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Primary ovarian insufficiency (POI) is a heterogeneous disorder associated with several genes. The majority of cases are still unsolved. Our aim was to identify the molecular diagnosis of a Brazilian cohort with POI. Genetic analysis was performed using a customized panel of targeted massively parallel sequencing (TMPS) and the candidate variants were confirmed by Sanger sequencing. Additional copy number variation (CNV) analysis of TMPS samples was performed by CONTRA. Fifty women with POI (29 primary amenorrhea and 21 secondary amenorrhea) of unknown molecular diagnosis were included in this study, which was conducted in a tertiary referral center of clinical endocrinology. A genetic defect was obtained in 70% women with POI using the customized TMPS panel. Twenty-four pathogenic variants and two CNVs were found in 48% of POI women. Of these variants, 16 genes were identified as BMP8B, CPEB1, INSL3, MCM9, GDF9, UBR2, ATM, STAG3, BMP15, BMPR2, DAZL, PRDM1, FSHR, EIF4ENIF1, NOBOX, and GATA4. Moreover, a microdeletion and microduplication in the CPEB1 and SYCE1 genes, respectively, were also identified in two distinct patients. The genetic analysis of eleven patients was classified as variants of uncertain clinical significance whereas this group of patients harbored at least two variants in different genes. Thirteen patients had benign or no rare variants, and therefore the genetic etiology remained unclear. In conclusion, next-generation sequencing (NGS) is a highly effective approach to identify the genetic diagnoses of heterogenous disorders, such as POI. A molecular etiology allowed us to improve the disease knowledge, guide decisions about prevention or treatment, and allow familial counseling avoiding future comorbidities.

We assessed viral co-infections in 155 patients with community-associated Clostridioides difficile infection in five U.S. sites during December 2012-February 2013. Eighteen patients (12%) tested positive for norovirus (n = 10), adenovirus (n = 4), rotavirus (n = 3), or sapovirus (n = 1). Co-infected patients were more likely than non-co-infected patients to have nausea or vomiting (56% vs 31%; p = 0.04), suggesting that viral co-pathogens contributed to symptoms in some patients. There were no significant differences in prior healthcare or medication exposures or in CDI complications.

The vast majority of surface water resources in the semi-arid western United States start as winter snowpack. Solar radiation is a primary driver of snowmelt, making snowpack water resources especially sensitive to even small increases in concentrations of light absorbing particles such as mineral dust and combustion-related black carbon (BC). Here we show, using fresh snow measurements and snowpack modeling at 51 widely distributed sites in the Rocky Mountain region, that BC dominated impurity-driven radiative forcing in 2018. BC contributed three times more radiative forcing on average than dust, and up to 17 times more at individual locations. Evaluation of 2015–2018 archived samples from most of the same sites yielded similar results. These findings, together with long-term observations of atmospheric concentrations and model studies, indicate that BC rather than dust has dominated radiative forcing by light absorbing impurities on snow for decades, indicating that mitigation strategies to reduce radiative forcing on headwater snow-water resources would need to focus on reducing winter and spring BC emissions.

This data is generated from the analysis of similarities and differences in gene expression levels and pathways among genes (VegfA, VegfB, VegfC, and Pgf) in Vegf family using whole genome expression data generated from normal retina of eighty strains of mice. The results have been published in doi:10.1016/j.exer.2018.06.024 (Cui et al., 2018) [1]. Fig. 1 shows the expression quantitative trait loci (eQTL) that regulate the expression level of each gene in the Vegf family. The other three figure show the overlapped genes among the top 500 genes that their expression levels are most closely correlated to each of the Vegf genes. The four tables contain the information of top 50 genes that their expression levels are most closely correlated to each of the Vegf genes, and the correlation of the top 50 genes from one gene to the other genes in the Vegf family. Keywords: Vegf family, eQTL, Mouse retina, Gene relationship, Expression levels

Introduction. High‑grade serous carcinoma of the ovary is an aggressive form of cancer, with unknown precursor lesions and often delayed diagnosis because of non‑specific, mild symptoms. Objective. We performed a clinical‑pathological study of ovarian high‑grade serous carcinomas, in order to evaluate morphological and new immunohistochemistry characteristics of this malignancy. Methods. This is a retrospective study of 10 cases of ovarian high‑grade serous carcinoma. We evaluated patients’ age, symptoms at presentation, macroscopic aspects, bilateral involvement, microscopic features: papillary/solid areas, mitotic index, psammoma bodies, tumoral extension, lymph node metastasis, immunohistochemistry markers: CD44, ER, AR, Ki67 index. Results. Mean age was 56.9 years old. Tumors were bilateral in 50% of cases. Only 30% were limited to the ovary. Maximum tumor diameter was 16 cm. Solid component in a proportion of 50‑95% was more characteristic. Most tumors had a mitotic index of 30‑50 mitosis/10HPF (70% of cases). 20% of cases contained psammoma bodies. 2 cases out of 7 had lymph node metastasis. We noticed one case with pleural metastasis (M1). We observed AR80% was noticed in 30% of cases. CD44 was positive in 50% of cases and one case had diffuse positivity of CD44 in corpus luteum cells near the tumoral bed. Conclusions. The majority of patients with ovarian high‑grade serous carcinomas presented with extraovarian extension and were characterized by high mitotic index, rare presence of psammoma bodies, AR expression

The ABCD twin study will elucidate the genetic and environmental contributions to a wide range of mental and physical health outcomes in children, including substance use, brain and behavioral development, and their interrelationship. Comparisons within and between monozygotic and dizygotic twin pairs, further powered by multiple assessments, provide information about genetic and environmental contributions to developmental associations, and enable stronger tests of causal hypotheses, than do comparisons involving unrelated children. Thus a sub-study of 800 pairs of same-sex twins was embedded within the overall Adolescent Brain and Cognitive Development (ABCD) design. The ABCD Twin Hub comprises four leading centers for twin research in Minnesota, Colorado, Virginia, and Missouri. Each site is enrolling 200 twin pairs, as well as singletons. The twins are recruited from registries of all twin births in each State during 2006–2008. Singletons at each site are recruited following the same school-based procedures as the rest of the ABCD study. This paper describes the background and rationale for the ABCD twin study, the ascertainment of twin pairs and implementation strategy at each site, and the details of the proposed analytic strategies to quantify genetic and environmental influences and test hypotheses critical to the aims of the ABCD study. Keywords: Twins, Heritability, Environment, Substance use, Brain structure, Brain function

Abstract Background To evaluate the clinical outcomes of patients treated with 3D conformal Hypo-fractionated, deep Inspiratory breath-hold (DIBH), Partial breast radiotherapy, termed “HIP.” HIP was implemented to merge the schedule of once-daily breast hypofractionation with partial breast treatment. Methods We identified 38 breast cancers in 37 patients from 2013 to 2014 treated at our institution with HIP following lumpectomy for early stage breast cancer. Patients received a hypo-fractionated course (≤ 20 fractions) of once daily radiation to the partial breast (lumpectomy cavity + margin) utilizing DIBH regardless of laterality. Clinical and treatment-related characteristics were obtained, including target volume and organ at risk (OAR) dosimetric characteristics. Patients were followed clinically and with at least yearly mammograms for up to 36 months (range 5–36 months). Acute and late toxicity was scored using the Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Results Patients received a median dose of 42.56 Gy in 16 Fractions (Fx) (range 40.05–53.2 Gy; and 15–20 Fx). OAR doses were low, with a mean heart dose of 0.37 Gy, an ipsilateral lung V20 mean of 4%, and a contralateral lung V5 of 1%. Acute toxicity (≤ grade 2) was present in 79% (n = 30) of the cases, with dermatitis being the most common finding (63%). Late grade 1–2 toxicity was present in 42% (n = 16) of the cases, with hyperpigmentation being the most common finding (n = 9). There were no severe acute or late toxicities (≥ grade 3). At a median follow up of 21 months, there were no local, regional, or distant failures. Conclusions We report limited toxicity in this low risk cohort of patients with early stage breast cancer treated with HIP, a unique and logical combination of 3-D conformal external beam radiotherapy, moderate hypo-fractionation, and DIBH.

Abstract Mycobacterium avium subspecies paratuberculosis (Map) is the cause of Johne’s disease, a chronic enteritis of cattle. A significant knowledge gap is how persistence of Map within the intestinal tract after infection contributes to progression of disease. To address this, we exposed calves to Map by direct ileocecal Peyer’s patch injection. Our objective was to characterize the persistence of Map in tissues, associated intestinal lesions, fecal Map shedding, and serum antibody responses, through the first 28-weeks post-inoculation (wpi). Previous work using this model showed 100% rate of Map infection in intestine and lymph node by 12 wpi. We hypothesized that direct inoculation of Map into the distal small intestine would induce intestinal Map infection with local persistence and progression towards clinical disease. However, our data show decreased persistence of Map in the distal small intestine and draining lymph nodes. We identified Map in multiple sections of distal ileum and draining lymph node of all calves at 4 and 12 wpi, but then we observed reduced Map in distal ileum at 20 wpi, and by 28 wpi we found that 50% of animals had no detectable Map in intestine or the lymph node. This provides evidence of resilience to Map infection following direct intestinal Map inoculation. Further work examining the immune responses and host–pathogen interactions associated with this infection model are needed to help elicit the mechanisms underlying resilience to Map infection.

Ceftriaxone remains a first-line treatment for patients infected by Neisseria gonorrhoeae in most settings. We investigated the possible spread of a ceftriaxone-resistant FC428 N. gonorrhoeae clone in Japan after recent isolation of similar strains in Denmark (GK124) and Canada (47707). We report 2 instances of the FC428 clone in Australia in heterosexual men traveling from Asia. Our bioinformatic analyses included core single-nucleotide variation phylogeny and in silico molecular typing; phylogenetic analysis showed close genetic relatedness among all 5 isolates. Results showed multilocus sequence type 1903; N. gonorrhoeae sequence typing for antimicrobial resistance (NG-STAR) 233; and harboring of mosaic penA allele encoding alterations A311V and T483S (penA-60.001), associated with ceftriaxone resistance. Our results provide further evidence of international transmission of ceftriaxone-resistant N. gonorrhoeae. We recommend increasing awareness of international spread of this drug-resistant strain, strengthening surveillance to include identifying treatment failures and contacts, and strengthening international sharing of data.

Purpose: In low- and middle-income countries with limited resources, the success of a hematopoietic stem-cell transplantation (HSCT) program relies directly on its affordability while obtaining similar outcomes to developed regions. The objective of this study was to describe the experience of a tertiary/referral center in Mexico City performing HSCT with the subsidy of a nongovernmental organization (NGO). Patients and Methods: We performed a retrospective analysis including 146 patients who underwent HSCT at the National Institutes of Health Sciences and Nutrition Salvador Zubiran and were subsidized by the NGO Unidos. Results: Seventy-five patients (51%) and 71 patients (49%) underwent autologous and allogeneic HSCT, respectively. The median age was 30 years, 56% did not obtain a bachelor’s degree, 79% had a low socioeconomic level, and 75% were unemployed. None had any health coverage. According to the real patient out-of-pocket expense, the subsidy by Unidos corresponded to 88% and 72% in autologous and allogeneic HSCT, respectively. Conclusion: Our results highlight that undergoing an HSCT was feasible for vulnerable patients because of the subsidy of medications and chemotherapy by Unidos. Therefore, creating NGOs in developing countries is important to provide complex medical procedures, such as HSCT, at limited-resource centers to underserved populations while obtaining good outcomes.

BXD recombinant inbred (RI) lines represent a genetic reference population derived from a cross between C57BL/6J mice (B6) and DBA/2J mice (D2), which through meiotic recombination events possesses recombinant chromosomes containing B6 or D2 haplotype segments. The quantitative trait loci (QTLs) are the locations of segregating genetic polymorphisms and are fundamental to understanding genetic diversity in human disease susceptibility and severity. QTL mapping represents the typical approach for identifying naturally occurring polymorphisms that influence complex phenotypes. In this process, genotypic values at markers of known genomic locations are associated with phenotypic values measured in a segregating population. Indeed, BXD RI strains provide a powerful tool to study neurotoxicity induced by different substances. In this review, we describe the use of BXD RI lines to understand the underlying mechanisms of neurotoxicity in response to ethanol and cocaine, as well as metals and pesticide exposures.

Retinitis pigmentosa (RP) is a hereditary disease of the retina that results in complete blindness. Currently, there are very few treatments for the disease and those that exist work only for the recessively inherited forms. To better understand the pathogenesis of RP, multiple mouse models have been generated bearing mutations found in human patients including the human Q344X rhodopsin knock-in mouse. In recent years, the immune system was shown to play an increasingly important role in RP degeneration. By way of electroretinography, optical coherence tomography, funduscopy, fluorescein angiography, and fluorescent immunohistochemistry, we show degenerative and vascular phenotypes, microglial activation, photoreceptor phagocytosis, and upregulation of proinflammatory pathway proteins in the retinas of the human Q344X rhodopsin knock-in mouse. We also show that an FDA-approved pharmacological agent indicated for the treatment of rheumatoid arthritis is able to halt activation of pro-inflammatory signaling in cultured retinal cells, setting the stage for pre-clinical trials using these mice to inhibit proinflammatory signaling in an attempt to preserve vision. We conclude from this work that pro- and autoinflammatory upregulation likely act to enhance the progression of the degenerative phenotype of rhodopsin Q344X-mediated RP and that inhibition of these pathways may lead to longer-lasting vision in not only the Q344X rhodopsin knock-in mice, but humans as well.

Glaucoma is a leading cause of permanent vision loss and current drugs do not halt disease progression. Thus, new therapies targeting different drug targets with novel mechanisms of action are urgently needed. Previously, we identified CACNA2D1 as a novel modulator of intraocular pressure (IOP) and demonstrated that a topically applied CACNA2D1 antagonist—pregabalin (PRG)—lowered IOP in a dose-dependent manner. To further validate this novel IOP modulator as a drug target for IOP-lowering pharmaceutics, a homology model of CACNA2D1 was built and docked against the NCI library, which is one of the world’s largest and most diverse compound libraries of natural products. Acivicin and zoledronic acid were identified using this method and together with PRG were tested for their plausible IOP-lowering effect on Dutch belted rabbits. Although they have inferior potency to PRG, both of the other compounds lower IOP, which in turn validates CACNA2D1 as a valuable drug target in treating glaucoma.

The statistical analysis of historic pressure and temperature profiles from radiosonde launches for use in the fitting of molecular oxygen line shapes is presented. As the O2 mixing ratio is nearly constant throughout the lower atmosphere, only variations in pressure and temperature profiles will affect the fit of observed O2 features in Laser Heterodyne Radiometry (LHR) spectra. Radiosonde temperature and pressure data are extracted from the Integrated Global Radiosonde Archive (IGRA) for a given station, date, and launch time. Data may be extracted for a single launch, for the same date over several years, and/or within a window centered on a target date. The temperature and pressure profiles are further characterized by the statistical variation in coefficients of polynomial fits in altitude. The properties of the probability distributions for each coefficient are used to constrain fits of O2 line shapes through Nelder–Mead optimization. The refined temperature and pressure profiles are then used in the retrieval of vertically resolved mixing ratios for greenhouse gases (GHGs) measured in the same instrument. In continuous collections, each vertical profile determination may be treated as a Bayesian prior to inform subsequent measurements and provide an estimate of uncertainties.

Elevated intraocular pressure (IOP) is a heritable risk factor for primary open angle glaucoma. Using forward mouse genetics, cell biology, pharmacology and human genetic data, the authors identify CACNA2D1 as an IOP risk gene that can be therapeutically targeted by the drug pregabalin in animal models.

Suicide is the 10th leading cause of death with 42,773 reported deaths in the United States in 2014, half of those by firearm. Although veterans comprise only 13% of the U.S. population, they account for 20% of all suicide deaths. About 67% of these deaths are by firearm in the veteran population, compared to about 50% in the general public. Although researchers are learning more about suicide, factors that place a person at risk for, or protect a person from suicide by firearms, are not well understood. Few studies have specifically examined survivors of an acute attempt or serious ideation of suicide with firearms among veterans. This theoretical paper aims to describe the conceptual framework, measures, lessons learned, and implications for veterans’ scholarship from a mixed methods study on veteran survivors of a suicide attempt or ideation requiring hospitalization. Using a Department of Veterans Affairs funded pilot study as an example, we present the quantitative measures and qualitative interview topics selected for use in this study. While rigorous mixed methods research requires the use of two forms of data from research participants, best practices for research administration requires maximum researcher sensitivity and protocol adherence to ensure safety for this subpopulation.

Veterans and military personnel may be at higher risk for developing addictions due to increased prevalence rates of co-occurring mental health disorders including posttraumatic stress and substance abuse disorders. However, clinicians may feel unprepared to assess and to treat these co-occurring disorders, especially when it includes a behavioral addiction such as gambling. Clinical social work and clinical behavior analysis are two fields with complementary interdisciplinary approaches that can lead to improved client-centered outcomes. Yet, limited evidence exists to guide interdisciplinary treatment teams in effective treatment of gambling addictions and Post Traumatic Stress Disorder (PTSD). The current article provides an interdisciplinary treatment model to assist clinicians in selecting appropriate evidence-based assessments and treatments. A case example focuses on the use of assessment tools and treatment approaches drawn from recommendations from best practice guidelines for veterans. Finally, resources related trauma and addictions are presented.

Neisseria gonorrhoeae antimicrobial resistance (AMR) is a globally recognized health threat; new strategies are needed to enhance AMR surveillance. The Northern Territory of Australia is unique in that 2 different first-line therapies, based primarily on geographic location, are used for gonorrhea treatment. We tested 1,629 N. gonorrhoeae nucleic acid amplification test–positive clinical samples, collected from regions where ceftriaxone plus azithromycin or amoxicillin plus azithromycin are recommended first-line treatments, by using 8 N. gonorrhoeae AMR PCR assays. We compared results with those from routine culture-based surveillance data. PCR data confirmed an absence of ceftriaxone resistance and a low level of azithromycin resistance (0.2%), and that penicillin resistance was

Abstract Background Very little is known about the incidence and prevalence of hydrocephalus in patients with mucopolysaccharidoses (MPS). The biggest challenge is to distinguish communicating hydrocephalus from ventricular dilatation secondary to brain atrophy, because both conditions share common clinical and neuroradiological features. The main purpose of this study is to assess the relationship between ventriculomegaly, brain and cerebrospinal fluid (CSF) volumes, aqueductal and cervical CSF flows, and CSF opening pressure in MPS patients, and to provide potential biomarkers for abnormal CSF circulation. Methods Forty-three MPS patients (12 MPS I, 15 MPS II, 5 MPS III, 9 MPS IV A and 2 MPS VI) performed clinical and developmental tests, and T1, T2, FLAIR and phase-contrast magnetic resonance imaging (MRI) followed by a lumbar puncture with the CSF opening pressure assessment. For the analysis of MRI variables, we measured the brain and CSF volumes, white matter (WM) lesion load, Evans’ index, third ventricle width, callosal angle, dilated perivascular spaces (PVS), craniocervical junction stenosis, aqueductal and cervical CSF stroke volumes, and CSF glycosaminoglycans concentration. Results All the scores used to assess the supratentorial ventricles enlargement and the ventricular CSF volume presented a moderate correlation with the aqueductal CSF stroke volume (ACSV). The CSF opening pressure did not correlate either with the three measures of ventriculomegaly, or the ventricular CSF volume, or with the ACSV. Dilated PVS showed a significant association with the ventriculomegaly, ventricular CSF volume and elevated ACSV. Conclusions In MPS patients ventriculomegaly is associated with a severe phenotype, increased cognitive decline, WM lesion severity and enlarged PVS. The authors have shown that there are associations between CSF flow measurements and measurements related to CSF volumetrics. There was also an association of volumetric measurements with the degree of dilated PVS.

Abstract Breast cancer survivors are more likely to develop mood disorders and cognitive deficits than women in the general population. Previous studies suggest that peripheral tumors elicit central pro-inflammatory cytokine production, in turn leading to depression and cognitive deficits. In the current study, two cohorts of female Balb/C mice received bilateral orthotopic injections of syngeneic 67NR, 4T07, or 4T1cells (1 × 105 cells per injection) to induce mammary tumors. Approximately three weeks later, learned fear (via fear conditioning) or depressive-like behavior (via tail suspension and forced swim test) was assessed. Proinflammatory cytokine levels were increased in the serum (IL-1β, TNFα, IFNγ) and livers (IL-1β, IL-6, TNFα) of mice with 4T07 or 4T1 tumors compared to 67NR tumors and the vehicle control. IL-1β was increased in both the hippocampus and cortex of mice injected with 4T07 or 4T1 cell lines relative to the other treatment groups. However, mammary tumors had no effect on hippocampal doublecortin + and did not alter depressive-like behavior or learned fear. These data demonstrate that similarly sized tumors can produce differential immune responses and that tumor-induced central pro-inflammatory cytokine production can exist in the absence of depressive-like behavior or cognitive deficits.

The zinc(II) atom in the title compound, [Zn(C48H31N4)(CF3SO3)](CF3SO3)·1.5CH2Cl2, adopts a distorted five-coordinate square-pyramidal geometry. It is coordinated by one trifluoromethanesulfonate ligand and four N atoms of the N2-[(benzo[h]quinolin-2-yl)methyl]-N2′-[(benzo[h]quinolin-2-yl)methylidene]-1,1′-binaphthyl-2,2′-diamine ligand. The complex is present as a single-stranded P-helimer monohelical structure incorporating π–π and/or σ–π interactions. One of the imine bonds present in the original ligand framework is reduced, leading to variations in bond lengths and torsion angles for each side of the ligand motif. The imine-bond reduction also affects the bond lengths involving the metal atom with the N-donor atoms located on the imine bond. There are two molecules of the complex in the asymmetric unit. One of the molecules exhibits positional disorder within the coordinating trifluoromethanesulfonate ion making the molecules symmetrically non-equivalent.

Abstract Background Corneal ulcerative disease (CUD) has the potential to adversely affect animal welfare by interfering with vision and causing pain. The study aimed to investigate for the first time the prevalence, breed-based risk factors and clinical management of CUD in the general population of dogs under primary veterinary care in England. Results Of 104,233 dogs attending 110 clinics participating within the VetCompass Programme from January 1st to December 31st 2013, there were 834 confirmed CUD cases (prevalence: 0.80%, 95% confidence interval (CI) 0.75–0.86). Breeds with the highest prevalence included Pug (5.42% of the breed affected), Boxer (4.98%), Shih Tzu (3.45%), Cavalier King Charles Spaniel (2.49%) and Bulldog (2.41%). Purebred dogs had 2.23 times the odds (95% CI 1.84–2.87, P

There is a clinical need to develop a bioengineering system to support ovary transplantation. Here, the authors generate a bioprosthetic ovary using 3D printed scaffolds of varying pore architectures to support follicle survival and ovarian function in sterilized mice.

Summary: Ebola hemorrhagic fever (EHF) is an emerging threat to public health. The last epidemic in West Africa had a great effect on the affected communities. Timely and effective interventions were necessary in addition to community participation to control the epidemic. The knowledge, attitude and practices of vulnerable communities remain unknown, particularly in Sudan.The aim of this study was to explore the knowledge, attitude and practices of rural residents in Sudan regarding Ebola hemorrhagic fever.We conducted a cross sectional, community-based large-scale study in Al Gaziera state in rural Sudan in eight localities. In total, 1500 random adult participants were selected. The participants were assessed by a predesigned pretested questionnaire regarding their knowledge, attitude and practices regarding Ebola. Their sources of information were determined, and we assessed demographic factors as predictors of knowledge.We found poor knowledge, a fair attitude and suboptimal practices among the participants. The main sources of information were the press and media. Education was the only predictor of knowledge regarding Ebola.A lack of knowledge and suboptimal preventive practices mandates orientation and education programs to raise public awareness. Health care providers are advised to engage more in educating the community. Keywords: Ebola knowledge, Attitude, Practice, Health care providers, Education

The female reproductive tract constitutes the ovary, fallopian tubes, uterus, and cervix, but it is challenging to engineer this systemin vitro. Here, the authors develop a microfluidic device (EVATAR) with reproductive tract and peripheral tissues to replicate hormone release of a 28-day menstrual cycle.

Neuroendocrine tumors of the breast are very rare accounting for less than 0.1% of all breast cancers and less than 1% of all neuroendocrine tumors. Focal neuroendocrine differentiation can be found in different histologic types of breast carcinoma including in situ and invasive ductal or invasive lobular. However, primary neuroendocrine carcinoma of the breast requires the expression of neuroendocrine markers in more than 50% of the cell population, the presence of ductal carcinoma in situ, and the absence of clinical evidence of concurrent primary neuroendocrine carcinoma of any other organ. Reports discussing the imaging characteristics of this rare carcinoma in different breast imaging modalities are scarce. We present 2 cases of primary neuroendocrine carcinoma of the breast for which mammography, ultrasound, and magnetic resonance imaging findings and pathology findings are described. A review of the medical literature on this particular topic was performed, and the results are presented.

Objective: To assess the results of an initial round of supplemental screening with hand-held bilateral breast ultrasound following a negative screening mammogram in asymptomatic women with dense breast tissue who are not at high risk for breast cancer. Materials and Methods: A retrospective, Health Insurance Portability and Accountability Act compliant, Institutional Research Board approved study was performed at a single academic tertiary breast center. Informed consent was waived. A systematic review of the breast imaging center database was conducted to identify and retrieve data for all asymptomatic women, who were found to have heterogeneously dense or extremely dense breast tissue on screening bilateral mammograms performed from July 1, 2010 through June 30, 2012 and who received a mammographic final assessment American College of Radiology's (ACR) Breast Imaging Reporting and Data System (BI-RADS) category 1 or BI-RADS category 2. Hand-held screening ultrasound was performed initially by a technologist followed by a radiologist. Chi-square and t-test were used and statistical significance was considered at P< 0.05. Results: A total of 1210 women were identified. Of these, 394 underwent the offered supplemental screening ultrasound. BI-RADS category 1 or 2 was assigned to 323 women (81.9%). BI-RADS category 3 was assigned to 50 women (12.9%). A total of 26 biopsies/aspirations were recommended and performed in 26 women (6.6%). The most common finding for which biopsy was recommended was a solid mass (88.5%) with an average size of 0.9 cm (0.5–1.7 cm). Most frequent pathology result was fibroadenoma (60.8%). No carcinoma was found. Conclusion: Our data support the reported occurrence of a relatively high number of false positives at supplemental screening with breast ultrasound following a negative screening mammogram in asymptomatic women with dense breast tissue, who are not at a high risk of developing breast cancer, and suggests that caution is necessary in establishing wide implementation of this type of supplemental screening for all women with dense breast tissue without considering other risk factors for breast cancer.

The ceftriaxone-resistant Neisseria gonorrhoeae FC428 clone was first observed in Japan in 2015, and in 2017, it was documented in Denmark, Canada, and Australia. Here, we describe a PCR for direct detection of the penA gene associated with this strain that can be used to enhance surveillance activities.

The Partnership for HIV-Free Survival initiative in Tanzania integrated postnatal nutrition and mother-to-child transmission (MTCT) cascades to reduce vertical HIV transmission. Quality improvement (QI) was implemented in 30 health facilities. Net positive gain resulted in overall improvement in all indicators (above 80%) by the end of the reporting period. Retention in postnatal care (mean = 49.8, standard deviation [SD] = 27.6) and in monthly HIV services (mean = 65.4, SD = 29.5) had the lowest average but showed consecutive and significant ( P ≤ .001) gains except for significant decreases in 1 of 6 periods assessed. Average antiretroviral therapy uptake among women (mean = 81.7, SD = 29.5) was highest, with an initial positive gain of 78.9% ( P ≤ .001). DNA/polymerase chain reaction for HIV-exposed infants (mean = 71.8, SD = 20.9) and nutrition counseling (mean = 71.2, SD = 26.3) showed similar average performance, with the latter being the only indicator with significant equal periods of gain and decreases. The collaborative QI approach improved process indicators for reducing MTCT in resource-constrained health systems.

The World Health Organization guidelines for treating pregnant HIV-positive women and preventing HIV transmission to infants now recommend lifelong antiretroviral treatment for pregnant and breastfeeding women. We applied quality improvement (QI) methods to support governments and facility staff to address service gaps in 5 countries under the Partnership for HIV-Free Survival (PHFS). We used 3 key strategies: break the complex problem of improving HIV-free survival into more easily implementable phases, support a national management team to oversee the project, and support facility-level staff to learn and apply QI methods to reducing mother-to-child transmission. The key results in each country were increases in data completeness and accuracy, increases in retention in care of mother–baby pairs (MBPs), increase in coverage of MBPs with appropriate services, and reduction in vertical transmission of HIV. The PHFS experience offers a model that other multicountry networks can adopt to improve service delivery and quality of care.

The rapid increase in the number of individuals with obesity, over the past four decades, is triggered by a number of complex interactions among factors. Despite the plethora of treatments available, side effects are commonly observed and, in this context, herbal medicines have been employed as an alternative form of therapy. Ginkgo biloba extract (GbE) has been described as a promising new pharmacological approach to treat obesity. In order to better comprehend the mechanisms involved with this potential effect, the present study evaluated the effects of GbE treatment on diet-induced obese rats, focusing on the proteome and the oxidative stress defense system of visceral adipose tissue. After 14 days treatment, GbE significantly modulated 25 proteins. Retroperitoneal adipose tissue of treated animals exhibited higher amounts of proteins associated with adipogenesis (decorin), carbon metabolism and mitochondrial function (citrate synthase), and a concomitant reduction in adipocyte hypertrophy. In parallel, GbE down-regulated proteins involved in oxidative stress (peroxiredoxin) and the inflammatory response (complement C3, mast cell protease 1, and Ig gamma-2B chain C region). Moreover, also related to oxidative stress defense, GbE stimulated catalase activity, reduced malondialdehyde levels (lipid peroxidation indicator), and increased lactoylglutathione lyase levels. It was concluded that GbE acts as an antioxidant agent, and improved the proteome profile and oxidative stress response in the adipose tissue of diet-induced obese rats.

Over half of mother-to-child HIV transmission (MTCT) occurs postdelivery. Keeping mother–infant pairs in care remains challenging. Health workers in 3 countries used quality improvement (QI) approaches to improve data systems, mother–infant retention, and facility-based care delivery. The number and proportion of infants with known HIV status at time of discharge from early infant diagnosis programs increased in Tanzania and Uganda. We analyzed data using statistical process control charts. Mother-to-child HIV transmission did not decrease in 15 Kenyan sites, decreased from 12.7% to 3.8% in 28 Tanzanian sites, and decreased from 17.2% to 1.5% in 10 Ugandan sites with baseline data. This improvement is likely due to the combination of option B+, service delivery improvements, and retention through QI approaches. Reaching the global MTCT elimination target and maximizing infant survival will require health systems to support mother–infant pairs to remain in care and support health workers to deliver care. Quality improvement approaches can support these changes.

Exacerbated expansion of adipose tissue seen in diet-induced obesity leads to endocrine dysfunction and disturbance in adipokine secretion, with such abnormal profile positively associated with type 2 diabetes and other mild chronic inflammatory conditions. Ginkgo biloba extract (GbE), a mixture of polyphenols with antioxidant properties, has been recently investigated in a variety of experimental models of endocrine dysfunction, with several potentially beneficial effects identified, including improvement in insulin sensitivity in obese rats, and reduction of weight gain in ovariectomy-induced obesity and diet-induced obesity. The aim of this study was to investigate in high fat diet-induced obese male rats the effects of GbE supplementation for 2 weeks on adipocyte volume and adipose tissue lipid accumulation. GbE supplementation was effective in reducing energy intake in obese rats compared to the saline-treated placebo group. Epididymal adipocyte volume was reduced in GbE-supplemented rats, as were epididymal [1-14C]-acetate incorporation into fatty acids, perilipin (Plin 1) and fatty acid synthase (Fasn) mRNA, and FAS protein levels. Adipocyte hypertrophy in obesity is associated with insulin resistance, and in the present study we observed a reduction in the adipocyte volume of GbE-supplemented obese rats to dimensions equivalent to adipocytes from non-obese rats. GbE supplementation significantly reduced acetate accumulation and tended to reduce [3H]-oleate incorporation, into epididymal adipose tissue, suggesting a potentially anti-obesogenic effect in longer term therapies. Further studies that investigate the effects of GbE supplementation in other experimental models are required to fully elucidate its suggested beneficial effects on mild chronic inflammatory conditions.

The lipophilic electron-transport cofactor rhodoquinone (RQ) facilitates anaerobic metabolism in a variety of bacteria and selected eukaryotic organisms in hypoxic environments. We have shown that an intact rquA gene in Rhodospirillum rubrum is required for RQ production and efficient growth of the bacterium under anoxic conditions. While the explicit details of RQ biosynthesis have yet to be fully delineated, ubiquinone (Q) is a required precursor to RQ in R. rubrum, and the RquA gene product is homologous to a class I methyltransferase. In order to identify any additional requirements for RQ biosynthesis or factors influencing RQ production in R. rubrum, we performed transcriptome analysis to identify differentially expressed genes in anoxic, illuminated R. rubrum cultures, compared with those aerobically grown in the dark. To further select target genes, we employed a bioinformatics approach to assess the likelihood that a given differentially expressed gene under anoxic conditions may also have a direct role in RQ production or regulation of its levels in vivo. Having thus compiled a list of candidate genes, nine were chosen for further study by generation of knockout strains. RQ and Q levels were quantified using liquid chromatography-mass spectrometry, and rquA gene expression was measured using the real-time quantitative polymerase chain reaction. In one case, Q and RQ levels were decreased relative to wild type; in another case, the opposite effect was observed. These results comport with the crucial roles of rquA and Q in RQ biosynthesis, and reveal the existence of potential modulators of RQ levels in R. rubrum.

Jackson Pollock's most celebrated abstract paintings were produced with the so-called dripping technique. By pouring liquid paint with the help of a stick or from a can, Pollock deposited viscous fluid filaments on a horizontal canvas, rhythmically moving around it. The intricate webs of lines, ubiquitous in his compositions, have fascinated art historians and scientists. Based on image analysis of historical video recordings, we experimentally reproduced the painting process. We conclude that Pollock avoided the appearance of the hydrodynamic instabilities, contrary to what was argued by previous studies. Pollock selected the physical properties of the paint to prevent filament fragmentation before deposition, and applied it while moving his hand sufficiently fast and at certain heights to avoid fluid filaments from coiling into themselves. An understanding of the physical conditions at which these patterns were created is important to further art research and it can be used as a tool in the authentication of paintings.

BackgroundAntimicrobial resistance in Neisseria gonorrhoeae is a global concern, with the ongoing emergence of ceftriaxone and azithromycin resistance threatening current treatment paradigms. To monitor the emergence of antimicrobial resistance in N. gonorrhoeae, the World Health Organization (WHO) Gonococcal Antimicrobial Surveillance Programme (GASP) has operated in the Western Pacific and South East Asian regions since 1992. The true burden of antimicrobial resistance remains unknown. In response, the objective of this study was to survey ceftriaxone and azithromycin susceptibility in N. gonorrhoeae across the western Pacific and south-east Asia, and interlink this data with systematically reviewed reports of ceftriaxone and azithromycin resistance.Methods and findingsThe WHO Collaborating Centre for Sexually Transmitted Infections and Antimicrobial Resistance, Sydney, coordinated annual surveys of gonococcal susceptibilities with participating laboratories, and additionally undertook a systematic review of reports detailing gonococcal ceftriaxone and azithromycin susceptibility data for locations geographically in the Asia Pacific from 2011 to 2016. It was found that surveillance of gonococcal antimicrobial resistance remains limited in the Asia Pacific, with weaker surveillance of azithromycin versus ceftriaxone. Ninety-three published reports were identified (including national reports) which documented susceptibility data for ceftriaxone and azithromycin. GASP survey data was available for 21 countries, territories or areas, and suggested MICs are increasing for ceftriaxone and azithromycin. Between 2011 and 2016, the percentage of locations reporting >5% of gonococcal isolates with MICs to ceftriaxone meeting WHO's definition of decreased susceptibility (MIC ≥ 0.125 mg/L) increased from 14.3% to 35.3% and the percentage of locations reporting >5% of gonococcal isolates with azithromycin resistance (MIC ≥ 1 mg/L) increased from 14.3% to 38.9%. Published reports were available for several countries that did not provide GASP surveillance responses for ceftriaxone (n = 5) and azithromycin (n = 3) respectively. Over the study period, there was a 183% increase in the number of countries providing surveillance data for GASP for both ceftriaxone and azithromycin, and a 30.6% increase in ceftriaxone MIC testing across the Asia Pacific facilitated by this project.ConclusionThis study provides the first comprehensive illustration of increasing MICs to ceftriaxone in the Asia Pacific. The survey and literature review additionally detail increasing resistance to azithromycin. Further surveillance system strengthening is required to monitor these trends in order to address and curb gonococcal AMR in the region.

Background"Horizontal strokes should be level and vertical strokes should be straight" is a common guideline in the teaching of Chinese handwriting. Measuring deviations in level horizontal and straight vertical strokes in students' Chinese handwriting is usually assessed manually. However, this task is time-consuming and may have inconsistent outcomes when judged by different people. In this paper, we aim to formulate a method to automatically evaluate the tilt and slant degrees of students' Chinese handwriting using digital handwriting tablets. Furthermore, we analyze the relationship between the tilt and slant features of students' Chinese handwriting and other demographic and handwriting features.MethodsFive hundred and ninety-one primary school students from grades 1 to 6 were recruited in Hong Kong. Before the assessment, a grid paper was attached to a digital handwriting tablet. The participants were then asked to copy 90 Chinese characters from a template to the grid paper. Their handwriting processes were recorded as two-dimensional points and then analyzed. The tilt and slant of the students' handwriting were calculated based on the inclination level of their horizontal and vertical strokes. Linear regressions between slant/tilt degree of the manuscripts and other handwriting features were performed. The students' demographic information was also explored.ResultsSlant was found to be significantly correlated to Gender (p < 0.001) and tilt×standard deviation of pen pressure (p < 0.001). Tilt was found to be significantly correlated to ground time (p < 0.001), slant (p < 0.001) and slant×special education need (p = 0.021).ConclusionsOur results demonstrate the relationship between slant, tilt and Chinese handwriting performance in primary school children. Slant and tilt can be adopted as an indicator in students' special education need diagnosis, as tilt level in the students' Chinese handwriting was related to ground time and slant× special education need, while slant is related to tilt×standard deviation of pen pressure and female students. These findings may also inspire ways to increase special education need students' writing speed.

Streptococcus pneumoniae is a highly impactful bacterial pathogen on a global scale. The principal pneumococcal virulence factor and target of effective vaccines is its polysaccharide capsule, of which there are many structurally distinct forms. Here, we describe four distinct strains of three Mitis group commensal species (Streptococcus infantis, Streptococcus mitis, and Streptococcus oralis) recovered from upper respiratory tract specimens from adults in Kenya and the United States that were PCR-positive for the pneumococcal serotype 5 specific gene, wzy5. For each of the four strains, the 15 genes comprising the capsular polysaccharide biosynthetic gene cluster (cps5) shared the same order found in serotype 5 pneumococci, and each of the serotype 5-specific genes from the serotype 5 pneumococcal reference strain shared 76–99% sequence identity with the non-pneumococcal counterparts. Double-diffusion experiments demonstrated specific reactivity of the non-pneumococcal strains with pneumococcal serotype 5 typing sera. Antiserum raised against S. mitis strain KE67013 specifically reacted with serotype 5 pneumococci for a positive Quellung reaction and stimulated serotype 5 specific opsonophagocytic killing of pneumococci. Four additional commensal strains, identified using PCR serotyping assays on pharyngeal specimens, revealed loci highly homologous to those of pneumococci of serotypes 12F, 15A, 18C, and 33F. These data, in particular the species and strain diversity shown for serotype 5, highlight the existence of a broad non-pneumococcal species reservoir in the upper respiratory tract for the expression of capsular polysaccharides that are structurally related or identical to those corresponding to epidemiologically significant serotypes. Very little is known about the genetic and antigenic capsular diversity among the vast array of commensal streptococcal strains that represent multiple diverse species. The discovery of serotype 5 strains within three different commensal species suggests that extensive capsular serologic overlap exists between pneumococci and other members of the diverse Mitis group. These findings may have implications for our current understanding of naturally acquired immunity to S. pneumoniae and pneumococcal serotype distributions in different global regions. Further characterization of commensal strains carrying homologs of serotype-specific genes previously thought to be specific for pneumococci of known serotypes may shed light on the evolution of these important loci.

Summary: Complement-mediated cytotoxicity may act as a selective pressure for tumor overexpression of complement regulators. We hypothesize that the same selective pressure could lead to complement alterations at the genetic level. We find that, when analyzed as a pathway, mutations in complement genes occur at a relatively high frequency and are associated with changes in overall survival across a number of cancer types. Analysis of pathways expressed in patients with complement mutations that are associated with poor overall survival reveals crosstalk between complement and hypoxia in colorectal cancer. The importance of this crosstalk is highlighted by two key findings: hypoxic signaling is increased in tumors harboring complement mutations, and hypoxic tumor cells are resistant to complement-mediated cytotoxicity due, in part, to hypoxia-induced expression of complement regulator CD55. The range of strategies employed by tumors to dysregulate the complement system testifies to the importance of this pathway in tumor progression. : Mutations in the complement system are prevalent across cancers. Olcina et al. find that colorectal cancers with complement component mutations are associated with increased hypoxic signaling and poor overall survival outcomes. Hypoxia-induced expression of complement regulator CD55 controls complement-mediated cytotoxicity. Keywords: innate immunity, cancer, mutations, hypoxia, complement system, complement-mediated cytotoxicity

An amendment to this paper has been published and can be accessed via the original article.

Rheumatoid arthritis (RA) management leans toward achieving remission or low disease activity. In this study, we conducted single-cell RNA sequencing (scRNA-Seq) of peripheral blood mononuclear cells (PBMCs) from 36 individuals (18 patients with RA and 18 matched controls, accounting for age, sex, race, and ethnicity), to identify disease-relevant cell subsets and cell type-specific signatures associated with disease activity. Our analysis revealed 18 distinct PBMC subsets, including an IFN-induced transmembrane 3-overexpressing (IFITM3-overexpressing) IFN-activated monocyte subset. We observed an increase in CD4+ T effector memory cells in patients with moderate-high disease activity (DAS28-CRP ≥ 3.2) and a decrease in nonclassical monocytes in patients with low disease activity or remission (DAS28-CRP < 3.2). Pseudobulk analysis by cell type identified 168 differentially expressed genes between RA and matched controls, with a downregulation of proinflammatory genes in the γδ T cell subset, alteration of genes associated with RA predisposition in the IFN-activated subset, and nonclassical monocytes. Additionally, we identified a gene signature associated with moderate-high disease activity, characterized by upregulation of proinflammatory genes such as TNF, JUN, EGR1, IFIT2, MAFB, and G0S2 and downregulation of genes including HLA-DQB1, HLA-DRB5, and TNFSF13B. Notably, cell-cell communication analysis revealed an upregulation of signaling pathways, including VISTA, in both moderate-high and remission-low disease activity contexts. Our findings provide valuable insights into the systemic cellular and molecular mechanisms underlying RA disease activity.

Distal sensory polyneuropathy (DSP) is a disabling, chronic condition in people with HIV (PWH), even those with viral suppression of antiretroviral therapy (ART), and with a wide range of complications, such as reduced quality of life. Previous studies demonstrated that DSP is associated with inflammatory cytokines in PWH. Adhesion molecules, essential for normal vascular function, are perturbed in HIV and other conditions linked to DSP, but the link between adhesion molecules and DSP in PWH is unknown. This study aimed to determine whether DSP signs and symptoms were associated with a panel of plasma biomarkers of inflammation (d-dimer, sTNFRII, MCP-1, IL-6, IL-8, IP-10, sCD14) and vascular I integrity (ICAM-1, VCAM-1, uPAR, MMP-2, VEGF, uPAR, TIMP-1, TIMP-2) and differed between PWH and people without HIV (PWoH). A cross-sectional study was conducted among 143 participants (69 PWH and 74 PWoH) assessed by studies at the UC San Diego HIV Neurobehavioral Research Program. DSP signs and symptoms were clinically assessed for all participants. DSP was defined as two or more DSP signs: bilateral symmetrically reduced distal vibration, sharp sensation, and ankle reflexes. Participant-reported symptoms were neuropathic pain, paresthesias, and loss of sensation. Factor analyses reduced the dimensionality of the 15 biomarkers among all participants, yielding six factors. Logistic regression was used to assess the associations between biomarkers and DSP signs and symptoms, controlling for relevant demographic and clinical covariates. The 143 participants were 48.3% PWH, 47 (32.9%) women, and 47 (33.6%) Hispanics, with a mean age of 44.3 ± 12.9 years. Among PWH, the median (IQR) nadir and current CD4+ T-cells were 300 (178-448) and 643 (502-839), respectively. Participants with DSP were older but had similar distributions of gender and ethnicity to those without DSP. Multiple logistic regression showed that Factor 2 (sTNFRII and VCAM-1) and Factor 4 (MMP-2) were independently associated with DSP signs in both PWH and PWoH (OR [95% CI]: 5.45 [1.42-21.00], and 15.16 [1.07-215.22]), respectively. These findings suggest that inflammation and vascular integrity alterations may contribute to DSP pathogenesis in PWH, but not PWoH, possibly through endothelial dysfunction and axonal degeneration.

Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma-associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging- and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissues from 38 SSc-ILD and 18 healthy controls and found that markers (GDF15, COMP, and CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found that epithelial and fibroblast senescence signatures had a 3.6- and 3.7-fold enrichment, respectively, in the lung tissue of SSc-ILD and that lung aging genes (CDKN2A, FRZB, PDE1A, and NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in the lung tissue and found that, independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis.