bluuebunny/crossref_metadata_2025 huggingface dataset:
P088 Presence versus absence of flow limitation during stable breathing in patients with obstructive sleep apnoea
Authors: Mann D , Georgeson T , Landry S , Azarbarzin A , Vena D , Wellman A , Sands S , Terrill P
Published: October 2021

Introduction

Flow limitation is the distinguishing characteristic of obstructive sleep apnoea. Critically, periods of flow limitation can occur without overt reductions in airflow (e.g. disproportionate increase in ventilatory drive vs. achieved ventilation), however, such periods are ignored by clinical scoring. Here we investigate flow limitation during so-called “stable breathing”, i.e. periods of sleep without scored events, by applying our recently-validated model to estimate flow limitation from the airflow signal.

Methods

Flow limitation was visually-scored (N=117,871 breaths) from N=40 participants attending an overnight sleep study for suspected sleep apnoea. Scoring was aided by physiological signals (e.g. intra-oesophageal diaphragm EMG). Model flow limitation classification used features extracted from the pneumotach signal (cross-validated accuracy=92.4%). We applied this method to investigate the occurrence of flow limitation during stable breathing, defined as periods of sleep >3 min duration without scored arousals or respiratory events.

Results

Model predicted flow limitation frequency was strongly correlated with visual scoring (R²=0.84 p<0.001). The median flow limitation frequency during stable breathing ranged from 8–91%, with an overall median of 59% (IQR 37%-75%). Flow limitation frequency during stable breathing was only modestly associated with the apnoea-hypopnea index (R²=0.12 p<0.05).

Discussion

Flow limitation occurs surprisingly frequently during stable breathing. While some individuals achieve stable breathing with minimal flow limitation, others demonstrate substantial flow limitation. Heterogeneity in frequency of flow limitation (within and between individuals) may provide further insights into emergent phenotypic variability within sleep disordered breathing. Finally, this model performed similarly in nasal pressure (88.2% accuracy), indicating potential application to clinical studies.
P097 Incidence of abnormal dreams and nightmares with lemborexant in adults with insomnia: results from two Phase 3 studies
Authors: Roth T , Yardley J , Pinner K , Kumar D , Cheng J , Moline M
Published: October 2021

Introduction

Abnormal dreams and nightmares have been reported by insomnia patients before and after treatment with sedative-hypnotics. Since dual-orexin-receptor-antagonists such as lemborexant (LEM; approved in multiple countries for adult insomnia) increase REM sleep, during which dream content is more likely to be recalled, we assessed the frequency of nightmares/abnormal dreams in Phase 3 studies.

Methods

Study 303 (SUNRISE-2) was a 12mo, randomized, double-blind, placebo (PBO)-controlled (first 6mo [Period 1]), phase 3 study that enrolled subjects ≥18y with insomnia disorder and ISI scores ≥15. During Period 1, the safety analysis set (SAS) included: PBO, n=319; LEM 5mg, (LEM5), n=314; LEM 10mg (LEM10), n=314. Study 304 (SUNRISE-1) was a 1mo, randomized, double-blind, PBO- and active-controlled (zolpidem tartrate extended-release 6.25mg [ZOL-ER]) study of LEM5 and LEM10. The SAS included: PBO, n=209; ZOL-ER, n=263; LEM5, n=266; LEM10, n=268.

Results

In Study 303, Period 1, 28/947 subjects (3.0%) reported nightmares (n=12; PBO-1; LEM5-4; LEM10-7) or abnormal dreams (n=17; PBO-6; LEM5-7; LEM10-4) as treatment-emergent adverse events (TEAEs). In Study 304, 12/1006 subjects (1.2%) reported nightmares (n=4; PBO-1; ZOL-ER-0; LEM5-2; LEM10-1) or abnormal dreams (n=8; PBO-1; ZOL-ER-3; LEM5-0; LEM10-4). 32/40 subjects (80.0%) reporting these events were female (% females in the studies: 303=67.9%; 304=86.4%). In the LEM groups, 11/28 subjects (39.3%) reported the TEAE within 3 days of treatment initiation. There were 2 TEAEs of nightmare/abnormal dreams during the PBO run-in prior to randomization.

Conclusion

Abnormal dreams/nightmares were not common events in either study. Incidence was slightly higher with LEM10 and proportional to enrollment based on sex.
P098 Predicting delays in or failure to initiate CPAP therapy: A retrospective cohort study
Authors: Moore S , Duce B , Ellender C , Hukins C
Published: October 2021

Background

Suboptimal CPAP usage is associated with negative outcomes and inefficient use of medical resources. Demographic and polysomnographic characteristics are well established predictors of poor adherence, however the literature regarding patients who fail to initiate treatment is limited. This audit aimed to identify features associated with the delayed commencement or failure to initiate CPAP therapy.

Methods

A single institution, retrospective cohort study was performed. The cohort comprised adults with obstructive sleep apnoea prescribed CPAP between 2017 and 2018. The demographic, clinical and polysomnographic features of this cohort were identified. Comparisons were conducted between patients who initiated therapy and those who did not, as well as between early and delayed initiators of treatment, which was defined as uptake after one month. Multiple logistic regression was performed with significance defined as a p<0.05.

Results

916 patients were identified. 38.2% of patients did not uptake prescribed CPAP, with male gender (p < 0.001), younger age (p=0.007) and lower pressure (p=0.016) identified as prognostic factors. Socioeconomic disadvantage (p=0.774) and Epworth Sleepiness Scale (p=0.111) were not associated with failure to start treatment. Of the 61.8% of patients who initiated CPAP therapy, 33% exhibited a delayed start to therapy, with indigenous status a significant feature of this cohort (p=0.002).

Discussion

A large portion of patients displayed either delayed commencement or failure to initiate CPAP therapy. Younger age, male gender and lower prescribed pressures were identified as negative predictive factors. These characteristics, as well as delayed treatment experienced in the indigenous population, provide focus points for intervention.
P100 Modified BRP and Tongue Channelling: Can we cure Friedman III?
Authors: Nasserallah M
Published: October 2021

Aim

The primary aim of this study was to determine the success rate of modified barbed reposition pharyngoplasty (BRP) and coblation tongue channelling (CCT) in adult patients with obstructive sleep apnoea (OSA). The secondary objective was to determine the anatomical sites that were most amenable to surgical intervention. We predicted that Friedman would be a poor predictor of success for this surgical technique and that a new prognostic index would be required.

Methodology

Adult patients with OSA underwent combined MODIFIED BRP and CCT (n = 40) in this prospective, 2-centre cohort trial. Data analysed included pre- and post-operative (3 months) polysomnography, Epworth sleepiness scale (ESS) and VOTE anatomy assessment (using awake nasoendoscopy) performed by a single investigator.

Results

40 participants have enrolled in this study. So far, 26 patients have pre- and post-operative data. 42% of these patients had Friedman 3 anatomy. Statistically significant decreases in AHI 20.3 + 24 to 4.9 + 8.6 (p=0.001) and ESS 12.4 + 4.9 to 4.8±3.4 (p=0.001) were observed in pre- to post-operative measurements. Friedman stage 3 patients had an 82% surgical success rate and 64% cure rate. Oropharyngeal lateral collapse and velum anteroposterior collapse were the most correctable forms of anatomical collapse.

Conclusion

MODIFIED BRP with CCT is a safe and effective surgical option for patients with OSA, as indicated by the reduction in AHI and ESS. Friedman stage III is no longer a barrier for surgical success, and therefore a newer staging system is required to help prognosticate success with modern sleep surgery techniques.
P108 Effects of different pillow designs on promoting sleep quality and spinal alignment by reducing neck pain, waking symptoms, neck disability in adults: a systematic review and meta-analysis
Authors: PANG J
Published: October 2021

Introduction

Poor sleep quality is more prevalent in patients with neck pain than in the control without neck pain. The effectiveness of using different pillows in the management of neck pain, waking symptoms and sleep quality is inconclusive.

Objectives

To identify the randomized controlled trials assessing the effect of different types of pillows on sleep quality, spinal alignment, neck pain, waking symptoms and neck disability.

Methods

A systematic review was conducted by searching CINAHL Complete, Cochrane Library, EMBASE, Medline, Pubmed and Psychinfo databases from inception to September 2020. Two reviewers independently assessed the articles and evaluated the methodological quality using the Physiotherapy Evidence Database (PEDro) scale.

Results

Thirty-five articles fulfilled the inclusion criteria of the study. There were nine high-quality studies involving 555 participants. The meta-analysis revealed significant differences favouring the use of rubber pillows to reduce neck pain [standardized mean difference (SMD: -0.263; P < 0.001). Moreover, favourable outcomes by using rubber and spring pillows were found in waking pain (SMD: -0.228; P < 0.001), neck disability (SMD: -0.506; P = 0.020) and pillow satisfaction (SMD: 1.144; P < 0.001). However, pillow designs did not influence sleep quality (SMD = 0.047; P = 0.703) or spinal alignment at side-lying position (SMD=0.049; P=0.280) in patients with chronic neck pain.

Discussion

The use of spring and rubber pillows shows positive effects on reducing neck pain and disability. Although pillow designs do not change the sleep quality, waking symptoms can be reduced with positive pillow satisfaction in patients with chronic neck pain.
P139 Co-morbid insomnia and sleep apnoea (COMISA): Identifying patients that are responsive to continuous positive airway pressure therapy
Authors: Sweetman A , Lack L , Smith S , Chai-Coetzer C , Catcheside P , Antic N , Douglas J , O’Grady M , Dunn N , Robinson J , Paul D , McEvoy D
Published: October 2021

Introduction

Co-morbid insomnia and sleep apnoea (COMISA) is a prevalent and debilitating condition that is difficult to treat. COMISA patients have lower average adherence to continuous positive airway pressure (CPAP) therapy compared to patients with sleep apnoea alone. However, a sub-sample of COMISA patients may show adequate CPAP use that improves both the insomnia and sleep apnoea. It is important to identify this group of CPAP-responsive COMISA patients to guide personalised-medicine approaches.

Methods

Seventy-three COMISA patients (AHI≥15; ICSD-3 insomnia; 55% male, Age M=57y) completed questionnaires, home-based polysomnography, and one-week sleep diaries before and 6-months after commencing CPAP therapy. No patients accessed CBTi. We investigated baseline predictors of CPAP adherence (min/night) and overall change in Insomnia Severity Index (ISI) scores during treatment.

Results

Average CPAP adherence was 205 minutes/night (SD=153). 56% of patients used CPAP at least 4h/night. Average CPAP adherence was predicted by higher baseline AHI (r=0.39), arousal index (r=0.28), N1 sleep (r=0.32) and age (r=0.26), and lower N3 sleep (r=-0.28). The ISI decreased from baseline (17.9, CI=1.2) to 6-month follow-up (11.6, CI=1.3; p<0.001). There was a significant positive association between ISI reduction and CPAP use (r=0.31). 26% of patients reported an ISI<8 at 6-month follow-up.

Conclusion

Approximately half of COMISA patients show CPAP adherence of ≥4h/night and one quarter experience insomnia remission with CPAP. CPAP use is positively associated with AHI, light sleep, and age at baseline, and reduction of insomnia severity during treatment. Future randomized controlled trials are required to confirm the results of this small un-controlled study.
P157 Modelling the developmental trajectory of infant and child sleep
Authors: Webb L , Phillips A , Roberts J
Published: October 2021

Introduction

Sleep is important for infant and child neurodevelopment, yet there is a lack of mechanistic understanding of what drives the changes in sleep over the early years of life. While sleep in the adult brain has been studied and modelled extensively, very little has been done in infants and children, mainly limited to descriptive studies of sleep behaviour.

Methods

We adapted an existing, physiologically based model of adult sleep to study infant and child sleep behaviour. We compared modelled sleep behaviour to published data on sleep characteristics over a range of ages, both cross sectional from 0 to 5 years and densely-sampled individual data in the first year of life. We performed Bayesian inference to estimate the likely physiological parameters underpinning population-level diversity in sleep characteristics as a function of age from 0 to 5 years. We also fitted the model to individual sleep architecture in the first year of life.

Results

The empirically observed decrease in total sleep duration and consolidation of sleep bouts with increasing age are well explained by decreases in the constant inhibitory input to the ventrolateral preoptic nucleus and increases in the characteristic somnogen clearance time during sleep. Further, our model produced realistic sleep-wake dynamics consistent with early maturation of sleep in the heavily sampled, single infant data.

Discussion

Our results show that a greater understanding of the neurophysiology of sleep in infants and children can be achieved through the use of physiologically based models.
P159 Successful treatment of sleep disordered breathing improves comorbidities in patients with nocturia
Authors: Wilson C , Goldin J , Bower W , Stonehouse J , Perkins A , Kee K
Published: October 2021

Introduction

Sleep disordered breathing (SDB) has been shown to increase nocturia (waking with the need to void urine) frequency. Nocturia negatively affects sleep, autonomic dysfunction, mental health and mortality. Nocturia and these co-morbidities share central control areas in the brainstem. We hypothesised that treatment of SDB would decrease nocturia frequency and impact these co-morbidities.

Methods

A prospective repeated measures study with participants ≥40 years, naïve to treatment, with an AHI ≥30/hr and experiencing ≥1 episodes of nocturia was conducted. Participants undertook two months of CPAP with before and after measures of lower urinary tract symptoms (Overactive Bladder Symptom Score (OABSS) and urine volume), sleep quality (PSQI and actigraphy), autonomic dysfunction (blood pressure and orthostatic change) and wellbeing (Nocturia quality of life score (NQoL) and the Hospital anxiety and depression scores (HADS)).

Results

490 diagnostic studies screened, 36 patients met criteria, and 30 participants (57% male) were recruited. 15 patients completed treatment with 55% of completed participants meeting the required compliance of >4 hours. Significant changes in OABSS (p=0.035), nocturnal voiding frequency (p=0.007), nocturnal urine volume (p=0.013) and nocturnal diuresis (p=0.013). Improvement was observed in PSQI perceived sleep quality (p=0.018) and actigraphy derived sleep efficiency (p=0.002). NQoL global score also showed significant improvement (p=0.037).No change was observed in autonomic dysfunction measurements.

Conclusion

With appropriate treatment of SDB an improvement was observed in nocturia frequency and associated co-morbidities in a sample of relatively healthy individuals. These results suggests that significant nocturia should prompt the assessment for and treatment of SDB.
P162 Heated humidified high flow nasal cannula versus continuous positive airway pressure therapy for obstructive sleep apnoea in children: the patients’ perspective
Authors: Wong M , Taylor E , Longland R , Leclerc M , Williams G , Neylan M , Kilner D , Chawla J
Published: October 2021

Introduction

Approximately 30% of otherwise healthy children will have residual obstructive sleep apnoea (OSA) after first line therapy with adenotonsillectomy (AT) with lower success rates in children with risk factors. Continuous positive airway pressure (CPAP) is often the next treatment option and, whilst highly effective therapy, can be challenging to sustain in children. A pilot study is underway at our centre to evaluate the efficacy of heated humidified high flow nasal cannula therapy (HFNC) compared to CPAP in children with residual OSA. A secondary aim of this study is to determine which therapy (HFNC versus CPAP) the patients prefer. This abstract will report preliminary findings.

Methods

Children under 18 years old identified as requiring a CPAP trial for residual OSA management were invited to undergo an additional polysomnography, where they underwent a trial of HFNC overnight, which was undertaken in a similar manner to the CPAP trial. Participants and caregivers completed a questionnaire regarding comfort level following both the HFNC and CPAP titration nights.

Results

11 participants (4 males) between 4 months and 15 years old have completed the study to date. Using an 11-point Likert scale, the average reported comfort level grading for HFNC was 1.5 points higher than CPAP.

Discussion

This preliminary data suggests that on average caregivers and participants found HFNC more comfortable than CPAP. Alternative therapies such as HFNC may be effective in managing OSA and may be better tolerated in children non-adherent to CPAP.
P169 Comparison of Work of Breathing: Heart failure versus Interstitial Lung Disease
Authors: Yu C , Heng A , Cuesta R , Roebuck T , Prasad J , Naughton M
Published: October 2021

Background

Heart failure with central sleep apnoea and Cheyne Stokes respiration (HF-CSA-CSR) and interstitial lung disease (ILD) are characterised by tachypnoea, reflecting an increased work of breathing (WOB). Whilst tachypnoea is continuous in ILD, it is periodic in HF-CSA-CSF. Our hypothesis is that the periodicity reflects adaptive efficiency.

Methods

We assessed polysomnograms of male patients attending for either heart transplant or ILD assessment. WOB during non-REM sleep was estimated by the breath to breath interval (BBI), from which respiratory rate (RR) was calculated. An age matched control group with snoring, AHI<5 and neither HF or ILD was included.

Progress to date: Four patients (mean age 70 years) were identified in each group. The HF-CSA-CSR and ILD groups had similar awake PaCO2. The HF-CSA-CSR group had a lower LVEF and higher TLCO than the ILD group. There was similar BBI in the HF-CSA-CSR group during hyperpneic phase mean = 3.4±0.1 seconds and ILD group mean = 3.5±0.3 seconds, p=0.31. However, the RR during slow wave sleep was significantly lower in the HF-CSA-CSR group compared with ILD and control groups: HF-CSA-CSR mean = 10.3±0.8 breaths/min, control mean = 14.3±1.0 breaths/min, ILD mean 18.2±2.3 breaths/min, P=0.0002.

Intended outcome and Impact: This data would suggest that both HF-CSA-CSR and ILD have similar severities of tachypnoea (aka work of breathing) compared with controls, however the RR is significantly lower in the HF-CSA-CSR group compared with ILD, despite similar PaCO2. This would indicate HF-CSA-CSR has similar WOB, yet greater efficiency, than ILD during non-REM sleep.
Theta Dynamics Contribute to Retrieving Motor Plans after Interruptions in the Primate Premotor Area
Authors: Hosaka Ryosuke , Watanabe Hidenori , Nakajima Toshi , Mushiake Hajime
Published: October 2021

To achieve a behavioral goal, we often need to maintain an internal action plan against external interruption and thereafter retrieve the action plan. We recently found that the maintenance and updating of motor plans are reflected by reciprocal changes in the beta and gamma power of the local field potential (LFP) of the primate medial motor areas. In particular, the maintenance of the immediate motor plan is supported by enhanced beta oscillations. However, it is unclear how the brain manages to maintain and retrieve the internal action plan against interruptions. Here, we show that dynamic theta changes contribute to the maintenance of the action plan. Specifically, the power of the theta frequency band (4–10 Hz) of LFPs increased before and during the interruption in the dorsal premotor areas in two monkeys. Without theta enhancement before the interruption, retrieval of the internal action plan was impaired. Theta and beta oscillations showed distinct changes depending on the behavioral context. Our results demonstrate that immediate and suspended motor plans are supported by the beta and theta oscillatory components of LFPs. Motor cortical theta oscillations may contribute to bridging motor plans across behavioral interruptions in a prospective manner.
Phloem transport limitation in Huanglongbing-affected sweet orange is dependent on phloem-limited bacteria and callose
Authors: Welker Stacy , Pierre Myrtho , Santiago James P , Dutt Manjul , Vincent Christopher , Levy Amit
Published: October 2021

Huanglongbing (HLB), caused by Candidatus `Liberibacter asiaticus' (CLas), is a phloem-limited disease that disrupts citrus production in affected areas. In HLB-affected plants, phloem sieve plate pores accumulate callose, and leaf carbohydrate export is reduced. However, whether HLB causes a reduction in carbohydrate phloem translocation speed and the quantitative relationships among callose, CLas population and phloem translocation are still unknown. In this work, a procedure was developed to concurrently measure sugar transport, callose deposition and relative pathogen population at different locations throughout the stem. Increasing quantities of CLas genetic material were positively correlated with quantity and density of callose deposits and negatively correlated with phloem translocation speed. Callose deposit quantity was position and rootstock dependent and was negatively correlated with phloem translocation speed, suggesting a localized relationship. Remarkably, callose accumulation and phloem translocation disruption in the scion were dependent on rootstock genotype. Regression results suggested that the interaction of Ct values and number of phloem callose depositions, but not their size or density, explained the effects on translocation speed. Sucrose, starch and sink 14C label allocation data support the interpretation of a transport pathway limitation by CLas infection. This work shows that the interaction of local accumulation of callose and CLas affects phloem transport. Furthermore, the extent of this accumulation is attenuated by the rootstock and provides important information about the disease mechanism of phloem-inhabiting bacteria. Together, these results constitute the first example of a demonstrated transport limitation of phloem function by a microbial infection.
The Endophytic Fungus Cyanodermella asteris Influences Growth of the Nonnatural Host Plant Arabidopsis thaliana
Authors: Jahn Linda , Storm-Johannsen Lisa , Seidler Diana , Noack Jasmin , Gao Wei , Schafhauser Thomas , Wohlleben Wolfgang , van Berkel Willem J. H. , Jacques Philippe , Kar Tambi , Piechulla Birgit , Ludwig-Müller Jutta
Published: October 2021

Cyanodermella asteris is a fungal endophyte from Aster tataricus, a perennial plant from the northern part of Asia. Here, we demonstrated an interaction of C. asteris with Arabidopsis thaliana, Chinese cabbage, rapeseed, tomato, maize, or sunflower resulting in different phenotypes such as shorter main roots, massive lateral root growth, higher leaf and root biomass, and increased anthocyanin levels. In a variety of cocultivation assays, it was shown that these altered phenotypes are caused by fungal CO2, volatile organic compounds, and soluble compounds, notably astins. Astins A, C, and G induced plant growth when they were individually included in the medium. In return, A. thaliana stimulates the fungal astin C production during cocultivation. Taken together, our results indicate a bilateral interaction between the fungus and the plant. A stress response in plants is induced by fungal metabolites while plant stress hormones induced astin C production of the fungus. Interestingly, our results not only show unidirectional influence of the fungus on the plant but also vice versa. The plant is able to influence growth and secondary metabolite production in the endophyte, even when both organisms do not live in close contact, suggesting the involvement of volatile compounds.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
The Association of Lumbosacral Transitional Vertebrae with Low Back Pain and Lumbar Degenerative Findings in MRI
Authors: Hanhivaara Jaakko , Määttä Juhani H. , Karppinen Jaro , Niinimäki Jaakko , Nevalainen Mika T.
Published: October 2021

Study Design.

A cross-sectional study of the Northern Finland Birth Cohort 1966 (NFBC1966).

Objective.

To evaluate the association of lumbosacral transitional vertebrae (LSTV) with low back pain (LBP) and associated degenerative findings using magnetic resonance (MR) imaging.

Summary of Background Data.

LSTV is a common finding with a prevalence of 10% to 29%. LSTV causes biomechanical alterations leading to accelerated lumbar degeneration. However, its association with degenerative findings on MRI and LBP is unclear.

Methods.

One thousand four hundred sixty eight lumbar spine MRI scans from the NFBC1966 acquired at a mean age of 47 years were assessed for the presence of LSTV and degenerative changes. Castellvi classification was utilized to identify LSTV anatomy. Additionally, 100 controls without LSTV were collected. Self-reported LBP with a duration of more than 30 days in the past year was deemed clinically relevant. For the statistical analyses, chi square test, independent samples t test and multinomial logistic regression analyses were used.

Results.

LSTV was found in 310 (21.1%) subjects. After adjusting for age, sex, and disc degeneration (DD) sum, subjects with Castellvi type III reported prolonged LBP significantly more frequently than the controls (odds ratio [OR] = 8.9, P = 0.001). We observed a higher prevalence of facet degeneration (FD) at all levels from L3/L4 to L5/S1 in type I, and L3/L4 to L4/L5 in types II–IV. DD was more prevalent at L4/L5 in types II–IV. Disc protrusion/extrusion occurred more frequently at L3/L4 and L4/L5 in type II, and at L3/L4 in type III. Castellvi type II had a higher prevalence of type 1 Modic changes at levels from L3/L4 to L4/L5.

Conclusion.

LSTVs were a common finding within this study, and Castellvi type III LSTVs were associated with LBP. Degenerative findings were associated with LSTV anatomy and occurred more commonly above the transitional level.

Level of Evidence: 3
Effects of methylene blue on microcirculatory alterations following cardiac surgery
Authors: Maurin Carole , Portran Philippe , Schweizer Remi , Allaouchiche Bernard , Junot Stéphane , Jacquet-Lagrèze Matthias , Fellahi Jean-Luc
Published: October 2021

BACKGROUND

Methylene blue is used as rescue therapy to treat catecholamine-refractory vasoplegic syndrome after cardiac surgery. However, its microcirculatory effects remain poorly documented.

OBJECTIVE

We aimed to study microcirculatory abnormalities in refractory vasoplegic syndrome following cardiac surgery with cardiopulmonary bypass and assess the effects of methylene blue.

DESIGN

A prospective open-label cohort study.

SETTING

20-Bed ICU of a tertiary care hospital.

PATIENTS

25 Adult patients receiving 1.5 mg kg−1 of methylene blue intravenously for refractory vasoplegic syndrome (defined as norepinephrine requirement more than 0.5 μg kg−1 min−1) to maintain mean arterial pressure (MAP) more than 65 mmHg and cardiac index (CI) more than 2.0 l min−1 m−2.

MAIN OUTCOME MEASURES

Complete haemodynamic set of measurements at baseline and 1 h after the administration of methylene blue. Sublingual microcirculation was investigated by sidestream dark field imaging to obtain microvascular flow index (MFI), total vessel density, perfused vessel density and heterogeneity index. Microvascular reactivity was assessed by peripheral near-infrared (IR) spectroscopy combined with a vascular occlusion test. We also performed a standardised measurement of capillary refill time.

RESULTS

Despite normalised CI (2.6 [2.0 to 3.8] l min−1 m−2) and MAP (66 [55 to 76] mmHg), patients with refractory vasoplegic syndrome showed severe microcirculatory alterations (MFI < 2.6). After methylene blue infusion, MFI significantly increased from 2.0 [0.1 to 2.5] to 2.2 [0.2 to 2.8] (P = 0.008), as did total vessel density from 13.5 [8.3 to 18.5] to 14.9 [10.1 to 14.7] mm mm−2 (P = 0.02) and perfused vessel density density from 7.4 [0.1 to 11.5] to 9.1 [0 to 20.1] mm mm−2 (P = 0.02), but with wide individual variation. Microvascular reactivity assessed by tissue oxygen resaturation speed also increased from 0.5 [0.1 to 1.8] to 0.7 [0.1 to 2.7]% s−1 (P = 0.002). Capillary refill time remained unchanged throughout the study.

CONCLUSION

In refractory vasoplegic syndrome following cardiac surgery, we found microcirculatory alterations despite normalised CI and MAP. The administration of methylene blue could improve microvascular perfusion and reactivity, and partially restore the loss of haemodynamic coherence.

TRIAL REGISTRATION

ClinicalTrials.gov identifier: NCT04250389.
Therapeutic Drug Monitoring of Ganciclovir: Where Are We?
Authors: Märtson Anne-Grete , Edwina Angela E. , Kim Hannah Yejin , Knoester Marjolein , Touw Daan J. , Sturkenboom Marieke G. G. , Alffenaar Jan-Willem C.
Published: October 2021

Background:

Ganciclovir is the mainstay of therapy for the prophylaxis and treatment of Cytomegalovirus. However, therapy with this antiviral agent is hindered by side effects such as myelosuppression, which often leads to therapy cessation. Underdosing, as an attempt to prevent side effects, can lead to drug resistance and therapy failure. Therapeutic drug monitoring (TDM) has been used to overcome these problems. The purpose of this narrative review was to give an overview of ganciclovir TDM, available assays, population pharmacokinetic models, and discuss the current knowledge gaps.

Methods:

For this narrative review, a nonsystematic literature search was performed on the PubMed database in April 2021. The following search terms were used: ganciclovir, valganciclovir, pharmacokinetics, pharmacodynamics, population pharmacokinetics, therapeutic drug monitoring, bioassay, liquid chromatography coupled with tandem mass spectrometry, liquid chromatography, chromatography, spectrophotometry, and toxicity. In addition, the reference lists of the included articles were screened.

Results:

The most common bioanalysis method identified was liquid chromatography coupled with tandem mass spectrometry. There are different models presenting ganciclovir IC50; however, establishing a pharmacokinetic/pharmacodynamic target for ganciclovir based on preclinical data is difficult because there are no studies combining dynamic drug exposure in relation to inhibition of viral replication. The data on ganciclovir TDM show large interindividual variability, indicating that TDM may play a role in modifying the dose to reduce toxicity and prevent treatment failure related to low concentrations. The main hurdle for implementing TDM is the lack of robust data to define a therapeutic window.

Conclusions:

Although the pharmacokinetics (PK) involved is relatively well-described, both the pharmacodynamics (PD) and pharmacokinetic/pharmacodynamic relationship are not. This is because the studies conducted to date have mainly focused on estimating ganciclovir exposure, and owing to the limited therapeutic options for CMV infections, future studies on ganciclovir are warranted.
Successful Novel Treatment of Granuloma Faciale Using CO2 Emulated Er:YAG Laser Ablation
Authors: Bayne Kilee , Fornwalt Brandon E. , Jonda Christopher F. , Cash Adam D.
Published: October 2021

Granuloma faciale is a rare, benign inflammatory skin disease that has multiple medical treatment modalities due to its frequent unresponsiveness to treatment. This skin disease presents as a single, well-demarcated red-brown to violaceous, raised lesion, most commonly on the face, in middle-aged White men. Its etiology is unknown; sun exposure is thought to have some implications in its formation. Treatment modalities for granuloma faciale include topical therapy, intralesional injections, systemic therapies, phototherapy, lasers, cryotherapy, and surgical excision. In this article, we will highlight a rare case of granuloma faciale and its novel and successful treatment with a carbon dioxide emulated Er:YAG laser.
Late-onset persistent corneal hydrops after crosslinking treated with 24% C3F8
Authors: Scott Tabitha M. , Lee Graham A.
Published: October 2021

Corneal hydrops can occur in an apparently stable cornea many years after crosslinking. This case describes the management of persistent hydrops unresponsive to conservative treatment. A 31-year-old woman presented with right acute corneal hydrops 9 years after crosslinking for keratoconus. No clear precipitant was identified, and corneal topography had been stable over the past 9 years. The right cornea demonstrated inferior hydrops with gross thickening of the stroma. The hydrops persisted and failed to resolve after 6 months, despite 2 intracameral 14% C3F8 gas injections and topical hypertonic saline. An intracameral concentration of 24% C3F8, with 65% fill of the anterior chamber was performed, with the gas partially released after day 3, resulting in resolution of the hydrops. Corneal hydrops after crosslinking is a rare phenomenon, but it is likely an underreported complication. The hydrops in this case was recalcitrant to conservative measures. An expansile concentration of intracameral C3F8 was used to achieve a full gas fill to tamponade the inferior Descemet tear. Close follow-up is required to monitor for intraocular pressure spikes and perform paracentesis as required.
Focusing on the Medically Ready for Discharge Patient Using a Reliable Design Strategy: A Quality Improvement Project to Improve Length of Stay on a Medicine Service
Authors: Meo Nicholas , Cornia Paul B.
Published: October 2021

Background and Objectives:

Length of stay is a common measure of efficiency of care. We aimed to reduce length of stay on a general medicine service through a structured quality improvement project.

Methods:

A reliable design strategy was implemented in successive stages at a 238-bed academically-affiliated VA hospital. Over a 2-year period, continuous improvement efforts were directed at discrete cohorts of patients deemed medically appropriate for discharge but who remained hospitalized because of discharge barriers. We compared the mean length of stay and medically-ready bed days of care for a hospital in statistical control charts. Pre- and post-intervention comparisons were made using t-tests.

Results:

In total, 5321 discharges were included in this improvement project, accounting for 35 852 bed days of care. Overall, average length of stay was reduced by 15.7%, from 7.62 to 6.40 days (P < .05). There was a significant reduction in the mean number of medically-ready bed days of care from 2.3 to 1.72. Statistical process control charts demonstrated special cause variation across patient cohorts.

Conclusion:

A quality improvement project using reliable design principles was associated with shorter length of stay.
Reperfusion Therapies for Children With Arterial Ischemic Stroke
Authors: Heit Jeremy J. , Muthusami Prakash , Chandra Ronil V. , Hui Ferdinand , Negrotto Matias , Lee Sarah , Wasserman Bruce A. , Abruzzo Todd A.
Published: October 2021

Modern hyperacute reperfusion therapies including intravenous thrombolysis and mechanical thrombectomy have transformed the management of arterial ischemic stroke (AIS) in adults. Multiple randomized clinical trials have demonstrated that these therapies enable remarkable improvements in clinical outcome for properly selected patients with AIS. Because pediatric patients were excluded from predicate clinical trials, there is a conspicuous lack of data to guide selection of therapies and inform age-adjusted and pathology-oriented treatment modifications for children. Specifically, technical guidance concerning treatment eligibility, drug dosing, and device implementation is lacking. This review aims to outline important features that differentiate pediatric AIS from adult AIS and provide practical strategies that will assist the stroke specialist with therapeutic decision making.
A twelve-month projection to September 2022 of the Covid-19 epidemic in the UK using a Dynamic Causal Model
Authors: Bowie Cam , Friston Karl
Published: October 2021

Objectives

Predicting the future UK Covid-19 epidemic allows other countries to compare their epidemic with one unfolding without public health measures except a vaccine programme.

Methods

A Dynamic Causal Model (DCM) is used to estimate the model parameters of the epidemic such as vaccine effectiveness and increased transmissibility of alpha and delta variants, the vaccine programme roll-out and changes in contact rates. The model predicts the future trends in infections, long-Covid, hospital admissions and deaths.

Results

Two dose vaccination given to 66% of the UK population prevents transmission following infection by 44%, serious illness by 86% and death by 93%. Despite this, with no other public health measures used, cases will increase from 37 million to 61 million, hospital admission from 536,000 to 684,000 and deaths from 136,000 to 142,000 over twelve months.

Discussion

Vaccination alone will not control the epidemic. Relaxation of mitigating public health measures carries several risks – overwhelming the health services, the creation of vaccine resistant variants and the economic cost of huge numbers of acute and chronic cases.
Factors affecting the choice of a future medical specialty of the junior doctors in a third world country
Authors: Malik Ifrah J. , Tameez-ud-din Ahsan , Tameez Ud Din Asim , Mohyud Din Farooq
Published: October 2021

Background and Objective

Pakistan is facing a major brain drain and as long as there is not a better understanding of the needs and desires of the junior doctors, this exodus towards the greener pastures shall continue. This study is an effort to recognize the factors which influence the choice of a future specialty of young Pakistani doctors in order to help identify the areas which need improvement.

Study design

This descriptive cross-sectional study was conducted from 12th May, 2021 to 2nd August, 2021. Young doctors who had completed their one-year internship in hospitals of Punjab were invited to fill the questionnaire via social media platforms. Data were entered and analyzed using the Statistical Package for Social Sciences (SPSS) version 23.0. Chi-square tests were applied for qualitative variables. A p-value of less than 0.05 was considered significant.

Results

Out of a total 105 participants, 60 (57.1%) were females. More females as compared to males decided the future specialty based on work-life balance (20/27, p= 0.039). Internal medicine and general surgery were the most sought-after fields both before and after the internship. Forty-three (41%) participants wished to change their choice of specialty after their house job experiences. Fifty-eight (55.2%) participants considered the future prospects of the field while deciding their specialty while sixty-three (60%) reported the attitude of the senior doctors as an important deciding factor. The Covid-19 pandemic had an effect on 12 (11.4%) participants’ decision regarding their choice of future specialty.

Conclusion

Many elements such as internship play a pivotal role in helping the young doctors to narrow their choices. It is important to understand the factors considered by young doctors during their choice of a medical specialty to ensure that a significant proportion of medical work force does not slip through the cracks in our health infrastructure.
SparsePro: an efficient fine-mapping method integrating summary statistics and functional annotations
Authors: Zhang Wenmin , Najafabadi Hamed , Li Yue
Published: October 2021

Identifying causal variants from genome-wide association studies (GWAS) is challenging due to widespread linkage disequilibrium (LD) and the possible existence of multiple causal variants in the same genomic locus. Functional annotations of the genome may help to prioritize variants that are biologically relevant and thus improve fine-mapping of GWAS results. Classical fine-mapping methods conducting an exhaustive search of variant-level causal configurations have a high computational cost, especially when the underlying genetic architecture and LD patterns are complex. SuSiE provided an iterative Bayesian stepwise selection algorithm for efficient fine-mapping. In this work, we build connections between SuSiE and a paired mean field variational inference algorithm through the implementation of a sparse projection, and propose effective strategies for estimating hyperparameters and summarizing posterior probabilities. Moreover, we incorporate functional annotations into fine-mapping by jointly estimating enrichment weights to derive functionally-informed priors. We evaluate the performance of SparsePro through extensive simulations using resources from the UK Biobank. Compared to state-of-the-art methods, SparsePro achieved improved power for fine-mapping with reduced computation time. We demonstrate the utility of SparsePro through fine-mapping of five functional biomarkers of clinically relevant phenotypes. In summary, we have developed an efficient fine-mapping method for integrating summary statistics and functional annotations. Our method can have wide utility in understanding the genetics of complex traits and increasing the yield of functional follow-up studies of GWAS. SparsePro software is available on GitHub athttps://github.com/zhwm/SparsePro.

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Author Summary

Accurately identifying causal variants from genome-wide association studies summary statistics is important for understanding genetic architecture of complex traits and identifying therapeutic targets. Functional annotations are commonly used as additional evidence for prioritizing causal variants. In this study, we present SparsePro to integrate summary statistics and functional annotations for accurate identification of causal variants. SparsePro extends the capabilities of a popular fine-mapping method, SuSiE, with important contributions in hyperparameter estimation, posterior summaries and integration of function annotations. Through extensive simulations, we demonstrate that our proposed approach can effectively integrate summary statistics and functional annotation, leading to improved power for identifying causal variants. Furthermore, we evaluate the benefits of incorporating functional annotations through real data analyses of five functional biomarkers. In summary, by improving power and providing valuable insights into complex disease genetics, SparsePro will have wide utility in advancing our knowledge and facilitating follow-up discoveries.
Detection and quantification of SARS-CoV-2 RNA in wastewater influent in relation to reported COVID-19 incidence in Finland
Authors: Tiwari Ananda , Lipponen Anssi , Hokajärvi Anna-Maria , Luomala Oskari , Sarekoski Anniina , Rytkönen Annastiina , Österlund Pamela , Al-Hello Haider , Juutinen Aapo , Miettinen Ilkka T. , Savolainen-Kopra Carita , Pitkänen Tarja
Published: October 2021

Wastewater-based surveillance is a cost-effective concept for monitoring COVID-19 pandemics at a population level. Here, SARS-CoV-2 RNA was monitored from a total of 693 wastewater (WW) influent samples from 28 wastewater treatment plants (WWTP, N = 21–42 samples per WWTP) in Finland from August 2020 to May 2021, covering WW of ca. 3.3 million inhabitants (∼ 60% of the Finnish population). The relative quantity of SARS-CoV-2 RNA fragments in the 24h-composite samples was determined by using the ultrafiltration method followed by nucleic acid extraction and RT-qPCR assay targeted with N2-assay. SARS-CoV-2 RNA signals at each WWTP were compared over time to the numbers of new and confirmed COVID-19 cases in the sewer network area.

Over the 10-month surveillance period, the detection rate of SARS-CoV-2 RNA in WW was 79% (including 6% uncertain results), while only 24% of all samples exhibited gene copy (GC) numbers above the quantification limit. The range of the SARS-CoV-2 detection rate in WW varied from 33% (including 10% uncertain results) in Pietarsaari to 100% in Espoo. Only six out of 693 WW samples were positive with SARS-COV-2 RNA when the reported COVID-19 case number from the preceding 14 days was zero. Overall, the 14-day COVID-19 incidence was 7, 18 and 36 cases within the sewer network area when the probability to detect SARS-CoV-2 RNA in wastewater samples was 50%, 75% and 95%, respectively. The quantification of SARS-CoV-2 GC required significantly more COVID-19 cases: the quantification rate was 50%, 75% and 95% when the 14-day incidence was 110, 152 and 223 COVID-19 cases, respectively, per 100 000 persons. Multiple linear regression confirmed the relationship between the COVID-19 incidence and the SARS-CoV-2 GC quantified in WW at 15 out of 28 WWTPs (overall R2 = 0.36, p < 0.001). At four of the 13 WWTPs where a significant relationship was not found, the GC of SARS-CoV-2 RNA remained below the quantification limit during the whole study period. In the five other WWTPs, the sewer coverage was less than 80% of the total population in the area and thus the COVID-19 cases may have been inhabitants from the areas not covered.

Based on the results obtained, WW-based surveillance of SARS-CoV-2 could be used as an indicator for local and national COVID-19 incidence trends. Importantly, the determination of SARS-CoV-2 RNA fragments from WW is a powerful and non-invasive public health surveillance measure, independent of possible changes in the clinical testing strategies or in the willingness of individuals to be tested for COVID-19.