Zinc-Mediated Radiosynthesis of Unprotected Fluorine-18 Labelled α-Tertiary Amides.

This report describes the development of a Zn(OTf)2 -mediated method for converting α-tertiary haloamides to the corresponding fluorine-18 labelled α-tertiary fluoroamides with no-carrier-added [18 F]tetramethylammonium fluoride. 1,5,7-Triazabicyclo[4.4.0]dec-5-ene is an essential additive for achieving high radiochemical conversion. Under the optimised conditions, radiofluorination proceeds at sterically hindered tertiary sites in high radiochemical conversions, yields, and purities. This method has been successfully automated and applied to access >200 mCi (>7.4 GBq) of several model radiofluorides. Mechanistic studies led to the development of a new, nucleophilic C-H radiofluorination process using N-sulphonyloxyamide substrates.

Psychometric Properties of an Adapted Stigma Scale and Experiences of Stigma Associated with HIV Pre-exposure Prophylaxis Use Among Men Who have Sex with Men: A Mixed Methods Study.

Stigma may influence the use of HIV pre-exposure prophylaxis (PrEP). However, there is an absence of robust measures for PrEP-related stigma. We describe an adaptation of a HIV stigma scale for use in PrEP users and experiences of PrEP users in Wales (UK) with regards to PrEP-related stigma. A mixed methods study was conducted where PrEP users completed questionnaire items about PrEP-related stigma and a subset were interviewed about their experiences of taking PrEP. We adapted items from the HIV stigma scale and assessed construct validity and internal consistency. We analysed interview data using a framework approach, with themes focussing on enacted and anticipated stigma in order to identify areas for scale refinement. Our measure had good psychometric properties but additional items may be useful (e.g. specific instances of enacted stigma, concerns around homonegativity). Further work is needed to develop this scale and validate it in a larger sample.

Between- and Within-Individual Sociodemographic and Psychological Determinants of PrEP Adherence Among Men Who have Sex with Men Prescribed a Daily PrEP Regimen in Wales.

We investigated the determinants of daily PrEP use and coverage of condomless anal sex (CAS) by PrEP among men who have sex with men in Wales, UK. We measured PrEP use by electronic monitors and CAS by secure online surveys. We defined PrEP use based on daily medication cap openings and coverage as CAS episodes preceded by ≥ 3 days of PrEP use and followed by ≥ 2 days of PrEP use. We included 57 participants (5463 observations). An STI diagnosis was associated with lower PrEP use but also lower PrEP coverage. Older adults had higher PrEP use. A belief that other PrEP users took PrEP as prescribed was associated with lower PrEP coverage. An STI diagnosis is an important cue for an intervention, reflecting episodes of high-risk sexual behaviour and low PrEP coverage. Other results provide a basis for the development of an evidence-informed intervention for promoting coverage of PrEP.

Experiences of men who have sex with men when initiating, implementing and persisting with HIV pre-exposure prophylaxis.

INTRODUCTION: HIV pre-exposure prophylaxis (PrEP) involves the use of antiretroviral medication in HIV-negative individuals considered to be at risk of acquiring HIV. It has been shown to prevent HIV and has been available in Wales since July 2017. Measuring and understanding adherence to PrEP is complex as it relies on the simultaneous understanding of both PrEP use and sexual activity. We aimed to understand the experiences of men who have sex with men (MSM) living in Wales initiating, implementing and persisting with HIV PrEP. METHODS: We conducted semistructured interviews with MSM PrEP users in Wales who participated in a cohort study of PrEP use and sexual behaviour. Following completion of the cohort study, participants were invited to take part in a semistructured interview about their experiences of taking PrEP. We aimed to include both individuals who had persisted with and discontinued PrEP during the study. The interview topic guide was informed by the ABC taxonomy for medication adherence and the theory of planned behaviour. We analysed our data using reflexive thematic analysis. RESULTS: Twenty-one participants were interviewed, five having discontinued PrEP during the cohort study. The developed themes focused on triggers for initiating PrEP, habitual behaviour, drivers for discontinuation and engagement with sexual health services. Stigma surrounding both PrEP and HIV permeated most topics, acting as a driver for initiating PrEP, an opportunity to reduce discrimination against people living with HIV, but also a concern around the perception of PrEP users. CONCLUSION: This is the first study to investigate PrEP-taking experiences incorporating established medication adherence taxonomy. We highlight key experiences regarding the initiation, implementation and persistence with PrEP and describe how taking PrEP may promote positive engagement with sexual health services. These findings may be useful for informing PrEP rollout programmes and need to be explored in other key populations. PATIENT AND PUBLIC CONTRIBUTION: PrEP users, in addition to PrEP providers and representatives of HIV advocacy and policy, were involved in developing the topic guide for this study.

Bench to Bedside: A Multidisciplinary Approach toward the Unknowns after ACL Injuries to Drive Individual Success.

ACL injury and surgery are increasing in prevalence. Several challenges exist that can be obstacles to an individual achieving success after ACL surgery. A knowledge of these risk factors alongside a multidisciplinary collaborative team approach can result in a greater likelihood of achieving individual success after ACL surgery.

Early impact of COVID-19 social distancing measures on reported sexual behaviour of HIV pre-exposure prophylaxis users in Wales.

OBJECTIVES: To describe the early impact of COVID-19 and associated control measures on the sexual behaviour of pre-exposure prophylaxis (PrEP) users in Wales. METHODS: Data were obtained from an ecological momentary assessment study of PrEP use and sexual behaviour. Participants were individuals accessing PrEP through the National Health Service (NHS) sexual health clinics across four health boards in Wales. Weekly data documenting condomless sex in the preceding week were analysed between 03/02/2020 and 10/05/2020. The introduction of social distancing measures and changes to sexual health clinics in Wales occurred on the week starting 16/03/2020. Two-level logistic regression models were fitted to condomless sex (yes/no) over time, included an indicator for the week starting 16/03/2020, and were extended to explore differential associations by relationship status and sexual health clinic. RESULTS: Data were available from 56 participants and included 697 person-weeks (89% of the maximum number that could have been obtained). On average, 42% of participants reported condomless sex in the period prior to the introduction of social distancing measures and 20% reported condomless sex after (OR=0.16, 95% CI 0.07 to 0.37, p<0.001). There was some evidence to suggest that this association was moderated by relationship status (OR for single participants=0.09, 95% CI 0.06 to 0.23; OR for not single participants=0.46, 95% CI 0.16 to 1.25). CONCLUSIONS: The introduction of social distancing measures and changes to PrEP services across Wales was associated with a marked reduction in reported instances of condomless sexual intercourse among respondents, with a larger reduction in those who were single compared with those who were not. The long-term impact of COVID-19 and associated control measures on this population's physical and mental health and well-being requires close examination.

Impact of a pay-for-performance scheme for long-acting reversible contraceptive (LARC) advice on contraceptive uptake and abortion in British primary care: An interrupted time series study.

BACKGROUND: Long-acting reversible contraception (LARC) is among the most effective contraceptive methods, but uptake remains low even in high-income settings. In 2009/2010, a target-based pay-for-performance (P4P) scheme in Britain was introduced for primary care physicians (PCPs) to offer advice about LARC methods to a specified proportion of women attending for contraceptive care to improve contraceptive choice. We examined the impact and equity of this scheme on LARC uptake and abortions. METHODS AND FINDINGS: We examined records of 3,281,667 women aged 13 to 54 years registered with a primary care clinic in Britain (England, Wales, and Scotland) using Clinical Practice Research Datalink (CPRD) from 2004/2005 to 2013/2014. We used interrupted time series (ITS) analysis to examine trends in annual LARC and non-LARC hormonal contraception (NLHC) uptake and abortion rates, stratified by age and deprivation groups, before and after the P4P was introduced in 2009/2010. Between 2004/2005 and 2013/2014, crude LARC uptake rates increased by 32.0% from 29.6 per 1,000 women to 39.0 per 1,000 women, compared with 18.0% decrease in NLHC uptake. LARC uptake among women of all ages increased immediately after the P4P with step change of 5.36 per 1,000 women (all values are per 1,000 women unless stated, 95% CI 5.26-5.45, p < 0.001). Women aged 20 to 24 years had the largest step change (8.40, 8.34-8.47, p < 0.001) and sustained trend increase (3.14, 3.08-3.19, p < 0.001) compared with other age groups. NLHC uptake fell in all women with a step change of -22.8 (-24.5 to -21.2, p < 0.001), largely due to fall in combined hormonal contraception (CHC; -15.0, -15.5 to -14.5, p < 0.001). Abortion rates in all women fell immediately after the P4P with a step change of -2.28 (-2.98 to -1.57, p = 0.002) and sustained decrease in trend of -0.88 (-1.12 to -0.63, p < 0.001). The largest falls occurred in women aged 13 to 19 years (step change -5.04, -7.56 to -2.51, p = 0.011), women aged 20 to 24 years (step change -4.52, -7.48 to -1.57, p = 0.030), and women from the most deprived group (step change -4.40, -6.89 to -1.91, p = 0.018). We estimate that by 2013/2014, the P4P scheme resulted in an additional 4.53 LARC prescriptions per 1,000 women (relative increase of 13.4%) more than would have been expected without the scheme. There was a concurrent absolute reduction of -5.31 abortions per 1,000 women, or -38.3% relative reduction. Despite universal coverage of healthcare, some women might have obtained contraception elsewhere or had abortion procedure that was not recorded on CPRD. Other policies aiming to increase LARC use or reduce unplanned pregnancies around the same time could also explain the findings. CONCLUSIONS: In this study, we found that LARC uptake increased and abortions fell in the period after the P4P scheme in British primary care, with additional impact for young women aged 20-24 years and those from deprived backgrounds.

Impact of preventive primary care on children's unplanned hospital admissions: a population-based birth cohort study of UK children 2000-2013.

BACKGROUND: Universal health coverage (UHC) aims to improve child health through preventive primary care and vaccine coverage. Yet, in many developed countries with UHC, unplanned and ambulatory care sensitive (ACS) hospital admissions in childhood continue to rise. We investigated the relation between preventive primary care and risk of unplanned and ACS admission in children in a high-income country with UHC. METHODS: We followed 319,780 children registered from birth with 363 English practices in Clinical Practice Research Datalink linked to Hospital Episodes Statistics, born between January 2000 and March 2013. We used Cox regression estimating adjusted hazard ratios (HR) to examine subsequent risk of unplanned and ACS hospital admissions in children who received preventive primary care (development checks and vaccinations), compared with those who did not. RESULTS: Overall, 98% of children had complete vaccinations and 87% had development checks. Unplanned admission rates were 259, 105 and 42 per 1000 child-years in infants (aged < 1 year), preschool (1-4 years) and primary school (5-9 years) children, respectively. Lack of preventive care was associated with more unplanned admissions. Infants with incomplete vaccination had increased risk for all unplanned admissions (HR 1.89, 1.79-2.00) and vaccine-preventable admissions (HR 4.41, 2.59-7.49). Infants lacking development checks had higher risk for unplanned admission (HR 4.63, 4.55-4.71). These associations persisted across childhood. Children who had higher consulting rates with primary care providers also had higher risk of unplanned admission (preschool children: HR 1.17, 1.17-1.17). One third of all unplanned admissions (62,154/183,530) were for ACS infectious illness. Children with chronic ACS conditions, asthma, diabetes or epilepsy had increased risk of unplanned admission (HR 1.90, 1.77-2.04, HR 11.43, 8.48-15.39, and HR 4.82, 3.93-5.91, respectively). These associations were modified in children who consulted more in primary care. CONCLUSIONS: A high uptake of preventive primary care from birth is associated with fewer unplanned and ACS admissions in children. However, the clustering of poor health, a lack of preventive care uptake, and social deprivation puts some children with comorbid conditions at very high risk of admission. Strengthening immunisation coverage and preventive primary care in countries with poor UHC could potentially significantly reduce the health burden from hospital admission in children.

Comparison of Outcomes After Primary Versus Salvage Osteochondral Allograft Transplantation for Femoral Condyle Osteochondritis Dissecans Lesions.

Background: Osteochondral allograft transplantation (OCAT) allows the restoration of femoral condyle osteochondritis dissecans (OCD) lesions using an osteochondral unit. When OCD lesions are irreparable, or treatments have failed, OCAT is an appropriate approach for revision or salvage surgery. Based on its relative availability, cost-effectiveness, lack of donor site morbidity, and advances in preservation methods, OCAT is also an attractive option for primary surgical treatment for femoral condyle OCD. Hypothesis: OCAT for large femoral condyle OCD lesions would be highly successful (>90%) based on significant improvements in knee pain and function, with no significant differences between primary and salvage procedure outcomes. Study Design: Cohort study; Level of evidence, 3. Methods: Patients were enrolled into a registry for assessing outcomes after OCAT. Those patients who underwent OCAT for femoral condyle OCD and had a minimum of 2-year follow-up were included. Reoperations, treatment failures, and patient-reported outcomes were compared between primary and salvage OCAT cohorts. Results: A total of 22 consecutive patients were included for analysis, with none lost to the 2-year follow-up (mean, 40.3 months; range, 24-82 months). OCD lesions of the medial femoral condyle (n = 17), lateral femoral condyle (n = 4), or both condyles (n = 1) were analyzed. The mean patient age was 25.3 years (range, 12-50 years), and the mean body mass index was 25.2 kg/m2 (range, 17-42 kg/m2). No statistically significant differences were observed between the primary (n = 11) and salvage (n = 11) OCAT cohorts in patient and surgical characteristics. Also, 91% of patients had successful outcomes at a mean of >3 years after OCAT with 1 revision in the primary OCAT cohort and 1 conversion to total knee arthroplasty in the salvage OCAT cohort. For both primary and salvage OCATs, patient-reported measures of pain and function significantly improved at the 1-year and final follow-up, and >90% of patients reported that they were satisfied and would choose OCAT again for treatment. Conclusion: Based on the low treatment failure rates in conjunction with statistically significant and clinically meaningful improvements in patient-reported outcomes, OCAT can be considered an appropriate option for both primary and salvage surgical treatment in patients with irreparable OCD lesions of the femoral condyles.

Management of shoulder instability in the skeletally immature patient.

Several studies have focused on management of shoulder instability in the adolescent and young adult population. However, a paucity of literature exists regarding shoulder dislocation in the skeletally immature population. The presence of an open physis makes the dislocated pediatric shoulder a challenging clinical problem. In general, management includes prompt reduction and sling immobilization. In athletic patients aged ≥14 years with a Bankart lesion, early surgical intervention may be warranted because of the higher risk of recurrent instability. However, the literature on younger skeletally immature patients is less clear in terms of risk of further instability and the necessity of surgical intervention. In the skeletally immature population, a relatively low rate of recurrent instability after primary dislocation has been reported in the recent literature. Surgical intervention should be considered for patients with recurrent instability.

Costal cartilage fractures and disruptions in a rugby football player.

Costal cartilage fracture of the rib cage, or costochondral, is a rare sporting injury. For contact athletes, the instability of the rib cage may lead to potential serious complications, similar to rib fractures or thorax disruption. Most authors recommend initial conservative treatment with surgery reserved for only recalcitrant cases. We report a case of an amateur American male rugby football player who sustained a costal cartilage fracture and disruption involving the anterior left fifth and sixth rib costal cartilages. The case highlights the difficulty in establishing the diagnosis based on clinical examination and standard radiographs alone. Computed tomography was used to assist in diagnosing this destabilizing injury to the rib cage. Costal cartilage fractures and disruptions in athletes are rarely reported in the literature and can have serious implications for the athlete's ability to return to play if the rib cage is destabilized.

Prospective Randomized Controlled Clinical Trial Comparing Hyperosmolar Saline to Standard Isotonic Irrigation Fluid for Arthroscopic Knee Surgery: Initial Clinical Outcomes.

Numerous in vitro studies suggest higher osmolarity irrigation fluids potentiate a chondroprotective environment, and a recent clinical study using hyperosmolar saline for shoulder arthroscopy reported potential clinical advantages. This prospective randomized double-blind controlled clinical trial was designed to assess initial clinical outcomes associated with use of a hyperosmolar irrigation solution in patients undergoing arthroscopic knee surgery. With institutional review board approval and informed consent, patients scheduled for arthroscopic knee surgery were randomized to surgery with either isotonic lactated Ringer's (273 mOsm/L) or hyperosmolar saline (593 mOsm/L) irrigation solution. Outcomes included perioperative blood pressure, knee girth, visual analogue scale (VAS) pain scores, and narcotic pain medication consumption. Forty-six patients underwent arthroscopic knee surgery with isotonic (n = 23) or hyperosmolar (n = 23) irrigation fluids. There were 11 males and 12 females (mean age = 44.0 years) in the isotonic cohort and 8 males and 15 females (mean age = 40.2 years) in the hyperosmolar cohort. There were no significant differences with respect to surgical duration (pump time) or amount of irrigation fluid used between the two cohorts. There were no significant differences with respect to change in knee girth, blood pressure, or VAS pain scores. However, patients treated with hyperosmolar saline consumed less narcotic medication on postoperative day 3 (4.0 ± 7.6 vs. 15.5 ± 17.4 mg, p = 0.01). The results of this randomized clinical trial suggest that a hyperosmolar irrigation solution is safe and relatively inexpensive for use in patients undergoing arthroscopic knee surgery and contributes to a reduction in initial postoperative narcotic pain medication consumption. A hyperosmolar saline irrigation fluid was not associated with any detrimental effects on the execution of the surgical procedure, postoperative pain, or periarticular fluid extravasation. Taken together with previous basic science, translational, and clinical studies, hyperosmolar saline irrigation fluid is promising alternative to traditional isotonic irrigation fluids for knee arthroscopy. This study is a prospective trial and reflects level of evidence I.

Protective effects of macrophage-specific integrin α5 in myocardial infarction are associated with accentuated angiogenesis.

Macrophages sense changes in the extracellular matrix environment through the integrins and play a central role in regulation of the reparative response after myocardial infarction. Here we show that macrophage integrin α5 protects the infarcted heart from adverse remodeling and that the protective actions are associated with acquisition of an angiogenic macrophage phenotype. We demonstrate that myeloid cell- and macrophage-specific integrin α5 knockout mice have accentuated adverse post-infarction remodeling, accompanied by reduced angiogenesis in the infarct and border zone. Single cell RNA-sequencing identifies an angiogenic infarct macrophage population with high Itga5 expression. The angiogenic effects of integrin α5 in macrophages involve upregulation of Vascular Endothelial Growth Factor A. RNA-sequencing of the macrophage transcriptome in vivo and in vitro followed by bioinformatic analysis identifies several intracellular kinases as potential downstream targets of integrin α5. Neutralization assays demonstrate that the angiogenic actions of integrin α5-stimulated macrophages involve activation of Focal Adhesion Kinase and Phosphoinositide 3 Kinase cascades.

Superbase route to supertetrahedral chalcogenide clusters.

Supertetrahedral Tn clusters are exact fragments of a cubic ZnS type lattice. Thus far, Tn clusters up to T4 with 20 metal sites can be synthesized in a discrete molecular form. Yet, synthesis of larger discrete supertetrahedral clusters still remains a great challenge, likely due to the rapidly increasing negative charge on the cluster as the size goes up. By using organic superbases (DBN and DBU) to help stabilize the negative charge, a family of discrete supertetrahedral chalcogenide clusters with sizes spanning from T3 (10 metal sites) to T5 (35 metal sites) have been made. The T5 cluster represents the largest molecular supertetrahedral Tn cluster known to date.

Access to and use of contraceptive care during the first COVID-19 lockdown in the UK: a web-based survey.

BACKGROUND: The first wave of lockdown measures to control the COVID-19 pandemic in the UK resulted in suspension of 'non-essential' services, including contraceptive care. AIM: To examine women's perceptions and experiences of contraceptive care in the UK during the first lockdown. DESIGN & SETTING: A cross-sectional survey during the lockdown period from March-June 2020. METHOD: An online questionnaire was designed asking women aged 16-54 years their experiences of contraceptive care during lockdown. Questions were based on Maxwell's evaluation framework on access, acceptability, relevance or appropriateness, and equity. It was promoted on social media from 27 May-9 June 2020. A descriptive analysis was conducted of quantitative data and thematic analysis of free-text data. RESULTS: In total, 214 responses were analysed. General practice was the source of contraception for 43.4% (n = 49) and 52.3% (n = 34) of responders before and during the lockdown, respectively. The study found 55.1% (n = 118) of responders, including regular and new users, were uncertain where or how to get contraception during the pandemic. Responders reported reduced access to contraception during lockdown, and some thought sexual health clinics and general practices were closed. Remote consultations and electronic prescriptions facilitated contraceptive access for some responders. Long-acting reversible contraception (LARC) was unavailable in some areas owing to restrictions, and alternatives were not acceptable to those who used methods for non-contraceptive benefits to treat medical conditions; for example, menorrhagia. CONCLUSION: The study highlighted the need for better information and signposting for contraception during lockdown. Contraception, including LARC, should be reframed as an essential service with robust signposting for pandemic planning and beyond.

The Role of Bracing in ACL Injuries: The Current Evidentiary State of Play.

Anterior cruciate ligament (ACL) injuries and surgeries are both increasing in incidence. A notable rate of reinjury and failure does occur after ACL surgery. As a result, interventions that may reduce ACL injury or reinjury are needed and are active areas of innovation. Knee bracing as a strategy to either prevent primary ACL injury, reduce reinjury, or failure after ACL surgery is common. The evidence for bracing around ACL injuries is not straightforward. Clinicians therefore need to understand the relevant literature on bracing around ACL injuries to make personalized decisions for individuals who may be at risk for ACL injury. The purpose of this review is to provide an overview on bracing for ACL injuries and summarize the current available clinical evidence for its use in ACL injuries.

Small laboratory animal models of anterior cruciate ligament reconstruction.

Anterior cruciate ligament (ACL) injuries are common knee ligament injuries. While generally successful, ACL reconstruction that uses a tendon graft to stabilize the knee is still associated with a notable percentage of failures and long-term morbidities. Preclinical research that uses small laboratory species (i.e., mice, rats, and rabbits) to model ACL reconstruction are important to evaluate factors that can impact graft incorporation or posttraumatic osteoarthritis after ACL reconstruction. Small animal ACL reconstruction models are also used for proof-of-concept studies for the development of emerging biological strategies aimed at improving ACL reconstruction healing. The objective of this review is to provide an overview on the use of common small animal laboratory species to model ACL reconstruction. The review includes a discussion on comparative knee anatomy, technical considerations including types of tendon grafts employed amongst the small laboratory species (i.e., mice, rats, and rabbits), and common laboratory evaluative methods used to study healing and outcomes after ACL reconstruction in small laboratory animals. The review will also highlight common research questions addressed with small animal models of ACL reconstruction.

Utility of lateral scapular radiographs in initial evaluation of nontraumatic shoulder conditions.

Background: Lateral scapular radiographs have been routinely included in the initial radiographic examination of both traumatic and nontraumatic shoulder conditions. With the advance of modern imaging modalities, the clinical utility of the lateral scapular view has become questionable. The purpose of the study was to assess the utilization of the lateral scapular view among the members of the American Shoulder and Elbow Surgeons (ASES) and to determine the clinical utility of the lateral scapular view in the initial evaluation of nontraumatic shoulder conditions. Methods: The study consisted of two parts. The first part involved an online survey of ASES members, which asked them 3 questions regarding their preference for radiographic evaluation of new patients with nontraumatic shoulder pain. The second part involved a clinical vignette-based survey, where 4 shoulder surgeons at our institution were given 50 clinical vignettes and asked to independently answer 4 questions regarding the most probable diagnosis, abnormal radiographic findings, further imaging studies, and treatment plan for each case. The survey was repeated twice; the first was given without a lateral scapular view, and the second given 4 weeks later with a lateral scapular view included. We obtained diagnostic accuracy and percent agreement of each surgeon over two surveys and intraobserver and interobserver reliability on each variable. Results: Of a total of 235 ASES members who responded to the online survey, 193 (82.1%) indicated their routine use of a lateral scapular view. The most common reason for obtaining the view was better characterization of acromion morphology (75.4%). The clinical vignette-based survey showed substantial intrarater reliability (κ > 0.6) of the 4 surgeons between the two surveys for the most probable diagnosis, abnormal x-ray findings, and further imaging studies, while the intrarater reliability for treatment plan was moderate (κ = 0.548). The mean diagnostic accuracy of the 4 surgeons was almost equal (74% vs. 75%) between the surveys. Overall, each surgeon's percent agreement across the 2 surveys was over 70%. None of the 4 surgeons recommended a lateral scapular view for further imaging during the first survey; each wanted either advanced imaging (computed tomography, magnetic resonance imaging) or none. Discussion: The addition of a lateral scapular radiograph in the presence of other orthogonal views does not appear to improve surgeons' diagnostic accuracy or affect their decision-making on the treatment plan in nontraumatic shoulder conditions. The clinical utility of the lateral scapular view may need to be reassessed in this setting.