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Salivary gland cancers (SGC) are rare tumours with limited availability of systemic therapies. Some SGC subtypes overexpress HER2, and this represents a potential therapeutic target, but the evidence base is limited. This study sought to analyse real-world data on the efficacy of HER2-directed therapies in SGC. This is a retrospective observational study using anonymised data from commercial compassionate-use access registrations and a privately funded pharmacy prescribing register. Treatment duration was defined as the time from drug initiation to treatment discontinuation. Kaplan–Meier analysis of treatment duration was performed using R for Windows (v4.3.2). A case report is also provided of an exceptional responder. Eighteen patients were identified who received HER2-directed therapies for HER2-positive recurrent/metastatic SGC, and complete data on treatment duration was available for 15/18. Histology was salivary duct carcinoma in 13/18 patients, adenocarcinoma NOS in 4/18, and carcinoma ex pleomorphic adenoma in 1/18. The median treatment duration was 8.3 months (95% CI: 6.41-not reached), and the range was 1.0–47.0 months. Choice of HER2-directed therapy varied, with ado-trastuzumab emtasine being the most common (9/18). At the time of analysis, HER2-directed therapy was ongoing for 9/15, discontinued due to disease progression for 4/15, discontinued due to toxicity for 1/15, and 1/15 was discontinued for an unspecified reason. An exceptional responder experienced a complete response with a treatment duration of 47.0 months. These real-world data are comparable to the median PFS observed with HER2-directed therapies in phase II trials and support the use of HER2-directed therapies in this group.

Abstract Background Hospitalization is a “reachable moment” for people who inject drugs (PWID), but preventive care including HIV testing, prevention and treatment is rarely offered within inpatient settings. Methods We conducted a multisite, retrospective cohort study of patients with opioid use disorder with infectious complications of injection drug use hospitalized between 1/1/2018–12/31/2018. We evaluated HIV care continuum outcomes using descriptive statistics and hypothesis tests for intergroup differences. Results 322 patients were included. Of 300 patients without known HIV, only 2 had a documented discussion of PrEP, while only 1 was prescribed PrEP on discharge. Among the 22 people with HIV (PWH), only 13 (59%) had a viral load collected during admission of whom all were viremic and 10 (45%) were successfully linked to care post-discharge. Rates of readmission, Medicaid or uninsured status, and unstable housing were high in both groups. Discussion We observed poor provision of HIV testing, PrEP and other HIV services for hospitalized PWID across multiple U.S. medical centers. Future initiatives should focus on providing this group with comprehensive HIV testing and treatment services through a status neutral approach.

Nanotechnology, nanosensors in particular, has increasingly drawn researchers’ attention in recent years since it has been shown to be a powerful tool for several fields like mining, robotics, medicine and agriculture amongst others. Challenges ahead, such as food availability, climate change and sustainability, have promoted such attention and pushed forward the use of nanosensors in agroindustry and environmental applications. However, issues with noise and confounding signals make the use of these tools a non-trivial technical challenge. Great advances in artificial intelligence, and more particularly machine learning, have provided new tools that have allowed researchers to improve the quality and functionality of nanosensor systems. This short review presents the latest work in the analysis of data from nanosensors using machine learning for agroenvironmental applications. It consists of an introduction to the topics of nanosensors and machine learning and the application of machine learning to the field of nanosensors. The rest of the paper consists of examples of the application of machine learning techniques to the utilisation of electrochemical, luminescent, SERS and colourimetric nanosensor classes. The final section consists of a short discussion and conclusion concerning the relevance of the material discussed in the review to the future of the agroenvironmental sector.

Transportation planning focuses on access to destinations, getting from point A to B. Yet, cycling does more and creates a connection between the cyclist and movements during the journey. Drawing from cycling ethnographic work, I use video recordings of three groups of cyclists, commuter, recreational, and athletic, in Tucson, AZ, to contextualize their movements and interactions with the built environment, drivers, and other cyclists. Cycling can be utilitarian for commuters and a social, leisure, and athletic activity for recreational and athletic riders. Depending on their reason for riding, cyclists utilize infrastructure to suit their needs and protect themselves from drivers. Confidence levels also influence where and how people ride. Commuters rode defensively and sought out less-trafficked facilities. Recreational riders rode solo on paths and in groups on open roads. Athletic riders claimed space from drivers by riding in packs while being mindful of group safety. Video ethnography helps improve the understanding of the different reasons for cycling and those experiences. With this information, planners can provide more accurate maps and overcome pushback from some cyclists by designing infrastructure accordingly—such as providing both a path and bicycle lane along the same corridor to serve various cycling needs.

The increasing population that occurs in the metropolis of Indonesia often causes problems with the structure of urban space utilization. It’s triggered by the phenomenon of urban sprawl that occurs in the outskirts of Jakarta, especially Tangerang, causing a transformation of the landscape. The existence of Lippo Karawaci which is supported by road accessibility and supporting facilities and infrastructures encourages the growth of a new city center titled independent city. The development of independent cities has the potential to change the structure of urban spaces that cause changes in the pattern of development of residential areas, especially in rural areas. This research emphasizes the condition of distance in the residential areas in Karawaci, namely Kampung Bencongan, Binong Village, Dadap Village, and Kampung Kelapa Dua as icons of traditional settlements associated with the city center. The purpose of this research is to know the transformation of land use and analyze spatial patterns of independent urban settlements in Karawaci Village. In conducting the analysis, the method used is descriptive spatial analysis with NNA (Nearest Neighbor Analysis) method to produce the pattern of settlements formed and land use transformation in residential areas through ArcMap 10.8 software. The required data was obtained through participatory mapping using the Google Earth platform for the 2003-2020 recording year as well as field observations by comparing the conditions of village distance to independent cities. The results showed an increase in settlement area of 11.4% (2.51 ha) in Binong Village, 14.2% (2.08 ha) in Dadap Village, 15.7% (4.84 ha) in Kampung Kelapa Dua, and 9.7% (3.67 ha) in Kampung Bencongan from 2003 to 2020. Spatial patterns formed in residential areas in Karawaci Village show that the closer the residential area with an independent city center will form a cluster settlement pattern. Meanwhile, the further the residential area from the city center independently will form a pattern of random settlements. So, it can be concluded that the transformation of the city space structure with the development of independent cities increases the area of settlements and forms different patterns of settlements to the city center.

Objective: Atogepant is a newly approved medication for the prevention of migraine. This review aims to discuss the efficacy, safety, cost, and place in therapy of atogepant. Methods: The authors performed a systematic search for sources, including articles, abstracts, and poster presentations. Queried databases were the National Institute of Health, US National Library of Medicine Clinical Trials, PubMed, European PMC, and the Cochrane Library. Search terms included atogepant, QULIPTA™, AGN-241689, MK-803, and N02CD07. Full-text, English language, randomized-controlled trials from 1 February 2012 to 1 February 2022 were included in the review. Additional relevant prescribing information, abstracts, and articles identified through the search were considered for inclusion in this review. A total of 193 database entries were evaluated for inclusion in this narrative review. Three articles representing two randomized controlled trials were reviewed. Results and conclusions: Atogepant, a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is a daily oral treatment for migraine prevention. In placebo-controlled clinical trials, atogepant decreased mean monthly migraine days (MMD) over 12 weeks in patients with episodic migraine. Major treatment-related adverse effects include nausea and constipation. Long-term placebo-controlled efficacy and safety studies, chronic migraine studies, and studies in patients that failed more than two classes of preventive therapies are still pending. Atogepant represents one of many novel therapies for the prevention of migraine. To date, no head-to-head comparisons of atogepant versus other agents indicated for migraine prevention have been published. Atogepant offers patients an alternative therapy to injectable or infusion monoclonal antibody treatments and offers an alternative to non-specific migraine medications that are associated with poor tolerability. Due to its high cost and narrower therapeutic indications, atogepant may be reserved for a small subset of migraineurs who prefer oral therapy.

Background: The American Academy of Physical Medicine and Rehabilitation (AAPM&R) conducted a comprehensive review in 2021 to identify opportunities for enhancing the care of adult and pediatric patients with spasticity. A technical expert panel (TEP) was convened to develop consensus‐based practice recommendations aimed at addressing gaps in spasticity care. Objective: To develop consensus‐based practice recommendations to identify and address gaps in spasticity care. Methods: The Spasticity TEP engaged in a 16‐month virtual meeting process, focusing on formulating search terms, refining research questions, and conducting a structured evidence review. Evidence quality was assessed by the AAPM&R Evidence, Quality and Performance Committee (EQPC), and a modified Delphi process was employed to achieve consensus on recommendation statements and evidence grading. The Strength of Recommendation Taxonomy (SORT) guided the rating of individual studies and the strength of recommendations. Results: The TEP approved five recommendations for spasticity management and five best practices for assessment and management, with one recommendation unable to be graded due to evidence limitations. Best practices were defined as widely accepted components of care, while recommendations required structured evidence reviews and grading. The consensus guidance statement represents current best practices and evidence‐based treatment options, intended for use by PM&R physicians caring for patients with spasticity. Conclusion: This consensus guidance provides clinicians with practical recommendations for spasticity assessment and management based on the best available evidence and expert opinion. Clinical judgment should be exercised, and recommendations tailored to individual patient needs, preferences, and risk profiles. The accompanying table summarizes the best practice recommendations for spasticity assessment and management, reflecting principles with little controversy in care delivery. [ABSTRACT FROM AUTHOR]

In the sprawling megalopolis of Metro Manila, the failure or inability of centralized public and privatized water service utilities to connect outlying and poor communities within their service areas led to the emergence of community-owned water providers run by cooperatives and neighborhood associations, often led and initiated by women. Born out of necessity and daily struggles to provide water for their households, communities organize themselves as water service cooperatives or associative water systems that assume the traditional role of the state as duty-bearers in ensuring universal access and human rights to water. Employing long-term ethnographic fieldwork, participant observation, key informant interviews and literature review, this paper critically examines urban poor communities’ experimentations of water service provisioning whereby women have taken on the cudgels to effectively deliver water to their own people and in the process, practice self-governance and autonomy. Using neo-institutionalist (Ostrom and Cox, 2010) and critical socio-institutionalist frameworks (Cleaver, 2002), we critically interrogate the praxes of women-led associative water systems, a model whereby water consumers both control and own the service in their capacity as consumers, using the cases of Bagong Silang and Recomville Two water service cooperatives located in Caloocan City. By illustrating on-the-ground experiences, we stress the crucial role that waterless citizens and communities play in bridging the gap in the country’s water service provision, thereby expanding the private/public dichotomies that often dominate water governance debates. Through these case studies, we argue that associative water systems were borne out of collective desire to have safe, clean, and affordable water to flow to waterless communities. As Metro Manila remains under a privatized water set up, these community-owned initiatives are legitimate expressions of social transformation. We problematize how these women-led associative water systems progress in the face of neoliberal governance marked by hegemonic power of private and public actors. We also investigate how democracy is exercised —or not— within these systems as well as surface the various contestations they face. This paper therefore scrutinizes the principles and pitfalls of, the ups and downs and lessons learnt from associative water systems in providing piped connections to waterless communities. Our aim is to shed light on the reconstruction of public services anchored on collective action. We find that the political possibility for collective self-organization and bottom-up social governance are facilitated or constrained by a combination of political, socioeconomic factors such as access to technical inputs and financing, social acceptability and legitimacy of the cooperative, sustained social organizing, and understanding of micro-politics and power in the community. Afterall, community-led initiatives operate in a highly contentious local politics marked by clientelism and heterogeneity. We posit that the successes of associative water systems lie on their ability to practice democracy, transparency, and accountability as well as mobilize social capital, trust, and cooperation. However, the experiences of urban poor communities in Caloocan City reveal a more complicated picture in which water service cooperatives are plagued by multiple governance issues, internal corruption, power struggles, and affordability issues. The process of building cooperatives is tension-laden, revealing the challenges of creating the commons through sociopolitical and institutional arrangements on the ground. The paper further reveals how state and market institutions successfully managed to define the terms of engagement with the urban poor communities that constrain the latter’s capability to expand water service in their areas, on one hand. On the other, private and public actors have distanced themselves from the people and obscured their objectives and economic interests from the communities they are supposed to serve. This generated a situation where dissatisfaction and capitalistic exploitation are directed toward cooperatives, instead, further redefining social relations within communities (Cheng, 2014; Chng, 2008). The paper is organized into six sections. The first parts provide a short introduction of the topic as well as a brief overview of the history and socio-political underpinnings of Metro Manila’s water privatization and neoliberal undercurrents that gave way to the rise of associative water systems. The second section outlines methodological considerations that detail our general approach in gathering empirical material. The third part offers a conceptual and literature review of associative water systems in theory and practice, outlining the positive and promising principles as well as the pitfalls of the model as commons or bottom-up social governance. Examples from Bolivia and the Philippines are mentioned that offered inspiration for urban poor communities in Caloocan City to embark on their own cooperative-building and water service provisioning. The fourth part narrates the dynamics, history, and experiences of Bagong Silang and Recomville Two water service cooperatives, underlining the similarities in the contexts where they operate as well as the various tensions and challenges they faced in the process of creating cooperatives and delivering quality and safe water to the urban poor households. We pay special attention to the role of women as leaders and changemakers amid a generally masculinized culture. The part played by two NGOs as wayfinders and supporters that accompanied the cooperatives accentuate the importance of having allies and partners in the process. We also detail how the uneven and inequitable relationship between Maynilad and the cooperatives produced a culture of payment for water which partially contributed to strained social relationships in the community. This culture restructured the roles and responsibilities among community, state, and market actors. The fifth part sketches the lessons learnt from these experiences, underlining the communities’ struggle for self-governance and autonomy to remake public services through collective action and participation in water service provision and stressing the crucial role that women played in the process. This section also identifies three challenges around issues of non-participation, power, and outcomes/impacts, underscoring the dangers of fetishizing communities (Cleaver, 2002) as homogenous, idealized forms or sources of social innovation. Divided along the lines of gender and class, women empowerment facilitated by the cooperative through trainings and skills enhancement did not sit well with some men in the communities. Further, the capacity to pay for water of the urban poor that is greatly tied to precarity of work and informality affects the operations and management of the system. We conclude by reiterating the pivotal role played by communities in enabling water to flow to their homes. But associative water systems are far from perfect. As on-going works-in-progress, the urban poor’s desired water services can only be discovered and constructed through daily —democratic— political struggles, collective action, and contestations. The praxes of associative water systems accentuate what Dahl and Soss (2012, as mentioned in McDonald, 2016) argue that “democratic conceptions of the common good will always be partial and provisional, never universal or static” (p. 4).

Diseases of the central nervous system (CNS) have historically been among the most difficult to treat using conventional pharmacological approaches. This is due to a confluence of factors, including the limited regenerative capacity and overall complexity of the brain, problems associated with repeated drug administration, and difficulties delivering drugs across the blood-brain barrier (BBB). Viral-mediated gene transfer represents an attractive alternative for the delivery of therapeutic cargo to the nervous system. Crucially, it usually requires only a single injection, whether that be a gene replacement strategy for an inherited disorder or the delivery of a genome- or epigenome-modifying construct for treatment of CNS diseases and disorders. It is thus understandable that considerable effort has been put towards the development of improved vector systems for gene transfer into the CNS. Different viral vectors are of course tailored to their specific applications, but they generally should share several key properties. The ideal viral vector incorporates a high-packaging capacity, efficient gene transfer paired with robust and sustained expression, lack of oncogenicity, toxicity and pathogenicity, and scalable manufacturing for clinical applications. In this review, we will devote attention to viral vectors derived from human immunodeficiency virus type 1 (lentiviral vectors; LVs) and adeno-associated virus (AAVs). The high interest in these viral delivery systems vectors is due to: (i) robust delivery and long-lasting expression; (ii) efficient transduction into postmitotic cells, including the brain; (iii) low immunogenicity and toxicity; and (iv) compatibility with advanced manufacturing techniques. Here, we will outline basic aspects of LV and AAV biology, particularly focusing on approaches and techniques aiming to enhance viral safety. We will also allocate a significant portion of this review to the development and use of LVs and AAVs for delivery into the CNS, with a focus on the genome and epigenome-editing tools based on clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas 9) and the development of novel strategies for the treatment of neurodegenerative diseases (NDDs).

The detection of impending collisions and the subsequent choice and regulation of maneuvers to deal with them are general problems of locomotor control that arise in many situations, both human and non-human. When an object moves towards an observer, the size of the image that it projects onto the retina of the observer’s eyes increases, providing a powerful sensation of motion. Physiological and psychophysical research into this “looming” effect provides strong evidence for the existence of neural “looming detectors” that are used by humans and non-humans alike to detect and respond to oncoming objects. Automotive applications constitute an important context for the study of the visual perception of looming. To date, however, this aspect of the driver’s performance has largely been neglected, and human driver models typically incorporate representations of the visual system that are based upon idealized behavior and in some cases questionable assumptions.In this three part study we begin to address the deficiency by quantifying the visual system’s ability to detect and track an object’s approach, as represented by the rate of change of the angle θ that its image subtends on the retina of the eye. In the first part we tested a long-standing assumption of an absolute threshold in the human’s ability to detect dθ/dt, below which humans are unable to discern that θ is changing (and thus that a collision is imminent). The results provide evidence contradicting the threshold assumption, and indicate instead that the detection task is more accurately described as one of signal detection (detection of the signal dθ/dt in the presence of noise) with no threshold limitation. Collision avoidance requires that an observer accurately and continuously track an approaching object’s distance and closing speed. In the second part of this study we investigated the dynamic response of the visual system to changes in θ, employing both psychophysical and classical frequency response techniques. We found that the visual system exhibits a band-pass characteristic in this task that is well described by a linear, minimum phase, second order transfer function. Further analysis revealed that this aspect of the visual system exhibits a biphasic impulse response, which is the focus for the third part of our study. According to the model, certain pairs of “impulsive” stimuli presented in the proper sequence will reinforce one another, and thus be more easily detected, while others will cancel each other and be less so. This final series of experiments provided evidence consistent with this hypothesis.The shortcomings of human driver models based upon current assumptions are discussed, and the development of improved models based the dynamic response characteristics of the visual system and the principles of signal detection are described. To focus our efforts we have assumed a fairly constrained driving scenario (the “Lead Vehicle Braking” scenario), but these results are applicable to any scenario (automotive or not) in which the observer has an unobstructed view of the approach of an object or stationary obstacle.

Microsporidian strains are usually classified on the basis of their ribosomal DNA (rDNA) sequences. Although rDNA occurs as multiple copies, in most non-microsporidian species copies within a genome occur as tandem arrays and are homogenised by concerted evolution. In contrast, microsporidian rDNA units are dispersed throughout the genome in some species, and on this basis are predicted to undergo reduced concerted evolution. Furthermore many microsporidian species appear to be asexual and should therefore exhibit reduced genetic diversity due to a lack of recombination. Here, DNA sequences are compared between microsporidia with different life cycles in order to determine the effects of concerted evolution and sexual reproduction upon the diversity of rDNA and protein coding genes. Comparisons of cloned rDNA sequences between microsporidia of the genus Nosema with different life cycles provide evidence of intragenomic variability coupled with strong purifying selection. This suggests a birth and death process of evolution. However, some concerted evolution is suggested by clustering of rDNA sequences within species. Variability of protein-coding sequences indicates that considerable intergenomic variation also occurs between microsporidian cells within a single host. Patterns of variation in microsporidian DNA sequences indicate that additional diversity is generated by intragenomic and/or intergenomic recombination between sequence variants. The discovery of intragenomic variability coupled with strong purifying selection in microsporidian rRNA sequences supports the hypothesis that concerted evolution is reduced when copies of a gene are dispersed rather than repeated tandemly. The presence of intragenomic variability also renders the use of rDNA sequences for barcoding microsporidia questionable. Evidence of recombination in the single-copy genes of putatively asexual microsporidia suggests that these species may undergo cryptic sexual reproduction, a possibility with profound implications for the evolution of virulence, host range and drug resistance in these species.

Among the many ecosystems services of winter covers, winter legumes have an advantage over winter grain covers by fixing N that may be used by subsequent crops. A 5‐yr study was conducted to compare the biomass yields of five leguminous winter cover crops [Austrian winter pea (Pisum sativum L.), fava bean (Vicia fava L.), narrow‐leaf lupin (Lupinus angustifolius L.), cahaba vetch (Vicia spp.), crimson clover (Trifolium incarnatum L.)] plus rye (Secale cereale L.) and determine the effects of these winter cover crops either harvested or left on the soil on subsequent biomass sorghum [Sorghum bicolor (L.) Moench] and cotton (Gossypium hirsutum L.) yields at two field locations in Georgia. Lupin produced between 4.16 and 9.54 Mg ha−1 biomass, approximately two to four times more than any other cover at both locations every year. Lupin, followed by vetch and winter pea had the greatest positive effect on biomass sorghum yields. Biomass‐sorghum yields after lupin cover were not significantly different whether biomass was retained on the soil by rolling or removed. Seed cotton yields were higher after lupin and vetch. Significantly higher sorghum and cotton yields occurred for rolled covers with crimson clover, winter pea, and fava bean. Averaged over the years and locations, lupin biomass produced approximately 143 kg ha−1 N, more than any other cover. The study suggests that harvested or grazed lupin or vetch covers could give similar benefits to summer row crops compared with traditionally leaving the cover on the soil. Core Ideas: Narrow leaf lupin produced the highest biomass among the six covers tested.Harvested or unharvested lupin and vetch winter covers enhanced subsequent sorghum and cotton yields.Lupin biomass contained approximately 143 kg ha−1 N, more than any other cover. [ABSTRACT FROM AUTHOR]

21st Century Skills include learners to be Creators, Collaborators, Communicators and Critical Thinkers. It is important to be aware that 21st Century learners are digital natives and aspire to be (if not already) world-class learners. In India, education at most levels has become important in order to be employable. The fact that most young graduates are not job-ready despite possessing degrees is worrisome and stressful for both the job seekers and the employers. This trend is disturbing and needs addressing on a war footing. For years, educators have been talking about English Language Learning and training in Soft Skills being like two peas in a pod. Although they belong to the same skin yet they are two separate identities which have almost similar features and tastes. Honing English Language Skills and Soft Skills is becoming increasingly important in the 21st Century. This is because young graduates are technically sound but their soft skills are next to negligible. Most of them do not know how to conduct themselves in a group, how to communicate effectively or how to lead a team to reach a target. This paper intends to look at learners understanding of Soft Skills. It also further probes what these learners consider as important Soft Skills. [ABSTRACT FROM AUTHOR]