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STUDY OBJECTIVES: To determine whether adherence to continuous positive airway pressure (CPAP) in adults with uncomplicated obstructive sleep apnea differs by rural vs urban residential address. METHODS: In this prospective cohort study, we recruited adults who initiated CPAP for uncomplicated obstructive sleep apnea that was diagnosed by a physician using sleep specialist-interpreted diagnostic testing. Participants were classified as urban (community size > 100,000) or rural (community size < 100,000) by translating residential postal code into geographic census area. The primary outcome was mean daily hours of CPAP use compared between rural and urban patients. Secondary outcomes included the proportion of patients who were adherent to CPAP, change in Epworth Sleepiness Scale score, change in EuroQOL-5D visual analog score, and Visit-Specific Satisfaction Instrument score. All outcomes were measured 3 months after CPAP initiation. RESULTS: We enrolled 242 patients (100 rural) with a mean (standard deviation) age of 51 (13) years and a respiratory event index of 24 (18) events/h. The mean (95% confidence interval) CPAP use was 3.19 (2.8–3.58) hours/night and 35% were CPAP-adherent, with no difference between urban and rural patients. Among the 65% of patients who were using CPAP at 3 months, the mean CPAP use was 4.89 (4.51–5.28) hours/night and was not different between rural and urban patients. Improvement in the Epworth Sleepiness Scale score and patient satisfaction was similar between groups, but the EuroQOL-5D score improved to a greater extent in rural patients. Urban or rural residence was not associated with CPAP adherence according to multivariable regression analysis. CONCLUSIONS: Rural vs urban residence was not associated with differences in CPAP adherence among patients with uncomplicated OSA diagnosed by a physician using specialist-interpreted sleep diagnostic testing. CITATION: Corrigan J, Tsai WH, Ip-Buting A, et al. Treatment outcomes among rural and urban patients with obstructive sleep apnea: a prospective cohort study. J Clin Sleep Med. 2022;18(4):1013–1020.

Supplementary Figure Legends

Supplementary Figure 7. INPP4B loss does not produce any morphological or cytoskeletal differences.

PDF - 14407K, Supporting histology for Olaparib treatment in vivo.

Supplementary Figure 3. INPP4B's promoter is not directly methylated.

Supplementary Figure S3. ERG binding to CHK1 promoter.

PDF - 632K, Preclinical assessment of Olaparib and BKM120 treatment in vivo.

Supplementary Figure Legends

PDF - 546K, Olaparib induces a differing response in vitro depending on the genetic background.

PDF - 2951K, Olaparib induces a differing response in vivo depending on the genetic background.

Supplementary Figure 2. Validation of INPP4B antibody.

Supplementary Figure 1. Generation of Pten+/-Inpp4b+/- and Pten+/-Inpp4b-/- mice.

PDF - 114k, Supporting western blot analysis and drug treatment in prostate cancer cell lines.

PDF - 116K, Supplementary Materials and Methods and Supplementary Figure Legends.

Supplementary Figure 4. Loss of Inpp4b in MEFs lead to increased Akt activation.

Supplementary Figure 5. Loss of INPP4B results in increased AKT2 activation.

PDF - 138K, Survival curves of the in vivo treatment of Olaparib and BKM120.

Depletion of FZR1 leads to BRAF stabilization and subsequent ERK activation. Supplementary Figure S2. Depletion of FZR1 triggers the onset of premature senescence in primary melanocytes. Supplementary Figure S3. APCFZR1 promotes BRAF ubiquitination and subsequent degradation in a D-box dependent manner. Supplementary Figure S4. FZR1 disrupts the BRAF dimerization process. Supplementary Figure S5. Phosphorylation of FZR1 N-terminus by ERK and CYCLIN D1/CDK4 inhibits the APCFZR1 E3 ubiquitin ligase activity. Supplementary Figure S6. Pharmacologically inhibiting BRAF/ERK and CDK4 restores the APCFZR1 E3 ligase activity. Supplementary Figure S7. Depletion of FZR1 co-operates with PTEN deficiency to promote co-activation of BRAF/ERK and AKT oncogenic signaling both in vitro and in vivo. Supplementary Table S1. Mutation and deletion of FZR1 and 14 APC core complex subunits identified in melanoma patients from the TCGA melanoma dataset (cbioportal.org).

Krüppel-like Factor 5 (KLF5) is a zinc-finger transcription factor associated with cell cycle progression and cell survival. KLF5 plays a key role in mammalian intestinal epithelium development and maintenance, expressed at high levels in basal proliferating cells and low levels in terminally differentiated cells. Considering Barrett's esophagus (BE) and esophageal adenocarcinoma's (EAC) histopathological similarities to intestinal epithelium, we sought to determine KLF5’s role in BE and EAC, as well as KLF5’s possible connection to the sonic hedgehog (SHH) pathway which is highly active in BE and EAC development. Low levels of KLF5 mRNA were found in BE cell lines and tissue– similar to what has been reported in differentiated intestinal epithelium. In contrast, higher KLF5 levels were observed in EAC cells and tissues. KLF5 knockdown in EAC cells caused significant decreases in cell migration, proliferation, and EAC-associated gene expression. Moreover, KLF5 knockdown led to decreased SHH signaling. These results suggest that KLF5 is connected to the SHH pathway in BE and EAC and may represent a potential drug target in EAC; further studies are now indicated to verify these findings and elucidate underlying mechanisms involved.

Objective The aim of the study was to investigate whether inhibition of Sonic Hedgehog (SHH) pathway would prevent progression of Barrett's Esophagus (BE) to esophageal adenocarcinoma. Background The hedgehog signaling pathway is a leading candidate as a molecular mediator of BE and esophageal adenocarcinoma (EAC). Repurposed use of existing off-patent, safe and tolerable drugs that can inhibit hedgehog, such as itraconazole, could prevent progression of BE to EAC. Methods The efficacy of itraconazole was investigated using a surgical rat reflux model of Barrett's Metaplasia (BM). Weekly intraperitoneal injections of saline (control group) or itraconazole (treatment group; 200 mg/kg) were started at 24 weeks postsurgery. Esophageal tissue was harvested at 40 weeks. The role of the Hh pathway was also evaluated clinically. Esophageal tissue was harvested after 40 weeks for pathological examination and evaluation of the SHH pathway by immunohistochemistry. Results BM was present in control animals 29 of 31 (93%) versus itraconazole 22 of 24 (91%). EAC was significantly lower in itraconazole 2 of 24 (8%) versus control 10 of 31 (32%), respectively (P = 0.033). Esophageal SHH levels were lower in itraconazole vs control (P = 0.12). In esophageal tissue from humans with recurrent or persistent dysplastic BE within 24 months of ablative treatment, strong SHH and Indian Hedgehog expression occurred in distal BE versus proximal squamous epithelium, odds ratio = 6.1 (95% confidence interval: 1.6, 23.4) and odds ratio = 6.4 (95% confidence interval: 1.2, 32.8), respectively. Conclusion Itraconazole significantly decreases EAC development and SHH expression in a preclinical animal model of BM. In humans, BE tissue expresses higher SHH, Indian Hedgehog, and bone morphogenic protein levels than normal squamous esophageal epithelium.

Pneumocephalus is commonly seen on imaging in the setting of craniofacial trauma, skull base tumours, intracranial infection and after neurological intervention. Spontaneous pneumocephalus in the absence of these conditions is exceedingly rare, with only approximately 30 cases reported in the literature to date. Spontaneous otogenic pneumocephalus (SOP) is believed to occur as a result of anomalous communication between the intracranial space and a hyper-pneumatised temporal bone, with either positive extra-to-intracranial pressure or negative intracranial pressure gradient. These anomalous communicating channels may only become clinically apparent when triggered by episodes of acute increase in middle ear pressure during coughing, sneezing, Valsalva manoeuvre or significant change in atmospheric pressure. Patients may exhibit a wide range of neurological symptoms and the aim of treatment is to reduce the risk of complications such as infection and intracranial hypertension. Both conservative and neurosurgical approaches have been described. We report a case of SOP in which the patient was conservatively managed, and spontaneous resolution of pneumocephalus was documented on serial computed tomography (CT) scans. This unique case clearly demonstrates the natural history and temporal evolution of SOP without surgical intervention. This knowledge may potentially obviate the need for surgery, thus reducing morbidity and mortality in patients who are poor surgical candidates.

Deterministic execution for GPUs is a desirable property as it helps with debuggability and reproducibility. It is also important for safety regulations, as safety critical workloads are starting to be deployed onto GPUs. Prior deterministic architectures, such as GPUDet, attempt to provide strong determinism for all types of workloads, incurring significant performance overheads due to the many restrictions that are required to satisfy determinism. We observe that a class of reduction workloads, such as graph applications and neural architecture search for machine learning, do not require such severe restrictions to preserve determinism. This motivates the design of our system, Deterministic Atomic Buffering (DAB), which provides deterministic execution with low area and performance overheads by focusing solely on ordering atomic instructions instead of all memory instructions. By scheduling atomic instructions deterministically with atomic buffering, the results of atomic operations are isolated initially and made visible in the future in a deterministic order. This allows the GPU to execute deterministically in parallel without having to serialize its threads for atomic operations as opposed to GPUDet. Our simulation results show that, for atomic-intensive applications, DAB performs 4× better than GPUDet and incurs only a 23% slowdown on average compared to a non-deterministic GPU architecture. We also characterize the bottlenecks and provide insights for future optimizations.

Background: Concerns regarding personal, professional, administrative, and institutional implications of medical assistance in dying (MAiD) are of particular interest to palliative and hospice care...

AimThe presence of biallelic CEBPA mutations is a favourable prognostic feature in acute myeloid leukaemia (AML). CEBPA mutations are currently identified through conventional capillary sequencing (CCS). With the increasing adoption of next-generation sequencing (NGS) platforms, challenges with regard to amplification efficiency of CEBPA due to the high GC content may be encountered, potentially resulting in suboptimal coverage. Here, the performance of an amplicon-based NGS method using a laboratory-developed CEBPA-specific Nextera XT (CEBNX) was evaluated.MethodsMutational analyses of the CEBPA gene of 137 AML bone marrow or peripheral blood retrospective specimens were performed by the amplification of the CEBPA gene using the Expand Long Range dNTPack and the amplicons processed by CCS and NGS. CEBPA-specific libraries were then constructed using the Nextera XT V.2 kit. All FASTQ files were then processed with the MiSeq Reporter V.2.6.2.3 using the PCR Amplicon workflow via the customised CEBPA-specific manifest file. The variant calling format files were analysed using the Illumina Variant Studio V.2.2.ResultsA coverage per base of 3631X to 28184X was achieved. 22 samples (16.1%) were found to contain CEBPA mutations, with variant allele frequencies (VAF) ranging from 3.8% to 58.2%. Taking CCS as the ‘gold standard’, sensitivity and specificity of 97% and 97% was achieved. For the transactivation domain 2 polymorphism (c.584_589dupACCCGC/p.His195_Pro196dup), the CEBNX achieved 100% sensitivity and 100% specificity relative to CCS.ConclusionsOur laboratory-developed CEBNX workflow shows high coverage and thus overcomes the challenges associated with amplification efficiency and low coverage of CEBPA. Therefore, our assay is suitable for deployment in the clinical laboratory.

The Cepheid Xpert® Norovirus kit automates sample processing, nucleic acid extraction, and real-time reverse transcription polymerase chain reactions (RT-PCRs) to detect norovirus genogroups I (GI) and II (GII). Eighty-five stool samples collected between February 2015 and May 2017 were used to compare the performance of a user-modified Xpert assay against a clinically validated laboratory-developed test (LDT). Of the 85 samples, 54 were previously archived in -80°C freezer. The remaining 31 were fresh samples tested concurrently with the LDT. The results of all samples tested using the Xpert kit and LDT were found to be concordant, including 12 GI- and 42 GII-positive samples, 1 GI and GII coinfection, and 30 negative samples. Comparison of the assays showed perfect concordance with a kappa coefficient score of 1.00 (95%CI from 1.00 to 1.00). Of the 30 negative stool samples tested, three samples were positive for rotavirus detected using an immunochromatographic assay, with no cross-reactivity shown in both LDT and Xpert assays. In-run sample processing control of the Xpert assay for all negative samples tested showed no/minor inhibition. Compared to the LDT, the Xpert assay produced similar or better Ct values for detection. It also showed better mitigation of PCR inhibition in stool sample testing.

There have been no reports describing the effects of cancer cell–derived extracellular vesicles (EVs) on three-dimensional organoids. In this study, we delineated the proneoplastic effects of esophageal adenocarcinoma (EAC)–derived EVs on gastric organoids (gastroids) and elucidated molecular mechanisms underlying these effects. EVs were identified using PKH-67 staining. Morphologic changes, Ki-67 immunochemistry, cell viability, growth rates, and expression levels of miR-25 and miR-210, as well as of their target mRNAs, were determined in gastroids co-cultured with EAC-derived extracellular vesicles (c-EVs). C-EVs were efficiently taken up by gastroids. Notably, c-EV–treated gastroids were more crowded, compact, and multilayered and contained smaller lumens than did those cultured in organoid medium alone or in EAC-conditioned medium that had been depleted of EVs. Moreover, c-EV–treated gastroids manifested increased proliferation and cellular viability relative to medium-only or EV-depleted controls. Expression levels of miR-25 and miR-210 were significantly higher, and those of PTEN and AIFM3 significantly lower, in c-EV–treated versus medium-only or EV-depleted control groups. Inhibitors of miR-25 and miR-210 reversed the increased cell proliferation induced by c-exosomes in co-cultured gastroids by lowering miR-25 and miR-210 levels. In conclusion, we have constructed a novel model system featuring the co-culture of c-EVs with three-dimensional gastroids. Using this model, we discovered that cancer-derived EVs induce a neoplastic phenotype in gastroids. These changes are due, at least in part, to EV transfer of miR-25 and miR-210.

Targeted next generation sequencing platforms have been increasingly utilised for identification of novel mutations in myeloid neoplasms, such as acute myeloid leukaemia (AML), and hold great promise for use in routine clinical diagnostics. In this study, we evaluated the utility of an open source variant caller in detecting large indels in a targeted sequencing of AML samples. While we found that this bioinformatics pipeline has the potential to accurately capture large indels (>20 bp) in patient samples, we highlighted the pitfall of a confounding ZRSR1 pseudogene that led to an erroneous ZRSR2 variant call. We further discuss possible clinical implications of the ZRSR1 pseudogene in myeloid neoplasms based on its molecular features. Knowledge of the confounding ZRSR1 pseudogene in ZRSR2 sequencing assays could be particularly important in AML diagnostics because the detection of ZRSR2 in AML patients is highly specific for an s-AML diagnosis.

Our knowledge of nasopharyngeal carcinoma (NPC) is rapidly changing. This article is a snapshot of the present state of NPC imaging in relation to the latest staging system, current standards of care, and treatment complications. The article’s emphasis on pathophysiology and important radiological anatomy will improve the interpretation of radiological findings and allow the radiologist to optimize the role of imaging in a multidisciplinary team.

During embryonic gonad coalescence, primordial germ cells (PGCs) follow a carefully choreographed migratory route circumscribed by guidance signals towards somatic gonadal precursor cells (SGPs). In Drosophila melanogaster, SGP-derived Hedgehog (Hh), which serves as a guidance cue for the PGCs, is potentiated by mesodermally restricted HMGCoA-reductase (Hmgcr) and the ABC transporter Multi-drug-resistant-49 (Mdr49). Given the importance of cholesterol modification in the processing and long-distance transmission of the Hh ligand, we have analyzed the involvement of the Niemann-Pick disease type C-1a (NPC1a) protein, a cholesterol transporter, in germ cell migration and Hedgehog signaling. We show that mesoderm-specific inactivation of Npc1a results in germ cell migration defects. Similar to Mdr49, PGC migration defects in the Npc1a embryos are ameliorated by a cholesterol-rich diet. Consistently, reduction in Npc1a weakens the ability of ectopic HMG Coenzyme A reductase (Hmgcr) to induce germ cell migration defects. Moreover, compromising Npc1a levels influences Hh signaling adversely during wing development, a process that relies upon long-range Hh signaling. Last, doubly heterozygous embryos (Mdr49/Npc1a) display enhanced germ cell migration defects when compared with single mutants (Npc1a/+ or Mdr49/+), supporting cooperative interaction between the two.

Most deep neural networks deployed today are trained using GPUs via high-level frameworks such as TensorFlow and PyTorch. This paper describes changes we made to the GPGPU-Sim simulator to enable it to run PyTorch by running PTX kernels included in NVIDIA's cuDNN library. We use the resulting modified simulator, which has been made available publicly with this paper, to study some simple deep learning workloads. With our changes to GPGPU-Sim's functional simulation model, we find GPGPU-Sim performance model running a cuDNN enabled implementation of LeNet for MNIST reports results within 30% of real hardware. Using GPGPU-Sim's AerialVision performance analysis tool we observe that cuDNN API calls contain many varying phases and appear to include potentially inefficient microarchitecture behaviour such as DRAM partition bank camping, at least when executed on GPGPU-Sim's current performance model., Source code available at: https://github.com/gpgpu-sim/gpgpu-sim_distribution/tree/dev

Although bulk high-throughput genomic profiling studies have led to a significant increase in the understanding of cancer biology, there is increasing awareness that bulk profiling approaches do not completely elucidate tumor heterogeneity. Single-cell genomic profiling enables the distinction of tumor heterogeneity, and may improve clinical diagnosis through the identification and characterization of putative subclonal populations. In the present study, the challenges associated with a single-cell genomics profiling workflow for clinical diagnostics were investigated. Single-cell RNA-sequencing (RNA-seq) was performed on 20 cells from an acute myeloid leukemia bone marrow sample. Putative blasts were identified based on their gene expression profiles and principal component analysis was performed to identify outlier cells. Variant calling was performed on the single-cell RNA-seq data. The present pilot study demonstrates a proof of concept for clinical single-cell genomic profiling. The recognized limitations include significant stochastic RNA loss and the relatively low throughput of the current proposed platform. Although the results of the present study are promising, further technological advances and protocol optimization are necessary for single-cell genomic profiling to be clinically viable.

Aims In recent years, genomic technologies have enabled the identification of mutations in acute myeloid leukaemia (AML). DNMT3A is a recurrently mutated epigenetic modifier gene in AML. To date, the prognostic significance of DNMT3A mutations has not been studied in a Southeast Asian AML population. We sought to investigate the clinical implications of DNMT3A mutations in a Southeast Asian cohort of AML patients. Methods DNMT3A mutations were identified using a targeted next-generation sequencing panel in 157 AML patients. We studied the molecular and clinical features of patients with DNMT3A mutations and assessed the prognostic impact of DNMT3A mutations. Results DNMT3A mutations were found in 33 of 157 (21.0%) AML patients. 114 patients were included for statistical analysis. Pretreatment data revealed that patients with DNMT3A mutations were older (≥60 years old), had a higher white blood cell count at diagnosis, had more adverse cytogenetic risk profiles and were more often associated with NPM1 mutations compared with patients with wild-type DNMT3A . Survival analysis showed that DNMT3A mutations were associated with poorer clinical outcomes. This was especially when associated with NPM1 and FLT3-ITD mutations (AML NPM1/FLT3/DNMT3A ), which are common. The AML NPM1/FLT3/DNMT3A subtype was an independent predictor for poorer overall survival (OS). Other independent risk factors for poorer OS include advanced age at diagnosis and adverse cytogenetic risk stratification. Conclusions DNMT3A mutations are associated with an unfavourable clinical outcome in our Southeast Asian AML patient cohort. In particular, AML NPM1/FLT3/DNMT3A patients had the poorest prognosis.

Experimental study. The objective of this study was to establish a non-invasive model to produce pressure ulcers of varying severity in animals with spinal cord injury (SCI). The study was conducted at the Johns Hopkins Hospital in Baltimore, Maryland, USA. A mid-thoracic (T7–T9) left hemisection was performed on Sprague-Dawley rats. At 7 days post SCI, rats received varying degrees of pressure on the left posterior thigh region. Laser Doppler Flowmetry was used to record blood flow. Animals were killed 12 days after SCI. A cardiac puncture was performed for blood chemistry, and full-thickness tissue was harvested for histology. Doppler blood flow after SCI prior to pressure application was 237.808±16.175 PFUs at day 7. Following pressure application, there was a statistically significant decrease in blood flow in all pressure-applied groups in comparison with controls with a mean perfusion of 118.361±18.223 (P

In this chapter, we discuss the different pharmacological interventions for psychiatric diseases in the geriatric population. We specifically divide these treatments into five categories: anxiolytics and sedative-hypnotics, antipsychotics, antidepressants, mood stabilizers, and cognitive enhancers. These categories are further divided into disease-specific medications. The utility, general recommendations, mechanism of action, dosing, and adverse reactions of drugs are covered for the medications in this chapter. The treatment of mental illness in the geriatric population is a complicated process due to the physiologic changes of metabolism, drug absorption, and drug excretion. These transformations specifically alter the dosing of pharmacological treatments in older adults. The shift in metabolism inherently changes the side effect profile of medications compared to the general adult population, which further complicates the utilization of pharmaceutical interventions for older adults with psychiatric conditions. It is our goal to provide a solid background for clinicians to make prudent decisions in the treatment approach of psychiatric diseases in the geriatric population.

As operational and information technologies converge to allow for remote and real-time access to plant operating data and control functions, the process industry could become increasingly susceptible to cyber-attacks. Traditional hazard and risk analysis methods appear inadequate to identify, prevent, and mitigate such attacks. This paper discusses the significance of incorporating cybersecurity vulnerability analysis not just as part of process hazard analysis (PHA), but also in terms of protecting the process control network and implementing adequate safeguards in general against cyber threats. A layer of protection analysis (LOPA) is adapted to evaluate potential weaknesses and ensure safeguards for critical applications would be resistant to cyber-attacks. Integrating cybersecurity into hazard and risk analyses as well as other elements of process safety management (PSM) is demonstrated with examples, making the plant more resilient against both traditional and cyber threats.

Acute stroke care systems in Southeast Asian countries are at various stages of development, with disparate treatment availability and practice in terms of intravenous thrombolysis and endovascular therapy. With the advent of successful endovascular therapy stroke trials over the past decade, the pressure to revise and advance acute stroke management has greatly intensified. Southeast Asian patients exhibit unique stroke features, such as increased susceptibility to intracranial atherosclerosis and higher prevalence of intracranial haemorrhage, likely secondary to modified vascular risk factors from differing dietary and lifestyle habits. Accordingly, the practice of acute endovascular stroke interventions needs to take into account these considerations. Acute stroke care systems in Southeast Asia also face a unique challenge of huge stroke burden against a background of ageing population, differing political landscape and healthcare systems in these countries. Building on existing published data, further complemented by multi-national interaction and collaboration over the past few years, the current state of acute stroke care systems with existing endovascular therapy services in Southeast Asian countries are consolidated and analysed in this review. The challenges facing acute stroke care strategies in this region are discussed.

See related articles at [[www.cmaj.ca/lookup/doi/10.1503/cmaj.171076][2]][2] and [[www.cmaj.ca/lookup/doi/10.1503/cmaj.170371][3]][3] KEY POINTS Against a background of growing concern that rates of cesarean delivery in Canada and globally are rising, trial of labour after previous cesarean