The experience of entering residential aged care: The views of residents, family members and staff-an Appreciative Inquiry.

OBJECTIVES: To understand resident, family and staff perspectives of older people's transition to residential aged care and initiatives that support this transition. METHODS: A qualitative Appreciative Inquiry was undertaken with residents, family members and staff in residential aged care. It included semistructured interviews (n = 40), three focus groups (n = 17) and an organisational summit (n = 72). Each stage sought to build on the previous one, deepening understanding of the issues experienced and identifying positive strategies for change. Data were analysed thematically using framework analysis. RESULTS: The transition experience was characterised by grief and guilt felt by family members and the challenges they faced in participating in a decision to admit a relative to residential aged care. Residents found the transition challenging but stressed the need to adjust to the situation. Family members struggled with trusting others to provide appropriate care and both residents and relatives reported challenges in communicating with staff. Initiatives were recommended by the organisational summit to assist in the transition to residential aged care. These included developing a service navigator role, co-designing new systems and resources with residents and relatives, and ensuring more consistent staffing. CONCLUSIONS: Improved communication strategies and resources are needed to support the resident's identity, build trust in the organisation and support transition to residential aged care. Staff should continue to value the contribution family members play in the life of the resident and the culture of the aged care community.

Design and Preclinical Evaluation of a Novel B7-H4-Directed Antibody-Drug Conjugate, AZD8205, Alone and in Combination with the PARP1-Selective Inhibitor AZD5305.

PURPOSE: We evaluated the activity of AZD8205, a B7-H4-directed antibody-drug conjugate (ADC) bearing a novel topoisomerase I inhibitor (TOP1i) payload, alone and in combination with the PARP1-selective inhibitor AZD5305, in preclinical models. EXPERIMENTAL DESIGN: IHC and deep-learning-based image analysis algorithms were used to assess prevalence and intratumoral heterogeneity of B7-H4 expression in human tumors. Several TOP1i-ADCs, prepared with Val-Ala or Gly-Gly-Phe-Gly peptide linkers, with or without a PEG8 spacer, were compared in biophysical, in vivo efficacy, and rat toxicology studies. AZD8205 mechanism of action and efficacy studies were conducted in human cancer cell line and patient-derived xenograft (PDX) models. RESULTS: Evaluation of IHC-staining density on a per-cell basis revealed a range of heterogeneous B7-H4 expression across patient tumors. This informed selection of bystander-capable Val-Ala-PEG8-TOP1i payload AZ14170133 and development of AZD8205, which demonstrated improved stability, efficacy, and safety compared with other linker-payload ADCs. In a study of 26 PDX tumors, single administration of 3.5 mg/kg AZD8205 provided a 69% overall response rate, according to modified RECIST criteria, which correlated with homologous recombination repair (HRR) deficiency (HRD) and elevated levels of B7-H4 in HRR-proficient models. Addition of AZD5305 sensitized very low B7-H4-expressing tumors to AZD8205 treatment, independent of HRD status and in models representing clinically relevant mechanisms of PARPi resistance. CONCLUSIONS: These data provide evidence for the potential utility of AZD8205 for treatment of B7-H4-expressing tumors and support the rationale for an ongoing phase 1 clinical study (NCT05123482). See related commentary by Pommier and Thomas, p. 991.

Situating Eden-Culture change in residential aged care: A scoping review.

OBJECTIVE: This review explored the knowledge of the Eden Alternative [Eden] as a well-being model for aged care and the current research of relationship-centred care in a residential setting to identify gaps in the literature. METHODS: The search commenced in July 2017 and was updated in January 2020. Eight electronic databases were systematically searched for peer-reviewed studies published in English between 2000 and 2020. The search revealed 13 papers for final inclusion. RESULTS: The Eden model has the potential to reduce loneliness, helplessness and boredom in older people. Implementation requires committed leadership and the inclusion of residents, families and staff in decision-making. CONCLUSIONS: There remain gaps in the empirical evidence of the benefit of the Eden model. The challenge is for researchers to provide rigorous study design that can evidence well-being outcomes for residents with complex needs.

Vascular plant extinction in the continental United States and Canada.

Extinction rates are expected to increase during the Anthropocene. Current extinction rates of plants and many animals remain unknown. We quantified extinctions among the vascular flora of the continental United States and Canada since European settlement. We compiled data on apparently extinct species by querying plant conservation databases, searching the literature, and vetting the resulting list with botanical experts. Because taxonomic opinion varies widely, we developed an index of taxonomic uncertainty (ITU). The ITU ranges from A to F, with A indicating unanimous taxonomic recognition and F indicating taxonomic recognition by only a single author. The ITU allowed us to rigorously evaluate extinction rates. Our data suggest that 51 species and 14 infraspecific taxa, representing 33 families and 49 genera of vascular plants, have become extinct in our study area since European settlement. Seven of these taxa exist in cultivation but are extinct in the wild. Most extinctions occurred in the west, but this outcome may reflect the timing of botanical exploration relative to settlement. Sixty-four percent of extinct plants were single-site endemics, and many occurred outside recognized biodiversity hotspots. Given the paucity of plant surveys in many areas, particularly prior to European settlement, the actual extinction rate of vascular plants is undoubtedly much higher than indicated here.

Extinción de las Plantas Vasculares en Canadá y los Estados Unidos Continentales Resumen Se espera que las tasas de extinción aumenten durante el Antropoceno. Todavía desconocemos las tasas de extinción actuales de las plantas y muchos animales. Cuantificamos las tasas de extinción de la flora vascular de los Estados Unidos Continentales y Canadá a partir del asentamiento de los europeos. Recopilamos datos sobre especies aparentemente extintas mediante la consulta de bases de datos sobre conservación, búsquedas en la literatura y el escrutinio de la lista resultante con botánicos expertos. Ya que la opinión taxonómica varía ampliamente, desarrollamos un índice de incertidumbre taxonómica (ITU). La ITU abarca desde la A hasta la F, en donde la A indica un reconocimiento taxonómico unánime y la F indica el reconocimiento taxonómico por un sólo autor. La ITU nos permitió evaluar rigurosamente las tasas de extinción. Nuestros datos sugieren que 51 especies y 14 taxones infraespecíficos, que en conjunto representan a 33 familias y a 49 géneros de plantas vasculares, se han extinguido en nuestra área de estudio desde el asentamiento de los europeos. Siete de estos taxones existen en cultivos, pero se encuentran extintos en vida libre. La mayoría de las extinciones ocurrieron en la parte oeste del área de estudio, aunque este resultado puede reflejar el momento de la exploración botánica en relación con el asentamiento europeo. El 64% de las plantas extintas eran endémicas de un sitio único y muchas tuvieron presencia fuera de los puntos calientes de biodiversidad. Dada la escasez de los censos botánicos en muchas áreas, particularmente previo al asentamiento europeo, la tasa actual de extinción de las plantas vasculares es sin duda mucho más alta de lo que se indica en este estudio.

Crop wild relatives of the United States require urgent conservation action.

The contributions of crop wild relatives (CWR) to food security depend on their conservation and accessibility for use. The United States contains a diverse native flora of CWR, including those of important cereal, fruit, nut, oil, pulse, root and tuber, and vegetable crops, which may be threatened in their natural habitats and underrepresented in plant conservation repositories. To determine conservation priorities for these plants, we developed a national inventory, compiled occurrence information, modeled potential distributions, and conducted threat assessments and conservation gap analyses for 600 native taxa. We found that 7.1% of the taxa may be critically endangered in their natural habitats, 50% may be endangered, and 28% may be vulnerable. We categorized 58.8% of the taxa as of urgent priority for further action, 37% as high priority, and 4.2% as medium priority. Major ex situ conservation gaps were identified for 93.3% of the wild relatives (categorized as urgent or high priority), with 83 taxa absent from conservation repositories, while 93.1% of the plants were equivalently prioritized for further habitat protection. Various taxonomic richness hotspots across the US represent focal regions for further conservation action. Related needs include facilitating greater access to and characterization of these cultural-genetic-natural resources and raising public awareness of their existence, value, and plight.

Assessing the Validity and Accuracy of Online Videos on Vaccine Health Risks.

Incongruent vaccination rates have been found in multiple US cities, one cause possibly being misleading information that is easily available on the internet through text and videos. Health care providers should be aware of the extent and content of online health information available to patients and their guardians to enhance the effectiveness of patient-physician communication. This study obtained data on vaccine-related YouTube videos and analyzed the videos' content. When misleading information was found in a video, the timing and specific type of misleading information was noted. More than two thirds of the YouTube videos contained some type of unreliable information regarding vaccine safety and effectiveness. Much of the information accessible to patients and parents vaccinating their children is misleading to a potentially dangerous extent. Health care providers should be aware of and able to provide clear counter-evidence to misleading information on YouTube in light of the findings.

Metastatic melanoma: Surgical treatment of brain metastases - Analysis of 110 patients.

New Zealand has one of the highest rates of melanoma in the world. In up to 10% of cases, the disease is metastatic at diagnosis. Cerebral metastatic involvement carries a particularly poor prognosis. 110 patients were included in the analysis. A retrospective consecutive series of patients treated surgically at Auckland City Hospital were studied, with parameters of demographics, tumour characteristics, surgery, pathology, systemic therapy and survival analysed. Mean age was 59.9 years (range 22-81 years). Median survival from date of surgery was 8.1 months (95% CI 6.9-9.4 months). Of the 58 patients tested for BRAF mutation, 28 were positive, similar to previously published data. This conferred a better prognosis with median overall survival of 12.3 months (95% CI 7.2-17.3 months) compared to 7.8 months (95% CI 5.6-10 months) for those who were negative (p < 0.05). Survival correlated positively with extent of surgical resection. Both BRAF positive status and targeted and/or immunotherapy were significant predictors of improved survival. In this cohort, radiation therapy did not show a statistically significant improvement in overall survival. Survival from resection of cerebral metastases from melanoma is improving. Survival benefit is conferred by BRAF mutation, solitary metastasis and gross total resection of lesion.

What drives prioritized visual processing? A motivational relevance account.

Emotion is fundamental to our being, and an essential aspect guiding behavior when rapid responding is required. This includes whether we approach or avoid a stimulus, and the accompanying physiological responses. A common tenet is that threat-related content drives stimulus processing and biases visual attention, so that rapid responding can be initiated. In this paper, it will be argued instead that prioritization of threatening stimuli should be encompassed within a motivational relevance framework. To more fully understand what is, or is not, prioritized for visual processing one must, however, additionally consider: (i) stimulus ambiguity and perceptual saliency; (ii) task demands, including both perceptual load and cognitive load; and (iii) endogenous/affective states of the individual. Combined with motivational relevance, this then leads to a multifactorial approach to understanding the drivers of prioritized visual processing. This accords with current recognition that the brain basis allowing for visual prioritization is also multifactorial, including transient, dynamic and overlapping networks. Taken together, the paper provides a reconceptualization of how "emotional" information prioritizes visual processing.

Interplay of primary sequence, position and secondary RNA structure determines alternative splicing of LMNA in a pre-mature aging syndrome.

Aberrant splicing in exon 11 of the LMNA gene causes the premature aging disorder Hutchinson-Gilford Progeria Syndrome. A de novo C1824T mutation activates an internal alternative 5' splice site, resulting in formation of the disease-causing progerin protein. The underlying mechanism for this 5' splice site selection is unknown. Here, we have applied a combination of targeted mutational analysis in a cell-based system and structural mapping by SHAPE-MaP to comprehensively probe the contributions of primary sequence, secondary RNA structure and linear splice site position in determining in vivo mechanisms of splice site choice in LMNA. While splice site choice is in part defined by sequence complementarity to U1 snRNA, we identify RNA secondary structural elements near the alternative 5' splice sites and show that splice site choice is significantly influenced by the structural context of the available splice sites. Furthermore, relative positioning of the competing sites within the primary sequence of the pre-mRNA is a predictor of 5' splice site usage, with the distal position favored over the proximal, regardless of sequence composition. Together, these results demonstrate that 5' splice site selection in LMNA is determined by an intricate interplay among RNA sequence, secondary structure and splice site position.

High proportion of cactus species threatened with extinction.

A high proportion of plant species is predicted to be threatened with extinction in the near future. However, the threat status of only a small number has been evaluated compared with key animal groups, rendering the magnitude and nature of the risks plants face unclear. Here we report the results of a global species assessment for the largest plant taxon evaluated to date under the International Union for Conservation of Nature (IUCN) Red List Categories and Criteria, the iconic Cactaceae (cacti). We show that cacti are among the most threatened taxonomic groups assessed to date, with 31% of the 1,478 evaluated species threatened, demonstrating the high anthropogenic pressures on biodiversity in arid lands. The distribution of threatened species and the predominant threatening processes and drivers are different to those described for other taxa. The most significant threat processes comprise land conversion to agriculture and aquaculture, collection as biological resources, and residential and commercial development. The dominant drivers of extinction risk are the unscrupulous collection of live plants and seeds for horticultural trade and private ornamental collections, smallholder livestock ranching and smallholder annual agriculture. Our findings demonstrate that global species assessments are readily achievable for major groups of plants with relatively moderate resources, and highlight different conservation priorities and actions to those derived from species assessments of key animal groups.

Retrospective analysis of the learning curve associated with laparoscopic ovariectomy in dogs and associated perioperative complication rates.

OBJECTIVE: To assess the learning curve associated with laparoscopic ovariectomy (LOE) in 618 dogs and to report perioperative complication rates. STUDY DESIGN: Case series. ANIMALS: Dogs (n = 618). METHODS: Data retrieved from the medical records of bitches admitted for LOE over 42 months included date of surgery, breed, weight (kg), age (months), surgeon, suture material used, intraoperative complications and postoperative complications. Each LOE was defined as "successful" or "unsuccessful" by the absence or presence of an intraoperative complication and "failure" rate described using a CUSUM technique. RESULTS: Follow-up time ranged from 152 to 1,435 days (median, 737 days). Intraoperative complications occurred in 10 dogs (1.6%) and included: splenic laceration (6 dogs; 1%), urinary bladder perforation (3 dogs; 0.5%), and subcutaneous emphysema (1 dog; 0.2%). Postoperative complications occurred in 99 dogs (16%) and included: incisional inflammation treated with antibiotics (87 dogs [14%]; 96/1,854 incisions; 5.1%), incisional seroma (5 dogs [0.8%]; 5/1,854 incisions, 0.3%), incisional hernia (4 dogs [0.6%]; 4/1,854 incisions, 0.2%), and ovarian remnant syndrome (3 dogs; 0.5%). CUSUM charts indicated an initial "learning curve" of ∼80 LOE. CONCLUSIONS: LOE is a technique with an initial learning curve but once surgical proficiency is reached after ∼80 procedures then intraoperative complication rates associated with the procedure can be low.

Changing facial phenotype in Cohen syndrome: towards clues for an earlier diagnosis.

Cohen syndrome (CS) is a rare autosomal recessive condition caused by mutations and/or large rearrangements in the VPS13B gene. CS clinical features, including developmental delay, the typical facial gestalt, chorioretinal dystrophy (CRD) and neutropenia, are well described. CS diagnosis is generally raised after school age, when visual disturbances lead to CRD diagnosis and to VPS13B gene testing. This relatively late diagnosis precludes accurate genetic counselling. The aim of this study was to analyse the evolution of CS facial features in the early period of life, particularly before school age (6 years), to find clues for an earlier diagnosis. Photographs of 17 patients with molecularly confirmed CS were analysed, from birth to preschool age. By comparing their facial phenotype when growing, we show that there are no special facial characteristics before 1 year. However, between 2 and 6 years, CS children already share common facial features such as a short neck, a square face with micrognathia and full cheeks, a hypotonic facial appearance, epicanthic folds, long ears with an everted upper part of the auricle and/or a prominent lobe, a relatively short philtrum, a small and open mouth with downturned corners, a thick lower lip and abnormal eye shapes. These early transient facial features evolve to typical CS facial features with aging. These observations emphasize the importance of ophthalmological tests and neutrophil count in children in preschool age presenting with developmental delay, hypotonia and the facial features we described here, for an earlier CS diagnosis.

Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis.

BACKGROUND: Usher syndrome (USH) combines sensorineural deafness with blindness. It is inherited in an autosomal recessive mode. Early diagnosis is critical for adapted educational and patient management choices, and for genetic counseling. To date, nine causative genes have been identified for the three clinical subtypes (USH1, USH2 and USH3). Current diagnostic strategies make use of a genotyping microarray that is based on the previously reported mutations. The purpose of this study was to design a more accurate molecular diagnosis tool. METHODS: We sequenced the 366 coding exons and flanking regions of the nine known USH genes, in 54 USH patients (27 USH1, 21 USH2 and 6 USH3). RESULTS: Biallelic mutations were detected in 39 patients (72%) and monoallelic mutations in an additional 10 patients (18.5%). In addition to biallelic mutations in one of the USH genes, presumably pathogenic mutations in another USH gene were detected in seven patients (13%), and another patient carried monoallelic mutations in three different USH genes. Notably, none of the USH3 patients carried detectable mutations in the only known USH3 gene, whereas they all carried mutations in USH2 genes. Most importantly, the currently used microarray would have detected only 30 of the 81 different mutations that we found, of which 39 (48%) were novel. CONCLUSIONS: Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy.

Complete deletion of the AZFb interval from the Y chromosome in an oligozoospermic man.

BACKGROUND: Deletion of the entire AZFb interval from the Y chromosome is strictly associated with azoospermia arising from maturation arrest during meiosis. Here, we describe the exceptional case of an oligozoospermic man, 13-1217, with an AZFb + c (P5/distal-P1) deletion. Through the characterization of this patient, and two AZFb (P5/proximal-P1) patients with maturation arrest, we have explored three possible explanations for his exceptionally progressive spermatogenesis. METHODS AND RESULTS: We have determined the precise breakpoints of the deletion in 13-1217, and shown that 13-1217 is deleted for more AZFb material than one of the AZFb-deleted men (13-5349). Immunocytochemical analysis of spermatocytes with an antibody against a synaptonemal complex component indicates synapsis to be largely unaffected in 13-1217, in contrast to 13-5349 where extended asynapsis is frequent. Using PCR-based analyses of RNA and DNA from the same testicular biopsy, we show that 13-1217 expresses post-meiotic germ cell markers in the absence of genomic DNA and transcripts from the AZFb and AZFc intervals. We have determined the Y chromosome haplogroup of 13-1217 to be HgL-M185. CONCLUSIONS: Our results indicate that the post-meiotic spermatogenesis in 13-1217 is not a consequence of mosaicism or retention of a key AZFb gene. On the contrary, since the Hg-L Y chromosome carried by 13-1217 is uncommon in Western Europe, a Y-linked modifier locus remains a possible explanation for the oligozoospermia observed in patient 13-1217. Further cases must now be studied to understand how germ cells complete spermatogenesis in the absence of the AZFb interval.

Steroidogenic factor-1 (SF-1) gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with low testosterone concentration.

BACKGROUND: Primary amenorrhea due to 46,XY disorders of sex differentiation (DSD) is a frequent reason for consultation in endocrine and gynecology clinics. Among the genetic causes of low-testosterone primary amenorrhea due to 46,XY DSD, SRY gene is reported to be frequently involved, but other genes, such as SF1 and WT1, have never been studied for their prevalence. METHODS: We directly sequenced SRY, SF1 and WT1 genes in 15 adolescent girls with primary amenorrhea, low testosterone concentration, and XY karyotype, to determine the prevalence of mutations. We also analyzed the LH receptor gene in patients with high LH and normal FSH concentrations. RESULTS: Among the 15 adolescents with primary amenorrhea and low testosterone concentration, we identified two new SRY mutations, five new SF1 mutations and one new LH receptor gene mutation. Our study confirms the 10-15% prevalence of SRY mutations and shows the high prevalence (33%) of SF1 abnormalities in primary amenorrhea due to 46,XY DSD with low plasma testosterone concentration. CONCLUSIONS: The genetic analysis of low-testosterone primary amenorrhea is complex as several factors may be involved. This work underlines the need to systematically analyze the SF1 sequence in girls with primary amenorrhea due to 46,XY DSD and low testosterone, as well as in newborns with 46,XY DSD.