Enhanced immune responses following heterologous vaccination with self-amplifying RNA and mRNA COVID-19 vaccines.

The optimal vaccination strategy to boost responses in the context of pre-existing immune memory to the SARS-CoV-2 spike (S) glycoprotein is an important question for global public health. To address this, we explored the SARS-CoV-2-specific humoral and cellular immune responses to a novel self-amplifying RNA (saRNA) vaccine followed by a UK authorised mRNA vaccine (BNT162b2) in individuals with and without previous COVID-19, and compared these responses with those who received an authorised vaccine alone. 35 subjects receiving saRNA (saRNA group) as part of the COVAC1 clinical trial and an additional 40 participants receiving an authorised SARS-CoV-2 vaccine only (non-saRNA group) were recruited. Antibody responses were measured by ELISA and a pseudoneutralisation assay for wildtype, Delta and Omicron variants. Cellular responses were measured by IFN-Æ´ ELISpot and an activation induced marker (AIM) assay. Approximately 50% in each group had previous COVID-19 prior to vaccination, confirmed by PCR or antibody positivity on ELISA. All of those who received saRNA subsequently received a full course of an authorised vaccine. The majority (83%) of those receiving saRNA who were COVID-19 naïve at baseline seroconverted following the second dose, and those with previous COVID-19 had an increase in antibody titres two weeks following saRNA vaccination (median 27-fold), however titres were lower when compared to mRNA vaccination. Two weeks following the 2nd authorised mRNA vaccine dose, binding and neutralising antibody titres were significantly higher in the saRNA participants with previous COVID-19, compared to non-saRNA, or COVID-19 naive saRNA participants. Cellular responses were again highest in this group, with a higher proportion of spike specific CD8+ than CD4+ T cells when compared to those receiving the mRNA vaccine only. These findings suggest an immunological benefit of increased antigen exposure, both from natural infection and vaccination, particularly evident in those receiving heterologous vaccination with saRNA and mRNA.

One dose versus two doses of COVID-19 vaccine for the prevention of breakthrough infections among people previously infected with SARS-Cov-2.

Studies have suggested the effectiveness of COVID-19 vaccines in preventing SARS-CoV-2 reinfection among those previously infected. However, it is not yet clear if one dose of the vaccine is enough to prevent breakthrough infections compared to two doses. Using data from Optum deidentified COVID-19 Electronic Health Record (EHR) data set, we assessed breakthrough infection risks in individuals previously infected, comparing those with one vaccine dose to those with two doses. Propensity scores were applied to mitigate confounding factors. Follow-up spanned 6 months, beginning 2 weeks postvaccination. Among 213 845 individuals, those receiving one vaccine dose had a significantly higher breakthrough infection risk than the two-dose group (HR 1.69, 95% CI 1.54-1.85). This pattern was observed across genders, racial/ethnic groups, age categories, and vaccine types. This study reveals a substantial disparity in the risk of breakthrough infections between individuals receiving one versus two doses of the COVID-19 vaccine, suggesting that a single dose may not provide adequate protection against reinfection.

Pilot Study to Investigate the Use of In-Clinic Sensing to Identify Optimal Stimulation Parameters for Deep Brain Stimulation Therapy in Parkinson's Disease.

BACKGROUND: Deep brain stimulation (DBS) programming is time intensive. Recent advances in sensing technology of local field potentials (LFPs) may enable improvements. Few studies have compared the use of this technology with standard of care. OBJECTIVE/HYPOTHESIS: Sensing technology of subthalamic nucleus (STN) DBS leads in Parkinson's disease (PD) is reliable and predicts the optimal contacts and settings as predicted by clinical assessment. MATERIALS AND METHODS: Five subjects with PD (n = 9 hemispheres) with bilateral STN DBS and sensing capable battery replacement were recruited. An LFP sensing review of all bipolar contact pairs was performed three times. Contact with the maximal beta peak power (MBP) was then clinically assessed in a double-blinded fashion, and five conditions were tested: 1) entry settings, 2) off stimulation, 3) MBP at 30 µs, 4) MBP at 60 µs, and 5) MBP at 90 µs. RESULTS: Contact and frequency of the MBP power in all hemispheres did not differ across sessions. The entry settings matched with the contact with the MBP power in 5 of 9 hemispheres. No clinical difference was evident in the stimulation conditions. The clinician and subject preferred settings determined by MBP power in 7 of 9 and 5 of 7 hemispheres, respectively. CONCLUSIONS: This study indicates that STN LFPs in PD recorded directly from contacts of the DBS lead provide consistent recordings across the frequency range and a reliably detected beta peak. Furthermore, programming based on the MBP power provides at least clinical equivalence to standard of care programming with STN DBS.

Assessing incident depression among older people with and without HIV in U.S.

PURPOSE: Despite substantially higher prevalence of depression among people living with HIV/AIDS (PLWHA), few data exist on the incidence and correlates of depression in this population. This study assessed the effect of HIV infection, age, and cohort period on the risk of developing depression by sex among older U.S. Medicare beneficiaries. METHODS: We constructed a retrospective matched cohort using a 5% nationally representative sample of Medicare beneficiaries (1996-2015). People with newly diagnosed (n = 1309) and previously diagnosed (n = 1057) HIV were individually matched with up to three beneficiaries without HIV (n = 6805). Fine-Gray models adjusted for baseline covariates were used to assess the effect of HIV status on developing depression by sex strata. RESULTS: PLWHA, especially females, had higher risk of developing depression within five years. The relative subdistribution hazards (sHR) for depression among three HIV exposure groups differed between males and females and indicated a marginally significant interaction (p = 0.08). The sHR (95% CI) for newly and previously diagnosed HIV (vs. people without HIV) were 1.6 (1.3, 1.9) and 1.9 (1.5, 2.4) for males, and 1.5 (1.2, 1.8) and 1.2 (0.9, 1.7) for females. The risk of depression increased with age [sHR 1.3 (1.1, 1.5), 80 + vs. 65-69] and cohort period [sHR 1.3 (1.1, 1.5), 2011-2015 vs. 1995-2000]. CONCLUSIONS: HIV infection increased the risk of developing depression within 5 years, especially among people with newly diagnosed HIV and females. This risk increased with older age and in recent HIV epidemic periods, suggesting a need for robust mental health treatment in HIV primary care.

Adaptations of an Effective Evidence-Based Pediatric Weight Management Intervention.

Current childhood obesity treatment programs do not address medically underserved populations or settings where all members of an interdisciplinary team may not exist-either within one organization or within the community. In this paper, we describe the use of a community-academic partnership to iteratively adapt Epstein's Traffic Light Diet (TLD), into Building Healthy Families (BHF), a community-placed evidence-based pediatric weight management intervention (PWMI) and evaluate its effectiveness in reducing BMI z scores. Nine cohorts of families completed BHF. Participants included children aged 6-12 years with obesity (M = 9.46, SD = 1.74). The Framework for Reporting Adaptations and Modifications-Expanded guided our classification of modifications across BHF cohorts. Using the FRAME reporting structure, the changes that were documented were (1) planned and occurred pre-implementation, (2) based on decisions from local stakeholders (e.g., school administrator, members of the implementation team), and (3) specific to changes in content and context-with a focus on implementation and potential for local scale-up. The nature of the adaptations included adding elements (whole of family approach), removing elements (calorie counting), and substituting elements (steps for minutes of physical activity). Across 9 cohorts, 84 families initiated the BHF program, 69 families successfully completed the 12-week program, and 45 families returned for 6-month follow-up assessments. Results indicated that the BMI z score in children was reduced by 0.31 ± 0.17 at 6 months across all cohorts. Reduction in BMI z score ranged from 0.41 in cohort 4 to 0.13 in cohort 5. Iterative adaptations to BHF were completed to improve the fit of BHF to the setting and participants and have contributed to a sustained community PWMI that adheres to the underlying principles and core elements of other evidence-based PWMIs. Monitoring adaptations and related changes to outcomes can play a role in long-term sustainability and effectiveness.

Prevalence of Oral Human Papillomavirus Infection: Impact of Sex, Race/Ethnicity, and Vaccination Status.

BACKGROUND: Prior studies have demonstrated differences in oral human papillomavirus (HPV) prevalence by sex and race/ethnicity. In this study, we examined the impact of vaccination on these disparities. METHODS: We examined participants aged 18-59 years in the National Health and Nutrition Examination Survey from 2011 to 2016 who reported their HPV vaccination status and submitted an adequate oral sample (N = 9437). Oral prevalence of HPV, grouped by any, low-risk, high-risk, 4 valent (4v) HPV, 9 valent (9v) HPV, and nonvaccine types, was examined by sex, race/ethnicity, and vaccination status. Binary logistic regression was used to estimate prevalence ratios by vaccination status. Multivariable logistic regression models controlled for age, sex, and race/ethnicity. RESULTS: The prevalence of any, nonvaccine, low-risk, high-risk, 4vHPV, and 9vHPV types was higher among males than females, even among vaccinated participants. Examination of racial/ethnic differences demonstrated differences in all HPV groups among unvaccinated males and among low-risk types in females. In all but the 2 vaccine-type groups, the prevalence of oral HPV was notably higher among Black males compared with other groups. Significant differences were not observed by race/ethnicity among vaccinated males or females. CONCLUSIONS: Males tested positive for oral HPV more frequently than females, even among those vaccinated. This may have resulted from a lower frequency of males being vaccinated before initiating oral sex than females. Vaccination of males at the recommended age, therefore, may decrease differences in oral HPV by sex. Racial/ethnic differences were observed only in unvaccinated individuals, suggesting these disparities will decrease as more individuals are vaccinated.

Impact assessment of a provider-targeted national vaccine messaging campaign on human papillomavirus vaccination rates among US adolescent males.

Initial uptake of the cancer-preventative human papillomavirus (HPV) vaccine in the US was slow, especially among adolescent males. To address this, the US Centers for Disease Control and Prevention (CDC) partnered with the Hager Sharp communications development company to launch a national campaign in 2015 to improve physician counseling and rebrand the vaccine as cancer prevention. In this study, we compared HPV vaccination rates among 13-17-year-old males before (2010-2014) and after (2015-2019) the CDC-Hager Sharp campaign using National Immunization Survey-Teen data to determine the potential impact of this campaign on improving vaccine uptake among adolescent males. Employing provider-verified vaccination data available for 49,644 males from 2010 to 2014 and 47,943 males from 2015 to 2019, we found that the adjusted prevalence ratios of 13-17-year-old males who initiated and completed the vaccine series increased approximately 5-fold between the 2010-2014 and 2015-2019 periods. Increases in post-campaign initiation/completion rates were greatest among respondents with mothers who were married or had attended college, respondents who lived in the Northeast or Midwest, and those from households with annual incomes > $75,000. Together, these data suggest that the campaign contributed to the observed increase in HPV vaccine uptake among adolescent males. Although sociodemographic disparities were identified, the greater improvement in vaccination rates observed among individuals with higher socio-demographic status may simply reflect their relatively poorer rates of initial vaccine uptake. Overall, the data suggest that provider-targeted campaigns can be a useful tool to boost vaccinations and should be considered for inclusion in future vaccination campaigns.

Temporal evolution of beta bursts in the parkinsonian cortical and basal ganglia network.

Beta frequency oscillations (15 to 35 Hz) in cortical and basal ganglia circuits become abnormally synchronized in Parkinson's disease (PD). How excessive beta oscillations emerge in these circuits is unclear. We addressed this issue by defining the firing properties of basal ganglia neurons around the emergence of cortical beta bursts (ß bursts), transient (50 to 350 ms) increases in the beta amplitude of cortical signals. In PD patients, the phase locking of background spiking activity in the subthalamic nucleus (STN) to frontal electroencephalograms preceded the onset and followed the temporal profile of cortical ß bursts, with conditions of synchronization consistent within and across bursts. Neuronal ensemble recordings in multiple basal ganglia structures of parkinsonian rats revealed that these dynamics were recapitulated in STN, but also in external globus pallidus and striatum. The onset of consistent phase-locking conditions was preceded by abrupt phase slips between cortical and basal ganglia ensemble signals. Single-unit recordings demonstrated that ensemble-level properties of synchronization were not underlain by changes in firing rate but, rather, by the timing of action potentials in relation to cortical oscillation phase. Notably, the preferred angle of phase-locked action potential firing in each basal ganglia structure was shifted during burst initiation, then maintained stable phase relations during the burst. Subthalamic, pallidal, and striatal neurons engaged and disengaged with cortical ß bursts to different extents and timings. The temporal evolution of cortical and basal ganglia synchronization is cell type-selective, which could be key for the generation/ maintenance of excessive beta oscillations in parkinsonism.

Knowledge, Attitudes, Willingness to Pay, and Patient Preferences About Genetic Testing and Subsequent Risk Management for Cancer Prevention.

Knowledge, attitudes, and patient preferences about genetic testing and subsequent risk management for cancer prevention among average risk populations are understudied, especially among Hispanics. This study was to assess these items by conducting an in-person survey in this understudied population. We conducted in-person surveys using a self-administered, structured questionnaire among young women in 2017. Survey questions were adapted from other validated surveys. This study had 677 participants in the final analyses. Data were collected in 2017 and analyzed in 2018 and 2019. Participants had little knowledge about genes or breast cancer risk, but most felt that genetic testing for cancer prevention is "a good idea" (87.0%), "a reassuring idea" (84.0%), and that "everyone should get the test" (87.7%). Most (64.0%) of these women would pay up to $25 for the test, 29.3% would pay $25-$500, and < 10% would pay more than $500 for the test. When asked about a hypothetical scenario of high breast cancer risk, 34.2% Hispanics and 24.5% non-Hispanics would choose chemoprevention. Women would be less likely to choose risk reduction procedures, such as mastectomy (19.6% among Hispanics and 15.1% among non-Hispanics) and salpingo-oophorectomy (11.8% among Hispanics and 10.7% among non-Hispanics). In this low-income, mostly Hispanic population, knowledge about genetic testing and cancer risk is poor, but most have positive opinions about genetic testing for cancer prevention. However, their strong preference for chemoprevention and lesser preference for prophylactic surgeries in a hypothetical scenario underscore the importance of genetic counseling and education.

Prevalence of Genital Human Papillomavirus by Age and Race/Ethnicity Among Males.

BACKGROUND: Genital and oral cancers are often caused by human papillomavirus (HPV) types that can be prevented through HPV vaccination. Since HPV is sexually transmitted, knowledge of penile prevalence of vaccine-type HPV among US males can help predict potential disparities in these cancers. This study examines penile HPV prevalence by age and race/ethnicity among males. METHODS: This study was a secondary analysis of publicly available data from the National Health and Nutrition Examination Survey (NHANES). Using data from penile swab samples collected from males between 2013 and 2016, the prevalence of 4vHPV and 9vHPV vaccine types was examined across age groups and by race/ethnicity. Logistic regression models adjusting for demographics, sexual behavior, and circumcision were examined to determine whether associations remained after accounting for confounders. RESULTS: Among 2548 males evaluated, HPV infection prevalence differed by race/ethnicity, with Black males exhibiting a higher prevalence of HPV. Examination of 4vHPV type prevalence by age group showed that 18-26-year-old males had a lower prevalence than older age groups. After controlling for confounders, 4vHPV prevalence was only significantly elevated among 27-34-year-old males, those who were single, and males with ≥3 lifetime sex partners. In adjusted models, 9vHPV type prevalence remained elevated among Black males compared with White males. CONCLUSIONS: Variations in 9vHPV type prevalence between Black and White individuals indicate future disparities in HPV-related genital cancers may continue in the United States during the next decade. Revaccinating certain populations with the 9vHPV vaccine may be appropriate to help mitigate this.

Quantitative and qualitative assessment of an all-inclusive postpartum human papillomavirus vaccination program.

BACKGROUND: A postpartum human papillomavirus vaccination program was locally implemented to address low initiation rates among young adults. Within 20 months, the program achieved high vaccine initiation and series completion rates. Based on the program's success, it was expanded to all 36 counties served by a public hospital. OBJECTIVE: This study aimed to conduct a quantitative and qualitative evaluation to examine the success and limitations of the program when expanded from 1 county to 36 counties, many of which are home to rural and medically underserved communities. STUDY DESIGN: Patient navigators reviewed the electronic medical records and immunization registry records of women aged ≤26 years, who delivered an infant at the public hospital, to determine whether they needed to initiate or complete the human papillomavirus vaccine series. Eligible women were counseled and offered the human papillomavirus vaccine during their hospital stay. Patient navigators scheduled follow-up injections in addition to the mother's postpartum or her infant's well-child visits, made reminder phone calls, and rescheduled missed appointments. Descriptive statistics, including frequencies and proportions, were used for patients approached in the initial and expansion programs. Frequencies from the initial and expansion programs were examined separately. Qualitative interviews were conducted with the clinic staff to evaluate the program. The qualitative analyses were conducted using NVivo (QSR International, Melbourne, Australia, version 10). RESULTS: Both initial and expanded programs achieved vaccine completion rates above 70%. Of the 2631 eligible postpartum women enrolled in the initial program, 785 (30%) had already been fully vaccinated. Of the remaining 1846 women, 1265 (69%) women received their first dose, and 196 (11%) women received their second or third dose on the postpartum unit. Of the 1461 women who received at least 1 dose through the initial program, 1124 (77%) completed all 3 doses. Of the 4330 eligible postpartum women enrolled in the expanded program, 886 (21%) had already been fully vaccinated. Of the remaining 3444 women, 2284 (66%) received their first dose, and 343 (10%) received their second or third dose on the postpartum unit. Of the 2627 women receiving at least 1 dose through the expanded program, 1932 (74%) completed all 3 doses. Clinic staff interviewed felt the program benefited the postpartum unit and clinics, because it increased patient knowledge of the vaccine, increased patient volume for vaccination, and gave healthcare providers more time to focus on other tasks. CONCLUSION: Human papillomavirus vaccination on the postpartum unit is an effective way to increase catchup rates and is well accepted by healthcare providers. High completion rates can be achieved if adequate support is provided, even among patients residing in rural or underserved areas who need extensive support to access primary healthcare services. Although this particular program may be considered costly, it is overall effective because the vaccine prevents 5 different types of cancer in women. The inclusion of human papillomavirus vaccination in routine postpartum care is a relatively easy way to reach many adults not vaccinated at a younger age and could help address low vaccination rates among young women in the United States, including hard-to-reach populations.

Phase-Dependent Suppression of Beta Oscillations in Parkinson's Disease Patients.

Synchronized oscillations within and between brain areas facilitate normal processing, but are often amplified in disease. A prominent example is the abnormally sustained beta-frequency (∼20 Hz) oscillations recorded from the cortex and subthalamic nucleus of Parkinson's disease patients. Computational modeling suggests that the amplitude of such oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Here, activity was recorded from 10 awake, parkinsonian patients (6 male, 4 female human subjects) undergoing functional neurosurgery. We demonstrate that stimulation arriving on a particular patient-specific phase of the beta oscillation over consecutive cycles could suppress the amplitude of this pathophysiological activity by up to 40%, while amplification effects were relatively weak. Suppressive effects were accompanied by a reduction in the rhythmic output of subthalamic nucleus (STN) neurons and synchronization with the mesial cortex. While stimulation could alter the spiking pattern of STN neurons, there was no net effect on firing rate, suggesting that reduced beta synchrony was a result of alterations to the relative timing of spiking activity, rather than an overall change in excitability. Together, these results identify a novel intrinsic property of cortico-basal ganglia synchrony that suggests the phase of ongoing neural oscillations could be a viable and effective control signal for the treatment of Parkinson's disease. This work has potential implications for other brain diseases with exaggerated neuronal synchronization and for probing the function of rhythmic activity in the healthy brain.SIGNIFICANCE STATEMENT In Parkinson's disease (PD), movement impairment is correlated with exaggerated beta frequency oscillations in the cerebral cortex and subthalamic nucleus (STN). Using a novel method of stimulation in PD patients undergoing neurosurgery, we demonstrate that STN beta oscillations can be suppressed when consecutive electrical pulses arrive at a specific phase of the oscillation. This effect is likely because of interrupting the timing of neuronal activity rather than excitability, as stimulation altered the firing pattern of STN spiking without changing overall rate. These findings show the potential of oscillation phase as an input for "closed-loop" stimulation, which could provide a valuable neuromodulation strategy for the treatment of brain disorders and for elucidating the role of neuronal oscillations in the healthy brain.

Parkinson's disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input in vivo.

Abnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinson's disease (PD). It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35 Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake human PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In these patients, we demonstrate that a subset of putative STN neurons is strongly and selectively sensitive to magnitude fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to the full range of instantaneous amplitude in the beta-frequency range. In rats, we probed the frequency response of STN neurons in the cortico-basal-ganglia-network more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40 Hz) and constant amplitude. In both healthy and dopamine-depleted rats, only beta-frequency stimulation led to a progressive reduction in the variability of spike timing through the stimulation train. This suggests, that the interval of beta-frequency input provides an optimal window for eliciting the next spike with high fidelity. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input.

BRCA testing in unaffected young women in the United States, 2006-2017.

BACKGROUND: The discovery of the BRCA gene in the 1990s created an opportunity for individualized cancer prevention. BRCA testing in young women before cancer onset enables early detection of those with an increased cancer risk and creates an opportunity to offer lifesaving prophylactic procedures and medications. This study assessed trends in BRCA testing in women younger than 40 years without diagnosed breast or ovarian cancer (unaffected young women [UYW]) for cancer prevention between 2006 and 2017 in the United States. METHODS: This study included 93,278 adult women 18 to 65 years old with insurance claims for BRCA testing between 2006 and 2017 from the de-identified Optum Clinformatics Data Mart database. The data contained medical claims and administrative information from privately insured individuals in the United States. The proportion of BRCA testing in UYW younger than 40 years among adult women aged 18 to 65 years who received BRCA testing was assessed. RESULTS: In 2006, only 10.5% of the tests were performed in UYW. The proportion of BRCA tests performed in UYW increased significantly to 25.5% in 2017 (annual percentage change for the 2006-2017 period, 6.9; 95% confidence interval, 6.4-7.3; P < .001). The increased trend in the proportion of BRCA tests in UYW significantly differed by region of residence and family history of breast or ovarian cancer. CONCLUSIONS: Over the past decade, there was increased use of BRCA testing for cancer prevention. Additional efforts are needed to maximize the early detection of women with BRCA pathogenic variants so that these cancers may be prevented.

Prenatal vaccination of mothers and hepatitis B vaccination of their infants.

Tetanus, diphtheria, and acellular pertussis (Tdap) vaccination and influenza vaccination are recommended during pregnancy primarily to prevent influenza and pertussis in mothers and their infants. This study examines associations between prenatal Tdap vaccination and influenza vaccination of mothers and hepatitis B vaccination of their infants. A retrospective cohort study was conducted using data from electronic medical records from 15,468 deliveries to 14,925 mothers occurring April 2, 2014-December 3, 2016 at a university hospital in Texas. Hepatitis B vaccine receipt in the first 3 days of life was dichotomized. Margins post-estimation commands in Stata SE 15.1 were used to obtain predicted probabilities and risk differences after estimating odds ratios in logistic regression with robust variance estimates. Adjusted models included maternal age, race/ethnicity, Medicaid use, year of delivery, parity, and gravidity. Infants of mothers who received prenatal influenza vaccination in the 2014-2015 and 2015-2016 influenza seasons were more likely than those of mothers who did not to receive a hepatitis B vaccine in their first 3 days of life (adjusted risk difference (RD) 2.8%, 95% confidence interval (CI) 1.5-4.1% and RD 2.2%, 95% CI 0.9-3.5%, respectively). Hepatitis B vaccination was also higher among infants of Tdap-eligible mothers who received prenatal Tdap vaccination during pregnancy compared to those of mothers who did not (adjusted RD 9.1%, 95% CI 7.6-10.5%). Overall, prenatal vaccination was significantly associated with uptake of infant hepatitis B vaccine.

Trends in breast cancer mortality by stage at diagnosis among young women in the United States.

BACKGROUND: Assessing trends in breast cancer survival among young women who are largely unaffected by breast cancer screening will provide important information regarding improvements in the effectiveness of cancer care for breast cancer in the last few decades. METHODS: The cohort for this study consisted of women who were diagnosed with breast cancer between ages 20 and 39 years from the Surveillance, Epidemiology, and End Results program's 9-registry areas from 1975 to 2015. Trends in the breast cancer incidence rate and survival were assessed among young women. RESULTS: Among women aged 20 to 39 years, breast cancer incidence increased from 24.6 per 100,000 in 1975 to 31.7 per 100,000 in 2015 (annual percent change, 0.5; 95% confidence interval [CI], 0.4-0.6). Among women with breast cancer, 5-year breast-cancer-specific survival increased significantly from 74.0% during 1975 to 1979 to 88.5% during 2010 to 2015 (hazard ratio for dying from breast cancer for 2010-2015 vs 1975-1979, 0.37; 95% CI, 0.32-0.41). The increase in cancer-specific survival reached a plateau in 2005; however, among young women with metastatic breast cancer, it continued to increase after 2005, from 45.6% during 2005 to 2009 to 56.5% during 2010 to 2015 (hazard ratio for dying from breast cancer for 2010-2015 vs 2005-2009, 0.74; 95% CI, 0.60-0.92). Similar patterns also were observed for 5-year overall survival and among women aged 20 to 29 years and those aged 30 to 39 years. CONCLUSIONS: There were substantial improvements in the effectiveness of breast cancer treatment on overall and cancer-specific survival from 1975 to 2015. However, improvements appeared to have reached a plateau after 2005, except among young women with metastatic breast cancer, in whom survival continued to improve throughout the period.

Broadly Neutralizing Antibodies Display Potential for Prevention of HIV-1 Infection of Mucosal Tissue Superior to That of Nonneutralizing Antibodies.

Definition of the key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue may prove critical to effective vaccine development and the prophylactic use of monoclonal antibodies. Although direct antibody-mediated neutralization is highly effective against cell-free virus, antibodies targeting different sites of envelope vulnerability may display differential activity against mucosal infection. Nonneutralizing antibodies (nnAbs) may also impact mucosal transmission events through Fc-gamma receptor (FcγR)-mediated inhibition. In this study, a panel of broadly neutralizing antibodies (bnAbs) and nnAbs, including those associated with protection in the RV144 vaccine trial, were screened for the ability to block HIV-1 acquisition and replication across a range of cellular and mucosal tissue models. Neutralization potency, as determined by the TZM-bl infection assay, did not fully predict activity in mucosal tissue. CD4-binding site (CD4bs)-specific bnAbs, in particular VRC01, were consistent in blocking HIV-1 infection across all cellular and tissue models. Membrane-proximal external region (MPER) (2F5) and outer domain glycan (2G12) bnAbs were also efficient in preventing infection of mucosal tissues, while the protective efficacy of bnAbs targeting V1-V2 glycans (PG9 and PG16) was more variable. In contrast, nnAbs alone and in combinations, while active in a range of cellular assays, were poorly protective against HIV-1 infection of mucosal tissues. These data suggest that tissue resident effector cell numbers and low FcγR expression may limit the potential of nnAbs to prevent establishment of the initial foci of infection. The solid protection provided by specific bnAbs clearly demonstrates their superior potential over that of nonneutralizing antibodies for preventing HIV-1 infection at the mucosal portals of infection. IMPORTANCE: Key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue have not been defined. While bnAbs are highly effective against cell-free virus, they are not induced by current vaccine candidates. However, nnAbs, readily induced by vaccines, can trigger antibody-dependent cellular effector functions, through engagement of their Fc-gamma receptors. Fc-mediated antiviral activity has been implicated as a secondary correlate of decreased HIV-1 risk in the RV144 vaccine efficacy trial, suggesting that protection might be mediated in the absence of classical neutralization. To aid vaccine design and selection of antibodies for use in passive protection strategies, we assessed a range of bnAbs and nnAbs for their potential to block ex vivo challenge of mucosal tissues. Our data clearly indicate the superior efficacy of neutralizing antibodies in preventing mucosal acquisition of infection. These results underscore the importance of maintaining the central focus of HIV-1 vaccine research on the induction of potently neutralizing antibodies.

Bragg coherent diffraction imaging and metrics for radiation damage in protein micro-crystallography.

The proliferation of extremely intense synchrotron sources has enabled ever higher-resolution structures to be obtained using data collected from smaller and often more imperfect biological crystals (Helliwell, 1984). Synchrotron beamlines now exist that are capable of measuring data from single crystals that are just a few micrometres in size. This provides renewed motivation to study and understand the radiation damage behaviour of small protein crystals. Reciprocal-space mapping and Bragg coherent diffractive imaging experiments have been performed on cryo-cooled microcrystals of hen egg-white lysozyme as they undergo radiation damage. Several well established metrics, such as intensity-loss and lattice expansion, are applied to the diffraction data and the results are compared with several new metrics that can be extracted from the coherent imaging experiments. Individually some of these metrics are inconclusive. However, combining metrics, the results suggest that radiation damage behaviour in protein micro-crystals differs from that of larger protein crystals and may allow them to continue to diffract for longer. A possible mechanism to account for these observations is proposed.

Phasic Burst Stimulation: A Closed-Loop Approach to Tuning Deep Brain Stimulation Parameters for Parkinson's Disease.

We propose a novel, closed-loop approach to tuning deep brain stimulation (DBS) for Parkinson's disease (PD). The approach, termed Phasic Burst Stimulation (PhaBS), applies a burst of stimulus pulses over a range of phases predicted to disrupt pathological oscillations seen in PD. Stimulation parameters are optimized based on phase response curves (PRCs), which would be measured from each patient. This approach is tested in a computational model of PD with an emergent population oscillation. We show that the stimulus phase can be optimized using the PRC, and that PhaBS is more effective at suppressing the pathological oscillation than a single phasic stimulus pulse. PhaBS provides a closed-loop approach to DBS that can be optimized for each patient.

Adherence to ACIP Recommendation for Human Papillomavirus Vaccine Among US Adolescent Girls.

The objective of this study was to examine correlates of human papillomavirus (HPV) vaccine use according to Advisory Committee on Immunization Practices (ACIP)'s recommendations among US adolescent girls. We used National Immunization Survey of Teens 2013 data. Based on provider-verified (n = 9403) information, 57.3, 39.1 and 19.0 % of adolescent girls, initiated, completed and completed the HPV vaccine according to ACIP's recommendation (by age 12), respectively. Hispanic race/ethnicity, a physician recommendation for HPV vaccine and ≥1 influenza vaccine in the past 3 years were all associated with a higher likelihood of compliance with ACIP's recommendation. Girls from a larger family and those whose immunization provider was a STD/school/teen clinic were less likely to receive the vaccine at the recommended age compared to a girl raised in a smaller sized family and received immunization from a hospital facility, respectively. Only one-fifth of 13-17 yo girls receive the HPV vaccine by age 12 as recommended by ACIP. Physician visits and influenza vaccination settings are opportunities to improve vaccine series completion at the recommended age.