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Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic revealed a worldwide lack of effective molecular surveillance networks at local, state, and national levels, which are essential to identify, monitor, and limit viral community spread. SARS-CoV-2 variants of concern (VOCs) such as Alpha and Omicron, which show increased transmissibility and immune evasion, rapidly became dominant VOCs worldwide. Our objective was to develop an evidenced-based genomic surveillance algorithm, combining reverse transcription polymerase chain reaction (RT-PCR) and sequencing technologies to quickly identify highly contagious VOCs, before cases accumulate exponentially., Methods: Deidentified data were obtained from 508,969 patients tested for coronavirus disease 2019 (COVID-19) with the TaqPath COVID-19 RT-PCR Combo Kit (ThermoFisher) in four CLIA-certified clinical laboratories in Puerto Rico (n = 86,639) and in three CLIA-certified clinical laboratories in the United States (n = 422,330)., Results: TaqPath data revealed a frequency of S Gene Target Failure (SGTF) > 47% for the last week of March 2021 in both, Puerto Rico and US laboratories. The monthly frequency of SGTF in Puerto Rico steadily increased exponentially from 4% in November 2020 to 47% in March 2021. The weekly SGTF rate in US samples was high (>8%) from late December to early January and then also increased exponentially through April (48%). The exponential increase in SGFT prevalence in Puerto Rico was concurrent with a sharp increase in VOCs among all SARS-CoV-2 sequences from Puerto Rico uploaded to Global Influenza Surveillance and Response System (GISAID) (n = 461). Alpha variant frequency increased from <1% in the last week of January 2021 to 51.5% of viral sequences from Puerto Rico collected in the last week of March 2021., Conclusions: According to the proposed evidence-based algorithm, approximately 50% of all SGTF patients should be managed with VOCs self-quarantine and contact tracing protocols, while WGS confirms their lineage in genomic surveillance laboratories. Our results suggest this workflow is useful for tracking VOCs with SGTF., (© 2022 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Objective: Explore influenza and Tdap immunization knowledge, attitudes, and practices among Hispanics patients attending prenatal care in a tertiary hospital in Puerto Rico as well as barriers encountered by patients regarding vaccination practices during pregnancy., Methods: Descriptive study conducted at the University District Hospital prenatal care clinics in the Medical Sciences Campus of Puerto Rico from September 2016 to June 2017., Results: A total of 189 pregnant women were recruited. Regarding Influenza vaccine: 75.6% were offered or oriented about Influenza vaccination, 51.8% had received the vaccine at least once (only 12.2% during current pregnancy) and, 57.1% reported receiving information about influenza infection risks in pregnancy, mainly from health care professionals and media. For Tdap only 20.6% of women were offered or oriented about the vaccine and 7.4% received the vaccine during pregnancy. 55.6% of patients had not been oriented about potential dangers of the pertussis infection; for the few oriented, health professionals were their predominant source. In terms of barriers, lack of information about vaccination and its benefits during pregnancy were the most frequent., Conclusion: Our study identifies the existing gap of information regarding Influenza and Tdap vaccine. Physicians play a pivotal role in preventive care and new strategies are needed to optimize education to our patients.

Objective: To evaluate the perception of women living in Puerto Rico regarding their genitalia and explore the associations of those perceptions with female sexual distress., Methods: Women from Puerto Rico willing to complete a self-administered online survey from June 2018 through July 2020 were included in this cross-sectional study. Inclusion criteria included being between 21 and 65 years of age, living in Puerto Rico, having identified as heterosexual, bisexual, or lesbian, and having been sexually active. Descriptive statistics were calculated. The Mann-Whitney test, Pearson's correlation, and robust linear regression were used to associate female genital self-image and sexual distress., Results: The most common negative thought and perception within women was dissatisfaction with the size of their genitalia (21.9%), and 21.3% of women contemplated undergoing cosmetic surgery, mainly to increase and improve sensation. For each 1-unit increase in the Female Genital Self-Image Scale score, the Female Sexual Distress Scale-Revised score decreased by 1.24 units (95% confidence interval -1.67 to -0.82)., Conclusion: A better genital self-image perception might lower levels of sexual distress. Screening instruments could help to identify poor genital perception and sexual distress., (© 2021 International Federation of Gynecology and Obstetrics.)

Motivational states are regulated by complex networks across brain regions that are composed of genetically and functionally distinct neuronal populations. Disruption within these neural circuits leads to aberrant motivational states and are thought to be the root cause of psychiatric disorders related to reward processing and addiction. Critical technological advances in the field have revolutionized the study of neural systems by allowing the use of optical strategies to precisely control and visualize neural activity within genetically identified neural populations in the brain. This review will provide a brief introduction into the history of how technological advances in single-cell strategies have been applied to elucidate the neural circuits that underlie aberrant motivational states that often lead to dysfunction in reward processing and addiction., (Copyright © 2022 Cold Spring Harbor Laboratory Press; all rights reserved.)

Although autism spectrum disorder (ASD) is defined by impaired social communication and restricted and repetitive behaviors and interests, ASD is also characterized by impaired motivational processes. The "social motivation theory of autism" describes how social motivation disruptions in ASD in early childhood may impede the drive to engage in reciprocal social behaviors and ultimately interfere with the development of neural networks critical for social communication (Chevallier et al., Trends Cogn Sci 16:231-239, 2012b). Importantly, clinical studies and preclinical research using model organisms for ASD indicate that motivational impairments in ASD are not constrained to social rewards but are evident in response to a range of nonsocial rewards as well. Additionally, translational studies on certain genetically defined neurodevelopmental disorders associated with ASD indicate that these syndromic forms of ASD are also characterized by motivational deficits and mesolimbic dopamine impairments. In this chapter we summarize clinical and preclinical research relevant to reward processing impairments in ASD and related neurodevelopmental disorders. We also propose a nosology to describe reward processing impairments in these disorders that uses a three-axes model. In this triaxial nosology, the first axis defines the direction of the reward response (i.e., anhedonic, hyperhedonic); the second axis defines the construct of the reward process (e.g., reward liking, reward wanting); and the third axis defines the context of the reward response (e.g., social, nonsocial). A more precise nosology for describing reward processing impairments in ASD and related neurodevelopmental disorders will aid in the translation of preclinical research to clinical investigations which will ultimately help to speed up the development of interventions that target motivational systems for ASD and related neurodevelopmental disorders., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Objective: Gestational Diabetes Mellitus (GDM) and Type 2 Diabetes Mellitus (DM2) are metabolic disorders characterized by increased insulin resistance. Although insulin is the treatment of choice in pregnant patients with DM, the prescription of oral hypoglycemic agents (OHA) has been increasing among practitioners. This study aimed to evaluate the maternal and neonatal outcomes when oral hypoglycemic agents were used in diabetic pregnant women., Methods: Medical records from the Maternal-Infant Care Unit Clinics SoM-UPR (n=149) were reviewed. Patients that were treated with metformin, sulfonylurea or insulin were included. Maternal and neonatal outcomes were compared between groups., Results: Patient's mean age was 28 ± 6 years. The majority had GDM (91%). The most common comorbidity was hypertension (9.9%). Lifestyle modification was used as treatment in 77% of patients during the second trimester, but its use decreased to 33% during the third trimester. Insulin was the treatment of choice. Among the OHA, sulfonylurea was preferred. Postprandial glucose levels were lower in patients who used insulin as compared to those without medications., Conclusion: No significant differences were found in maternal outcomes such as C-section, induction of labor, episiotomy or preterm labor, or neonatal outcomes such as macrosomia, neonatal hypoglycemia or congenital abnormalities among treatment groups. OHA can be considered as an alternative to insulin for the treatment of DM during pregnancy in selected cases.

Over the past few decades, the bed nucleus of the stria terminalis (BNST) gained popularity as a unique brain region involved in regulating motivated behaviors related to neuropsychiatric disorders. The BNST, a component of the extended amygdala, consists of a variety of subnuclei and neuronal ensembles. Multiple studies have highlighted the BNST as playing a fundamental role in integrating information by interfacing with other brain regions to regulate distinct aspects of motivated behaviors associated with stress, anxiety, depression, and decision-making. However, due to the high molecular heterogeneity found within BNST neurons, the precise mechanisms by which this region regulates distinct motivational states remains largely unclear. Single-cell RNA sequencing data have revealed that the BNST consists of multiple genetically identifiable cell-type clusters. Contemporary tools can therefore be leveraged to target and study such cell-types and elucidate their precise functional role. In this review, we discuss the different subsets of neurons found in the BNST, their anatomical distribution, and what is currently known about BNST cell-types in regulating motivated behaviors., (Published by Elsevier B.V.)

Objective: Anal cancer screening has been recommended for women with lower genital tract neoplasia, lupus, Crohn disease, HIV, and/or organ transplantation recipients. This study described and compared knowledge, attitudes, and experiences related to anal cancer and anal cancer screening between women at high risk for anal cancer and their counterparts., Methods: This is a cross-sectional study within colposcopy and gynecology oncology clinics in Puerto Rico; 278 women 21 years or older and with prior diagnosis of gynecological neoplasia completed an interviewer-administered questionnaire. Women were categorized according to their medical history as being high risk or non-high risk for anal cancer. The high-risk group included women with a history of lower genital tract neoplasia, lupus, Crohn disease, HIV, and/or organ transplantation., Results: Overall, 40.7% of the study population were at high risk for developing anal cancer. History of anal cancer screening was low among high-risk and non-high-risk women (11.5% vs 5.6%, p > .05). Less than 1% of all women reported to have had a high-resolution anoscopy. Most women (87.6%) had little knowledge about anal Pap test but were willing to have one if their doctors recommended it (96.5%). No major differences in knowledge, attitudes, or screening history were observed between high-risk and non-high-risk women., Conclusions: Although experts do not recommend routine anal cancer screening for the general population, they do recommend it for women within certain high-risk groups. Study findings highlight the importance of increasing education and awareness of anal cancer among high-risk patients and physicians, to promote better preventive methods, achieve early detection, and improve disease outcomes., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2021, ASCCP.)

Motivational states consist of cognitive, emotional, and physiological components controlled by multiple brain regions. An integral component of this neural circuitry is the bed nucleus of the stria terminalis (BNST). Here, we identify that neurons within BNST that express the gene prepronociceptin (Pnoc BNST ) modulate rapid changes in physiological arousal that occur upon exposure to motivationally salient stimuli. Using in vivo two-photon calcium imaging, we find that Pnoc BNST neuronal responses directly correspond with rapid increases in pupillary size when mice are exposed to aversive and rewarding odors. Furthermore, optogenetic activation of these neurons increases pupillary size and anxiety-like behaviors but does not induce approach, avoidance, or locomotion. These findings suggest that excitatory responses in Pnoc BNST neurons encode rapid arousal responses that modulate anxiety states. Further histological, electrophysiological, and single-cell RNA sequencing data reveal that Pnoc BNST neurons are composed of genetically and anatomically identifiable subpopulations that may differentially tune rapid arousal responses to motivational stimuli., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Our study sought to evaluate how aware the women attending gynecology clinics at the University of Puerto Rico Medical Sciences Campus (UPRMSC) were of the association between infertility and excess body weight (i.e., overweight and obesity)., Methods: Women 21 years old and older attending gynecology clinics at UPR-MSC were invited to participate in this study (n = 234). A self-administered survey was provided to all the women. Logistic regression models were performed to determine associations., Results: About 56.8% of the women were found to be aware of the effects of obesity on fertility; their main source of medical information was their primary doctor. The odds (adjusted for age and annual income) of being aware of the association between obesity and infertility were about 2.41 (95% CI: 1.07-5.42) times higher in women with a BMI greater than or equal to 25 kg/m2 than they were in those with a BMI of less than 25 kg/m2. An interaction by age group (adjusted for BMI) was found for the association between annual income and knowledge of the obesity-infertility association (OR≥40 years old: 3.51, 95% CI: 1.41-8.72; OR<40 years old: 0.57, 95% CI: 0.15-2.13)., Conclusion: Our study revealed that there is a lack of knowledge regarding the effects of obesity on fertility and identifies characteristics associated with this knowledge. The contents of health-care-provider counseling and the barriers affecting communication between patients and health care providers could be assessed in further studies.

Venetoclax is effective in relapsed patients with mantle cell lymphoma (MCL). Mechanisms of resistance to venetoclax in MCL are poorly understood. We describe the clinical outcomes and genomic characteristics of 24 multiply relapsed patients (median of five prior lines of therapy) who received venetoclax-based therapies; 67% had progressed on BTK inhibitors (BTKi) and 54% had blastoid or pleomorphic histology. Median follow up after venetoclax treatment was 17 months. The overall response rate was 50% and complete response (CR) rate was 21%, 16 patients had progressed and 15 died. The median progression free, overall and post venetoclax survival were 8, 13.5 and 7.3 months respectively. Whole-exome sequencing (WES) was performed on samples collected from seven patients (including five pairs; before starting venetoclax and after progression on venetoclax). The SMARCA4 and BCL2 alterations were noted only after progression, while TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2 and ATM were altered 2-4-fold more frequently after progression. In two patients with serial samples, we demonstrated clonal evolution of novel SMARCA4 and KMT2C/D mutations at progression. Mutation dynamics in venetoclax resistant MCL is demonstrated. Our data indicates that venetoclax resistance in MCL is predominantly associated with non-BCL2 gene mutations. Further studies are ongoing in MCL patients to evaluate the efficacy of venetoclax in combination with other agents and understand the biology of venetoclax resistance in MCL., (© 2020 Wiley Periodicals, Inc.)

Blastoid and pleomorphic mantle cell lymphomas (MCLs) are variants of aggressive histology MCL (AH-MCL). AH-MCL can arise de novo (AH-DN) or transform from prior classic variant MCL (AH-t). This study is the first integrated analysis of clinical and genomic characteristics of AH-MCL. Patient characteristics were collected from diagnosis (AH-DN) and at transformation (AH-t). Survival after initial diagnosis (AH-DN) and after transformation (AH-t) was calculated. Regression tree analysis was performed to evaluate prognostic variables and in univariate and multivariate analyses for survival. Whole-exome sequencing was performed in evaluable biopsy specimens. We identified 183 patients with AH-MCL (108 were AH-DN, and 75 were AH-t; 152 were blastoid, and 31 were pleomorphic). Median survival was 33 months (48 and 14 months for AH-DN and AH-t, respectively; P = .001). Factors associated with inferior survival were age (≥72 years), AH-t category, Ki-67 ≥50% and poor performance status. AH-t had a significantly higher degree of aneuploidy compared with AH-DN. Transformed MCL patients exhibited KMT2B mutations. AH-MCL patients with Ki-67 ≥50% had exclusive mutations in CCND1, NOTCH1, TP53, SPEN, SMARCA4, RANBP2, KMT2C, NOTCH2, NOTCH3, and NSD2 compared with low Ki-67 (<50%). AH-t patients have poor outcomes and distinct genomic profile. This is the first study to report that AH-MCL patients with high Ki-67 (≥50%) exhibit a distinct mutation profile and very poor survival., (© 2020 by The American Society of Hematology.)

Oxytocin (OT) is critical for the expression of social behavior across a wide array of species; however, the role of this system in the encoding of socially relevant information is not well understood. In the present study, we show that chemogenetic activation of OT neurons within the paraventricular nucleus of the hypothalamus (PVH) of male mice (OT-Ires-Cre) enhanced social investigation during a social choice test, while chemogenetic inhibition of these neurons abolished typical social preferences. These data suggest that activation of the OT system is necessary to direct behavior preferentially toward social stimuli. To determine whether the presence of a social stimulus is sufficient to induce activation of PVH-OT neurons, we performed the first definitive recording of OT neurons in awake mice using two-photon calcium imaging. These recordings demonstrate that social stimuli activate PVH-OT neurons and that these neurons differentially encode social and nonsocial stimuli, suggesting that PVH-OT neurons may act to convey social salience of environmental stimuli. Finally, an attenuation of social salience is associated with social disorders, such as autism. We therefore also examined possible OT system dysfunction in a mouse model of autism, Shank3b knock-out (KO) mice. Male Shank3b KO mice showed a marked reduction in PVH-OT neuron number and administration of an OT receptor agonist improved social deficits. Overall, these data suggest that the presence of a social stimulus induces activation of the PVH-OT neurons to promote adaptive social behavior responses. SIGNIFICANCE STATEMENT Although the oxytocin (OT) system is well known to regulate a diverse array of social behaviors, the mechanism in which OT acts to promote the appropriate social response is poorly understood. One hypothesis is that the presence of social conspecifics activates the OT system to generate an adaptive social response. Here, we selectively recorded from OT neurons in the paraventricular hypothalamic nucleus (PVH) to show that social stimulus exposure indeed induces activation of the OT system. We also show that activation of the OT system is necessary to promote social behavior and that mice with abnormal social behavior have reduced numbers of PVH-OT neurons. Finally, aberrant social behavior in these mice was rescued by administration of an OT receptor agonist., (Copyright © 2020 the authors.)

In this study, we evaluate the association between vaginal and cervical human papillomavirus infections high-risk types (HPV+H), negative controls (HPV-), the bacterial biota, and urinary metabolites via integration of metagenomics, metabolomics, and bioinformatics analysis. We recently proposed that testing urine as a biofluid could be a non-invasive method for the detection of cervical HPV+H infections by evaluating the association between cervical HPV types and a total of 24 urinary metabolites identified in the samples. As a follow-up study, we expanded the analysis by pairing the urine metabolome data with vaginal and cervical microbiota in selected samples from 19 Puerto Rican women diagnosed with HPV+H infections and HPV- controls, using a novel comprehensive framework, Model-based Integration of Metabolite Observations and Species Abundances 2 (MIMOSA2). This approach enabled us to estimate the functional activities of the cervicovaginal microbiome associated with HPV+H infections. Our results suggest that HPV+H infections could induce changes in physicochemical properties of the genital tract through which niche partitioning may occur. As a result, Lactobacillus sp. enrichment coincided with the depletion of L. iners and Shuttleworthia , which dominate under normal physiological conditions. Changes in the diversity of microbial species in HPV+H groups influence the capacity of new community members to produce or consume metabolites. In particular, the functionalities of four metabolic enzymes were predicted to be associated with the microbiota, including acylphosphatase, prolyl aminopeptidase, prolyl-tRNA synthetase, and threonyl-tRNA synthetase. Such metabolic changes may influence systemic health effects in women at risk of developing cervical cancer. Overall, even assuming the limitation of the power due to the small sample number, our study adds to current knowledge by suggesting how microbial taxonomic and metabolic shifts induced by HPV infections may influence the maintenance of microbial homeostasis and indicate that HPV+H infections may alter the ecological balance of the cervicovaginal microbiota, resulting in higher bacterial diversity.

Background: The goals of health disparities research are to identify facilitators and barriers to healthcare use to help eliminate health inequalities. There are few studies on disparities in healthcare access and use trends for patients with endometriosis that may lead to differences in appropriate care based on socioeconomic status., Objective: This retrospective, cross-sectional study was conducted to compare health services use patterns and prevalence of co-morbidities of women with endometriosis with public (government-based) vs private (purchased or provided by employer) health insurance., Study Design: A total of 342 deidentified datasets (171 randomly-selected cases per study group) from women with endometriosis 14-50 years old who were members of one health insurance company that provides both public and private health insurance coverage in Puerto Rico were analyzed. Patients were defined as having at least 1 endometriosis-related medical claim (ICD-9-617.xx; International Classification of Diseases, Ninth Revision, Clinical Modification) during the 3-year study period., Results: Medical service (eg, hospital, laboratory, pathology, and radiology) use trends were 3 times lower in the public vs the private sector. Women in the public sector were 3.5 times less likely to have a laparoscopy, 2.7 times more likely to be prescribed opioid/narcotics, and were the only study subjects reporting emergency department use. Obstetrics and gynecology services were used >2-fold less by women in the public (29.5%) vs the private sector (70.5%) (P=.087)., Conclusions: We report significant differences in the use trends of endometriosis-related medical services and prescriptions, indicating differences in healthcare access based on socioeconomic parameters. Our results support the development of public health programs to promote access to healthcare for patients with endometriosis irrespective of socioeconomic status and promote health disparity research in other healthcare systems., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The paraventricular thalamus (PVT) is an interface for brain reward circuits, with input signals arising from structures, such as prefrontal cortex and hypothalamus, that are broadcast to downstream limbic targets. However, the precise synaptic connectivity, activity, and function of PVT circuitry for reward processing are unclear. Here, using in vivo two-photon calcium imaging, we find that PVT neurons projecting to the nucleus accumbens (PVT-NAc) develop inhibitory responses to reward-predictive cues coding for both cue-reward associative information and behavior. The multiplexed activity in PVT-NAc neurons is directed by opposing activity patterns in prefrontal and lateral hypothalamic afferent axons. Further, we find that prefrontal cue encoding may maintain accurate cue-reward processing, as optogenetic disruption of this encoding induced long-lasting effects on downstream PVT-NAc cue responses and behavioral cue discrimination. Together, these data reveal that PVT-NAc neurons act as an interface for reward processing by integrating relevant inputs to accurately inform reward-seeking behavior., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Mantle cell lymphoma (MCL) represents 4% to 9% of all non-Hodgkin lymphomas and is characterized by CD5 and cyclin D1 expression and t(11;14)(q13;q32). However, about 5% of MCL lack CD5 expression and is poorly characterized. Here, we present 58 patients with CD5 negative (CD5) MCL and compared them with a group of 212 typical CD5 positive (CD5) MCL cases. There were 39 men and 19 women with a median age of 66 years (range, 36 to 88). Compared with CD5 positive (CD5) MCL patients, patients with CD5 MCL showed a lower male-to-female ratio (P=0.006) and a higher frequency of "bone marrow non-nodal" presentation (P=0.01). All other clinicopathologic features, including the frequency of SOX11 expression, were similar between the 2 groups. Treated with similar regimens, patients with CD5 MCL showed a significantly longer progression-free survival (PFS) (P=0.01) and a tendency for longer overall survival (OS; P=0.078) than CD5 positive (CD5) MCL patients. Univariate analysis showed of the well-known poor prognostic factors, only Mantle Cell Lymphoma International Prognostic Index was an inferior prognostic factor and blastoid/pleomorphic morphology and high Ki67 were not associated with prognosis in CD5 MCL patients. Multivariate Cox regression analysis showed CD5 expression was an independent prognostic factor for PFS (P=0.031) but not OS in MCL patients. In conclusion, the results suggest that patients with CD5 MCL have a more favorable prognosis than CD5 MCL patients, although the clinicopathologic features of both groups are largely similar. CD5 MCL may represent a distinct variant of MCL and needs to be included in the differential diagnosis of CD5 small B-cell lymphomas.

Learning to predict rewards based on environmental cues is essential for survival. The orbitofrontal cortex (OFC) contributes to such learning by conveying reward-related information to brain areas such as the ventral tegmental area (VTA). Despite this, how cue-reward memory representations form in individual OFC neurons and are modified based on new information is unknown. To address this, using in vivo two-photon calcium imaging in mice, we tracked the response evolution of thousands of OFC output neurons, including those projecting to VTA, through multiple days and stages of cue-reward learning. Collectively, we show that OFC contains several functional clusters of neurons distinctly encoding cue-reward memory representations, with only select responses routed downstream to VTA. Unexpectedly, these representations were stably maintained by the same neurons even after extinction of the cue-reward pairing, and supported behavioral learning and memory. Thus, OFC neuronal activity represents a long-term cue-reward associative memory to support behavioral adaptation.

The most common subtype of non-Hodgkin lymphoma, diffuse large B-cell lymphoma, is cured in approximately two thirds of patients after initial therapy. The remaining one-third of patients who suffer relapse or become refractory have very poor survival outcomes despite salvage chemotherapy with or without stem cell transplantation. A considerable proportion of relapsed or refractory large B cells belong to the WHO subtype known as high-grade B-cell lymphoma with rearrangement of MYC and BCL2 and/or BCL6, also known as double-hit lymphoma (DHL). Most DHL patients present with Ann Arbor's stage III/IV, a comparatively higher rate of extranodal involvement including bone marrow and central nervous system infiltration, high levels of lactate dehydrogenase, and an elevated Ki67 expression in the tumor cells. Newer therapeutic approaches, including targeted therapy against BCL2, MYC, or other associated pathways, are needed. In addition, recent therapies that harness the immune system, such as checkpoint inhibitors and chimeric antigen receptor T-cell therapy, are changing the paradigm of treatment for non-Hodgkin lymphoma and could impact the outcome of DHL.

Genital human papillomavirus (HPV) is the world's most commonly diagnosed sexually transmitted infection, and high-risk HPV types are strongly linked to cervical dysplasia and carcinoma. Puerto Ricans are among the US citizens with higher HPV prevalence and lower screening rates and access to treatment. This bleak statistic was as a motivation to detect biomarkers for early diagnosis of HPV in this population. We collected both urine and cervical swabs from 43 patients attending San Juan Clinics. Cervical swabs were used for genomic DNA extractions and HPV genotyping with the HPV SPF10-LiPA25 kit, and gas chromatography-mass spectrometry (GC-MS) was employed on the urine-derived products for metabolomics analyses. We aimed at discriminating between patients with different HPV categories: HPV negative (HPV-), HPV positive with simultaneous low and high-risk infections (HPV+B) and HPV positive exclusively high-risk (HPV+H). We found that the metabolome of HPV+B is closer to HPV- than to HPV+H supporting evidence that suggests HPV co-infections may be antagonistic due to viral interference leading to a lower propensity for cervical cancer development. In contrast, metabolites of patients with HPV+H were significantly different from those that were HPV-. We identified three urinary metabolites 5-Oxoprolinate, Erythronic acid and N-Acetylaspartic acid that discriminate HPV+H cases from negative controls. These metabolites are known to be involved in a variety of biochemical processes related to energy and metabolism and may likely be biomarkers for HPV high-risk cervical infection. However, further validation should follow using a larger patient cohort and diverse populations to confirm our finding., Competing Interests: The authors have declared that no competing interests exist.

Objective: To describe the level of knowledge about Zika virus exposure, symptoms, complications, and transmission prevention in Hispanic women living in Puerto Rico., Methods: A sample of 168 women aged 21 to 64 at the general community, consented to complete a self-administered questionnaire of 112 questions from October 2016 to July 2017., Results: A univariate analysis showed that the participating women recognized that the Zika virus was transmitted through mosquito bites (95.2%), sexual intercourse (78.0%), and from a mother to her fetus (41.1%); participants also believed that other, incorrect, routes of transmission were plausible. Regarding their knowledge of Zika infection prevention, the participants' correct answers included the following: using mosquito repellent (94.1%), eliminating standing water (83.9%), and using condoms (83.3%). When asked about fetal risks associated with Zika, they believed that the fetus would not develop normally (75.6%), would be born with a disability (69.6%), or would experience nervous system problems (54.2%). Only 22.6% of the participants had taken precautions to prevent pregnancy during the Zika outbreak, of which 65.8% reported that they had used condoms during all sexual relationships., Conclusion: There is a need to educate the general population about the Zika virus to reduce the misconceptions about disease prevention and transmission as well as about the complications associated with Zika during pregnancy. Awareness efforts should emphasize the prevention of infections during pregnancy and the use of available contraceptive methods.

The natural history of mantle cell lymphoma (MCL) undergoing chemotherapy is a cyclical pattern of remission followed by recurrence of disease due to acquired chemotherapy resistance. The median age of the occurrence of MCL is 65 years, so half of the newly diagnosed MCL patients are considered "elderly." The tolerance to long-term chemotherapy in elderly patients is decreased; hence, the response to frontline therapy used is of paramount importance. We hope that our review may guide clinicians in treating such populations in a more personalized and evidence-based manner.In the older patients with risk variables, frontline treatment is determined according to different body status of fit, unfit or compromised, and frail. In the fit patients, the pursuit of remission and prolongation of survival might currently justify the use of more intense and toxic therapies. For unfit or compromised older patients, disease control needs to be prioritized, maintaining a balance between the benefits and toxicities of the treatment. For frail patients, tolerance of treatment and minimizing myelotoxicity should be the primary focus. "Chemotherapy-free" regimens are likely to be considered as the first-line strategy for this population. On the other hand, in the older MCL population without risk variables, observation or "watch and wait" can prevent overtreatment. Furthermore, more clinical trials and research studies on novel agents and targeted therapies need to be translated into the general population to provide optimal treatment and to guide personalized treatment. IMPLICATIONS FOR PRACTICE: This review emphasizes the importance of frontline therapies for older MCL patients. MCL patients commonly experience a cyclical pattern of remission followed by recurrence of disease due to acquired chemotherapy resistance. As a special population, elderly patients have various comorbidities and decreased organ function, which may reduce the chances of undergoing treatment for recurrent disease. Thus, this older population of patients with MCL should be treated separately and exceptionally. So far, systematic reviews with regard to frontline treatment for older patients with MCL have not been encountered, but the hope is that this review may guide clinicians in treating such populations in a more personalized and evidence-based manner., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Long term outcomes and mutations in patients with mantle cell lymphoma (MCL) who discontinued ibrutinib have not been described. Using deep targeted next generation sequencing, we performed somatic mutation profiling from 15 MCL patients (including 5 patients with paired samples; before and after progression on ibrutinib). We identified 80 patients with MCL who discontinued ibrutinib therapy for various reasons. Median follow-up after ibrutinib discontinuation was 38 months. The median duration on ibrutinib was 7·6 months. Forty-one (51%) patients discontinued ibrutinib due to disease progression/transformation, 20 (25%) for intolerance, 7 (9%) due to patient choice, 5 (6%) for stem cell transplant, 4 (5%) due to second cancers and 3 (4%) other causes. The median survival after ibrutinib was 10 and 6 months for disease progression and transformation, respectively, and 25 months for patients with ibrutinib intolerance. Overall, BTK mutations were observed in 17% patients after progression on ibrutinib. Notably, TP53 alterations were observed after progression in 75% patients. Among the 4 patients with blastoid transformation, 3 (75%) had NSD2 mutations (co-existing with TP53). Ibrutinib-refractory MCL patients had a short survival. Demonstration of TP53 and NSD2 mutations in patients who developed blastoid transformation and ATM and TP53 mutations in patients who progressed, opens the door for future investigations in ibrutinib-refractory MCL., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

The human cervicovaginal microbiota resides at an interface between the host and the environment and may affect susceptibility to disease. Puerto Rican women have high human papillomavirus (HPV) infection and cervical cancer rates. We hypothesized that the population structure of the cervicovaginal bacterial and fungal biota changed with cervical squamous intraepithelial lesions and HPV infections. DNA was extracted from cervix, introitus, and anal sites of 62 patients attending high-risk San Juan clinics. The 16S rRNA V4 region and ITS-2 fungal regions were amplified and sequenced using Illumina technology. HPV genotyping was determined by reverse hybridization with the HPV SPF10-LiPA25 kit. HPV prevalence was 84% of which ∼44% subjects were infected with high-risk HPV, ∼35% were co-infected with as many as 9 HPV types and ∼5% were infected with exclusively low-risk HPV types. HPV diversity did not change with cervical dysplasia. Cervical bacteria were more diverse in patients with CIN3 pre-cancerous lesions. We found enrichment of Atopobium vaginae and Gardnerella vaginalis in patients with CIN3 lesions. We found no significant bacterial biomarkers associated with HPV infections. Fungal diversity was significantly higher in cervical samples with high-risk HPV and introitus samples of patients with Atypical Squamous Cells of Undetermined Significance (ASCUS). Fungal biomarker signatures for vagina and cervix include Sporidiobolaceae and Sacharomyces for ASCUS, and Malassezia for high-risk HPV infections. Our combined data suggests that specific cervicovaginal bacterial and fungal populations are related to the host epithelial microenvironment, and could play roles in cervical dysplasia.

Objective: To assess HPV knowledge as well as knowledge and acceptance of HPV vaccines., Methods: The present cross-sectional study surveyed women with cervical cytology anomalies referred to colposcopy clinics at the University of Puerto Rico and San Juan City Hospital between November 1, 2013, and November 30, 2015. The data were analyzed using descriptive statistics and multivariate logistic regression models., Results: Of 418 participants, 333 had heard of HPV. Of these, 273 of 331 (82.5%) knew it causes cervical cancer and 284 of 332 (85.8%) knew it is sexually transmitted; 313 were aware of the vaccine(s). Of 278 participants, 270 (97.1%) were willing to vaccinate their children and 125 of 285 (43.9%) desired vaccination. Only 13 (10.9%) of 119 age-eligible women had been vaccinated. Women who had completed high school had increased odds of having heard of HPV (adjusted OR 2.3, 95% CI 1.2-4.4; P=0.014), with a similar increase in the odds of having heard of the vaccine(s). Women who knew about HPV had greatly increased odds of knowing about the vaccine(s) (adjusted OR 19.7, 95% CI 9.8-41.6)., Conclusion: Knowledge of HPV and HPV vaccine(s) was high, but vaccine uptake was low in the study population. Physicians' active roles in HPV education and vaccination are crucial., (© 2018 International Federation of Gynecology and Obstetrics.)

Ibrutinib has shown significant activity in patients with relapsed or refractory mantle cell lymphoma (RR-MCL). We report the long-term outcome and safety profile of a single-centre, single arm, open-label, phase 2 study of RR-MCL treated with IR. Overall, the median follow-up time was 47 months (range 1-52 months), median duration on treatment was 16 months (range 1-53 months) and median number of treatment cycles was 17 (range 1-56). Twenty-nine patients (58%) achieved complete remission and of these, 12 patients continue on study. Thirty-eight patients discontinued treatment, 14 due to disease progression (2 transformed). Patients with blastoid morphology, high risk MCL International Prognostic Index score and high Ki67% had inferior survival. The commonest grade 1-2 toxicities were fatigue, diarrhoea, nausea, arthralgias and myalgias. None had long term toxicities. Median progression-free survival was 43 months. Eighteen patients (36%) died (14 deaths were MCL-related). The median overall survival has not been reached. Treatment with IR can provide durable remissions in a subset of patients with RR-MCL, especially those with low Ki67%. The possible benefit of adding other therapies in combination with IR in RR-MCL is under exploration., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

The natural history of mantle cell lymphoma (MCL) is a continuous process with the vicious cycle of remission and recurrence. Because MCL cells are most vulnerable before their exposure to therapeutic agents, front-line therapy could eliminate MCL cells at the first strike, reduce the chance for secondary resistance, and cause long-term remissions. If optimized, it could become an alternative to cure MCL. The key is the intensity of front-line therapy. Both the Nordic 2 and the MD Anderson Cancer Center HCVAD trials, with follow-up times greater than 10 years, achieved long-term survivals exceeding 10 years. But the Achilles heel in both trials were the severe toxicities, such as secondary malignancies including myelodysplastic syndromes /leukemia. Therefore, intensive therapies can act as a double-edged sword providing long term survival at the cost of severe toxicities. In our opinion, although intensive chemotherapy can cause detrimental side effects, it is indispensable given that we run the risk of sacrificing long-term survivals in these young and fit patients. We must seek for a powerful alternative at the front-line. Furthermore, minimal residual disease negativity should be the optimal therapeutic goal to achieve before and after autologous stem cell transplantation. Some novel therapeutic strategies have shown to improve outcomes, but it is not yet clear as to how these results translate in population. Of note, MCL patients need to be stratified at diagnosis and be provided with different intensities of front-line regimen. In this review, we discuss current strategies for the treatment of young patients with newly diagnosed MCL.

Background: To understand risk factors for HPV exposure in Puerto Rican women, we evaluated HPV 6, 11, 16, and 18 serology in women aged living in the San Juan metropolitan area., Methods: As part of a cross-sectional study, a population-based sample of 524 HPV unvaccinated Hispanic women ages 16-64 years completed face-to-face and computer assisted interviews and provided blood and self-collected anal and cervical specimens. Serology used multiplex virus-like particle based-IgG ELISA and HPV DNA was detected with L1-consensus PCR., Results: 32% and 47% were seropositive to HPV types included in the bivalent (16/18) and quadrivalent (6/11/16/18) vaccines, respectively. Type-specific seroprevalence was HPV6 - 29%, HPV11 - 18%, HPV16 - 23%, and HPV18 - 17%; seroprevalence was high in the youngest age-group (16-19: 26-37%). HPV seropositivity was associated with having ≥ 3 lifetime sexual partners (OR=2.5, 95% CI=1.7-3.9) and detection of anogenital HPV DNA (OR=1.8, 95% CI=1.2-2.6)., Conclusions: The high cumulative exposure of HPV vaccine types 6/11/16/18 in this Hispanic population was influenced by factors related to HPV exposure through sexual behavior. High seroprevalence in the youngest age-group indicates early age of exposure to HPV in Puerto Rico, highlighting the need for HPV vaccination starting prior to age 16., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Much is known about the neural circuits of conditioned fear and its relevance to understanding anxiety disorders, but less is known about other anxiety-related behaviors such as active avoidance. Using a tone-signaled, platform-mediated avoidance task, we observed that pharmacological inactivation of the prelimbic prefrontal cortex (PL) delayed avoidance. Surprisingly, optogenetic silencing of PL glutamatergic neurons did not delay avoidance. Consistent with this, inhibitory but not excitatory responses of rostral PL neurons were associated with avoidance training. To test the importance of these inhibitory responses, we optogenetically stimulated PL neurons to counteract the tone-elicited reduction in firing rate. Photoactivation of rostral (but not caudal) PL neurons at 4 Hz impaired avoidance. These findings suggest that inhibitory responses of rostral PL neurons signal the avoidability of a potential threat and underscore the importance of designing behavioral optogenetic studies based on neuronal firing responses., Competing Interests: MD, CB, JR, PP, AB, CR, GQ No competing interests declared, (© 2018, Diehl et al.)

Background: Spontaneous regression has been reported in some indolent forms of lymphoma. Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm and has a poor prognosis. However, approximately 30% of MCL patients can exhibit indolent clinical behavior. To date, complete spontaneous regression of MCL has not been reported., Case Presentation: We describe four cases of spontaneous regression of MCL. At the time of presentation, these patients were asymptomatic, with lymph node enlargement and mild to moderate fluorodeoxyglucose (FDG) uptake on FDG-positron emission tomography combined with computed tomography. One of the possible mechanisms of spontaneous regression of the tumor could be due to the host immune response through humoral and cellular immunity, which may have a role in the clearance of tumor cells., Conclusions: In this report, we support the use of a "wait and watch" strategy for MCL patients with no risk factors and indolent behavior. This strategy helps spare patients from further potentially harmful chemotherapy. In addition, we describe the phenomenon of spontaneous regression in MCL patients who are asymptomatic and have low-volume disease.

Social isolation is a stressful condition that often leads to maladaptive behaviors. In this issue of Cell, Zelikowsky et al. find that chronic social isolation stress triggers an increase in neuronal tachykinin signaling across distinct brain regions that mediate fear and aggression, elucidating the neural basis of these maladaptive responses., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: Most patients with cancer are not screened for hepatitis B virus (HBV) infection before undergoing anticancer therapy, and optimal screening strategies are unknown. We sought to develop selective HBV screening strategies for patients who require systemic anticancer therapy., Methods: This prospective cohort study included adults age ≥ 18 years with solid or hematologic malignancies who received systemic anticancer therapy at a comprehensive cancer center during 2013 and 2014. Patients underwent hepatitis B surface antigen, hepatitis B core antibody, and hepatitis B surface antibody testing, and completed a 19-question modified Centers for Disease Control and Prevention (CDC) HBV survey. Multivariable models that predict chronic or past HBV infection were developed and validated using bootstrapping., Results: A total of 2,124 patients (mean age, 58 ± 13 years) completed the risk survey and HBV testing. Of these, 54% were women; 77% were non-Hispanic white, 11% Hispanic, 8% black, and 4% Asian; and 20% had a hematologic malignancy and 80% a solid tumor. Almost 12% were born outside the United States. The prevalence was 0.3% for chronic HBV infection and 6% for past HBV infection. Significant predictors of positive hepatitis B surface antigen or hepatitis B core antibody tests were as follows: men who had sex with men, black or Asian race, birthplace outside the United States, parent's birthplace outside the United States, household exposure to HBV, age ≥ 50 years, and history of injection drug use. The area under the receiver operating characteristic curve of the model on the basis of these seven predictors was 0.79 (95% CI, 0.73 to 0.82). The modified CDC survey and brief tools with fewer than seven questions yielded similar false-negative rates (0% and 0% to 0.7%, respectively)., Conclusion: An internally validated risk tool performed as well as the modified CDC survey; however, more than 90% of patients who completed the tool would still require HBV testing. Universal HBV testing is more efficient than risk-based screening.

This phase-I/phase-II study evaluated panobinostat in combination with ifosfamide, carboplatin, etoposide (P-ICE) in relapsed/refractory classical Hodgkin lymphoma. During phase I, panobinostat was given daily on Monday/Wednesday/Friday starting one week prior to Cycle 1 (C1) of ICE and during two weeks of C1-2 of ICE (Schedule A). No DLT was observed at 30 mg. However, frequent (84%) grade-4 thrombocytopenia during second week prompted us to omit the second week of panobinostat 30 mg (Schedule B) for phase II, where this regimen was compared to ICE. In the randomized phase-II study, CR was seen in 9/11 (82%) and 8/12 (67%) for P-ICE and ICE, respectively (p = .64). Grade-4 neutropenia (55% vs. 8%) and thrombocytopenia (100% vs. 33%) were more common in P-ICE. In summary, combination therapy using panobinostat produced high CR rate at the cost of greater bone marrow toxicity. Investigation of panobinostat with less myelosuppressive agents is of interest.

In vivo calcium imaging through microendoscopic lenses enables imaging of previously inaccessible neuronal populations deep within the brains of freely moving animals. However, it is computationally challenging to extract single-neuronal activity from microendoscopic data, because of the very large background fluctuations and high spatial overlaps intrinsic to this recording modality. Here, we describe a new constrained matrix factorization approach to accurately separate the background and then demix and denoise the neuronal signals of interest. We compared the proposed method against previous independent components analysis and constrained nonnegative matrix factorization approaches. On both simulated and experimental data recorded from mice, our method substantially improved the quality of extracted cellular signals and detected more well-isolated neural signals, especially in noisy data regimes. These advances can in turn significantly enhance the statistical power of downstream analyses, and ultimately improve scientific conclusions derived from microendoscopic data., Competing Interests: PZ, SR, JR, JJ, SN, AG, JF, EP, GS, RH, MK, BS, RK, LP No competing interests declared, (© 2018, Zhou et al.)

Mantle cell lymphoma (MCL) is a rare and incurable subtype of non-Hodgkin's lymphoma that generally affects older individuals. However, the use of high-dose therapy and autologous stem cell transplant has improved significantly the prognosis of this hematological malignancy, but at the cost of increased toxicities, such as acute toxic death and secondary malignancies. But thanks to a rising understanding of the biology of MCL, the explosion of specifically targeted new efficacious agents, immunotherapy agents, and cellular therapies in the frontline setting, the prognosis of MCL is expected to improve dramatically.The initial treatment of MCL is currently not standardized and the therapeutic landscape of MCL is rapidly evolving. This review provides an extensive overview of the current frontline therapy trials for MCL and presents the results of innovative regimen, including some integrating novel agents and desintensified chemotherapy.

Background: Mantle cell lymphoma (MCL) is an aggressive disease, with poor prognosis and a limited survival. However, some patients with indolent MCL can survive beyond 7~10 years. These patients remain largely asymptomatic and can be in observation for a long time without any treatment. The process of "wait and watch" leaves these patients with the potential risk of evolution to classic, aggressive MCL. On the other hand, early treatment for these patients may not impact overall survival but rather affects the quality of life. Therefore, it is essential to clearly identify this type of indolent MCL at the time of diagnosis., Results: Reported findings of indolent presentation of MCL include: lack of B symptoms, normal serum lactic dehydrogenase (LDH) and β2-microglobulin levels (β2M), low MCL-International Prognostic Index (MIPI) score, maximum tumor diameter less than 3 cm, spleen size < 20 cm, positron emission tomography/computerized tomography with the Standard Uptake Value max <6, Ki-67 less than 30%, with some particular immunophenotype, such as CD5 and CD38 negative, markedly increased CD23 positive lymphocytes proportions, high expression of CD200, kappa light chain restriction, without C-myc, TP53 and NOTCH1/2 mutations, non-blastoid/pleomorphic histology, and no tumor growth on reevaluation every 2~3 months (followed for at least 6 months). Imaging evaluation may only be performed in the presence of disease-related symptoms or organ involvement. Meanwhile, if novel nodal or extranodal lesion is found, biopsy is mandatory to exclude lymphoma. Common clinopathological forms of indolent presentations include monoclonal B lymphocytosis with t (11; 14); "indolent leukemic" presentation of MCL with involvement of peripheral blood, bone marrow involvement, splenomegaly, and minimal lymphadenopathies and in situ lymphoma (often found in lymph nodes removed for other reasons, and in gastrointestinal biopsies)., Conclusions: Considering these distinct indolent clinical presentations with particular features in cytology and gene mutational status, we propose to include these MCL clinical presentations under the umbrella of "Smoldering Mantle Cell Lymphoma".

Background: The purpose of this study was to report the response to and toxicity of ultra-low-dose radiotherapy (RT) for B-cell ocular adnexal lymphoma (OAL)., Methods: We conducted a retrospective review of patients with indolent B-cell and mantle cell OAL treated with 4 Gy to the orbit(s) in two 2-Gy fractions. Disease response was assessed clinically and/or radiographically at 2 to 4-month intervals after RT. Data collected included rates of overall response, complete response (CR), partial response (PR), and treatment-related toxic effects., Results: Twenty-two patients (median age, 65 years) had the following histologic subtypes: mucosa-associated lymphoid tissue (MALT; 14 patients; 64%); follicular lymphoma (5 patients; 23%); mantle cell lymphoma (MCL; 2 patients; 9%); and unclassifiable (1 patient, 4%). The overall response rate was 100%; 19 patients (86%) had a CR and 3 patients (14%) had a PR. The only acute toxic effect was grade 1 dry eye syndrome in 1 patient., Conclusion: Ultra-low-dose RT in patients with OAL is associated with high response rates and minimal toxic effects, and is much shorter in duration and cost. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1095-1100, 2017., (© 2017 Wiley Periodicals, Inc.)

Objective: Peripartum cardiomyopathy is a rare type of heart failure to which only pregnant women are susceptible. In Puerto Rico there is a paucity of information regarding this condition. In this report we describe our experience with peripartum cardiomyopathy., Methods: This was a descriptive retrospective study. We conducted a chart review of all the patients with peripartum cardiomyopathy managed at our institution from January 2006 through December 2012. A total of 12 patients qualified for our analysis., Results: The mean age of our population was 27 (± 8) years. Eight of the twelve (67%) patients were multigravid women, with a mean parity of 2.6 (± 1.6). Most patients (75%) showed clinical evidence of anemia while pregnant, and more than half (58%) delivered prematurely. Six patients (50%) had a prior history of preeclampsia. Cardiac imaging detected a mean ejection fraction of 35% (± 8%) at the time of diagnosis. Only 1 maternal death was documented., Conclusion: Our study cohort was very similar to those in most case series in which the same condition has been studied. In order to better understand the pathophysiology of this entity and, thus, improve treatment for these patients, prospective studies are needed.

Background: Oncogenic HPV infection is associated to anogenital cancer. We estimate the prevalence and correlates of anogenital HPV infection among a population-based sample of women aged 16-64 years living in the metropolitan area of Puerto Rico., Methods: 564 women completed face-to-face and computer assisted interviews and self-collected anal and cervical specimens. HPV DNA testing used MY09/MY11 consensus HPV L1 primers and beta-globin as an internal control for sample amplification. Positive specimens were typed by dot-blot hybridization., Results: Weighted prevalence of cervical, anal, and cervical/anal co-infection was 29.4%, 38.6%, and 17.1%, respectively. The commonest oncogenic HPV types detected in the cervix and anus were: 68 (8% vs. 7%) and 16 (5.5% vs. 5.1%), correspondingly. Having ≥3 lifetime sexual partners (OR: 2.3; 95% CI: 1.5-3.5) and last year anal intercourse (OR: 1.6; 95% CI: 1.1-2.5) increased the odds of anogenital HPV infection. Cervical infection was independently associated to anal infection (OR: 3.0; 95% CI: 2.0-4.6)., Conclusions: Similar to others, our results confirm the burden of anogenital HPV infection in women and its relationship with sexual behavior. As vaccination increases, future studies should monitor changing trends in HPV infection in this population, and the relationship between anal and cervical HPV-related disease., (Published by Elsevier B.V.)

Clinically useful molecular tools to triage women for a biopsy upon referral to colposcopy are not available. We aimed to develop a molecular panel to detect cervical intraepithelial neoplasia (CIN) grade 2 or higher lesions (CIN2 + ) in women with abnormal cervical cytology and high-risk HPV (HPV + ). We tested a biomarker panel in cervical epithelium DNA obtained from 211 women evaluated in a cervical cancer clinic in Chile from 2006 to 2008. Results were verified in a prospective cohort of 107 women evaluated in a high-risk clinic in Puerto Rico from 2013 to 2015. Promoter methylation of ZNF516, FKBP6, and INTS1 discriminated cervical brush samples with CIN2 + lesions from samples with no intraepithelial lesions or malignancy (NILM) with 90% sensitivity, 88.9% specificity, 0.94 area under the curve (AUC), 93.1% positive predictive value (PPV), and 84.2% negative predictive value (NPV). The panel results were verified in liquid-based cervical cytology samples from an independent cohort with 90.9% sensitivity, 60.9% specificity, 0.90 AUC, 52.6% PPV, and 93.3% NPV, after adding HPV16-L1 methylation to the panel. Next-generation sequencing results in HPV + cultured cells, and urine circulating cell-free DNA (ccfDNA) were used to design assays that show clinical feasibility in a subset (n = 40) of paired plasma (AUC = 0.81) and urine (AUC = 0.86) ccfDNA samples obtained from the prospective cohort. Viral and host DNA methylation panels can be tested in liquid cytology and urine ccfDNA from women referred to colposcopy, to triage CIN2 + lesions for biopsy and inform personalized screening algorithms. Cancer Prev Res; 9(12); 915-24. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: Recent research in humans and rodents has explored the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VS) as a possible treatment for drug addiction. However, the optimum electrode placement and optimum DBS parameters have not been thoroughly studied. Here we varied stimulation sites and frequencies to determine whether DBS of the VS could facilitate the extinction of morphine-induced conditioned place preference in rats., Methods: Rats were implanted with DBS electrodes in the dorsal or ventral subregions of the VS and trained to the morphine conditioned place preference. Subsequently, rats received extinction sessions over 9 days, combined with 60 min of either high- (130 Hz) or low- (20 Hz) frequency DBS. To study circuit-wide activations after DBS of the VS, c-fos immunohistochemistry was performed in regions involved in the extinction of drug-seeking behaviors., Results: High-frequency DBS of the dorsal-VS impaired both extinction training and extinction memory, whereas high-frequency DBS of the ventral-VS had no effect. In contrast, low-frequency DBS of the dorsal-VS strengthened extinction memory when tested 2 or 9 days after the cessation of stimulation. Both DBS frequencies increased c-fos expression in the infralimbic prefrontal cortex, but only low-frequency DBS increased c-fos expression in the basal amygdala and the medial portion of the central amygdala., Conclusions: Our results suggest that low-frequency (rather than high-frequency) DBS of the dorsal-VS strengthens extinction memory and may be a potential adjunct for extinction-based therapies for treatment-refractory opioid addiction., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The habenula is a tiny brain region the size of a pea in humans. This region is highly conserved across vertebrates and has been traditionally overlooked by neuroscientists. The name habenula is derived from the Latin word habena, meaning "little rein", because of its elongated shape. Originally its function was thought to be related to the regulation of the nearby pineal gland (which Rene Descartes described as the "principal seat of the soul"). More recent evidence, however, demonstrates that the habenula acts as a critical neuroanatomical hub that connects and regulates brain regions important for divergent motivational states and cognition. In this Primer, we will discuss the recent and converging evidence that points to the habenula as a key brain region for motivation and decision-making., (Copyright © 2016. Published by Elsevier Ltd.)