Spiral packing and chiral selectivity in model membranes probed by phase-resolved sum-frequency generation microscopy.

Since the lipid raft model was developed at the end of the last century, it became clear that the specific molecular arrangements of phospholipid assemblies within a membrane have profound implications in a vast range of physiological functions. Studies of such condensed lipid islands in model systems using fluorescence and Brewster angle microscopies have shown a wide range of sizes and morphologies, with suggestions of substantial in-plane molecular anisotropy and mesoscopic structural chirality. Whilst these variations can significantly alter many membrane properties including its fluidity, permeability and molecular recognition, the details of the in-plane molecular orientations underlying these traits remain largely unknown. Here, we use phase-resolved sum-frequency generation microscopy on model membranes of mixed chirality phospholipid monolayers to fully determine the three-dimensional molecular structure of the constituent micron-scale condensed domains. We find that the domains possess curved molecular directionality with spiralling mesoscopic packing, where both the molecular and spiral turning directions depend on the lipid chirality, but form structures clearly deviating from mirror symmetry for different enantiomeric mixtures. This demonstrates strong enantioselectivity in the domain growth process and indicates fundamental thermodynamic differences between homo- and heterochiral membranes, which may be relevant in the evolution of homochirality in all living organisms.

Obtaining extended insight into molecular systems by probing multiple pathways in second-order nonlinear spectroscopy.

Second-order nonlinear spectroscopy is becoming an increasingly important technique in the study of interfacial systems owing to its marked ability to study molecular structures and interactions. The properties of such a system under investigation are contained within their intrinsic second-order susceptibilities which are mapped onto the measured nonlinear signals (e.g. sum-frequency generation) through the applied experimental settings. Despite this yielding a plethora of information, many crucial aspects of molecular systems typically remain elusive, for example the depth distributions, molecular orientation and local dielectric properties of its constituent chromophores. Here, it is shown that this information is contained within the phase of the measured signal and, critically, can be extracted through measurement of multiple nonlinear pathways (both the sum-frequency and difference-frequency output signals). Furthermore, it is shown that this novel information can directly be correlated to the characteristic vibrational spectra, enabling a new type of advanced sample characterization and a profound analysis of interfacial molecular structures. The theory underlying the different contributions to the measured phase of distinct nonlinear pathways is derived, after which the presented phase disentanglement methodology is experimentally demonstrated for model systems of self-assembled monolayers on several metallic substrates. The obtained phases of the local fields are compared to the corresponding phases of the nonlinear Fresnel factors calculated through the commonly used theoretical model, the three-layer model. It is found that, despite its rather crude assumptions, the model yields remarkable similarity to the experimentally obtained values, thus providing validation of the model for many sample classes.

Compact oblique-incidence nonlinear widefield microscopy with paired-pixel balanced imaging.

Nonlinear (vibrational) microscopy has emerged as a successful tool for the investigation of molecular systems as it combines label-free chemical characterization with spatial resolution on the sub-micron scale. In addition to the molecular recognition, the physics of the nonlinear interactions allows in principle to obtain structural information on the molecular level such as molecular orientations. Due to technical limitations such as the relatively complex imaging geometry with the required oblique sample irradiation and insufficient sensitivity of the instrument this detailed molecular information is typically not accessible using widefield imaging. Here, we present, what we believe to be, a new microscope design that addresses both challenges. We introduce a simplified imaging geometry that enables the measurement of distortion-free widefield images with free space oblique sample irradiation achieving high spatial resolution (∼1 µm). Furthermore, we present a method based on a paired-pixel balanced detection system for sensitivity improvement. With this technique, we demonstrate a substantial enhancement of the signal-to-noise ratio of up to a factor of 10. While both experimental concepts presented in this work are very general and can, in principle, be applied to various microscopy techniques, we demonstrate their performance for the specific case of heterodyned, sum frequency generation (SFG) microscopy.

Leveraging Implementation Science to Integrate Digital Mental Health Interventions as part of Routine Care in a Practice Research Network.

The supply / demand issue in behavioral health care is a well-established fact, and the mental health toll of the COVID-19 pandemic continues to add challenges to an already taxed system. Existing healthcare models are not set up to adequately address the increasing mental health related needs. As such, innovative models are needed to provide patients with access to appropriate, evidence-based behavioral health care within routine clinical care. This paper introduces Precision Behavioral Health (PBH) as an example of such a model. PBH is an innovative, digital first care delivery model that provides an ecosystem of evidence-based digital mental health interventions to patients as a frontline behavioral health treatment within routine care in a large multispecialty group medical center in the United States. This paper describes the implementation of PBH within a practice research network set-up as part of an integrated behavioral health department. We will present how our team leveraged the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance; "What is RE-AIM?," n.d.) implementation science framework, which emphasizes the design, dissemination, and implementation processes at the individual, staff, and organizational levels, to prioritize key implementation constructs to enhance the successful integration of PBH within routine care. We describe how each of these constructs were operationalized to aid data gathering for rapid evaluation and lessons learned. We discuss the benefits of these types of initiatives across multiple stakeholders including patients, providers, organizations, payers, and digital intervention vendors.

Indirect Estimation of the Timing of First Union Dissolution With Incomplete Marriage Histories.

The lack of nationally representative data with detailed marriage histories in low- and middle-income countries (LMICs) impedes a comprehensive understanding of essential aspects of union dissolution, such as the timing of first union dissolution, in these countries. We propose a method for estimating quantum-adjusted measures of the timing of first union dissolution from incomplete marriage histories. This method, indirect life table of first union dissolution (ILTUD), estimates the first union survival function from a simple tabulation of ever-married women by duration since first union, classified by union dissolution status (intact vs. dissolved first union). It then uses the relationships between life table functions to generate the distribution of marriages ending each year (θt) for a given marriage cohort. Using this distribution, ILTUD generates quantum-adjusted first union survival rates from which the percentiles of first union dissolution are calculated. ILTUD estimates are consistent with estimates produced using traditional statistical methods, such as the Kaplan-Meier estimator. In addition, ILTUD is simple to implement and has minimal data requirements, which are available in most nationally representative surveys. Thus, the ILTUD method has the potential to broaden our understanding of union dissolution dynamics in LMICs.

Meeting demand-Obstetric hemorrhage and blood availability in Malawi, a qualitative study.

BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in Malawi. Despite the presence of a centralized institution supplying blood and blood products for hospitals across the country, a lack of timely blood transfusion has been identified as a critical barrier to successful PPH management. This study aims to understand the factors that affect the blood delivery pipeline and adequate access to blood products for postpartum haemorrhage patients. METHODS: Qualitative data were collected through in-depth interviews with key stakeholders across the blood delivery pipeline. Interviews were conducted from July 2020 to January 2021 at Queen Elizabeth Central Hospital and Mulanje District Hospital, a referral and district hospital respectively, as well as the Malawi Blood Transfusion Service. Line by line, open coding was used to perform a thematic analysis of the data using Nvivo and Atlas.ti software. RESULTS: Five key themes were identified: 1) Lack of blood availability due to an inadequate donor pool, 2) Transportation of blood products and PPH patients is impeded by distance to target sites and competing interests for blood delivery vehicles, 3) The Malawi Blood Transfusion Service has difficulty meeting demand for blood products due to inadequate funding and difficulty retaining blood donors, 4) Current PPH management protocols and practices lead to delays due to inconsistent guidelines on delivery and analysis of patient samples, and 5) Communication between health cadres is inconsistent and affected by a lack of adequate resources. CONCLUSIONS: Barriers to timely blood transfusion for PPH patients exist across the blood delivery pipeline. While an investment of infrastructure would alleviate many obstacles, several solutions identified in this study can be implemented without additional resources, such as establishing joint department meetings to improve communication between health cadres. Ultimately, given a resource limited setting, it may be worth considering de-centralizing the blood supply.

UV-Curable Bio-Based Pressure-Sensitive Adhesives: Tuning the Properties by Incorporating Liquid-Phase Alkali Lignin-Acrylates.

Renewable pressure-sensitive adhesive (PSA) is an emerging field in adhesive industries as it is an excellent green alternative to depleting petroleum-sourced adhesives. Herein, we report the development of novel bio-sourced UV-curable PSAs with ∼50% biomass content originating from alkali lignin, cardanol, and linseed oil. Bio-based prepolymers cardanoldiol acrylate (CDA) and acrylated epoxidized linseed oil (AELO) were synthesized and used to prepare polyurethane acrylate (PUA)-based PSA systems. Alkali-lignin-based acrylates (LAs) in the liquid phase were incorporated into the PUA/AELO PSA system at 10-30 wt % loading to tune the functional properties. The Fourier transform infrared spectroscopy (FTIR) analysis showed weakened cross-linking in the PSA systems on LA addition, which is desirable for removable PSA applications. The single glass-transition temperature (Tg) noticed in all of the PSA formulations revealed good miscibility among the oligomers/prepolymers. The viscoelastic window also confirmed that the incorporation of 10-20% LA could improve the viscoelastic properties effectively to be used as removable PSAs. The addition of 20% LA into the PUA-based PSA system showed reasonable tackiness, lap shear adhesion (166 kPa), and 180° peel strength (∼2.1 N/25 mm) for possible nonstructural or semistructural applications. Lignin improved the thermal stability by hindering the degradation rate even at higher temperatures. Therefore, lignin-based PSAs with a high bio-based content paved the way of replacing petro-sourced PSA by proper tuning of the lignin content and modifications.

Fertility decline in sub-Saharan Africa: Does remarriage matter?

The interplay between remarriage and fertility is among the most poorly documented subjects in sub-Saharan Africa (SSA), despite remarriage being one of the fundamental aspects of marriage dynamics in this region. We use Demographic and Health Survey data from 34 countries in SSA to document the association between remarriage and fertility during the reproductive years and over the fertility transition. The findings show that in 29 countries, remarried women end up having fewer children than women in intact unions, despite attaining similar or higher levels of fertility at early reproductive ages. However, remarriage is found to have a positive effect on fertility in Sierra Leone. The effects of remarriage on fertility diminish as fertility declines, with smaller effects generally observed in countries that are relatively advanced in their fertility transition and larger effects found elsewhere. These findings shed light on the role that remarriage might play in country-level fertility declines.

Patterns of proton therapy use in pediatric cancer management in 2016: An international survey.

PURPOSE: To facilitate the initiation of observational studies on late effects of proton therapy in pediatric patients, we report on current patterns of proton therapy use worldwide in patients aged less than 22 years. MATERIALS & METHODS: Fifty-four proton centers treating pediatric patients in 2016 in 11 countries were invited to respond to a survey about the number of patients treated during that year by age group, intent of treatment, delivery technique and tumor types. RESULTS: Among the 40 participating centers (participation rate: 74%), a total of 1,860 patients were treated in 2016 (North America: 1205, Europe: 432, Asia: 223). The numbers of patients per center ranged from 1 to 206 (median: 29). Twenty-four percent of the patients were <5 years of age, and 50% <10 years. More than 30 pediatric tumor types were identified, mainly treated with curative intent: 48% were CNS, 25% extra-cranial sarcomas, 7% neuroblastoma, and 5% hematopoietic tumors. About half of the patients were treated with pencil beam scanning. Treatment patterns were broadly similar across the three continents. CONCLUSION: To our knowledge, this survey provides the first worldwide assessment of proton therapy use for pediatric cancer management. Since previous estimates in the United States and Europe, CNS tumors remain the cancer types most commonly treated with protons in 2016. However, the proportion of extra-cranial tumors is growing worldwide. The typically low numbers of patients treated in each center indicate the need for international research collaborations to assess long-term outcomes of proton therapy in pediatric patients.

Ductal Carcinoma In Situ of the Breast: Evaluating the Role of Radiation Therapy in the Management and Attempts to Identify Low-risk Patients.

Ductal carcinoma in situ of the breast has rapidly increased in incidence over the past several decades secondary to an increased use of screening mammography. Local treatment options for women diagnosed with ductal carcinoma in situ include mastectomy or breast-conserving therapy. Although several randomized trials have confirmed a >50% reduction in the risk of local recurrence with the administration of radiation therapy (RT) compared with breast-conserving surgery alone, controversy persists regarding whether or not RT is needed in selected "low-risk" patients. Over the past two decades, two prospective single-arm studies and one randomized trial have been performed and confirm that the omission of RT after surgery is associated with higher rates of local recurrence even after selecting patients with optimal clinical and pathologic features. Importantly, these trials have failed to consistently and reproducibly identify a low-risk cohort of patients (based on clinical and pathologic features) that does not benefit from RT. As a result, adjuvant RT is still advocated in the majority of patients, even in low-risk cases. Future research is moving beyond traditional clinical and pathologic risk factors and instead focusing on approaches such as multigene assays and biomarkers with the hopes of identifying truly low-risk patients who may not require RT. However, recent studies confirm that even low-risk patients identified from multigene assays have higher rates of local recurrence with local excision alone than would be expected with the addition of RT.

Cost-effectiveness of 3-dimensional conformal radiotherapy and applicator-based brachytherapy in the delivery of accelerated partial breast irradiation.

PURPOSE: To compare reimbursement and cost efficacy between accelerated partial breast irradiation (APBI) techniques. MATERIALS/METHODS: Four hundred fifty-three patients were treated with APBI using either 3-dimensional conformal radiotherapy (3D-CRT, n=207) or balloon-based brachytherapy (BB) [single-lumen (SL, n=161) and multilumen (ML, n=85)] between March 2000 and October 2011. To evaluate cost-effectiveness, reimbursement by treatment technique was calculated based on 2011 Medicare schedules. Facility costs were generated by technique based on ICD-9 codes. Incremental cost effectiveness ratios (ICER), which compares cost with clinical outcomes, were calculated according to the difference in reimbursement to the criteria being evaluated. RESULTS: With a median follow-up of 3.6 years, the 5-year rate of local recurrence was 1.9% for all patients (3D-CRT, 0%; BB, 4.1%; P=0.23). When pooled, BB patients had a significant improvement in excellent/good cosmesis (91.6% vs. 80.0%; P=0.03). Rates of combined grade 2 or higher dermatitis, hyper/hypopigmentation, pain, or fibrosis per technique were 62%, 28%, and 34% for 3D-CRT, SL, and ML patients, respectively (P=0.26). The ICER per percent improved cosmesis for SL/ML was $519/$850 based on reimbursement and $301/$643 based on cost compared with 3D-CRT. CONCLUSIONS: On the basis of ICER, brachytherapy for APBI is a cost-effective option with regard to cosmesis and toxicity. This economic analysis suggests the increased cost of applicator-based brachytherapy may be justified in appropriately selected patients.

Long-term impact of young age at diagnosis on treatment outcome and patterns of failure in patients with ductal carcinoma in situ treated with breast-conserving therapy.

We reviewed our institution's long-term experience treating patients diagnosed with ductal carcinoma in situ (DCIS) of the breast with breast-conserving therapy (BCT) to determine the impact of patient age on outcome over time. All DCIS cases receiving BCT between 1980 and 1993 were reviewed. Patient demographics (including age <45) and pathologic factors were analyzed for effect on outcomes including ipsilateral breast tumor recurrence (IBTR) and survival. BCT included limited surgery (excisional biopsy or lumpectomy) followed by radiotherapy to the whole breast (median whole-breast dose: 50 Gy, median tumor bed dose: 60.4 Gy). One hundred and forty-five cases were evaluated; the median follow-up was 19.3 years. Twenty-five patients developed an IBTR, for 5-, 10-, 15-, and 20-year actuarial rates of 9.9%, 12.2%, 13.7%, and 17.5%, respectively. The 10-year ipsilateral rate of recurrence was 23.3% (<45 years) versus 9.1% (≥ 45 years) (p = 0.05). Younger patients more frequently developed invasive recurrences (20-year actuarial rates: 20.4% versus 12.8%, p = 0.22) and true recurrences/marginal misses of the index lesion (23.3% versus 9.7%, p = 0.04) with lower rates of contralateral breast cancer (0.0% and 0.0% versus 12.0% and 20.5%, p = < 0.01, at 10 and 20 years, respectively). Young women under the age of 45 diagnosed with DCIS have a greater risk of local recurrence with different patterns of failure following BCT, which is most notable within 10 years of diagnosis.

Predictors of local recurrence following accelerated partial breast irradiation: a pooled analysis.

PURPOSE: To analyze a pooled set of nearly 2,000 patients treated on the American Society of Breast Surgeons (ASBS) Mammosite Registry Trial and at William Beaumont Hospital (WBH) to identify factors associated with local recurrence following accelerated partial breast irradiation (APBI). METHODS AND MATERIALS: A total of 1,961 women underwent partial breast irradiation between April 1993 and November 2010 as part of the ASBS Registry Trial or at WBH. Rates of ipsilateral breast tumor recurrence (IBTR), regional recurrence (RR), distant metastases (DM), disease-free survival (DFS), cause-specific survival (CSS), and overall survival (OS) were analyzed for each group and for the pooled cohort. Clinical, pathologic, and treatment-related variables were analyzed including age, tumor stage/size, estrogen receptor status, surgical margins, and lymph node status to determine their association with IBTR. RESULTS: The two groups weres similar, but WBH patients were more frequently node positive, had positive margins, and were less likely to be within the American Society for Radiation Oncology-unsuitable group. At 5 years, the rates of IBTR, RR, DM, DFS, CSS, and OS for the pooled group of patients were 2.9%, 0.5%, 2.4%, 89.1%, 98.5%, and 91.8%, respectively. The 5-year rate of true recurrence/marginal miss was 0.8%. Univariate analysis of IBTR found that negative estrogen receptor status (odds ratio [OR], 2.83, 95% confidence interval 1.55-5.13, p = 0.0007) was the only factor significantly associated with IBTR, while a trend was seen for age less than 50 (OR 1.80, 95% confidence interval 0.90-3.58, p = 0.10). CONCLUSIONS: Excellent 5-year outcomes were seen following APBI in over 1,900 patients. Estrogen receptor negativity was the only factor associated with IBTR, while a trend for age less than 50 was noted. Significant differences in factors associated with IBTR were noted between cohorts, suggesting that factors driving IBTR may be predicated based on the risk stratification of the patients being treated.

Factors associated with the development of breast cancer-related lymphedema after whole-breast irradiation.

PURPOSE: To determine the rates of breast cancer-related lymphedema (BCRL) in patients undergoing whole-breast irradiation as part of breast-conserving therapy (BCT) and to identify clinical, pathologic, and treatment factors associated with its development. METHODS AND MATERIALS: A total of 1,861 patients with breast cancer were treated at William Beaumont Hospital with whole-breast irradiation as part of their BCT from January 1980 to February 2006, with 1,497 patients available for analysis. Determination of BCRL was based on clinical assessment. Differences in clinical, pathologic, and treatment characteristics between patients with BCRL and those without BCRL were evaluated, and the actuarial rates of BCRL by regional irradiation technique were determined. RESULTS: The actuarial rate of any BCRL was 7.4% for the entire cohort and 9.9%, 14.7%, and 8.3% for patients receiving a supraclavicular field, posterior axillary boost, and internal mammary irradiation, respectively. BCRL was more likely to develop in patients with advanced nodal status (11.4% vs. 6.3%, p = 0.001), those who had a greater number of lymph nodes removed (14 nodes) (9.5% vs. 6.0%, p = 0.01), those who had extracapsular extension (13.4% vs. 6.9%, p = 0.009), those with Grade II/III disease (10.8% vs. 2.9%, p < 0.001), and those who received adjuvant chemotherapy (10.5% vs. 6.7%, p = 0.02). Regional irradiation showed small increases in the rates of BCRL (p = not significant). CONCLUSIONS: These results suggest that clinically detectable BCRL will develop after traditional BCT in up to 10% of patients. High-risk subgroups include patients with advanced nodal status, those with more nodes removed, and those who receive chemotherapy, with patients receiving regional irradiation showing a trend toward increased rates.

Twelve-year clinical outcomes and patterns of failure with accelerated partial breast irradiation versus whole-breast irradiation: results of a matched-pair analysis.

BACKGROUND AND PURPOSE: To compare 12-year outcomes of accelerated partial breast irradiation (APBI) versus whole-breast irradiation (WBI) in patients treated with breast conservation. MATERIALS AND METHODS: A matched-pair analysis was performed using 199 patients receiving WBI and 199 patients receiving interstitial APBI. Match criteria included tumor size, age, nodal status, ER status, and the use of adjuvant hormonal therapy. Patterns of failure and efficacy of salvage treatments were examined. RESULTS: No differences were seen in the 12-year rates of local recurrence (3.8% vs. 5.0%, p=0.40), regional recurrence (0% vs. 1.1%, p=0.15), disease free survival (DFS) (87% vs. 91%, p=0.30), cause-specific survival (CSS) (93% vs. 95%, p=0.28), or overall survival (OS) (78% vs. 71%, p=0.06) between the WBI and APBI groups, respectively. The rate of distant metastases was lower in the APBI group (10.1% vs. 4.5%, p=.05). Following LR, no difference in outcome was seen between the two groups with 5year post-LR rates of DFS (80% vs. 86%, p=0.55), CSS (88% vs. 75%, p=0.77), and OS (88% vs. 75%, p=0.77), respectively. CONCLUSIONS: With 12-year follow-up, APBI produced outcomes equivalent to WBI. Following LR, patients treated with APBI also had similar failure patterns to those managed with WBI.