Transient IR spectroscopy of optically centrifuged CO2 (R186-R282) and collision dynamics for the J = 244-282 states.

Collisions of optically centrifuged CO2 molecules with J = 244-282 (Erot = 22 800-30 300 cm-1) are investigated with high-resolution transient IR absorption spectroscopy to reveal collisional and orientational phenomena of molecules with hyper-thermal rotational energies. The optical centrifuge is a non-resonant optical excitation technique that uses ultrafast, 800 nm chirped pulses to drive molecules to extreme rotational states through sequential Raman transitions. The extent of rotational excitation is controlled by tuning the optical bandwidth of the excitation pulses. Frequencies of 30 R-branch ν3 fundamental IR probe transitions are measured for the J = 186-282 states of CO2, expanding beyond previously reported IR transitions up to J = 128. The optically centrifuged molecules have oriented angular momentum and unidirectional rotation. Polarization-sensitive transient IR absorption of individual rotational states of optically centrifuged molecules and their collision products reveals information about collisional energy transfer, relaxation kinetics, and dynamics of rotation-to-translation energy transfer. The transient IR probe also measures the extent of polarization anisotropy. Rotational energy transfer for lower energy molecules is discussed in terms of statistical models and a comparison highlights the role of increasing energy gap with J and angular momentum of the optically centrifuged molecules.

Nine-valent HPV vaccine efficacy against related diseases and definitive therapy: comparison with historic placebo population.

OBJECTIVE: Nine-valent human papillomavirus (9vHPV) vaccine efficacy against disease and cervical surgeries related to all nine vaccine components was assessed compared with a historic placebo population. This was not assessed in the 9vHPV vaccine efficacy trial since the trial was quadrivalent HPV (qHPV) vaccine-controlled, efficacy was measured for the five HPV types covered only by 9vHPV vaccine (HPV31/33/45/52/58), but not the four types covered by both vaccines (HPV6/11/16/18). METHODS: Three international, randomized, double-blind studies were conducted using the same methodology. In the 9vHPV vaccine study (NCT00543543), 7106 and 7109 women received 9vHPV or qHPV vaccine, respectively. In the historic qHPV vaccine studies (FUTURE I [NCT00092521] and II [NCT00092534]), 8810 and 8812 women received qHPV vaccine or placebo, respectively, based on the same eligibility criteria. Cervical cytological testing was performed regularly. Biopsy or definitive therapy specimens were assessed for HPV DNA. RESULTS: Among women negative for 14 HPV types prior to vaccination, incidence of high-grade cervical disease (9vHPV, n = 2 cases; placebo, n = 141 cases) and cervical surgery (9vHPV, n = 3 cases; placebo, n = 170 cases) related to the nine HPV types was reduced by 98.2% (95% confidence interval [CI], 93.6-99.7) and 97.8% (95% CI, 93.4-99.4), respectively. The 9vHPV vaccine did not prevent disease related to vaccine HPV types detected at baseline, but significantly reduced cervical, vulvar, and vaginal diseases related to other vaccine HPV types. CONCLUSIONS: Effective implementation of the 9vHPV vaccine may substantially reduce the burden of HPV-related diseases and related medical procedures. TRIAL REGISTRATIONS: clinicaltrials.gov: NCT00543543, NCT00092521, NCT00092534.

Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16-26 years: a randomised, double-blind trial.

BACKGROUND: Primary analyses of a study in young women aged 16-26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years. METHODS: We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16-26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor's study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543. FINDINGS: Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10 000 person-years in the 9vHPV and 19·0 cases per 10 000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0-99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related. INTERPRETATION: The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide. FUNDING: Merck & Co, Inc.

A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women.

BACKGROUND: The investigational 9-valent viruslike particle vaccine against human papillomavirus (HPV) includes the HPV types in the quadrivalent HPV (qHPV) vaccine (6, 11, 16, and 18) and five additional oncogenic types (31, 33, 45, 52, and 58). Here we present the results of a study of the efficacy and immunogenicity of the 9vHPV vaccine in women 16 to 26 years of age. METHODS: We performed a randomized, international, double-blind, phase 2b-3 study of the 9vHPV vaccine in 14,215 women. Participants received the 9vHPV vaccine or the qHPV vaccine in a series of three intramuscular injections on day 1 and at months 2 and 6. Serum was collected for analysis of antibody responses. Swabs of labial, vulvar, perineal, perianal, endocervical, and ectocervical tissue were obtained and used for HPV DNA testing, and liquid-based cytologic testing (Papanicolaou testing) was performed regularly. Tissue obtained by means of biopsy or as part of definitive therapy (including a loop electrosurgical excision procedure and conization) was tested for HPV. RESULTS: The rate of high-grade cervical, vulvar, or vaginal disease irrespective of HPV type (i.e., disease caused by HPV types included in the 9vHPV vaccine and those not included) in the modified intention-to-treat population (which included participants with and those without prevalent infection or disease) was 14.0 per 1000 person-years in both vaccine groups. The rate of high-grade cervical, vulvar, or vaginal disease related to HPV-31, 33, 45, 52, and 58 in a prespecified per-protocol efficacy population (susceptible population) was 0.1 per 1000 person-years in the 9vHPV group and 1.6 per 1000 person-years in the qHPV group (efficacy of the 9vHPV vaccine, 96.7%; 95% confidence interval, 80.9 to 99.8). Antibody responses to HPV-6, 11, 16, and 18 were noninferior to those generated by the qHPV vaccine. Adverse events related to injection site were more common in the 9vHPV group than in the qHPV group. CONCLUSIONS: The 9vHPV vaccine prevented infection and disease related to HPV-31, 33, 45, 52, and 58 in a susceptible population and generated an antibody response to HPV-6, 11, 16, and 18 that was noninferior to that generated by the qHPV vaccine. The 9vHPV vaccine did not prevent infection and disease related to HPV types beyond the nine types covered by the vaccine. (Funded by Merck; ClinicalTrials.gov number, NCT00543543).

Immunogenicity of the 9-Valent HPV Vaccine Using 2-Dose Regimens in Girls and Boys vs a 3-Dose Regimen in Women.

Importance: Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts. Objective: To determine whether HPV type-specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses. Design, Setting, and Participants: Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314). Interventions: Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months. Main Outcomes and Measures: The primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers. Results: Of the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P < .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart. Conclusions and Relevance: Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01984697.

AN OPEN TRIAL OF EMOTION REGULATION THERAPY FOR GENERALIZED ANXIETY DISORDER AND COOCCURRING DEPRESSION.

BACKGROUND: Although CBT is efficacious for a wide variety of psychiatric conditions, relatively fewer GAD patients achieve high endstate functioning as compared to patients receiving CBTs for other disorders. Moreover, GAD trials that utilized patient samples without prominent depression have tended to report that effect sizes for depressive outcomes were small or diminished to pretreatment levels in the follow-up period. Emotion regulation therapy (ERT) integrates principles from traditional and contemporary cognitive behavioral treatments with basic and translational findings from affect science to offer a blueprint for improving intervention by focusing on motivational, regulatory, and contextual learning mechanisms. METHOD: The purpose of this investigation was to provide initial support for the efficacy of ERT in an open trial of patients with GAD and cooccurring depressive symptoms. Twenty-one patients received a 20-session version of ERT delivered in weekly individual sessions. Standardized clinician ratings and self-report measures were assessed at pre-, mid-, and posttreatment as well as at three- and nine-month follow-ups. Intent-to-treat analyzes were utilized. RESULTS: GAD patients, half with comorbid major depression, evidenced statistically, and clinically meaningful improvements in symptom severity, impairment, quality of life, and in model-related outcomes including emotional/motivational intensity, mindful attending/acceptance, decentering, and cognitive reappraisal. Patients maintained gains across the three and nine month follow-up periods. CONCLUSIONS: These findings, although preliminary, provide additional evidence for the role of emotion dysregulation in the onset, maintenance, and now treatment of conditions such as GAD and cooccurring depressive symptoms.

CD81 suppresses NF-κB signaling and is downregulated in hepatitis C virus expressing cells.

The tetraspanin CD81 is one of the main entry receptors for Hepatitis C virus, which is a major causative agent to develop liver cirrhosis and hepatocellular carcinoma (HCC). Here, we identify CD81 as one of few surface proteins that are downregulated in HCV expressing hepatoma cells, discovering a functional role of CD81 beyond mediating HCV entry. CD81 was downregulated at the mRNA level in hepatoma cells that replicate HCV. Kinetics of HCV expression were increased in CD81-knockout cells and accompanied by enhanced cellular growth. Furthermore, loss of CD81 compensated for inhibition of pro-survival TBK1-signaling in HCV expressing cells. Analysis of functional phenotypes that could be associated with pro-survival signaling revealed that CD81 is a negative regulator of NF-κB. Interaction of the NF-κB subunits p50 and p65 was increased in cells lacking CD81. Similarly, we witnessed an overall increase in the total levels of phosphorylated and cellular p65 upon CD81-knockout in hepatoma cells. Finally, translocation of p65 in CD81-negative hepatoma cells was markedly induced upon stimulation with TNFα or PMA. Altogether, CD81 emerges as a regulator of pro-survival NF-κB signaling. Considering the important and established role of NF-κB for HCV replication and tumorigenesis, the downregulation of CD81 by HCV and the associated increase in NF-κB signaling might be relevant for viral persistence and chronic infection.

Response of ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3.

Imatinib-resistant tyrosine kinase (TK) fusions involving FGFR1, JAK2, or FLT3 are rare but recurrent in patients with eosinophilia-associated neoplasms. We report here 2 male patients with ETV6-FLT3(+) myeloid/lymphoid neoplasms with eosinophilia who were treated with the multitargeted TK inhibitors sunitinib and sorafenib. Patient 1 achieved rapid complete hematologic response and complete cytogenetic response after 3 months of taking sunitinib. A secondary blast phase caused by clonal evolution was diagnosed after 6 months. He achieved a second complete hematologic response after taking sorafenib but relapsed 2 months later. An N841K point mutation within the TK domain of FLT3, previously reported in acute myeloid leukemia and potentially conferring resistance to sorafenib, was subsequently identified. Patient 2 was heavily pretreated according to the initial diagnosis of T-lymphoblastic lymphoma and died in sunitinib-induced pancytopenia. This report highlights the importance of a careful diagnostic workup for eosinophilia-associated neoplasms to evaluate the possibility of TK inhibitor therapy.

Unusual clinico-pathological features in primary Hodgkin's lymphomas of the central nervous system.

Primary Hodgkin's lymphomas of the central nervous system (CNS) as well as cerebral involvement as the first manifestation of a systemic Hodgkin's disease are very rare. CNS involvement usually occurs in patients with advanced or relapsing systemic disease. Because primary CNS Hodgkin's lymphoma may present unexpected and sometimes misleading clinical and neuroradiological features, the description of unusual cases is important for expanding the awareness of this rare disease of the central nervous system. We describe three cases of primary Hodgkin's lymphoma of the CNS with peculiar features. None of the three patients had a previous clinical history of systemic Hodgkin disease. Case 1 and case 2 presented an unusual localization in the cerebellar hemisphere and in the brainstem, respectively. The third case occurred as a temporal lesion in the settings of a Richter transformation of a chronic lymphocytic leukemia.

Emotion Regulation Therapy for Generalized Anxiety Disorder.

Despite the success of cognitive behavioral therapies (CBT) for emotional disorders, a sizable subgroup of patients with complex clinical presentations, such as patients with generalized anxiety disorder, fails to evidence adequate treatment response. Emotion Regulation Therapy (ERT) integrates facets of traditional and contemporary CBTs, mindfulness, and emotion-focused interventions within a framework that reflects basic and translational findings in affect science. Specifically, ERT is a mechanism-targeted intervention focusing on patterns of motivational dysfunction while cultivating emotion regulation skills. Open and randomized controlled psychotherapy trials have demonstrated considerable preliminary evidence for the utility of this approach as well as for the underlying proposed mechanisms. This article provides an illustration of ERT through the case of "William." In particular, this article includes a case-conceptualization of William from an ERT perspective while describing the flow and progression of the ERT treatment approach.

Safety, efficacy, and immunogenicity of a replication-defective human cytomegalovirus vaccine, V160, in cytomegalovirus-seronegative women: a double-blind, randomised, placebo-controlled, phase 2b trial.

BACKGROUND: A vaccine that prevents cytomegalovirus (CMV) infection in women could reduce the incidence of congenital CMV infection, a major cause of neurodevelopmental disability. We aimed to assess the safety and efficacy of a replication-defective investigational CMV vaccine, V160, in CMV-seronegative women. METHODS: This phase 2b, randomised, double-blind, placebo-controlled study was conducted at 90 sites in seven countries (USA, Finland, Canada, Israel, Spain, Russia, and Australia). Eligible participants were generally healthy, CMV-seronegative, non-pregnant, 16-35-year-old women of childbearing potential with exposure to children aged 5 years or younger. Participants were randomly assigned using central randomisation via an interactive response technology system 1:1:1 to one of three groups: V160 three-dose regimen (V160 at day 1, month 2, and month 6), V160 two-dose regimen (V160 on day 1, placebo at month 2, and V160 at month 6), or placebo (saline solution at day 1, month 2, and month 6). The primary outcomes were the efficacy of three doses of V160 in reducing the incidence of primary CMV infection during the follow-up period starting 30 days after the last dose of vaccine using a fixed event rate design, and the safety and tolerability of the two-dose and three-dose V160 regimens. We planned to test the efficacy of a two-dose regimen of V160 in reducing the incidence of primary CMV infection only if the primary efficacy hypothesis was met. Analyses for the primary efficacy endpoint were performed on the per-protocol efficacy population; safety analyses included all randomly assigned participants who received study vaccine. The primary efficacy hypothesis was tested at prespecified interim and final analyses. The study was ongoing and efficacy data continued to accrue at the time of final testing of the primary efficacy hypothesis. Vaccine efficacy was re-estimated after final testing of the primary efficacy hypothesis based on all available efficacy data at end of study. This trial is registered at ClinicalTrials.gov (NCT03486834) and EudraCT (2017-004233-86) and is complete. FINDINGS: Between April 30, 2018, and Aug 30, 2019, 7458 participants were screened, of whom 2220 were randomly assigned to the V160 three-dose group (n=733), V160 two-dose group (n=733), or placebo group (n=734). A total of 523 participants in the V160 three-dose group and 519 in the placebo group were included in the final hypothesis testing. Of these, there were 11 cases of CMV infection in the V160 three-dose group and 20 cases in the placebo group. The vaccine efficacy for the V160 three-dose group was 44·6% (95% CI -15·2 to 74·8) at the final testing of the primary efficacy hypothesis, a result corresponding to failure to demonstrate the primary efficacy hypothesis. On the basis of this result, the study was terminated for futility. The re-estimate of vaccine efficacy for the V160 three-dose group based on all available efficacy data at end of study (556 participants in the V160 three-dose group and 543 in the placebo group) was 42·4% (95% CI -13·5 to 71·1). A total of 728 participants in the V160 three-dose group, 729 in the V160 two-dose group, and 732 in the placebo group were included in the safety analyses. The most common solicited injection-site adverse event was injection-site pain (680 [93%] in the V160 three-dose group, 659 [90%] in the V160 two-dose group, and 232 [32%] in the placebo group). The most common solicited systemic adverse event was fatigue (457 [63%] in the V160 three-dose group, 461 [63%] in the V160 two-dose group, and 357 [49%] in the placebo group). No vaccine-related serious adverse events or deaths were reported. INTERPRETATION: V160 was generally well tolerated and immunogenic; however, three doses of the vaccine did not reduce the incidence of primary CMV infection in CMV-seronegative women compared with placebo. This study provides insights into the design of future CMV vaccine efficacy trials, particularly for the identification of CMV infection using molecular assays. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA (MSD).

A new transgenic rat model overexpressing the angiotensin II type 2 receptor provides evidence for inhibition of cell proliferation in the outer adrenal cortex.

This study aimed to elucidate the role of the AT(2) receptor (AT(2)R), which is expressed and upregulated in the adrenal zona glomerulosa (ZG) under conditions of increased aldosterone production. We developed a novel transgenic rat (TGR; TGRCXmAT(2)R) that overexpresses the AT(2)R in the adrenal gland, heart, kidney, brain, skeletal muscle, testes, lung, spleen, aorta, and vein. As a consequence the total angiotensin II (Ang II) binding sites increased 7.8-fold in the kidney, 25-fold in the heart, and twofold in the adrenals. The AT(2)R number amounted to 82-98% of total Ang II binding sites. In the ZG of TGRCXmAT(2)R, the AT(2)R density was elevated threefold relative to wild-type (WT) littermates, whereas AT(1)R density remained unchanged. TGRCXmAT(2)R rats were viable and exhibited normal reproduction, blood pressure, and kidney function. Notably, a slightly but significantly reduced body weight and a moderate increase in plasma urea were observed. With respect to adrenal function, 24-h urinary and plasma aldosterone concentrations were unaffected in TGRCXmAT(2)R at baseline. Three and 14 days of Ang II infusion (300 ng·min(-1)·kg(-1)) increased plasma aldosterone levels in WT and in TGR. These changes were completely abolished by the AT(1)R blocker losartan. Of note, glomerulosa cell proliferation, as indicated by the number of Ki-67-positive glomerulosa cells, was stimulated by Ang II in TGR and WT rats; however, this increase was significantly attenuated in TGR overexpressing the AT(2)R. In conclusion, AT(2)R in the adrenal ZG inhibits Ang II-induced cell proliferation but has no obvious lasting effect on the regulation of the aldosterone production at the investigated stages.

A zipper network model of the failure mechanics of extracellular matrices.

Mechanical failure of soft tissues is characteristic of life-threatening diseases, including capillary stress failure, pulmonary emphysema, and vessel wall aneurysms. Failure occurs when mechanical forces are sufficiently high to rupture the enzymatically weakened extracellular matrix (ECM). Elastin, an important structural ECM protein, is known to stretch beyond 200% strain before failing. However, ECM constructs and native vessel walls composed primarily of elastin and proteoglycans (PGs) have been found to fail at much lower strains. In this study, we hypothesized that PGs significantly contribute to tissue failure. To test this, we developed a zipper network model (ZNM), in which springs representing elastin are organized into long wavy fibers in a zipper-like formation and placed within a network of springs mimicking PGs. Elastin and PG springs possessed distinct mechanical and failure properties. Simulations using the ZNM showed that the failure of PGs alone reduces the global failure strain of the ECM well below that of elastin, and hence, digestion of elastin does not influence the failure strain. Network analysis suggested that whereas PGs drive the failure process and define the failure strain, elastin determines the peak and failure stresses. Predictions of the ZNM were experimentally confirmed by measuring the failure properties of engineered elastin-rich ECM constructs before and after digestion with trypsin, which cleaves the core protein of PGs without affecting elastin. This study reveals a role for PGs in the failure properties of engineered and native ECM with implications for the design of engineered tissues.

HCV egress - unconventional secretion of assembled viral particles.

It is believed that hepatitis C virus (HCV) particles are released through the canonical secretory route: from the endoplasmic reticulum (ER), via the Golgi, to the plasma membrane. While the Golgi is important for HCV release per se, its direct involvement in the trafficking of assembled virions has not yet been established. In fact, data from studies analyzing HCV egress are compatible with several potential pathways of HCV secretion. Here, we summarize and discuss the current knowledge related to the HCV export pathway. Apart from the prototypical anterograde transport, possible routes of HCV release include ER-to-endosomal transport, secretory autophagy, and poorly described mechanisms of unconventional protein secretion. Studying HCV egress promises to shed light on unconventional cellular trafficking and secretory routes.

Rescue me: saving the vulnerable non-ICU patient population.

BACKGROUND: From 2003-2005, a comprehensive review of all cardiac/respiratory arrests at Mission Hospital (Mission Viejo, California) uncovered deficits in knowledge and judgment in the hours preceding 75% of our non-ICU patients. Nearly half of all arrests were occurring outside the ICU, with an overall mortality rate of 60%. In addition, transfers into ICU from the floor averaged 96 patients per month. METHODS: A multidisciplinary team met for 12 months to develop a specialized nurse-driven rapid response team (RRT) to reduce the incidence and mortality of non-ICU arrests, reduce transfers to the ICU from the floor, and provide ICU-level nursing care for emergency department (ED) patients in extremis. The team developed an RRT protocol, a methodology for rounds and calls, and a data collection system. After gaining consensus among the nursing managers, 4.2 full-time equivalent (FTE) RRT nurse positions were created by each unit contributing portions of an FTE. RESULTS: Prospective data collected demonstrated an inpatient call frequency averaging 118 calls per 1,000 discharges; 138 calls per month were in support of the ED. Floor codes were reduced from 36 to 17 per year, and the mortality rate in the floor-code patients decreased from 61% to 26%. Unanticipated transfers from the floor units to the ICU decreased significantly. DISCUSSION: The RRT initiative delivered measurable outcomes demonstrating the hospital's commitment to saving the vulnerable hospitalized patient population. In addition, the identification of critical system and clinical issues resulted in efforts to improve processes and identify patient subpopulations at risk (for example, patients with congestive heart failure, end-stage heart disease, high-dose narcotics).

Efficacy, immunogenicity, and safety of a 9-valent human papillomavirus vaccine in Latin American girls, boys, and young women.

BACKGROUND: A 9-valent human papillomavirus (HPV6/11/16/18/31/33/45/52/58; 9vHPV) vaccine was developed to expand coverage of the previously developed quadrivalent (HPV6/11/16/18; qHPV) vaccine. METHODS: Efficacy, immunogenicity, and safety outcomes were assessed in Latin American participants enrolled in 2 international studies of the 9vHPV vaccine, including a randomized, double-blinded, controlled with qHPV vaccine, efficacy, immunogenicity, and safety study in young women aged 16-26 years, and an immunogenicity and safety study in girls and boys aged 9-15 years. Participants (N=5312) received vaccination at Day 1, Month 2, and Month 6. Gynecological swabs were collected regularly in young women for cytological and HPV DNA testing. Serum was analyzed for HPV antibodies in all participants. Adverse events (AEs) were also monitored in all participants. RESULTS: The 9vHPV vaccine prevented HPV 31-, 33-, 45-, 52-, and 58-related high-grade cervical, vulvar, and vaginal dysplasia with 92.3% efficacy (95% confidence interval 54.4, 99.6). Anti-HPV6, 11, 16, and 18 geometric mean titers at Month 7 were similar in the 9vHPV and qHPV vaccination groups. Anti-HPV antibody responses following vaccination were higher among girls and boys than in young women. Most (>99%) 9vHPV vaccine recipients seroconverted for all 9 HPV types at Month 7. Antibody responses to the 9 HPV types persisted over 5 years. The most common AEs were injection-site related, mostly of mild to moderate intensity. CONCLUSIONS: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Latin American young women, girls, and boys. These data support 9vHPV vaccination programs in Latin America, a region with substantial cervical cancer burden.

Optimizing Household Chlorination Marketing Strategies: A Randomized Controlled Trial on the Effect of Price and Promotion on Adoption in Haiti.

Household water treatment can reduce diarrheal morbidity and mortality in developing countries, but adoption remains low and supply is often unreliable. To test effects of marketing strategies on consumers and suppliers, we randomized 1,798 households in rural Haiti and collected data on purchases of a household chlorination product for 4 months. Households received randomly selected prices ($0.11-$0.56 per chlorine bottle), and half received monthly visits from sales agents. Each $0.22 drop in price increased purchases by 0.10 bottles per household per month (P < 0.001). At the mean price, each 1% drop in price increased purchases by 0.45% (elasticity = 0.45). There is suggestive evidence that household visits by some sales agents increased purchases at mid-range prices; however, the additional revenue did not offset visit cost. Choosing the lowest price and conducting visits maximizes chlorine purchase, whereas slightly raising the retail price and not conducting visits maximizes cost recovery. For the equivalent cost, price discounts increase purchases 4.2 times as much as adding visits at the current retail price. In this context, price subsidies may be a more cost-effective use of resources than household visits, though all marketing strategies tested offer cost-effective ways to achieve incremental health impact. Decisions about pricing and promotion for health products in developing countries affect health impact, cost recovery, and cost-effectiveness, and tradeoffs between these goals should be made explicit in program design.

A novel stop mutation (p.(Gln22*)) of DAX1 (NR0B1) results in late-onset X-linked adrenal hypoplasia congenita.

DAX1 (NR0B1) is an orphan nuclear receptor, which plays an important role in development and function of the adrenal glands and gonads. Mutations in DAX1 cause X-linked adrenal hypoplasia congenita (X-linked AHC), which is characterized by adrenal insufficiency (AI) and hypogonadotropic hypogonadism (HHG). Affected boys present with adrenal failure usually in childhood and, later in life, with delayed puberty. However, patients with a late-onset form of X-linked AHC have also been described in the past years. We report a male patient who presented with symptoms of an adrenal crisis at the age of 38 years and was later diagnosed with HHG. Family history was positive with several male relatives diagnosed with AI and compatible with the assumed X-chromosomal inheritance of the trait. Direct sequencing of DAX1 of the patient revealed a hemizygous cytosine-to-thymine substitution at nucleotide 64 in exon 1, which creates a novel nonsense mutation (p.(Gln22*)). In order to compare the clinical presentation of the patient to that of other patients with X-linked AHC, we searched the electronic database MEDLINE (PubMed) and found reports of nine other cases with delayed onset of X-linked AHC. In certain cases, genotype-phenotype correlation could be assumed. LEARNING POINTS: X-linked AHC is a rare disease characterized by primary AI and hypogonadotropic hypogonadism (HHG). The full-blown clinical picture is seen usually only in males with a typical onset in childhood.Patients with a late-onset form of X-linked AHC have also been described recently. Being aware of this late-onset form might help to reach an early diagnosis and prevent life-threatening adrenal crises.Adult men with primary AI of unknown etiology should be investigated for HHG. Detecting a DAX1 mutation may confirm the clinical diagnosis of late-onset X-linked AHC.In relatives of patients with genetically confirmed X-linked AHC, targeted mutation analysis may help to identify family members at risk and asymptomatic carriers, and discuss conscious family planning.