Accessible Autonomous Transportation and Services: Design Considerations From the Perspective of Consumers and Providers.

OBJECTIVE: To understand the priorities and preferences of people with disabilities (PwDs) and older adults regarding accessible autonomous vehicles (AVs) to address existing transportation barriers. DESIGN: Two national surveys, Voice of the Consumer and Voice of the Provider, were conducted to gather feedback from accessible AV consumers and providers, respectively, in the United States. SETTING: This U.S.-based study focused on PwDs and older adults who may face transportation challenges and those who provide or design AV solutions. PARTICIPANTS: The 922 consumers and 45 providers in the surveys encompassed a diverse range of disability types, caregiver roles, and age groups (N = 967). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The main outcomes were consumer usage needs and provider preferences for features in accessible autonomous transportation. Patterns in usage needs and feature preferences through 2-step clustering algorithm were applied subsequent to the descriptive analysis of participant demographics and their responses. RESULTS: Participants strongly preferred AV features enhancing personal transportation, especially for rural medical appointments. Most sought comprehensive AV automated features. Wheelchair users emphasized accessible entrances, particularly for lower-income brackets ($25,000-$49,000). Provider priorities closely aligned with consumer preferences, reinforcing content validity. CONCLUSIONS: The study highlights the importance of prioritizing wheelchair accessibility in AVs and improving access to medical appointments, especially in rural and low-income communities. Implications include developing inclusive AV services for PwDs and underserved populations. The research establishes a foundation for a more equitable and accessible transportation landscape through AV technology integration.

Diuretic Treatment in Patients with Heart Failure: Current Evidence and Future Directions - Part I: Loop Diuretics.

PURPOSE OF REVIEW: Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in disease-modifying therapy, the mainstay of treatment for congestion-loop diuretics-has remained largely unchanged for 50 years. In these two articles (part I: loop diuretics and part II: combination therapy), we will review the history of diuretic treatment and the current trial evidence for different diuretic strategies and explore potential future directions of research. RECENT FINDINGS: We will assess recent trials including DOSE, TRANSFORM, ADVOR, CLOROTIC, OSPREY-AHF, and PUSH-AHF amongst others, and assess how these may influence current practice and future research. There are few data on which to base diuretic therapy in clinical practice. The most robust evidence is for high dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF, yet this is not reflected in guidelines. There is an urgent need for more and better research on different diuretic strategies in patients with HF.

An Indocyanine Green-Based Nanoprobe for In Vivo Detection of Cellular Senescence.

There is an urgent need to improve conventional cancer-treatments by preventing detrimental side effects, cancer recurrence and metastases. Recent studies have shown that presence of senescent cells in tissues treated with chemo- or radiotherapy can be used to predict the effectiveness of cancer treatment. However, although the accumulation of senescent cells is one of the hallmarks of cancer, surprisingly little progress has been made in development of strategies for their detection in vivo. To address a lack of detection tools, we developed a biocompatible, injectable organic nanoprobe (NanoJagg), which is selectively taken up by senescent cells and accumulates in the lysosomes. The NanoJagg probe is obtained by self-assembly of indocyanine green (ICG) dimers using a scalable manufacturing process and characterized by a unique spectral signature suitable for both photoacoustic tomography (PAT) and fluorescence imaging. In vitro, ex vivo and in vivo studies all indicate that NanoJaggs are a clinically translatable probe for detection of senescence and their PAT signal makes them suitable for longitudinal monitoring of the senescence burden in solid tumors after chemotherapy or radiotherapy.

Qualitative Analysis of the Host-Perceived Impact of Unidirectional Global Surgery Training in Kijabe, Kenya: Benefits, Challenges, and a Desire for Bidirectional Exchange.

BACKGROUND: As globalization of surgical training increases, growing evidence demonstrates a positive impact of global surgery experiences on trainees from high-income countries (HIC). However, few studies have assessed the impact of these largely unidirectional experiences from the perspectives of host surgical personnel from low- and middle-income countries (LMIC). This study aimed to assess the impact of unidirectional visitor involvement from the perspectives of host surgical personnel in Kijabe, Kenya. METHODS: Voluntary semi-structured interviews were conducted with 43 host surgical personnel at a tertiary referral hospital in Kijabe, Kenya. Qualitative analysis was used to identify salient and recurring themes related to host experiences with visiting surgical personnel. Perceived benefits and challenges of HIC involvement and host interest in bidirectional exchange were assessed. RESULTS: Benefits of visitor involvement included positive learning experiences (95.3%), capacity building (83.7%), exposure to diverse practices and perspectives (74.4%), improved work ethic (51.2%), shared workload (44.2%), access to resources (41.9%), visitor contributions to patient care (41.9%), and mentorship opportunities (37.2%). Challenges included short stays (86.0%), visitor adaptation and integration (83.7%), cultural differences (67.4%), visitors with problematic behaviors (53.5%), learner saturation (34.9%), language barriers (32.6%), and perceived power imbalances between HIC and LMIC personnel (27.9%). Nearly half of host participants expressed concerns about the lack of balanced exchange between HIC and LMIC programs (48.8%). Almost all (96.9%) host trainees expressed interest in a bidirectional exchange program. CONCLUSION: As the field of global surgery continues to evolve, further assessment and representation of host perspectives is necessary to identify and address challenges and promote equitable, mutually beneficial partnerships between surgical programs in HIC and LMIC.

Multi-modal imaging of high-risk ductal carcinoma in situ of the breast using C2Am: a targeted cell death imaging agent.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-invasive form of early breast cancer, with a poorly understood natural history of invasive transformation. Necrosis is a well-recognized adverse prognostic feature of DCIS, and non-invasive detection of its presence and spatial extent could provide information not obtainable by biopsy. We describe here imaging of the distribution and extent of comedo-type necrosis in a model of human DCIS using C2Am, an imaging agent that binds to the phosphatidylserine exposed by necrotic cells. METHODS: We used an established xenograft model of human DCIS that mimics the histopathological features of the disease. Planar near-infrared and optoacoustic imaging, using fluorescently labeled C2Am, were used to image non-invasively the presence and extent of lesion necrosis. RESULTS: C2Am showed specific and sensitive binding to necrotic areas in DCIS tissue, detectable both in vivo and ex vivo. The imaging signal generated in vivo using near-infrared (NIR) fluorescence imaging was up to 6-fold higher in DCIS lesions than in surrounding fat pad or skin tissue. There was a correlation between the C2Am NIR fluorescence (Pearson R = 0.783, P = 0.0125) and optoacoustic signals (R > 0.875, P < 0.022) in the DCIS lesions in vivo and the corresponding levels of cell death detected histologically. CONCLUSIONS: C2Am is a targeted multi-modal imaging agent that could complement current anatomical imaging methods for detecting DCIS. Imaging the presence and spatial extent of necrosis may give better prognostic information than that obtained by biopsy alone.

Impact of aminated carbon quantum dots as a novel co-reactant for Ru(bpy)32+: resolving specific electrochemiluminescence for butein detection.

Development of novel nanomaterial-based co-reactant is highly desired for enhancing ECL intensity and widespread analytical applications. Herein, we report the distinct role of amine-functionalized carbon quantum dots (f-CQDs) as a co-reactant, for the first time, augmenting the ECL property of Ru(bpy)32+ and demonstrating for biopharmaceutical (butein) detection. Unlike conventional co-reactants like tripropylamine (TPrA), 2-(dibutylamino)ethanol (DBAE), and pristine CQDs, the f-CQDs as a co-reactant yield superior ECL of Ru(bpy)32+. More importantly, the ECL intensity is independent of types of noble metals, metal oxide surfaces, and dissolved oxygen. Notably, the ECL intensity of Ru(bpy)32+-f-CQDs is linearly quenched with an increased concentration of butein, whereas no changes were observed with conventional co-reactants. ECL functionality of Ru(bpy)32+-f-CQDs has no interference with other similar phytochemicals and antioxidants. Enhanced selectivity is observed due to the formation of polyaminoquinone-like structures, which is confirmed by in situ spectroelectrochemical (UV-vis) and FT-IR studies. The present result envisaged that f-CQDs could be an alternative co-reactant for TPrA/DBAE, raising the ECL of Ru(bpy)32+ suitable for analytical studies. Graphical abstract.

Full-field quantitative phase and polarisation-resolved imaging through an optical fibre bundle.

Flexible optical fibres, used in conventional medical endoscopy and industrial inspection, scramble phase and polarisation information, restricting users to amplitude-only imaging. Here, we exploit the near-diagonality of the multi-core fibre (MCF) transmission matrix in a parallelised fibre characterisation architecture, enabling accurate imaging of quantitative phase (error <0.3 rad) and polarisation-resolved (errors <10%) properties. We first demonstrate accurate recovery of optical amplitude and phase in two polarisations through the MCF by measuring and inverting the transmission matrix, and then present a robust Bayesian inference approach to resolving 5 polarimetric properties of samples. Our method produces high-resolution (9.0±2.6µm amplitude, phase; 36.0±10.4µm polarimetric) full-field images at working distances up to 1mm over a field-of-view up to 750×750µm 2 using an MCF with potential for flexible operation. We demonstrate the potential of using quantitative phase for computational image focusing and polarisation-resolved properties in imaging birefringence.

Selective estrogen receptor degraders with novel structural motifs induce regression in a tamoxifen-resistant breast cancer xenograft.

Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.

Efficient dual-mode colorimetric/fluorometric sensor for the detection of copper ions and vitamin C based on pH-sensitive amino-terminated nitrogen-doped carbon quantum dots: effect of reactive oxygen species and antioxidants.

We present a facile strategy for highly sensitive and selective determination of copper(II) ions and vitamin C (ascorbic acid, AA) using new amino-terminated nitrogen-doped carbon quantum dots (CQDs) synthesized from melamine as the carbon and nitrogen source by the hydrothermal method. The CQDs have superior optical features, including a pH-sensitive photoinduced electron transfer process. The CQDs form a complex with Cu2+ ions, leading to the development of naked-eye, colorimetric, and fluorometric determination. AA reduces the Cu2+ ions to Cu+ ions, which cannot form the complex. Thus the absorbance and fluorescence of the CQDs are recovered by addition of AA because of dissociation of the complex into Cu+ and CQD. The in situ generation of reactive oxygen species when AA is added to Cu-CQD complexes in the presence of dissolved oxygen leads to the sensitive determination of AA, proposed on CQDs for the first time. The in situ generation of reactive oxygen species was confirmed by a fluorescence method using a hydroxyl radical indicator (i.e., coumarin). This novel "turn-off/turn-on" sensing approach using amine-functionalized CQDs is potentially applicable to determining the concentration of Cu2+ ions and AA in the areas of materials chemistry, nanobiomedicine, nanobiotechnology, and bioengineering because of its high sensitivity, high selectivity, low cost, simple naked-eye readout, and good linearity. Graphical abstract.

Optoacoustic Imaging Detects Hormone-Related Physiological Changes of Breast Parenchyma.

PURPOSE: Optoacoustic imaging with ultrasound (OPUS) can assess in-vivo perfusion/oxygenation through surrogate measures of oxy, deoxy and total hemoglobin content in tissues. The primary aim of our study was to evaluate the ability of OPUS to detect physiological changes in the breast during the menstrual cycle and to determine qualitative/quantitative metrics of normal parenchymal tissue in pre-/post-menopausal women. The secondary aim was to assess the technique's repeatability. MATERIALS AND METHODS: We performed a prospective ethically approved study in volunteers using OPUS (700, 800 and 850 nm wavelengths) in the proliferative/follicular and secretory phase of the menstrual cycle. Regions of interest (ROIs) were drawn on the most superficial region of fibroglandular tissue and same-day intra-observer repeatability was assessed. We used t-tests to interrogate differences in the OPUS measurements due to hormonal changes and interclass correlation coefficients/Bland-Altman plots to evaluate the repeatability of mean ROI signal intensities. RESULTS: 22 pre-menopausal and 8 post-menopausal volunteers were recruited. 21 participants underwent repeatability examinations. OPUS intensity values were significantly higher (p < 0.0001) at all excitation wavelengths in the secretory compared to the proliferative/follicular phase. Post-menopausal volunteers showed similar optoacoustic values to the proliferative/follicular phase of pre-menopausal volunteers. The repeatability of the technique was comparable to other handheld ultrasound modalities. CONCLUSION: OPUS detects changes in perfusion/vascularity related to the menstrual cycle and menopausal status of breast parenchyma.

Dietary blueberry improves cognition among older adults in a randomized, double-blind, placebo-controlled trial.

PURPOSE: As populations shift to include a larger proportion of older adults, the necessity of research targeting older populations is becoming increasingly apparent. Dietary interventions with blueberry have been associated with positive outcomes in cell and rodent models of aging. We hypothesized that dietary blueberry would improve mobility and cognition among older adults. METHODS: In this study, 13 men and 24 women, between the ages of 60 and 75 years, were recruited into a randomized, double-blind, placebo-controlled trial in which they consumed either freeze-dried blueberry (24 g/day, equivalent to 1 cup of fresh blueberries) or a blueberry placebo for 90 days. Participants completed a battery of balance, gait, and cognitive tests at baseline and again at 45 and 90 days of intervention. RESULTS: Significant supplement group by study visit interactions were observed on tests of executive function. Participants in the blueberry group showed significantly fewer repetition errors in the California Verbal Learning test (p = 0.031, ηp2 = 0.126) and reduced switch cost on a task-switching test (p = 0.033, ηp2 = 0.09) across study visits, relative to controls. However, no improvement in gait or balance was observed. CONCLUSIONS: These findings show that the addition of easily achievable quantities of blueberry to the diets of older adults can improve some aspects of cognition.

The homeodomain protein HOXB13 regulates the cellular response to androgens.

HOXB13 is a member of the homeodomain family of sequence-specific transcription factors and, together with the androgen receptor (AR), plays a critical role in the normal development of the prostate gland. We demonstrate here that, in prostate cancer cells, HOXB13 is a key determinant of the response to androgens. Specifically, it was determined that HOXB13 interacts with the DNA-binding domain of AR and inhibits the transcription of genes that contain an androgen-response element (ARE). In contrast, the AR:HOXB13 complex confers androgen responsiveness to promoters that contain a specific HOXB13-response element. Further, HOXB13 and AR synergize to enhance the transcription of genes that contain a HOX element juxtaposed to an ARE. The profound effects of HOXB13 knockdown on androgen-regulated proliferation, migration, and lipogenesis in prostate cancer cells highlight the importance of the observed changes in gene expression.

Design and characterization of an integrated surface ion trap and micromirror optical cavity.

We have fabricated and characterized laser-ablated micromirrors on fused silica substrates for constructing stable Fabry-Perot optical cavities. We highlight several design features which allow these cavities to have lengths in the 250-300 µm range and be integrated directly with surface ion traps. We present a method to calculate the optical mode shape and losses of these micromirror cavities as functions of cavity length and mirror shape, and confirm that our simulation model is in good agreement with experimental measurements of the intracavity optical mode at a test wavelength of 780 nm. We have designed and tested a mechanical setup for dampening vibrations and stabilizing the cavity length, and explore applications for these cavities as efficient single-photon sources when combined with trapped Yb171+ ions.

K4[Fe(CN)6] immobilized anion sensitive protonated amine functionalized polysilsesquioxane films for ultra-low electrochemical detection of dsDNA.

Charge transport in polymeric films bound by redox reagents is a topic of current interest. The dynamics of electroinactive ions across the interface is studied by immobilizing ferrocyanide anion in a polysilsesquioxanes (PSQs) modified electrode. Redox reagents can stay in the polymeric film by either physical forces or electrostatic binding. The present work describes the immobilization of ferro/ferricyanide redox couples in PSQ films possessing protonated amine functional groups by electrostatic interactions. Charge transport in [Fe(CN)6](4-)-PSQs film was found to be anion dependent, and its formal potential value varied with the relative hydrophilic or hydrophobic nature of the anion used in the supporting electrolyte, unlike the observed dependence on solution cation for electrodes modified with metal hexacyanoferrates (Prussian Blue analogues). The [Fe(CN)6](4-) bound PSQs films were extensively characterized by varying different supporting electrolytes anions using cyclic voltammetry. The redox peak currents were linearly proportional to the square root of the scan rate, implying that the transport of charge carriers is accompanied with redox ion diffusion and electron hopping in a confined space. dsDNA molecules were found to interact with this polymer matrix through anionic phosphate groups. Both voltammetry and A.C. impedance spectroscopy studies revealed that these interactions could be exploited for the determination of ultra-low level (0.5 attomolar) of dsDNA present in aqueous solution.

Association of BCL11A genetic variant (rs11886868) with severity in ß-thalassaemia major & sickle cell anaemia.

BACKGROUND & OBJECTIVES: The amount of foetal haemoglobin that persists in adulthood affects the clinical severity of haemoglobinopathies including ß-thalassaemia major and sickle cell anaemia (SCA). The present study was undertaken to analyse ß-thalassaemia as well as SCA patients for the single nucleotide polymorphism (SNP), rs11886868 (T/C) in BCL11A gene and to evaluate the association between this polymorphism and severity of ß-thalassaemia major and SCA. METHODS: a total of 620 samples (420 ß-thalassaemia major and 200 SCA cases) were analysed before blood transfusion using basic screening tests like complete blood analysis and osmotic fragility and further confirmed by high performance liquid chromatography (HPLC), amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and reverse dot blot techniques. All patients were transfusion dependent. Patients with ß-thalassaemia and SCA were classified into mild, moderate, severe according to the severity score based on Hb levels, age of onset, age at which patients received their first blood transfusion, the degree of growth retardation and splenectomy. ß-thalassaemia as well as SCA patients were analysed for the SNP, rs11886868 (T/C) in BCL11A gene and association between this polymorphism and severity of ß-thalassaemia major as well as SCA was evaluated. RESULTS: There was a significant difference in genotypic and allelic frequencies of BCL11A gene polymorphism between mild and moderate and mild and severe cases in both the groups. A significant (P<0.001) difference was observed in the mean HbF levels between the three genotypes in different severity groups. HbF levels were found to be high in CC genotype bearing individuals followed by TC and TT in ß-thalassaemia major as well as SCA. INTERPRETATION & CONCLUSIONS: This study confirms that the T/C variant (rs11886868) of the BCL11A gene causing downregulation of BCL11A gene expression in adult erythroid precursors results in the induction of HbF and ameliorates the severity of ß-thalassaemia as well as SCA.

Single-pixel phase-corrected fiber bundle endomicroscopy with lensless focussing capability.

In this paper a novel single-pixel method for coherent imaging through an endoscopic fiber bundle is presented. The use of a single-pixel detector allows greater sensitivity over a wider range of wavelengths, which could have significant applications in endoscopic fluorescence microscopy. First, the principle of lensless focussing at the distal end of a coherent fiber bundle is simulated to examine the impact of pixelation at microscopic scales. Next, an experimental optical correlator system using spatial light modulators (SLMs) is presented. A simple contrast imaging method of characterizing and compensating phase aberrations introduced by fiber bundles is described. Experimental results are then presented showing that our phase compensation method enables characterization of the optical phase profile of individual fiberlets. After applying this correction, early results demonstrating the ability of the system to electronically adjust the focal plane at the distal end of the fiber bundle are presented. The structural similarity index (SSIM) between the simulated image and the experimental focus-adjusted image increases noticeably when the phase correction is applied and the retrieved image is visually recognizable. Strategies to improve image quality are discussed.

The beneficial effects of berries on cognition, motor behaviour and neuronal function in ageing.

Previously, it has been shown that strawberry (SB) or blueberry (BB) supplementations, when fed to rats from 19 to 21 months of age, reverse age-related decrements in motor and cognitive performance. We have postulated that these effects may be the result of a number of positive benefits of the berry polyphenols, including decreased stress signalling, increased neurogenesis, and increased signals involved in learning and memory. Thus, the present study was carried out to examine these mechanisms in aged animals by administering a control, 2 % SB- or 2 % BB-supplemented diet to aged Fischer 344 rats for 8 weeks to ascertain their effectiveness in reversing age-related deficits in behavioural and neuronal function. The results showed that rats consuming the berry diets exhibited enhanced motor performance and improved cognition, specifically working memory. In addition, the rats supplemented with BB and SB diets showed increased hippocampal neurogenesis and expression of insulin-like growth factor 1, although the improvements in working memory performance could not solely be explained by these increases. The diverse polyphenolics in these berry fruits may have additional mechanisms of action that could account for their relative differences in efficacy.

Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft.

Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.

Beyond crystal balls: crosscutting solutions in global health to prepare for an unpredictable future.

BACKGROUND: Efforts in global heath need to deal not only with current challenges, but also to anticipate new scenarios, which sometimes unfold at lightning speed. Predictive modeling is frequently used to assist planning, but outcomes depend heavily on a subset of critical assumptions, which are mostly hampered by our limited knowledge about the many factors, mechanisms and relationships that determine the dynamics of disease systems, by a lack of data to parameterize and validate models, and by uncertainties about future scenarios. DISCUSSION: We propose a shift from a focus on the prediction of individual disease patterns to the identification and mitigation of broader fragilities in public health systems. Modeling capabilities should be used to perform "stress tests" on how interrelated fragilities respond when faced with a range of possible or plausible threats of different nature and intensity. This system should be able to reveal crosscutting solutions with the potential to address not only one threat, but multiple areas of vulnerability to future health risks. Actionable knowledge not based on a narrow subset of threats and conditions can better guide policy, build societal resilience and ensure effective prevention in an uncertain world.