'They don't think I can do it': Experiences of self-advocates, employment specialists, and employers on employment of adults with intellectual disability.

BACKGROUND: A multi-phase Canadian study was conducted as part of a large-scale community and academic research partnership focused on understanding and improving the employment experiences of people with intellectual disabilities. METHOD: This multi-method study utilized a sequential approach, using findings from qualitative interviews (n = 28) to inform an online survey (n = 149). Participants were invited to share their experiences with paid employment or with persons with intellectual disabilities. RESULTS: Thematic analysis of data across interview and survey findings resulted in six themes: (1) assumptions and attitudes, (2) knowledge and awareness, (3) accessibility of processes, (4) use of accommodations, (5) workplace relationships, and (6) supports and resources. CONCLUSIONS: A holistic and systemic approach has the potential to improve inclusive employment experiences of people with intellectual disabilities. Action is needed mainly at the policy and employer level to reduce barriers and improve on facilitating measures reinforced by the themes shared in this study.

Talent identification in soccer: The influence of technical, physical and maturity-related characteristics on a national selection process.

The present study examines the influence of technical, physical, and relative age characteristics on players selection success within the Scottish Performance School trials. Ninety adolescent players (81 males, 9 females; mean ± standard deviation: age = 11.3 ± 0.4 years, height = 149.6 ± 6.9 cm, mass 38.1 ± 4.7 kg) performed a battery of physical fitness (20m Sprint, CMJ, 5-0-5 agility test), anthropometric, and 8 small-sided games (SSG; 9v9) as part of a talent identification (TID) programme. Players technical (ball touches, time on the ball, high-speed releases) and locomotor activities (high-speed running distance, sprint distance, accelerations, and decelerations) were monitored using foot-mounted inertial measurements units during SSG's. The data was analysed using independent sample T-tests. Mann-Whitney U analyses were conducted to examine the differences between groups whose data was determined as being (non)parametric, with Cohen effect sizes applied. Successful players performed significantly better during physical tests (Effect size ± confidence limits: Left 5-0-5 = -0.89±0.13, Right 5-0-5 = -0.51±0.11), had significantly higher locomotor activities during SSG (high-intensity distance = 0.4±26.6, horizontal accelerations = 0.59±1.19) and significantly higher technical outputs during SSG (touches = 0.71±6.1, releases = 0.49±2.5, high-speed releases = 0.59±2.7, time on the ball = 0.52±3.4) compared to unsuccessful players. Successful players had significantly higher locomotor activities and technical outputs during SSG than their unsuccessful counterparts. Monitoring technical and locomotor activities during SSG may compliment or replace physical testing batteries for assessing TID processes in soccer.

Engineering CREB-activated promoters for adenosine-induced gene expression.

Accumulation of the ribonucleoside, adenosine (ADO), triggers a cAMP response element binding protein (CREB)-mediated signaling pathway to suppress the function of immune cells in tumors. Here, we describe a collection of CREB-activated promoters that allow for strong and tunable ADO-induced gene expression in human cells. By optimizing number of CREB transcription factor binding sites and altering the core promoter region of CREB-based hybrid promoters, we created synthetic constructs that drive gene expression to higher levels than strong, endogenous mammalian promoters in the presence of ADO. These synthetic promoters are induced up to 47-fold by ADO, with minimal expression in their "off" state. We further determine that our CREB-based promoters are activated by other compounds that act as signaling analogs, and that combinatorial addition of ADO and these compounds has a synergistic impact on gene expression. Surprisingly, we also detail how background ADO degradation caused by the common cell culture media additive, fetal bovine serum (FBS), confounds experiments designed to determine ADO dose-responsiveness. We show that only after long-term heat deactivation of FBS can our synthetic promoters enable gene expression induction at physiologically relevant levels of ADO. Finally, we demonstrate that the strength of a CREB-based promoter is enhanced by incorporating other transcription factor binding sites.

Nutrient transport, shear strength and hydraulic characteristics of topsoils amended with mulch, compost and biosolids.

Anthropogenic disturbance of soils can disrupt soil structure, diminish fertility, alter soil chemical properties, and cause erosion. Current remediation practices involve amending degraded urban topsoils lacking in organic matter and nutrition with organic amendments (OA) to enhance vegetative growth. However, the impact of OAs on water quality and structural properties at rates that meet common topsoil organic matter specifications need to be studied and understood. This study tested three commonly available OAs: shredded wood mulch, leaf-based compost, and class A Exceptional Quality stabilized sewage sludge (or biosolids) for nutrient (nitrogen and phosphorus) water quality, soil shear strength, and hydraulic properties, through two greenhouse tub studies. Findings showed that nitrogen losses to leachate were greater in the biosolids amended topsoils compared to leaf-compost, mulch amended topsoils, and control treatments. Steady-state mean total nitrogen (N) concentrations from biosolids treatment exceeded typical highway stormwater concentrations by at least 25 times. Soil total N content combined with the carbon:nitrogen ratio were identified to be the governing properties of N leaching in soils. Study soils, irrespective of the type of amendment, reduced the applied (tap) water phosphorus (P) concentration of ∼0.3 mg-P/L throughout the experiment. Contrary to the effects on N leaching, P was successfully retained by the biosolids amendment, due to the presence of greater active iron contents. A breakthrough mechanism for P was observed in leaf compost amended soil, where the effluent concentrations of P continued to increase with each rainfall application, possibly due to an saturation of soil adsorption sites. The addition of OAs also improved the strength and hydraulic properties of soils. The effective interlocking mechanisms between the soil and OA surfaces could provide soil its required strength and stability, particularly on slopes. OAs also improved soil fertility to promote turf growth. Presence of vegetative root zones can further reinforce the soil and control erosion.

Plasticity in the cell division processes of obligate intracellular bacteria.

Most bacteria divide through a highly conserved process called binary fission, in which there is symmetric growth of daughter cells and the synthesis of peptidoglycan at the mid-cell to enable cytokinesis. During this process, the parental cell replicates its chromosomal DNA and segregates replicated chromosomes into the daughter cells. The mechanisms that regulate binary fission have been extensively studied in several model organisms, including Eschericia coli, Bacillus subtilis, and Caulobacter crescentus. These analyses have revealed that a multi-protein complex called the divisome forms at the mid-cell to enable peptidoglycan synthesis and septation during division. In addition, rod-shaped bacteria form a multi-protein complex called the elongasome that drives sidewall peptidoglycan synthesis necessary for the maintenance of rod shape and the lengthening of the cell prior to division. In adapting to their intracellular niche, the obligate intracellular bacteria discussed here have eliminated one to several of the divisome gene products essential for binary fission in E. coli. In addition, genes that encode components of the elongasome, which were mostly lost as rod-shaped bacteria evolved into coccoid organisms, have been retained during the reductive evolutionary process that some coccoid obligate intracellular bacteria have undergone. Although the precise molecular mechanisms that regulate the division of obligate intracellular bacteria remain undefined, the studies summarized here indicate that obligate intracellular bacteria exhibit remarkable plasticity in their cell division processes.

The Unique N-Terminal Domain of Chlamydial Bactofilin Mediates Its Membrane Localization and Ring-Forming Properties.

Chlamydia trachomatis is an obligate intracellular bacterial pathogen. In evolving to the intracellular niche, Chlamydia has reduced its genome size compared to other bacteria and, as a consequence, has a number of unique features. For example, Chlamydia engages the actin-like protein MreB, rather than the tubulin-like protein FtsZ, to direct peptidoglycan (PG) synthesis exclusively at the septum of cells undergoing polarized cell division. Interestingly, Chlamydia possesses another cytoskeletal element-a bactofilin ortholog, BacA. Recently, we reported BacA is a cell size-determining protein that forms dynamic membrane-associated ring structures in Chlamydia that have not been observed in other bacteria with bactofilins. Chlamydial BacA possesses a unique N-terminal domain, and we hypothesized this domain imparts the membrane-binding and ring-forming properties of BacA. We show that different truncations of the N terminus result in distinct phenotypes: removal of the first 50 amino acids (ΔN50) results in large ring structures at the membrane whereas removal of the first 81 amino acids (ΔN81) results in an inability to form filaments and rings and a loss of membrane association. Overexpression of the ΔN50 isoform altered cell size, similar to loss of BacA, suggesting that the dynamic properties of BacA are essential for the regulation of cell size. We further show that the region from amino acid 51 to 81 imparts membrane association as appending it to green fluorescent protein (GFP) resulted in the relocalization of GFP from the cytosol to the membrane. Overall, our findings suggest two important functions for the unique N-terminal domain of BacA and help explain its role as a cell size determinant. IMPORTANCE Bacteria use a variety of filament-forming cytoskeletal proteins to regulate and control various aspects of their physiology. For example, the tubulin-like FtsZ recruits division proteins to the septum whereas the actin-like MreB recruits peptidoglycan (PG) synthases to generate the cell wall in rod-shaped bacteria. Recently, a third class of cytoskeletal protein has been identified in bacteria-bactofilins. These proteins have been primarily linked to spatially localized PG synthesis. Interestingly, Chlamydia, an obligate intracellular bacterium, does not have PG in its cell wall and yet possesses a bactofilin ortholog. In this study, we characterize a unique N-terminal domain of chlamydial bactofilin and show that this domain controls two important functions that affect cell size: its ring-forming and membrane-associating properties.

Congenital Vertebral Malformation in a Neonatal Elk (Cervus canadensis) in Kentucky, USA.

We captured a <1-d-old male elk calf (Cervus canadensis) with a shortened neck. Postmortem examination revealed trauma, meconium aspiration syndrome, and cervical vertebral malformation (partial fusion and narrowed disc spaces). This observation is novel in a wild elk calf, although the gross lesions resembled complex vertebral malformation in neonatal cattle.

The Relationships Among Cash Prices, Negotiated Rates, And Chargemaster Prices For Shoppable Hospital Services.

Hospitals must disclose their cash prices, commercial negotiated rates, and chargemaster prices for seventy common, shoppable services under the hospital price transparency rule. Examining prices reported by 2,379 hospitals as of September 9, 2022, we found that a given hospital's cash prices and commercial negotiated rates both tended to reflect a predetermined and consistent percentage discount from its chargemaster prices. On average, cash prices and commercial negotiated rates were 64 percent and 58 percent of the corresponding chargemaster prices for the same procedures at the same hospital and in the same service setting, respectively. Cash prices were lower than the median commercial negotiated rates in 47 percent of instances, and most likely so at hospitals with government or nonprofit ownership, located outside of metropolitan areas, or located in counties with relatively high uninsurance rates or low median household incomes. Hospitals with stronger market power were most likely to offer cash prices below their median negotiated rates, whereas hospitals in areas where insurers had stronger market power were less likely to do so.

Development and Evaluation of the Algorithm CErtaInty Tool (ACE-IT) to Assess Electronic Medical Record and Claims-based Algorithms' Fit for Purpose for Safety Outcomes.

INTRODUCTION: Electronic health record (EHR) or medical claims-based algorithms (i.e., operational definitions) can be used to define safety outcomes using real-world data. However, existing tools do not allow researchers and decision-makers to adequately appraise whether a particular algorithm is fit for purpose (FFP) to support regulatory decisions on drug safety surveillance. Our objective was to develop a tool to enable regulatory decision-makers and other stakeholders to appraise whether a given algorithm is FFP for a specific decision context. METHODS: We drafted a set of 77 generic items informed by regulatory guidance documents, existing instruments, and publications. The outcome of ischemic stroke served as an exemplar to inform the development of draft items. The items were designed to be outcome independent. We conducted a three-round online Delphi panel to develop and refine the tool and achieve consensus on items (> 70% agreement) among panel participants composed of regulators, researchers from pharmaceutical organizations, academic clinicians, methodologists, pharmacoepidemiologists, and cardiologists. We conducted a qualitative analysis of panel responses. Five pairs of reviewers independently evaluated two ischemic stroke algorithm validation studies to test its application. We developed a user guide, with explanation and elaboration for each item, guidance on essential and additional elements for user responses, and an illustrative example of a complete assessment. Furthermore, we conducted a 2-h online stakeholder panel of 16 participants from regulatory agencies, academic institutions, and industry. We solicited input on key factors for an FFP assessment, their general reaction to the Algorithm CErtaInty Tool (ACE-IT), limitations of the tool, and its potential use. RESULTS: The expert panel reviewed and made changes to the initial list of 77 items. The panel achieved consensus on 38 items, and the final version of the ACE-IT includes 34 items after removal of duplicate items. Applying the tool to two ischemic stroke algorithms demonstrated challenges in its application and identified shared concepts addressed by more than one item. The ACE-IT was viewed positively by the majority of stakeholders. They identified that the tool could serve as an educational resource as well as an information-sharing platform. The time required to complete the assessment was identified as an important limitation. We consolidated items with shared concepts and added a preliminary screen section and a summary assessment box based on their input. The final version of the ACE-IT is a 34-item tool for assessing whether algorithm validation studies on safety outcomes are FFP. It comprises the domains of internal validity (24 items), external validity (seven items), and ethical conduct and reporting of the validation study (three items). The internal validity domain includes sections on objectives, data sources, population, outcomes, design and setting, statistical methods, reference standard, accuracy, and strengths and limitations. The external validity domain includes items that assess the generalizability to a proposed target study. The domain on ethics and transparency includes items on ethical conduct and reporting of the validation study. CONCLUSION: The ACE-IT supports a structured, transparent, and flexible approach for decision-makers to appraise whether electronic health record or medical claims-based algorithms for safety outcomes are FFP for a specific decision context. Reliability and validity testing using a larger sample of participants in other therapeutic areas and further modifications to reduce the time needed to complete the assessment are needed to fully evaluate its utility for regulatory decision-making.

Percutaneous Coronary Intervention With Dual Antiplatelet Therapy in a Patient With Chronic Subdural Hematoma: Novel Approach.

Subdural hematoma is a type of brain bleed characterized by the accumulation of blood beneath the dura matter. It usually occurs as a sequela of a traumatic event or following the use of antiplatelets and/or anticoagulants. The clinical presentation may include symptoms like headache, confusion, ataxia, and hemiparesis. However, it may even be asymptomatic, especially in the elderly population. The presence of subdural hematoma is a relative contraindication to antiplatelet therapy because of the associated risk of worsening bleeding. Hence, acute coronary syndrome or conditions requiring antiplatelet therapy presents a management dilemma when they coexist with subdural hematoma. This paper reports a case of successful use of dual antiplatelets post percutaneous coronary intervention in a patient with spontaneous chronic subdural hematoma. Our patient had a history of coronary artery disease six months prior to stent placement and was on dual antiplatelet therapy. He developed a headache some months later and his neurologist, on evaluating him, made a diagnosis of subdural hematoma, evident on magnetic resonance imaging of the brain. His antiplatelet therapy was discontinued, and he subsequently had a bilateral middle meningeal artery embolization. Following the procedure, a left heart catheterization was done with appropriate interventions for acute coronary syndrome diagnosed at the time of presentation. He was later discharged on dual antiplatelet therapy, followed up on outpatient at scheduled intervals, and was found stable. This case report suggests that individuals with chronic subdural hematoma who may require antiplatelet therapy can still go on to receive the medication after undergoing a bilateral middle meningeal artery embolization. More observational studies are needed to make this the standard of care.

Motivating deprescribing conversations for patients with Alzheimer's disease and related dementias: a descriptive study.

Introduction: Older adults with Alzheimer's disease and related dementias (ADRD) are at increased risk of harm due to prescribing of potentially inappropriate medications. Encouraging patients and caregivers to talk with their providers about potentially inappropriate medications could stimulate deprescribing. Our objective was to explore whether mailing educational materials to patients with ADRD might activate patients or caregivers to initiate a conversation with their provider about potentially inappropriate medications. Methods: We conducted semi-structured interviews with patients with ADRD, caregivers of patients with ADRD, and healthcare providers. All participants were shown educational materials referencing potentially inappropriate medications and suggestions to promote deprescribing. Interviews explored reactions to the materials, the idea of patients and caregivers initiating a conversation about deprescribing, and the deprescribing process. Interview transcripts were analyzed using inductive thematic analysis. Results: We conducted a total of 27 interviews: 9 with caregivers only, 2 with patients only, 3 with patient-caregiver dyads, and 13 with providers. Patients and caregivers reported that if a medication might cause harm, it would motivate them to talk to their provider about the medication. Trust in the provider could facilitate or inhibit such conversations; conversations would be more likely if there were prior positive experiences asking questions of the provider. Providers were receptive to patients and caregivers initiating conversations about their medications, as they valued deprescribing as part of their clinical practice and welcome informed patients and caregivers as participants in decision-making about medication. Conclusion: Mailing educational materials about potentially inappropriate medications to community-dwelling patients with ADRD may promote deprescribing conversations. Ongoing pragmatic trials will determine whether such interventions stimulate deprescribing conversations and achieve reductions in prescribing of inappropriate medications. Plain Language Summary: Encouraging patients with Alzheimer's disease to talk with their providers about medications that may cause harm Introduction: Older adults with Alzheimer's disease and related dementias (ADRD) are sometimes prescribed medications that may cause harm, especially when taken for extended periods of time. Patients and their caregivers may not know about the risks. Doctors know of the risks but may not address them due to competing priorities or other challenges in providing care to these patients with complex needs. Encouraging the patient or their caregiver to talk to their doctor about their medications might help to reduce the use of medications that are not beneficial. This study's goal was to explore whether sending educational materials to patients with ADRD might encourage patients or caregivers to ask their doctor about their medications.Methods: We interviewed patients with ADRD, caregivers, and doctors. We showed them educational materials that suggested patients and their caregivers talk to their doctor about reducing or stopping medications that may be harmful. We asked for reactions to the materials and to the idea of talking to the doctor about stopping the medication.Results: We conducted 27 interviews: 9 with caregivers only, 2 with patients only, 3 with patient-caregiver dyads, and 12 with doctors. Patients and caregivers said learning that a medication might cause harm would motivate them to talk to their doctor about the medication. Trust in their doctor was important. Some patients and caregivers were comfortable asking questions about medications, while others were reluctant to challenge the doctor. Doctors were open to patients and caregivers asking about medications and felt it was important that patients not take medications that are not needed.Conclusion: Sending educational materials to patients with ADRD and caregivers may encourage them to talk with their doctors about stopping or reducing medications. Studies are needed to learn whether such materials lead to reductions in prescribing of potential harmful medications.

Localized cardiolipin synthesis is required for the assembly of MreB during the polarized cell division of Chlamydia trachomatis.

Pathogenic Chlamydia species are coccoid bacteria that use the rod-shape determining protein MreB to direct septal peptidoglycan synthesis during their polarized cell division process. How the site of polarized budding is determined in this bacterium, where contextual features like membrane curvature are seemingly identical, is unclear. We hypothesized that the accumulation of the phospholipid, cardiolipin (CL), in specific regions of the cell membrane induces localized membrane changes that trigger the recruitment of MreB to the site where the bud will arise. To test this, we ectopically expressed cardiolipin synthase (Cls) and observed a polar distribution for this enzyme in Chlamydia trachomatis. In early division intermediates, Cls was restricted to the bud site where MreB is localized and peptidoglycan synthesis is initiated. The localization profile of 6xHis tagged Cls (Cls_6xH) throughout division mimicked the distribution of lipids that stain with NAO, a dye that labels CL. Treatment of Chlamydia with 3',6-dinonylneamine (diNN), an antibiotic targeting CL-containing membrane domains, resulted in redistribution of Cls_6xH and NAO-staining phospholipids. In addition, 6xHis tagged MreB localization was altered by diNN treatment, suggesting an upstream regulatory role for CL-containing membranes in directing the assembly of MreB. This hypothesis is consistent with the observation that the clustered localization of Cls_6xH is not dependent upon MreB function or peptidoglycan synthesis. Furthermore, expression of a CL-binding protein at the inner membrane of C. trachomatis dramatically inhibited bacterial growth supporting the importance of CL in the division process. Our findings implicate a critical role for localized CL synthesis in driving MreB assembly at the bud site during the polarized cell division of Chlamydia.

How Safe Is Cancer Care?

Cancer Morbidity, Mortality, and Improvement Rounds is a series of articles intended to explore the unique safety risks experienced by oncology patients through the lens of quality improvement, systems and human factors engineering, and cognitive psychology. For purposes of clarity, each case focuses on a single theme, although, as is true for all medical incidents, there are almost always multiple, overlapping, contributing factors. The quality improvement paradigm used here, which focuses on root cause analyses and opportunities to improve care delivery systems, was previously outlined in this journal.

In IBS, a smartphone application for self-managing a FODMAP-lowering diet vs. otilonium bromide reduced symptoms at 8 wk.

SOURCE CITATION: Carbone F, Van den Houte K, Besard L, et al. Diet or medication in primary care patients with IBS: the DOMINO study-a randomised trial supported by the Belgian Health Care Knowledge Centre (KCE Trials Programme) and the Rome Foundation Research Institute. Gut. 2022. [Epub ahead of print]. 35483886.

Increasing harms for bingo players: digitisation, commercialisation and regulatory inadequacy: a multi-site case study.

BACKGROUND: Bingo is often understood as a low-harm form of gambling. This view has been challenged by a growing body of literature identifying gambling harm to bingo players in a range of countries. In this study, we aimed to identify which conditions enabled, facilitated, intensified or mitigated gambling harm for bingo players in three populations in Victoria in the context of corporate, technological and regulatory changes. METHODS: Our qualitative study investigated experiences of bingo-related gambling harm in three populations in Victoria, Australia where bingo was popular and structural disadvantage common: Indigenous people in the east, Pacific people in the state's north and older people on low or fixed incomes in the capital. Data was generated through interviews with 53 bingo players and 13 stakeholders as well as 12 participant observations of bingo sessions. RESULTS: We found that while bingo is overwhelmingly positive for many players, a minority of bingo players and their families experience notable harm. Harm was generated through traditional paper-based bingo games, new technologies such as tablet-based bingo and by the widespread tactic of placing bingo sessions in close proximity to harmful electronic gambling machines. Overall, the risk of harm to bingo players appears to be escalating due to commercial, technological and regulatory changes. CONCLUSIONS: These changes can be better managed by regulators: reforms are needed to safeguard bingo's distinct character as a lower-risk form of gambling at a time when it, and its players, are under threat. Significantly, we found that harm to bingo players is intensified by factors external to gambling such as racialised poverty and adverse life events. Strategies that recognise these factors and grapple with gambling harm to bingo players are needed.

Acute Thrombosis of Left Anterior Descending Coronary Artery During Anaphylactic Reaction to Contrast Dye.

Anaphylaxis is a systemic inflammatory response to an antigen and can result in hemodynamic compromise. While uncommon, it remains an important differential diagnosis in the setting of intraprocedural hypotension. Acute thrombosis has been associated with anaphylaxis and should be suspected based on clinical symptoms. We describe a clinical case of intraprocedural anaphylaxis secondary to intravenous contrast dye leading to hypotension and acute thrombosis of the left anterior descending coronary artery.