Combined brachytherapy and external beam radiation therapy (EBRT) of the prostate and seminal vesicles (SVs) is evolving as a successful treatment option for high-risk prostate cancer. Dose-volume ...histogram (DVH) analysis of the SV was performed in patients with biopsy-positive SV who received implantation of the SV and prostate.
Fifteen consecutive patients with high-risk features (prostate-specific antigen PSA > or =10 ng/mL, Gleason score > or = 7, or clinical stage > or = T2b) and a positive SV biopsy were treated with a 103Pd implant of the prostate and SV followed by 45Gy of EBRT. DVHs were generated for the prostate and total SV volume (SVT). In addition, the SV was divided into 3-mm-thick volumes identified as SV1, SV2, SV3, SV4, SV5, and SV6 starting from the junction of the prostate and SV and extending distally. Delivered dose was defined as the D90 (dose delivered to 90% of the organ on DVH).
The median number of seeds implanted into the prostate and the SVT was 59 (41-94) and 9 (4-21), respectively. The median D90 values for the prostate, SVT, SV1, SV2, SV3, SV4, SV5, and SV6 were 103.2 (87.4-137.1), 46.2 (4.0-69.4), 76.0 (31.2-147), 63.4 (25.1-145.9), 49.7 (15.3-118), 27.4 (9.3-135.1), 14.2 (2.3-100.3), and 3.9 (0-61.5) Gy, respectively.
Implantation of the SV using a real-time intraoperative approach is technically feasible and results in higher doses to the SV than has been reported with implantation of the prostate alone. Although dose distribution in the SV can be variable and unpredictable, these doses, in combination with 45 Gy of EBRT, may be adequate to control disease spread in these organs.
Small cell lung cancer (SCLC) accounts for 15% of lung cancers and is almost always linked to inactivating
and
mutations. SCLC frequently responds, albeit briefly, to chemotherapy. The canonical ...function of the
gene product RB1 is to repress the E2F transcription factor family. RB1 also plays both E2F-dependent and E2F-independent mitotic roles. We performed a synthetic lethal CRISPR/Cas9 screen in an
SCLC cell line that conditionally expresses
to identify dependencies that are caused by RB1 loss and discovered that
SCLC cell lines are hyperdependent on multiple proteins linked to chromosomal segregation, including Aurora B kinase. Moreover, we show that an Aurora B kinase inhibitor is efficacious in multiple preclinical SCLC models at concentrations that are well tolerated in mice. These results suggest that RB1 loss is a predictive biomarker for sensitivity to Aurora B kinase inhibitors in SCLC and perhaps other
cancers. SIGNIFICANCE: SCLC is rarely associated with actionable protooncogene mutations. We did a CRISPR/Cas9-based screen that showed that
SCLC are hyperdependent on
, likely because both genes control mitotic fidelity, and confirmed that Aurora B kinase inhibitors are efficacious against
SCLC tumors in mice at nontoxic doses.
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To provide the best available evidence to determine the impact of nurse practitioner services on cost, quality of care, satisfaction and waiting times in the emergency department for adult patients.
...The delivery of quality care in the emergency department is emerging as one of the most important service indicators in health delivery. Increasing service pressures in the emergency department have resulted in the adoption of service innovation models: the most common and rapidly expanding of these is emergency nurse practitioner services. The rapid uptake of emergency nurse practitioner service in Australia has outpaced the capacity to evaluate this service model in terms of outcomes related to safety and quality of patient care. Previous research is now outdated and not commensurate with the changing domain of delivering emergency care with nurse practitioner services.
A comprehensive search of four electronic databases from 2006 to 2013 was conducted to identify research evaluating nurse practitioner service impact in the emergency department. English language articles were sought using MEDLINE, CINAHL, Embase and Cochrane and included two previous systematic reviews completed five and seven years ago.
A three step approach was used. Following a comprehensive search, two reviewers assessed all identified studies against the inclusion criteria. From the original 1013 studies, 14 papers were retained for critical appraisal on methodological quality by two independent reviewers and data were extracted using standardised tools.
Narrative synthesis was conducted to summarise and report the findings as insufficient data was available for meta-analysis of results. This systematic review has shown that emergency nurse practitioner service has a positive impact on quality of care, patient satisfaction and waiting times. There was insufficient evidence to draw conclusions regarding outcomes of a cost benefit analysis.
Synthesis of the available research attempts to provide an evidence base for emergency nurse practitioner service to guide healthcare leaders, policy makers and clinicians in reform of emergency service provision. The findings suggest that further high quality research is required for comparative measures of clinical and service effectiveness of emergency nurse practitioner service. In the context of increased health service demand and the need to provide timely and effective care to patients, such measures will assist in evidence based health service planning.
Drug repurposing is promoted as a cost- and time-effective mechanism for providing new medicines. Often, however, there is insufficient consideration by academic researchers of the processes required ...to ensure that a repurposed drug can be used for a new indication. This may explain the inability of drug repurposing to fulfill its promise. Important aspects, often overlooked, include financial and intellectual property considerations, the clinical and regulatory path, and clinical equipoise, which provides ethical justification for randomized controlled trials. The goal of drug repurposing is to obtain a new regulator-approved label for an existing drug, and so, the trajectory for drug repurposing and traditional drug development is similar. Here, we discuss factors critical for a successful repurposed medicine to help academic investigators better identify drug repurposing opportunities.
In this observational cross-sectional study, we investigated predictors of orthostatic intolerance (OI) in adults reporting long COVID symptoms. Participants underwent a 3-min active stand (AS) with ...Finapres
NOVA, followed by a 10-min unmedicated 70° head-up tilt test. Eighty-five participants were included (mean age 46 years, range 25-78; 74% women), of which 56 (66%) reported OI during AS (OI
). OI
seemed associated with female sex, more fatigue and depressive symptoms, and greater inability to perform activities of daily living (ADL), as well as a higher heart rate (HR) at the lowest systolic blood pressure (SBP) point before the first minute post-stand (mean HR
: 88 vs. 75 bpm,
= 0.004). In a regression model also including age, sex, fatigue, depression, ADL inability, and peak HR after the nadir SBP, HR
was the only OI
predictor (OR = 1.09, 95% CI: 1.01-1.18,
= 0.027). Twenty-two (26%) participants had initial (iOH) and 5 (6%) classical (cOH
) orthostatic hypotension, but neither correlated with OI
. Seventy-one participants proceeded to tilt, of which 28 (39%) had OI during tilt (OI
). Of the 53 who had a 10-min tilt, 7 (13%) had an HR increase >30 bpm without cOH
(2 to HR > 120 bpm), but six did not report OI
. In conclusion, OI
was associated with a higher initial HR on AS, which after 1 min equalised with the non-OI
group. Despite these initial orthostatic HR differences, POTS was infrequent (2%). ClinicalTrials.gov Identifier: NCT05027724 (retrospectively registered on August 30, 2021).
(1) Introduction: A subset of individuals experiencing long COVID symptoms are affected by ‘brain fog’, a lay term that often refers to general cognitive dysfunction but one that is still poorly ...characterised. In this study, a comprehensive clinical characterisation of self-reported brain fog was conducted vis-à-vis other long COVID symptoms and parameters of mental, cognitive, and physical health. (2) Methodology: Adult participants reporting long COVID symptoms were recruited from hospital clinics and as self-referrals. Participants completed a battery of questionnaires and clinical assessments, including COVID-19 history, symptomatology, self-reported scales (Chalder Fatigue Scale CFQ, Center for Epidemiological Studies Depression Scale, and Impact of Events Scale–Revised), computer-based cognitive assessments (simple response time and choice reaction time tasks), physical performance tests (gait velocity and muscle strength assessments), and an orthostatic active stand test. A systematic comparison between participants with and without self-reported brain fog was conducted, and a backwards binary logistic regression model was computed to identify the strongest independent associations with brain fog. This was complemented by an automatic cluster analysis to rank the importance of associations. Finally, a structural equation model was postulated with a causal model of key symptomatic indicators and functional consequences of brain fog as a latent variable. (3) Results: Of 108 participants assessed, brain fog was a self-reported symptom in 71 (65.7%) participants. Those with brain fog were at a longer point in time since COVID-19 onset and reported longer duration of low activity during the acute illness. When assessed, those with brain fog had higher frequencies of subjective memory impairment, word-finding difficulties, dizziness, myalgia, arthralgia, hyperhidrosis, cough, voice weakness, throat pain, visual and hearing problems, dysosmia, paraesthesia, chest pain, skin rashes, and hair loss; mean scores in fatigue, depression, and post-traumatic stress scales were higher; performance in both computer-based cognitive tasks was poorer; and measured gait speed and grip strength were lower. The logistic regression suggested that the best independent associations with brain fog were memory impairment, CFQ, and myalgia. The cluster analysis suggested that the most important associations with brain fog were CFQ, dizziness, myalgia, reduced gait speed, word-finding difficulties, reduced grip strength, and memory impairment. The SEM was consistent with key indicators of brain fog being CFQ, dizziness, myalgia, word-finding difficulties, and memory impairment; and reduced grip strength, gait speed, and cognitive response times its functional consequences. (4) Conclusions: The findings indicate that self-reported brain fog in long COVID is a recognisable symptom cluster primarily characterised by fatigue, dizziness, myalgia, word-finding difficulties, and memory impairment and has adverse psychological and psychomotor correlates. In long COVID, brain fog should be regarded as a wide-ranging symptom and addressed holistically with medical, psychological, and rehabilitative supports as guided by individual needs.
The interrogation of proteomes ("proteomics") in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology and medicine.
We present a new aptamer-based proteomic ...technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 µL of serum or plasma). Our current assay measures 813 proteins with low limits of detection (1 pM median), 7 logs of overall dynamic range (~100 fM-1 µM), and 5% median coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding signature of DNA aptamer concentrations, which is quantified on a DNA microarray. Our assay takes advantage of the dual nature of aptamers as both folded protein-binding entities with defined shapes and unique nucleotide sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to rapidly discover unique protein signatures characteristic of various disease states.
We describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine.
Reports suggest that adults with post-COVID-19 syndrome or long COVID may be affected by orthostatic intolerance syndromes, with autonomic nervous system dysfunction as a possible causal factor of ...neurocardiovascular instability (NCVI). Long COVID can also manifest as prolonged fatigue, which may be linked to neuromuscular function impairment (NMFI). The current clinical assessment for NCVI monitors neurocardiovascular performance upon the application of orthostatic stressors such as an active (i.e., self-induced) stand or a passive (tilt table) standing test. Lower limb muscle contractions may be important in orthostatic recovery via the skeletal muscle pump. In this study, adults with long COVID were assessed with a protocol that, in addition to the standard NCVI tests, incorporated simultaneous lower limb muscle monitoring for NMFI assessment.
To conduct such an investigation, a wide range of continuous non-invasive biomedical sensing technologies were employed, including digital artery photoplethysmography for the extraction of cardiovascular signals, near-infrared spectroscopy for the extraction of regional tissue oxygenation in brain and muscle, and electromyography for assessment of timed muscle contractions in the lower limbs.
With the proposed methodology described and exemplified in this paper, we were able to collect relevant physiological data for the assessment of neurocardiovascular and neuromuscular functioning. We were also able to integrate signals from a variety of instruments in a synchronized fashion and visualize the interactions between different physiological signals during the combined NCVI/NMFI assessment. Multiple counts of evidence were collected, which can capture the dynamics between skeletal muscle contractions and neurocardiovascular responses.
The proposed methodology can offer an overview of the functioning of the neurocardiovascular and neuromuscular systems in a combined NCVI/NMFI setup and is capable of conducting comparative studies with signals from multiple participants at any given time in the assessment. This could help clinicians and researchers generate and test hypotheses based on the multimodal inspection of raw data in long COVID and other cohorts.
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