all material risks" that a "reasonable patient" would want to know under his unique circumstances. Patient-centred communication is no longer an aspirational ideal but has become a legal mandate. Manpower, administrative, logistic and medical educational reforms should start now, so as to support the average physician transit from the era of the Bolam-Bolitho, to that of the Modified-Montgomery.

Prediction of Poor Short-Term Prognosis and Unmet Needs in Advanced Chronic Obstructive Pulmonary Disease: Use of the Two-Minute Walking Distance Extracted from a Six-Minute Walk Test.

OBJECTIVES: Prognostic challenges hinder the identification of patients with advanced chronic obstructive pulmonary disease (COPD) for timely palliative interventions. We postulate that a two-minute derivative (two-minute walking distance [2MWD]) of a standard six-minute walk test (6MWT) can identify frail subjects with poorer survival for early palliative intervention. The primary outcome of interest is mortality at 18 months. Secondary objectives include evaluation of the relationship between the 2MWD and ability to self-care, dyspnea-related disabilities, nutrition, forced expiratory volume in first second (FEV1), quality of life (QoL), and comorbidity burden. DESIGN AND SETTING: One hundred twenty-four subjects with stage 3 and 4 COPD were recruited and followed up. Ability to self-care, dyspnea-related disabilities, airflow limitation, nutrition, and QoL were measured by using modified Barthel index (MBI), Modified Medical Research Council (MMRC) dyspnea scale, FEV1 (% predicted), BODE [BMI(B), FEV1(O), MMRC(D), 6MWT(E)] index, updated ADO [Age(A), MMRC(D), FEV1(O)] index, Subjective Global Assessment (SGA), and St. George's Respiratory Questionnaire (SGRQ), respectively. Survival data were prospectively collected and analyzed. RESULTS: The 2MWD correlates highly with BODE and predicts updated ADO independent of age, co-morbidities, long-term oxygen therapy (LTOT), body mass index, and FEV1. Log-rank test performed with Kaplan-Meier plots demonstrates that 2MWD ≤80 m significantly predicts survival time (p < 0.05). Cox proportional hazard regression shows a 3.6-time greater probability of 18-month mortality (hazard ratio [HR] 3.57; 95% confidence interval [CI] 1.26-10.13; p < 0.05). In addition, 2MWD strongly predicted MBI and MMRC, independent of age, co-morbidities, LTOT, body mass index, and FEV1. Subjects with 2MWD ≤80 m have a poorer ability to self-care (median MBI 90 vs. 100), lower FEV1 (32.9% ± 9.8% vs. 38.1% ± 9.4%), poorer QoL (mean SGRQ 46.6 ± 16.2 vs. 36.6 ± 13.3), and greater dyspnea-related disability (mean MMRC 1.7 ± 0.7 vs. 0.9 ± 0.6), and they are more malnourished (40.4% vs. 9.7%; RR 1.51) (all p < 0.001). CONCLUSION: 2MWD ≤80 m identifies subjects with higher mortality, greater functional dependence, poorer in nutrition, greater dyspnea, and lower QoL. Incorporation of 2MWD into composite prognostic indices can enhance predictive accuracy and identify patients requiring early proactive palliative interventions.

From Bolam-Bolitho to Modified-Montgomery - A Paradigm Shift in the Legal Standard of Determining Medical Negligence in Singapore

In a recent landmark litigation, the Singapore Court of Appeal introduced a new legal standard for determining medical negligence with regards to information disclosure - the Modified-Montgomery test. This new test fundamentally shifts the legal position concerning the standard of care expected of a doctor when he dispenses medical advice. Previously, a doctor is expected to disclose what a "reasonable physician" would tell his patient. Now, a doctor must disclose "all material risks" that a "reasonable patient" would want to know under his unique circumstances. Patient-centred communication is no longer an aspirational ideal but has become a legal mandate. Manpower, administrative, logistic and medical educational reforms should start now, so as to support the average physician transit from the era of the Bolam-Bolitho, to that of the Modified-Montgomery.

Nanoparticle-based delivery system for application of siRNA in vivo.

Small interfering RNAs (siRNAs) silence the expression of specific target genes by mediating RNA interference (RNAi) in mammalian cells. siRNAs have not only been widely used as a valuable tool for functional genomics research, but they also have demonstrated great potential in biomedical therapeutic applications for diseases caused by abnormal gene overexpression or mutation. One of the most important issues to overcome before full clinical application is the development of effective administration methods for siRNAs to the target tissue or cells in vivo, which is highly dependent on the delivery system. Currently, there are two major kinds of in vivo delivery systems: viral or nonviral. As one of the nonviral carrier systems, nanoparticles, combinations of liposomes and cationic polymer complexes, have exhibited improved in vivo stability, target specificity, and cell/tissue uptake and internalization of the encapsulated RNAi oligos, which result in more effective silencing with less cellular toxicity and immune stimulation. This review will discuss the latest advancements in nanoparticle-mediated RNAi delivery systems, including nano-materials, preparation, and characteristics. In conjunction, the clinical trial cases related to the nanoparticle-siRNA complexes will be highlighted. The safety issues of nanoparticles used in vivo will also be mentioned. Finally, this review will summarize the perspectives for future applications of nanoparticle-mediated RNAi delivery systems.