Assessing sociodemographic differences in human papillomavirus vaccine impact studies in the United States: a systematic review using narrative synthesis.

OBJECTIVES: Sociodemographic disparities in the incidence and mortality of human papillomavirus (HPV)-associated conditions have been well documented in the pre-HPV vaccine era. It is still unknown if the introduction of routine vaccination has been effective in reducing these prevaccine era inequalities. The purpose of this review was to determine the utilization of sociodemographic variables to assess for disparities in population-level HPV vaccine impact research and to evaluate the current evidence for disparities in the reduction of HPV-associated conditions after vaccine introduction in the United States (US). STUDY DESIGN: A systematic review of the literature from January 2007 through March 2018 was carried out to identify studies evaluating the impact HPV vaccines have had on the rates of HPV infection, genital warts, and cervical dysplasia (cervical intraepithelial neoplasia grades 1+) in the US. An in-depth review was then performed to synthesize these data and to assess the way prior studies have reported and evaluated for potential disparities in the vaccine's impact within various racial, ethnic, and/or socio-economic subgroups of the population. METHODS: Vaccine impact studies measure the change in the population-level burden of disease prelicensure versus postlicensure of the vaccine. We systematically searched PubMed/Medline and Embase, combining search terms related to the HPV vaccine, sentinel surveillance, and HPV-associated conditions. Eligible studies were those with population-level, postvaccine introduction data that were conducted in the US. Finally, a cited reference search was conducted for all included articles using the Web of Science platform that accesses three major citation indexes: Science Citation Index, Social Sciences Citation Index, and Arts and Humanities Citation Index. This allowed us to screen not only the articles that were cited by our final collection of studies but also the articles that used our selected studies as one of their references. The study protocol is registered in PROSPERO (#CRD42018107579). RESULTS: Overall, 23 of the 4139 references retrieved assessed the population-level impact of HPV vaccines between January 1, 2007, and March 29, 2018. Among these, 13 (57%) reported sociodemographic data. Only two articles reported stratified results by sociodemographic factors, thereby allowing assessment for potential disparate impact. One of these studies described differences in the impact of the vaccine by race, ethnicity, and income. CONCLUSION: Although approximately half of the studies that assessed the impact of the HPV vaccine measured sociodemographic characteristics, few presented results in a way that allowed for the identification of potential differences in impact between the relevant subgroups of the population. Determining to what extent, if any, vaccines are reducing known sociodemographic disparities is an important public health priority and an essential step in developing immunization strategies that are beneficial for all.

Severe adenomyosis and CA125.

A total of 50 women having uterine enlargement of > 12 weeks' size due to severe adenomyosis with raised CA125, were carefully studied and compared with other cases. The greater the enlargement of the uterus over 240 cm(3) volume or 12 weeks' uterine size due to severe adenomyosis, the greater was the rise of CA125 levels and these were disturbingly high in some cases. However, similarly enlarged uteri due to fibroids did not show a rise in CA125 levels above normal. Raised CA125 thus need not instil anxiety, when the clinical findings are benign.

Safety and clinical activity of durvalumab combined with tremelimumab in recurrent/metastatic head and neck squamous cell carcinoma: a multicenter phase I study.

BACKGROUND: Programmed cell death protein 1 (PD-1) inhibitors prolong survival versus chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), which often expresses cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-ligand 1 (PD-L1), providing a rationale for combined PD-(L)1 and CTLA-4 blockade. We report a phase I, open-label study of the PD-L1 inhibitor durvalumab plus the CTLA-4 inhibitor tremelimumab (NCT02262741). METHODS: In dose exploration, two cohorts of previously treated patients received durvalumab 10 mg/kg plus tremelimumab 3 mg/kg, or durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, for up to 12 months. Dose expansion comprised two cohorts of previously untreated patients with R/M HNSCC having baseline PD-L1 tumor cell (TC) expression ≥25% and <25% and one cohort of immunotherapy-pretreated patients with any PD-L1 level. All received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, then durvalumab 10 mg/kg, for up to 12 months. The primary endpoint was safety. The secondary endpoints were objective response rate (ORR) by RECIST version 1.1, pharmacokinetics, pharmacodynamics, and immunogenicity. RESULTS: A total of 71 patients were treated. The median duration of exposure was 13.6 weeks for durvalumab and 13.1 weeks for tremelimumab. In dose exploration, no dose-limiting toxicities occurred. No maximum tolerated dose was identified. Treatment-related adverse events (TRAEs) occurred in 69.0% of patients; grade 3/4 and serious TRAEs occurred in 31.0% and 18.3%, respectively. TRAEs led to discontinuation in 9.9%. There were no treatment-related deaths. The ORR was 5.6% (95% confidence interval 1.6-13.8), including one complete response and three partial responses, all patients were in dose expansion with PD-L1 TC ≥25% and no prior immunotherapy exposure; three had ongoing responses ≥12 months. The median overall survival in the total population was 8.6 months. Soluble PD-L1 suppression was almost complete in all cohorts, suggesting target engagement. CD4+Ki67+ T cells were significantly elevated in all dose-expansion cohorts. CONCLUSIONS: Treatment was well tolerated. However, response rates were low despite target engagement, no drug-drug interactions, and no drug-neutralizing antibodies to durvalumab.

SELF-SUPERVISED LEARNING WITH RADIOLOGY REPORTS, A COMPARATIVE ANALYSIS OF STRATEGIES FOR LARGE VESSEL OCCLUSION AND BRAIN CTA IMAGES.

Scarcity of labels for medical images is a significant barrier for training representation learning approaches based on deep neural networks. This limitation is also present when using imaging data collected during routine clinical care stored in picture archiving communication systems (PACS), as these data rarely have attached the high-quality labels required for medical image computing tasks. However, medical images extracted from PACS are commonly coupled with descriptive radiology reports that contain significant information and could be leveraged to pre-train imaging models, which could serve as starting points for further task-specific fine-tuning. In this work, we perform a head-to-head comparison of three different self-supervised strategies to pre-train the same imaging model on 3D brain computed tomography angiogram (CTA) images, with large vessel occlusion (LVO) detection as the downstream task. These strategies evaluate two natural language processing (NLP) approaches, one to extract 100 explicit radiology concepts (Rad-SpatialNet) and the other to create general-purpose radiology reports embeddings (DistilBERT). In addition, we experiment with learning radiology concepts directly or by using a recent self-supervised learning approach (CLIP) that learns by ranking the distance between language and image vector embeddings. The LVO detection task was selected because it requires 3D imaging data, is clinically important, and requires the algorithm to learn outputs not explicitly stated in the radiology report. Pre-training was performed on an unlabeled dataset containing 1,542 3D CTA - reports pairs. The downstream task was tested on a labeled dataset of 402 subjects for LVO. We find that the pre-training performed with CLIP-based strategies improve the performance of the imaging model to detect LVO compared to a model trained only on the labeled data. The best performance was achieved by pre-training using the explicit radiology concepts and CLIP strategy.

Default mode network spatio-temporal electrophysiological signature and causal role in creativity.

The default mode network (DMN) is a widely distributed, intrinsic brain network thought to play a crucial role in internally-directed cognition. It subserves self-referential thinking, recollection of the past, mind wandering, and creativity. Knowledge about the electrophysiology underlying DMN activity is scarce, due to the difficulty to simultaneously record from multiple distant cortical areas with commonly-used techniques. The present study employs stereo-electroencephalography depth electrodes in 13 human patients undergoing monitoring for epilepsy, obtaining high spatiotemporal resolution neural recordings across multiple canonical DMN regions. Our results offer a rare insight into the temporal evolution and spatial origin of theta (4-8Hz) and gamma signals (30-70Hz) during two DMN-associated higher cognitive functions: mind-wandering and alternate uses. During the performance of these tasks, DMN activity is defined by a specific pattern of decreased theta coupled with increased gamma power. Critically, creativity and mind wandering engage the DMN with different dynamics: creativity recruits the DMN strongly during the covert search of ideas, while mind wandering displays the strongest modulation of DMN during the later recall of the train of thoughts. Theta band power modulations, predominantly occurring during mind wandering, do not show a predominant spatial origin within the DMN. In contrast, gamma power effects were similar for mind wandering and creativity and more strongly associated to lateral temporal nodes. Interfering with DMN activity through direct cortical stimulation within several DMN nodes caused a decrease in creativity, specifically reducing the originality of the alternate uses, without affecting creative fluency or mind wandering. These results suggest that DMN activity is flexibly modulated as a function of specific cognitive processes and supports its causal role in creative thinking. Our findings shed light on the neural constructs supporting creative cognition and provide causal evidence for the role of DMN in the generation of original connections among concepts.

Foveal avascular zone segmentation using deep learning-driven image-level optimization and fundus photographs.

The foveal avascular zone (FAZ) is a retinal area devoid of capillaries and associated with multiple retinal pathologies and visual acuity. Optical Coherence Tomography Angiography (OCT-A) is a very effective means of visualizing retinal vascular and avascular areas, but its use remains limited to research settings due to its complex optics limiting availability. On the other hand, fundus photography is widely available and often adopted in population studies. In this work, we test the feasibility of estimating the FAZ from fundus photos using three different approaches. The first two approaches rely on pixel-level and image-level FAZ information to segment FAZ pixels and regress FAZ area, respectively. The third is a training mask-free pipeline combining saliency maps with an active contours approach to segment FAZ pixels while being trained on image-level measures of the FAZ areas. This enables training FAZ segmentation methods without manual alignment of fundus and OCT-A images, a time-consuming process, which limits the dataset that can be used for training. Segmentation methods trained on pixel-level labels and image-level labels had good agreement with masks from a human grader (respectively DICE of 0.45 and 0.4). Results indicate the feasibility of using fundus images as a proxy to estimate the FAZ when angiography data is not available.

Aperiodic neural activity is a biomarker for depression severity.

A reliable physiological biomarker for Major Depressive Disorder (MDD) is necessary to improve treatment success rates by shoring up variability in outcome measures. In this study, we establish a passive biomarker that tracks with changes in mood on the order of minutes to hours. We record from intracranial electrodes implanted deep in the brain - a surgical setting providing exquisite temporal and spatial sensitivity to detect this relationship in a difficult-to-measure brain area, the ventromedial prefrontal cortex (VMPFC). The aperiodic slope of the power spectral density captures the balance of activity across all frequency bands and is construed as a putative proxy for excitatory/inhibitory balance in the brain. This study demonstrates how shifts in aperiodic slope correlate with depression severity in a clinical trial of deep brain stimulation for treatment-resistant depression (TRD). The correlation between depression severity scores and aperiodic slope is significant in N=5 subjects, indicating that flatter (less negative) slopes correspond to reduced depression severity, especially in the ventromedial prefrontal cortex. This biomarker offers a new way to track patient response to MDD treatment, facilitating individualized therapies in both intracranial and non-invasive monitoring scenarios.

Gamma knife capsulotomy for intractable OCD: Neuroimage analysis of lesion size, location, and clinical response.

Obsessive-compulsive disorder (OCD) affects 2-3% of the population. One-third of patients are poorly responsive to conventional therapies, and for a subgroup, gamma knife capsulotomy (GKC) is an option. We examined lesion characteristics in patients previously treated with GKC through well-established programs in Providence, RI (Butler Hospital/Rhode Island Hospital/Alpert Medical School of Brown University) and São Paulo, Brazil (University of São Paolo). Lesions were traced on T1 images from 26 patients who had received GKC targeting the ventral half of the anterior limb of the internal capsule (ALIC), and the masks were transformed into MNI space. Voxel-wise lesion-symptom mapping was performed to assess the influence of lesion location on Y-BOCS ratings. General linear models were built to compare the relationship between lesion size/location along different axes of the ALIC and above or below-average change in Y-BOCS ratings. Sixty-nine percent of this sample were full responders (≥35% improvement in OCD). Lesion occurrence anywhere within the targeted region was associated with clinical improvement, but modeling results demonstrated that lesions occurring posteriorly (closer to the anterior commissure) and dorsally (closer to the mid-ALIC) were associated with the greatest Y-BOCS reduction. No association was found between Y-BOCS reduction and overall lesion volume. GKC remains an effective treatment for refractory OCD. Our data suggest that continuing to target the bottom half of the ALIC in the coronal plane is likely to provide the dorsal-ventral height required to achieve optimal outcomes, as it will cover the white matter pathways relevant to change. Further analysis of individual variability will be essential for improving targeting and clinical outcomes, and potentially further reducing the lesion size necessary for beneficial outcomes.

Measurement and initial characterization of leukocyte telomere length in 474,074 participants in UK Biobank.

Leukocyte telomere length (LTL) is a proposed marker of biological age. Here we report the measurement and initial characterization of LTL in 474,074 participants in UK Biobank. We confirm that older age and male sex associate with shorter LTL, with women on average ~7 years younger in 'biological age' than men. Compared to white Europeans, LTL is markedly longer in African and Chinese ancestries. Older paternal age at birth is associated with longer individual LTL. Higher white cell count is associated with shorter LTL, but proportions of white cell subtypes show weaker associations. Age, ethnicity, sex and white cell count explain ~5.5% of LTL variance. Using paired samples from 1,351 participants taken ~5 years apart, we estimate the within-individual variability in LTL and provide a correction factor for this. This resource provides opportunities to investigate determinants and biomedical consequences of variation in LTL.

Assessment of prescribing pattern of drugs and completeness of prescriptions as per the World Health Organization prescribing indicators in various Indian tertiary care centers: A multicentric study by Rational Use of Medicines Centers-Indian Council of Medical Research network under National Virtual Centre Clinical Pharmacology activity.

OBJECTIVE: The rational use of medicines as per the World Health Organization (WHO) should be practiced globally. However, data regarding the completeness of the prescriptions and their rational use is lacking from developing countries like India. Thus, the aim of this study was to assess the prescribing patterns of drugs and completeness of prescriptions as per WHO core drug use and complementary indicators to provide real-life examples for the Indian Council of Medical Research (ICMR) online prescribing skill course for medical graduates. METHODS: Prescriptions of the patients, fulfilling inclusion criteria, attending Outpatient Departments of various specialties of tertiary care hospitals, were collected by thirteen ICMR Rational use of medicines centers located in tertiary care hospitals, throughout India. Prescriptions were evaluated for rational use of medicines according to the WHO guidelines and for appropriateness as per standard treatment guidelines using a common protocol approved by local Ethics committees. RESULTS: Among 4838 prescriptions, an average of about three drugs (3.34) was prescribed to the patients per prescription. Polypharmacy was noted in 83.05% of prescriptions. Generic drugs were prescribed in 47.58% of the prescriptions. Further, antimicrobials were prescribed in 17.63% of the prescriptions and only 4.98% of prescriptions were with injectables. During the prescription evaluation, 38.65% of the prescriptions were incomplete due to multiple omissions such as dose, duration, and formulation. CONCLUSION: Most of the parameters in the present study were out of the range of WHO-recommended prescribing indicators. Therefore, effective intervention program, like training, for the promotion of rational drug use practice was recommended to improve the prescribing pattern of drugs and the quality of prescriptions all over the country.

Vaginal route for breast cancer induced hysterectomy with oophorectomy.

A previous history of breast cancer can induce problems in some women, which may necessitate hysterectomy as well as oophorectomy. This study included 20 women with a history of breast cancer with endometrial hyperplasia and recurrent vaginal bleeding or the need for oophorectomy because of metastatic breast cancer along with concomitant hysterectomy. The aim of this study is to show that benign indications for hysterectomy with oophorectomy, arising out of management of breast cancer in the past, can be dealt with by the least invasive approach via the vaginal route, provided vaginal hysterectomy is not contraindicated and the abdomino-pelvic area is free of metastasis. All 20 women had an uneventful postoperative period with rapid recovery, economic benefit and short hospital stay.

Combination percutaneous and medical management of cardiac rhabdomyomas obstructing tricuspid valve inflow: Case report.

BACKGROUND: Cardiac rhabdomyomas can be prenatally diagnosed in patients with tuberous sclerosis complex. Many neonates require no intervention in early life other than close monitoring for regression of tumor over the period of months to years. In rare instances, cardiac rhabdomyomas can result in obstruction to blood flow or decreased ventricular function. CASE REPORT: We describe the case of a neonate who was prenatally diagnosed with multiple large cardiac rhabdomyomas, one of which caused clinically significant obstruction to prograde blood flow across the tricuspid valve in the newborn period. To address the disturbance to prograde pulmonary blood flow, the patient underwent successful ductal stent placement in the neonatal period. A troponin elevation was noted shortly after birth, but no evidence of coronary compression or involvement was demonstrated by coronary angiography. The patient has subsequently been treated with sirolimus over a period of three months, with noted regression in tumors and improvement in tricuspid valve inflow. CONCLUSIONS: A brief review of the literature regarding the diagnosis, treatment, and management of neonatal patients with cardiac rhabdomyomas is presented. A combined percutaneous and medical management approach may be of benefit in future cases of rhabdomyomas causing obstruction to pulmonary blood flow.

NeuroDAC: an open-source arbitrary biosignal waveform generator.

Objective.Researchers are developing biomedical devices with embedded closed-loop algorithms for providing advanced adaptive therapies. As these devices become more capable and algorithms become more complex, tasked with integrating and interpreting multi-channel, multi-modal electrophysiological signals, there is a need for flexible bench-top testing and prototyping. We present a methodology for leveraging off-the-shelf audio equipment to construct a biosignal waveform generator capable of streaming pre-recorded biosignals from a host computer. By re-playing known, well-characterized, but physiologically relevant real-world biosignals into a device under test, researchers can evaluate their systems without the need for expensivein vivoexperiments.Approach.An open-source design based on the proposed methodology is described and validated, the NeuroDAC. NeuroDAC allows for 8 independent channels of biosignal playback using a simple, custom designed attenuation and buffering circuit. Applications can communicate with the device over a USB interface using standard audio drivers. On-board analog amplitude adjustment is used to maximize the dynamic range for a given signal and can be independently tuned for each channel.Main results.Low noise component selection yields a no-signal noise floor of just 5.35 ± 0.063. NeuroDAC's frequency response is characterized with a high pass -3 dB rolloff at 0.57 Hz, and is capable of accurately reproducing a wide assortment of biosignals ranging from EMG, EEG, and ECG to extracellularly recorded neural activity. We also present an application example using the device to test embedded algorithms on a closed-loop neural modulation device, the Medtronic RC+S.Significance.By making the design of NeuroDAC open-source we aim to present an accessible tool for rapidly prototyping new biomedical devices and algorithms than can be easily modified based on individual testing needs.ClinicalTrials.gov Identifiers: NCT04281134, NCT03437928, NCT03582891.

Helicobacter pylori infection stimulates plasminogen activator inhibitor 1 production by gastric epithelial cells.

Chronic infection with the gastric pathogen Helicobacter pylori significantly increases the risk of developing atrophic gastritis, peptic ulcer disease, and gastric adenocarcinoma. H. pylori strains that possess the cag pathogenicity island, which translocates CagA into the host cells, augment these risks. The aim of this study was to determine the molecular mechanisms through which H. pylori upregulates the expression of plasminogen activator inhibitor 1 (PAI-1), a member of the urokinase activator system that is involved in tumor metastasis and angiogenesis. Levels of PAI-1 mRNA and protein were examined in tissues from H. pylori-infected patients and in vitro using AGS gastric epithelial cells. In vitro, cells were infected with toxigenic cag-positive or nontoxigenic cag-negative strains of H. pylori or isogenic mutants. The amount of PAI-1 secretion was measured by enzyme-linked immunosorbent assay, and mRNA levels were determined using real-time PCR. The regulation of PAI-1 was examined using the extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor and small interfering RNA. Analysis of human biopsy samples revealed an increase in both PAI-1 mRNA and protein levels in patients with H. pylori gastritis compared to those of uninfected controls. Infection of AGS cells with H. pylori significantly increased PAI-1 mRNA expression and the secretion of PAI-1 protein. Moreover, PAI-1 mRNA and protein production was more pronounced when AGS cells were infected by H. pylori strains carrying a functional cag secretion system than when cells were infected by strains lacking this system. PAI-1 secretion was also reduced when cells were infected with either cagE-negative or cagA-negative mutants. The ectopic overexpression of CagA significantly increased the levels of PAI-1 mRNA and protein, whereas blockade of the ERK1/2 pathway inhibited H. pylori-mediated PAI-1 upregulation. These findings suggest that the upregulation of PAI-1 in H. pylori-infected gastric epithelial cells may contribute to the carcinogenic process.

Medial temporal lobe functional connectivity predicts stimulation-induced theta power.

Focal electrical stimulation of the brain incites a cascade of neural activity that propagates from the stimulated region to both nearby and remote areas, offering the potential to control the activity of brain networks. Understanding how exogenous electrical signals perturb such networks in humans is key to its clinical translation. To investigate this, we applied electrical stimulation to subregions of the medial temporal lobe in 26 neurosurgical patients fitted with indwelling electrodes. Networks of low-frequency (5-13 Hz) spectral coherence predicted stimulation-evoked increases in theta (5-8 Hz) power, particularly when stimulation was applied in or adjacent to white matter. Stimulation tended to decrease power in the high-frequency broadband (HFB; 50-200 Hz) range, and these modulations were correlated with HFB-based networks in a subset of subjects. Our results demonstrate that functional connectivity is predictive of causal changes in the brain, capturing evoked activity across brain regions and frequency bands.

Hepatocellular carcinoma in Txnip-deficient mice.

The molecular pathogenesis and the genetic aberrations that lead to the progression of hepatocellular carcinoma (HCC) are largely unknown. Here, we demonstrate that the thioredoxin interacting protein (Txnip) gene is a candidate tumor suppressor gene in vivo. We previously showed that the recombinant inbred congenic strain HcB-19 has a spontaneous mutation of the Txnip gene, and we now show that the strain has dramatically increased incidence of HCC, and that the HCC cosegregates with the Txnip mutation. Approximately 40% of the Txnip-deficient mice developed hepatic tumors with an increased prevalence in male mice. Visible tumors develop as early as 8 months of age. Histological analysis confirmed the morphology of HCC in the Txnip-deficient mice. Molecular markers of HCC, alpha-fetoprotein and p53, were increased in tumors of Txnip-deficient mice. The upregulation of p53 preceded tumor development; however, bromodeoxyuridine (BrdU) labeling of normal hepatic tissue of Txnip-deficient mice did not reveal increased cell proliferation. Finally, microarray analyses of tumor, non-tumor adjacent, and normal tissue of Txnip-deficient mice highlighted the genetic differences leading to the predisposition and onset of HCC. Our findings suggest that Txnip deficiency is sufficient to initiate HCC and suggest novel mechanisms in hepatocarcinogenesis.

A Multiparametric Model for Mapping Cellularity in Glioblastoma Using Radiographically Localized Biopsies.

BACKGROUND AND PURPOSE: The complex MR imaging appearance of glioblastoma is a function of underlying histopathologic heterogeneity. A better understanding of these correlations, particularly the influence of infiltrating glioma cells and vasogenic edema on T2 and diffusivity signal in nonenhancing areas, has important implications in the management of these patients. With localized biopsies, the objective of this study was to generate a model capable of predicting cellularity at each voxel within an entire tumor volume as a function of signal intensity, thus providing a means of quantifying tumor infiltration into surrounding brain tissue. MATERIALS AND METHODS: Ninety-one localized biopsies were obtained from 36 patients with glioblastoma. Signal intensities corresponding to these samples were derived from T1-postcontrast subtraction, T2-FLAIR, and ADC sequences by using an automated coregistration algorithm. Cell density was calculated for each specimen by using an automated cell-counting algorithm. Signal intensity was plotted against cell density for each MR image. RESULTS: T2-FLAIR (r = -0.61) and ADC (r = -0.63) sequences were inversely correlated with cell density. T1-postcontrast (r = 0.69) subtraction was directly correlated with cell density. Combining these relationships yielded a multiparametric model with improved correlation (r = 0.74), suggesting that each sequence offers different and complementary information. CONCLUSIONS: Using localized biopsies, we have generated a model that illustrates a quantitative and significant relationship between MR signal and cell density. Projecting this relationship over the entire tumor volume allows mapping of the intratumoral heterogeneity in both the contrast-enhancing tumor core and nonenhancing margins of glioblastoma and may be used to guide extended surgical resection, localized biopsies, and radiation field mapping.