Nevin Manimala

Cancer Discov. 2021 Oct 11:candisc.0538.2021. doi: 10.1158/2159-8290.CD-21-0538. Online ahead of print.

ABSTRACT

Personalized medicine aims to match the right drug with the right patient by utilizing specific features of the individual patients’ tumor. However, current strategies of personalized therapy matching only provide treatment opportunities for less than 10% of cancer patients. A promising method may be drug profiling of patient biopsies with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival (PFS) compared to their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude, that therapy matching by scFPM is clinically feasible, and effective in advanced aggressive hematologic cancers.

PMID:34635570 | DOI:10.1158/2159-8290.CD-21-0538

J Neurol Neurosurg Psychiatry. 2021 Oct 11:jnnp-2021-327236. doi: 10.1136/jnnp-2021-327236. Online ahead of print.

ABSTRACT

OBJECTIVE: The optimal timing to start direct oral anticoagulants (DOACs) after an acute ischaemic stroke (AIS) related to atrial fibrillation (AF) remains unclear. We aimed to compare early (≤5 days of AIS) versus late (>5 days of AIS) DOAC-start.

METHODS: This is an individual patient data pooled analysis of eight prospective European and Japanese cohort studies. We included patients with AIS related to non-valvular AF where a DOAC was started within 30 days. Primary endpoints were 30-day rates of recurrent AIS and ICH.

RESULTS: A total of 2550 patients were included. DOACs were started early in 1362 (53%) patients, late in 1188 (47%). During 212 patient-years, 37 patients had a recurrent AIS (1.5%), 16 (43%) before a DOAC was started; 6 patients (0.2%) had an ICH, all after DOAC-start. In the early DOAC-start group, 23 patients (1.7%) suffered from a recurrent AIS, while 2 patients (0.1%) had an ICH. In the late DOAC-start group, 14 patients (1.2%) suffered from a recurrent AIS; 4 patients (0.3%) suffered from ICH. In the propensity score-adjusted comparison of late versus early DOAC-start groups, there was no statistically significant difference in the hazard of recurrent AIS (aHR=1.2, 95% CI 0.5 to 2.9, p=0.69), ICH (aHR=6.0, 95% CI 0.6 to 56.3, p=0.12) or any stroke.

CONCLUSIONS: Our results do not corroborate concerns that an early DOAC-start might excessively increase the risk of ICH. The sevenfold higher risk of recurrent AIS than ICH suggests that an early DOAC-start might be reasonable, supporting enrolment into randomised trials comparing an early versus late DOAC-start.

PMID:34635567 | DOI:10.1136/jnnp-2021-327236

Neurology. 2021 Oct 11:10.1212/WNL.0000000000012929. doi: 10.1212/WNL.0000000000012929. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Aerobic exercise has become a useful method to assist with post-concussion management. Exercise can exacerbate concussion symptoms even when symptoms are not apparent at rest. Few studies have examined the reasons for symptom exacerbation during exercise following a concussion. We had two primary objectives. 1) To delineate cardiopulmonary and cerebrovascular responses to exercise in adolescents and young adults with a concussion and healthy controls. 2) To determine the association between cerebrovascular responses and symptom burden.

METHODS: We recruited participants with a recent concussion from a sport concussion clinic between 9/1/2018-2/22/2020. They were included if their concussion occurred <3 weeks before initial testing and if they were symptomatic at rest. Participants were excluded if they sustained a concussion in the past year (excluding index injury), reported history of neurological disorders, or were using medications/devices that may alter neurological function. Participants completed a progressive, symptom-limited, sub-maximal exercise protocol on a stationary bike. We assessed heart rate, blood pressure, fraction of end tidal CO2 (FETCO₂) and middle cerebral artery blood flow velocity (CBF) and cerebrovascular function (vasoreactivity and autoregulation) at seated rest and during exercise.

RESULTS: We conducted 107 exercise tests (40 concussed, 37 healthy participants initially; 30 concussed at follow-up). Concussed participants were tested initially (mean=17.6±2.2 [SD] years old; 55% female; mean=12.5±4.7 days post-concussion) and again 8 weeks later (mean=73.3±9.5 days post-concussion). Control participants (mean=18.3±2.4 years; 62% female) were tested once. FETCO₂ increased throughout the exercise protocol as heart rate increased, reached a plateau, and declined at higher exercise intensities. CO₂ explained >25% of the variation in resting CBF (R²>0.25; p<0.01) in most (73% individuals). Within the concussion group, resting symptom severity and the heart rate at which FETCO₂ reached a plateau explained ∼two-thirds of variation in exercise-induced symptom exacerbation (R ² =0.65; FETCO₂ β=-1.210±0.517[S.E.], p<0.05). There was a moderate, statistically significant relationship between cerebrovascular responses to CO₂ at rest (cerebral vasoreactivity) and cerebrovascular responses to exercise-induced changes in FETCO₂ (R²=0.13, p=0.01).

DISCUSSION: The arterial CO₂ response and symptom exacerbation relationship during post-concussion aerobic exercise may be mediated by increased sensitivity of cerebral vasculature to exercise-related increase in CO₂.

PMID:34635563 | DOI:10.1212/WNL.0000000000012929

Neurology. 2021 Oct 11:10.1212/WNL.0000000000012930. doi: 10.1212/WNL.0000000000012930. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: One year since the onset of the COVID-19 pandemic, we aimed to summarize the frequency of neurological manifestations reported in COVID-19 patients and investigate the association of these manifestations with disease severity and mortality.

METHODS: We searched PubMed, Medline, Cochrane library, clinicaltrials.gov and EMBASE from 31^st December 2019 to 15^th December 2020 for studies enrolling consecutive COVID-19 patients presenting with neurological manifestations. Risk of bias was examined using Joanna Briggs Institute (JBI) scale. A random-effects meta-analysis was performed, and pooled prevalence and 95% Confidence Intervals (CI) were calculated for neurological manifestations. Odds ratio (OR) and 95%CI were calculated to determine the association of neurological manifestations with disease severity and mortality. Presence of heterogeneity was assessed using I-square, meta-regression, and subgroup analyses. Statistical analyses were conducted in R version 3.6.2.

RESULTS: Of 2,455 citations, 350 studies were included in this review, providing data on 145,721 COVID-19 patients, 89% of whom were hospitalized. Forty-one neurological manifestations (24 symptoms and 17 diagnoses) were identified. Pooled prevalence of the most common neurological symptoms included: fatigue (32%), myalgia (20%), taste impairment (21%), smell impairment (19%) and headache (13%). A low risk of bias was observed in 85% of studies; studies with higher risk of bias yielded higher prevalence estimates. Stroke was the most common neurological diagnosis (pooled prevalence- 2%). In COVID-19 patients aged ≥60, the pooled prevalence of acute confusion/delirium was 34% and the presence of any neurological manifestations in this age group was associated with mortality (OR 1.80; 95%CI 1.11 to 2.91).

DISCUSSION: Up to one-third of COVID-19 patients analysed in this review experienced at least one neurological manifestation. One in 50 patients experienced stroke. In those over 60, more than one-third had acute confusion/delirium; the presence of neurological manifestations in this group was associated with near doubling of mortality. Results must be interpreted keeping in view the limitations of observational studies and associated bias.

PMID:34635561 | DOI:10.1212/WNL.0000000000012930

Neurology. 2021 Oct 11:10.1212/WNL.0000000000012919. doi: 10.1212/WNL.0000000000012919. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: To evaluate phenotypic and genetic relationships between migraine and lipoprotein subfractions.

METHODS: We evaluated phenotypic associations between migraine and 19 lipoprotein subfractions measures in the Women’s Genome Health Study (WGHS, N=22,788). We then investigated genetic relationships between these traits using summary statistics from the International Headache Genetics Consortium (IHGC) for migraine (N_case=54,552, N_control=297,970) and combined summary data for lipoprotein subfractions (N up to 47,713).

RESULTS: There was a significant phenotypic association (odds ratio=1.27 [95% confidence interval:1.12-1.44]) and a significant genetic correlation at 0.18 (P=0.001) between migraine and triglyceride-rich lipoproteins (TRLP) concentration but not for LDL or HDL subfractions. Mendelian randomization (MR) estimates were largely null implying that pleiotropy rather than causality underlies the genetic correlation between migraine and lipoprotein subfractions. Pleiotropy was further supported in cross-trait meta-analysis revealing significant shared signals at four loci (chr2p21 harboring THADA, chr5q13.3 harboring HMGCR, chr6q22.31 harboring HEY2, and chr7q11.23 harboring MLXIPL) between migraine and lipoprotein subfractions. Three of these loci were replicated for migraine (P<0.05) in a smaller sample from the UK Biobank. The shared signal at chr5q13.3 colocalized with expression of HMGCR, ANKDD1B, and COL4A3BP in multiple tissues.

CONCLUSIONS: The current study supports the association between certain lipoprotein subfractions, especially for TRLP, and migraine in populations of European ancestry. The corresponding shared genetic components may be help identify potential targets for future migraine therapeutics.

CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that migraine is significantly associated with some lipoprotein subfractions.

PMID:34635557 | DOI:10.1212/WNL.0000000000012919

BMJ Open. 2021 Oct 11;11(10):e055575. doi: 10.1136/bmjopen-2021-055575.

ABSTRACT

OBJECTIVES: To compare the incidence and severity of invasive pneumococcal diseases (IPDs), pneumococcal pneumonia and all-cause pneumonia during the COVID-19 pandemic period with universal masking and social distancing with that of previous 5 years.

DESIGN: Retrospective observational study on incidence of IPDs, pneumococcal pneumonia and all-cause pneumonia between January 2015-December 2019 and March 2020-March 2021. January-February 2020 was excluded from analysis as it was treated as a transitional period between normal time and pandemic.

SETTING: Episode-based data by retrieval of hospitalisation records from the Hospital Authority’s territory-wide electronic medical record database in Hong Kong.

PARTICIPANTS: Hospitalised patients with IPD (n=742), pneumococcal pneumonia (n=2163) and all-cause pneumonia (including COVID-19 pneumonia, n=453 999) aged 18 years or above. Control diagnoses were included to assess confounding from health-seeking behaviours.

PRIMARY AND SECONDARY OUTCOMES: Primary outcome is the incidence of diseases between two periods. Secondary outcomes include disease severity surrogated by length of stay and mortality.

RESULTS: Monthly average number of IPD, pneumococcal pneumonia and all-cause pneumonia hospitalisation significantly decreased by 88.9% (95% CI 79.8% to 98.0%, p<0.0005), 72.5% (95% CI 65.9% to 79.1%, p<0.0005) and 17.5% (95% CI 16.8% to 18.2%, p<0.0005), respectively. Changes in trend from January 2015-December 2019 to March 2020-March 2021 were -70% (95% CI -87% to -35%, p=0.0025), -43% (95% CI -59% to -19%, p=0.0014) and -11% (95% CI -13% to -10%, p<0.0005), respectively. Length of stay for IPD and pneumococcal pneumonia episodes were insignificantly different in the two periods. No reductions in hospitalisations for control diagnoses were observed.

CONCLUSIONS: Incidence of IPD, pneumococcal pneumonia and all-cause pneumonia decreased during the COVID-19 pandemic. This was observed with universal masking and social distancing. We postulated this is related to reduced transmission of respiratory viruses and bacteria.

PMID:34635536 | DOI:10.1136/bmjopen-2021-055575

BMJ Open. 2021 Oct 11;11(10):e053179. doi: 10.1136/bmjopen-2021-053179.

ABSTRACT

OBJECTIVES: Previous studies have investigated the association between socioeconomic characteristics and fractures among children, producing different results. In a population-based study, we previously found an increased risk of fractures among children living in an urban municipality compared with rural municipalities. This study aimed to evaluate the importance of socioeconomic variables for the incidence of fractures among 0-17 year olds.

SETTING, DESIGN AND OUTCOME MEASURE: We present a longitudinal, observational study of a population 0-17 years of age. Data from an injury database were linked with additional socioeconomic data for the population at risk. These were 55 758 individuals residing within the primary catchment area of a regional hospital in northern Sweden. Using the number of fractures as the outcome, we fitted a generalised linear mixed model for a Poisson response with socioeconomic variables at the family level as independent variables while controlling for age, sex and place of residence.

RESULTS: We found a significant association between higher levels of family income and the risk of fracture, rate ratio 1.40 (1.28-1.52) p<0.001 when comparing the highest income quintile to the lowest as well as the number of siblings and the risk of fracture. Children with one or two siblings had a rate ratio of 1.28 (1.19-1.38) p<0.001 when compared with children with no siblings. Parents’ educational level and having a single parent showed no significant association with fractures. The previously observed association between municipalities and fracture risk was less pronounced when taking family-level socioeconomic variables into account.

CONCLUSION: Our results indicate that children from families with higher income and with siblings are at greater risk of sustaining fractures.

PMID:34635530 | DOI:10.1136/bmjopen-2021-053179

BMJ Open. 2021 Oct 11;11(10):e050827. doi: 10.1136/bmjopen-2021-050827.

ABSTRACT

OBJECTIVES: To analyse the empirical support of the functional ability concept in the healthy ageing framework developed by the WHO in a sample of the Philippine older population. According to this framework, environmental factors may enhance or hinder functional ability, which is the person’s ability to do what they value, broadly represented by subjective well-being. Moreover, this network of relationships may be moderated by personal characteristics such as gender.

DESIGN: Cross-sectional observational study.

SETTING: Philippines, general population.

PARTICIPANTS: Respondents of the 2016 National Disability Prevalence Survey/Model Functioning Survey aged 50+ (N=2825).

PRIMARY AND SECONDARY OUTCOME MEASURES: Latent (unobserved) measures of functional ability, environmental factors (physical environmental factors and social network and support) and subjective well-being (positive affect, negative affect and evaluative well-being) were obtained from different items from the survey questionnaire using a SEM framework.

RESULTS: We found that the relationship between environmental factors and the three components of subjective well-being considered in this study was partially explained by differences in functional ability. The portion of those effects accounted for by functional ability was comparatively larger for the physical than for the social environmental factors. We found no evidences of gender differences in this network of relationships.

CONCLUSIONS: These findings suggest the relevance of functional ability at explaining the relationship between environmental factors and subjective well-being in older adults. Future studies may replicate these findings longitudinally and including other relevant measures as the person’s objective level of intrinsic capacity.

PMID:34635522 | DOI:10.1136/bmjopen-2021-050827

BMJ Open. 2021 Oct 11;11(10):e047711. doi: 10.1136/bmjopen-2020-047711.

ABSTRACT

OBJECTIVES: To explore lay perceptions of bleeding during and after delivery, and measure the frequency of self-reported indicators of bleeding.

SETTING: Yola, North-East Nigeria.

PARTICIPANTS: Women aged 15-49 years who delivered in the preceding 2 years of data collection period (2015-2016), and their family members who played key roles.

METHODS: Data on perceptions of bleeding were collected through 7 focus group discussions, 21 in-depth interviews and 10 family interviews. Sampling was purposive and data were analysed thematically. A household survey was then conducted with 640 women using cluster sampling on postpartum bleeding indicators developed from the qualitative data; data were analysed descriptively.

RESULTS: Perceptions of excessive bleeding fell under four themes: quantity of blood lost; rate/duration of blood flow; symptoms related to blood loss and receiving birth interventions/hearing comments from birth attendants. Young and less educated rural women had difficulty quantifying blood loss objectively, including when shown quantities using bottles. Respondents felt that acceptable blood loss levels depended on the individual woman and whether the blood is ‘good’ or ‘diseased/bad.’ Respondents believed that ‘diseased’ blood was a normal result of delivery and universally took steps to help it ‘come out.’ In the quantitative survey, indicators representing less blood loss were reported more frequently than those representing greater loss, for example, more women reported staining their clothes (33.6%) than the bed (18.1%) and the floor (6.2%). Overall, indicators related to quantity and rate of blood flow had higher frequencies compared with symptom and intervention-related/comment-related indicators.

CONCLUSION: Women quantify bleeding during and after delivery in varied ways and some women do not see bleeding as problematic. This suggests the need for standard messaging to address subjectivity. The range of indicators and varied frequencies highlight the challenges of measuring excessive bleeding from self-reports. More work is needed in improving and testing validity of questions.

PMID:34635515 | DOI:10.1136/bmjopen-2020-047711

BMJ Open. 2021 Oct 11;11(10):e045086. doi: 10.1136/bmjopen-2020-045086.

ABSTRACT

OBJECTIVES: The influence of age on intensive care unit (ICU) decision-making is complex, and it is unclear if it is based on expected subjective or objective patient outcomes. To address recent concerns over age-based ICU decision-making, we explored patient-assessed quality of life (QoL) in ICU survivors before the COVID-19 pandemic.

DESIGN: A systematic review and meta-analysis of cohort studies published between January 2000 and April 2020, of elderly patients admitted to ICUs.

PRIMARY AND SECONDARY OUTCOME MEASURES: We extracted data on self-reported QoL (EQ-5D composite score), demographic and clinical variables. Using a random-effect meta-analysis, we then compared QoL scores at follow-up to scores either before admission, age-matched population controls or younger ICU survivors. We conducted sensitivity analyses to study heterogeneity and bias and a qualitative synthesis of subscores.

RESULTS: We identified 2536 studies and included 22 for qualitative synthesis and 18 for meta-analysis (n=2326 elderly survivors). Elderly survivors’ QoL was significantly worse than younger ICU survivors, with a small-to-medium effect size (d=0.35 (-0.53 and -0.16)). Elderly survivors’ QoL was also significantly greater when measured slightly before ICU, compared with follow-up, with a small effect size (d=0.26 (-0.44 and -0.08)). Finally, their QoL was also marginally significantly worse than age-matched community controls, also with a small effect size (d=0.21 (-0.43 and 0.00)). Mortality rates and length of follow-up partly explained heterogeneity. Reductions in QoL seemed primarily due to physical health, rather than mental health items.

CONCLUSIONS: The results suggest that the proportionality of age as a determinant of ICU resource allocation should be kept under close review and that subjective QoL outcomes should inform person-centred decision -aking in elderly ICU patients.

PROSPERO REGISTRATION NUMBER: CRD42020181181.

PMID:34635510 | DOI:10.1136/bmjopen-2020-045086