The application of artificial intelligence to accelerate G protein-coupled receptor drug discovery.

The application of artificial intelligence (AI) approaches to drug discovery for G protein-coupled receptors (GPCRs) is a rapidly expanding area. Artificial intelligence can be used at multiple stages during the drug discovery process, from aiding our understanding of the fundamental actions of GPCRs to the discovery of new ligand-GPCR interactions or the prediction of clinical responses. Here, we provide an overview of the concepts behind artificial intelligence, including the subfields of machine learning and deep learning. We summarise the published applications of artificial intelligence to different stages of the GPCR drug discovery process. Finally, we reflect on the benefits and limitations of artificial intelligence and share our vision for the exciting potential for further development of applications to aid GPCR drug discovery. In addition to making the drug discovery process "faster, smarter and cheaper," we anticipate that the application of artificial intelligence will create exciting new opportunities for GPCR drug discovery.

Efficacy and accuracy of faecal sampling by a digital rectal examination for faecal immunochemical testing.

AIM: A digital rectal examination (DRE) during routine assessment for patients with abdominal symptoms provides an opportunity to obtain faeces from the glove for faecal immunochemical testing (FIT). Here, we compared sampling via DRE to the standard faecal sampling by patients. METHOD: Patients were recruited to a prospective observational cohort study between July 2019 and March 2020. Patients provided a sample for the FOB Gold Wide® which was compared to a further sample taken at clinic via DRE. Clinicians reported whether they obtained a 'good' sample filling all the grooves, a 'poor' sample filling some of the grooves or no faecal sample. Cohen's kappa was used to compare percentage agreement around a negative threshold of <10 µg haemoglobin/g of faeces. Sensitivity for serious bowel disease (SBD) was calculated. RESULTS: Of 596 patients who underwent attempted DRE sampling, there were 258 (43.3%) 'good' samples, 117 (19.6%) 'poor' samples and 221 (37.1%) with no sample to wipe in the grooves. Cohen's kappa dropped from 0.70 to 0.30 for the 'good' and 'poor' samples, respectively. Of those with DRE samples and definitive diagnostic outcomes, the sensitivity for SBD dropped significantly from 76.0% to 41.7% between 'good' and 'poor' samples, respectively (p = 0.041). CONCLUSIONS: A 'good' sample obtained by DRE provides comparable results to samples obtained by patients. This creates potential benefit in speed and ease of testing for patients. However, not all DRE sampling attempts are successful, and the clinician must be satisfied that enough faeces is obtained to wipe adequately into all grooves.

Replicate and repeat faecal immunochemical tests in symptomatic patients: A systematic review.

BACKGROUND: Faecal Immunochemical tests (FITs) in the assessment of patients presenting with symptoms have generally used a single sample. Little evidence pertains to the use of replicate, where a number of tests are done prior to decision-making or repeat FIT, where additional FIT are performed following clinical decision-making. Overwhelmingly, research has focussed on FIT to help identify colorectal cancer (CRC). The aim of this review is to assess the available literature concerning replicate and repeat FIT in symptomatic patients to help generate consensus and guide future research. METHODS: The terms 'faecal immunochemical test' or 'FIT' were combined with 'multiple' or 'repeat'. EMBASE, Medline and PubMed database and other searches were conducted. All papers published in English were included with no exclusion date limits until November 2021. RESULTS: Of the 161 initial papers screened, seven were included for review. Qualitative and quantitative FIT outcomes were assessed in the studies. The primary aims of most related to whether replicate FIT increased diagnostic yield of CRC, with colonoscopy used as the reference standard. One publication assessed the impact of a new COVID-adapted pathway on CRC detection. No consensus on replicate FIT was apparent. Some concluded that FITs may help minimise missed CRC diagnoses: others showed no increase in diagnostic yield of CRC. CONCLUSIONS: Current evidence on replicate and repeat FIT is both minimal and conflicting. FIT is a superb clinical tool, but significant gaps surrounding application remain. Further studies relating to replicate and repeat FIT are required.

Comparison of the QuikRead go® point-of-care faecal immunochemical test for haemoglobin with the FOB Gold Wide® laboratory analyser to diagnose colorectal cancer in symptomatic patients.

OBJECTIVES: Faecal immunochemical testing for haemoglobin (FIT) is used to triage patients for colonic investigations. Point-of-care (POC) FIT devices on the market have limited data for their diagnostic accuracy for colorectal cancer (CRC). Here, a POC FIT device is compared with a laboratory-based FIT system using patient collected samples from the urgent referral pathway for suspected CRC. METHODS: A prospective, observational cohort study. Patients collected two samples from the same stool. These were measured by POC QuikRead go® (Aidian Oy, Espoo, Finland) and laboratory-based FOB Gold Wide® (Sentinel Diagnostics, Italy). Faecal haemoglobin <10 µg haemoglobin/g of faeces was considered as negative. At this threshold, comparisons between the two systems were made by calculating percentage agreement and Cohen's kappa coefficient. Proportion of negative results were compared with Chi squared testing. Sensitivities for CRC were calculated. RESULTS: A total of 629 included patients provided paired samples for FIT to compare the QuikRead go® and FOB Gold Wide®. The agreement around the negative threshold was 83.0% and Cohen's kappa coefficient was 0.54. The QuikRead go® reported 440/629 (70.0% of samples) as negative compared to 523/629 (83.1%) for the FOB Gold Wide®, this difference was significant (p-value<0.001). Sensitivities for CRC detection by the QuikRead go® and FOB Gold Wide® were 92.9% (95% confidence interval (CI): 68.5-98.7%) and 100% (CI: 78.5-100%) respectively. CONCLUSIONS: Both systems were accurate in their ability to detect CRC. Whilst good agreement around the negative threshold was identified, more patients would be triaged to further colonic investigation if using the QuikRead go®.

Determinants of Shielding Behavior During the COVID-19 Pandemic and Associations With Well-being Among National Health Service Patients: Longitudinal Observational Study.

BACKGROUND: The UK National Health Service (NHS) classified 2.2 million people as clinically extremely vulnerable (CEV) during the first wave of the 2020 COVID-19 pandemic, advising them to "shield" (to not leave home for any reason). OBJECTIVE: The aim of this study was to measure the determinants of shielding behavior and associations with well-being in a large NHS patient population for informing future health policy. METHODS: Patients contributing to an ongoing longitudinal participatory epidemiology study (Longitudinal Effects on Wellbeing of the COVID-19 Pandemic [LoC-19], n=42,924) received weekly email invitations to complete questionnaires (17-week shielding period starting April 9, 2020) within their NHS personal electronic health record. Question items focused on well-being. Participants were stratified into four groups by self-reported CEV status (qualifying condition) and adoption of shielding behavior (baselined at week 1 or 2). The distribution of CEV criteria was reported alongside situational variables and univariable and multivariable logistic regression. Longitudinal trends in physical and mental well-being were displayed graphically. Free-text responses reporting variables impacting well-being were semiquantified using natural language processing. In the lead up to a second national lockdown (October 23, 2020), a follow-up questionnaire evaluated subjective concern if further shielding was advised. RESULTS: The study included 7240 participants. In the CEV group (n=2391), 1133 (47.3%) assumed shielding behavior at baseline, compared with 633 (13.0%) in the non-CEV group (n=4849). CEV participants who shielded were more likely to be Asian (odds ratio [OR] 2.02, 95% CI 1.49-2.76), female (OR 1.24, 95% CI 1.05-1.45), older (OR per year increase 1.01, 95% CI 1.00-1.02), living in a home with an outdoor space (OR 1.34, 95% CI 1.06-1.70) or three to four other inhabitants (three: OR 1.49, 95% CI 1.15-1.94; four: OR 1.49, 95% CI 1.10-2.01), or solid organ transplant recipients (OR 2.85, 95% CI 2.18-3.77), or have severe chronic lung disease (OR 1.63, 95% CI 1.30-2.04). Receipt of a government letter advising shielding was reported in 1115 (46.6%) CEV participants and 180 (3.7%) non-CEV participants, and was associated with adopting shielding behavior (OR 3.34, 95% CI 2.82-3.95 and OR 2.88, 95% CI 2.04-3.99, respectively). In CEV participants, shielding at baseline was associated with a lower rating of mental well-being and physical well-being. Similar results were found for non-CEV participants. Concern for well-being if future shielding was required was most prevalent among CEV participants who had originally shielded. CONCLUSIONS: Future health policy must balance the potential protection from COVID-19 against our findings that shielding negatively impacted well-being and was adopted in many in whom it was not indicated and variably in whom it was indicated. This therefore also requires clearer public health messaging and support for well-being if shielding is to be advised in future pandemic scenarios.

Diagnostic accuracy of point of care faecal immunochemical testing using a portable high-speed quantitative analyser for diagnosis in 2-week wait patients.

AIM: Laboratory-based faecal immunochemical testing (FIT) is the gold standard for detecting the presence of blood in the stool. The aim was to perform a diagnostic accuracy study to confirm if a point of care (POC) analyser for FIT could be safely used as an adjunct in the triage and management of 2-week wait (TWW) colorectal patients. METHODS: The Point of Care Faecal Immunochemical Testing (POC FIT) prospective observational cohort study was designed for TWW patients at a regional referral centre. Between July 2019 and March 2020, patients were invited to perform and bring a FIT sample to clinic. FIT was completed within the clinic appointment using a POC quantitative analyser that has a 2-min processing time (QuikRead go®). Patients and clinicians were blinded to results within the clinic appointment. The results were compared with subsequent diagnostic outcomes. Faecal haemoglobin of <10 µg haemoglobin/g of faeces was considered a negative result. Sensitivities for colorectal cancer (CRC) and combined serious bowel disease (SBD) were calculated using this pre-determined cut-off. RESULTS: A total of 553 patients were included for analytical comparison with diagnostic outcomes. There were 14 (2.5%) patients with CRC and 52 (9.4%) with SBD. The sensitivities for CRC and SBD were 92.9% (95% CI 68.5%-98.7%) and 76.9% (95% CI 63.9%-86.3%) respectively. 379 (68.5%) patients had a negative FIT result (negative predictive value for CRC was 99.7%). CONCLUSIONS: This POC FIT device is a useful adjunct to better manage TWW patients. The high observed sensitivity for CRC offers opportunities, within a single consultation, for improved triage and rationalization of investigation for those with bowel symptoms.

Protocolo ERAS® en cirugía colorrectal / ERAS® in Colorectal Surgery

RESUMEN El protocolo de recuperación optimizada Enhanced Recovery After Surgery (ERAS®) en cirugía colo rrectal promueve un retorno más rápido a la función orgánica siguiendo la evidencia de las últimas investigaciones dirigidas a disminuir el estrés quirúrgico. La vía perioperatoria recomendada está per feccionada, es dinámica y se ajusta a las últimas investigaciones basadas en la evidencia para mejorar todos los aspectos de la atención quirúrgica del paciente. En este artículo describiremos los cuatro aspectos de un paciente a quien se le realizará una cirugía colorrectal: preadmisión, preoperatorio, in traoperatorio y posoperatorio El tema recurrente es disminuir el estrés fisiológico general relacionado con la cirugía; para ello, las intervenciones se superponen a lo largo del recorrido que hace el paciente. Utilizando un enfoque multidisciplinario, la adherencia al protocolo ERAS® en cirugía colorrectal cum pliendo con el 70% o más de las intervenciones de ERAS® ha demostrado una reducción del riesgo de muerte relacionada con el cáncer del 42% a los 5 años. Las intervenciones óptimas no solo se determi nan mediante la publicación de investigaciones de alta calidad, sino que la colaboración internacional periódica permite compartir experiencias e investigaciones y estandarizar los cuidados.

ABSTRACT Enhanced Recovery After Surgery (ERAS®) in colorectal surgery is a protocol that promotes quicker return to function. It follows the latest evidence-based research to promote stress reduction related to surgery. The recommended perioperative pathway is fine-tuned, dynamic and in line with the latest evidence-based research to enhance all aspects of the patient's surgical care. We describe the four aspects for a patient undergoing colorectal surgery - pre-admission, pre-operative, intra-operative and post-operative. The running theme is to reduce overall physiological stress related to surgery and interventions overlap throughout the patient's pathway. Using a multidisciplinary approach, adheren ce to ERAS® in colorectal surgery with ≥70 % compliance to the ERAS interventions has shown a risk reduction of 5-year cancer-related death by 42%. The optimum interventions are not only determined through the publication of high-quality research, but regular international collaboration enables expe rience and research to be shared and care standardized.

Assessment of the analytical performance of point-of-care faecal immunochemical tests for haemoglobin.

BACKGROUND: The faecal immunochemical test (FIT) detects the presence of haemoglobin (Hb) in faeces. It is used as a screening tool for colorectal cancer (CRC) and increasingly to triage patients presenting with symptoms of CRC. A number of quantitative point-of-care (POC) FIT systems marketed for professional use and intended for use in a clinical setting are available. Here we reviewed the POC FIT systems available; three (Eurolyser Cube, OC-Sensor iO and QuikRead go) were evaluated to assess their performance against manufacturers' claims and suitability for use in a clinical setting. METHODS: The analytical evaluation of the POC FIT systems was undertaken using Hb lysates, patient samples and an external quality assessment sample. The evaluation focused on linearity, recovery, imprecision, prozone effect, Hb variant detection and suitability for use in a clinical setting. RESULTS: All three POC FIT systems performed to their manufacturer's claims and demonstrated good analytical performance with acceptable linearity, recovery, within- and between-run imprecision. The QuikRead go and OC-Sensor iO were able to accurately detect samples with results above their measuring range. However, because of a prozone effect the Eurolyser Cube gave falsely low results when using high concentrations of Hb. The QuikRead go performed best in the usability assessment due to portability and timeliness of result. CONCLUSION: Each system performed according to their manufacturers' claims. The QuikRead go and OC-Sensor iO are suitable for use. The Eurolyser Cube is not recommended because of the risk of falsely low results.

Adoption of faecal immunochemical testing for 2-week-wait colorectal patients during the COVID-19 pandemic: an observational cohort study reporting a new service at a regional centre.

AIM: The COVID-19 pandemic has resulted in the near-complete loss of routine endoscopy services. We describe a major reorganization of service at a regional referral centre (Royal Surrey NHS Foundation Trust) to manage the crisis. Faecal immunochemical testing (FIT) was implemented for triage to make optimum use of limited diagnostic resources. Consultations were switched from face-to-face to telephone. Our aim was to evaluate the impact FIT had on resource allocation and patient diagnoses in the first 3 months of use. METHOD: All colorectal 2-week-wait patient referrals were posted a pack requesting FIT and notification of telephone consultation. A prepaid envelope was included for return of the samples. At consultation, FIT was incorporated with the presenting symptoms to guide the choice of investigation and triage urgency. FIT ≥10 µg/g was interpreted as positive. Outcome data were collected prospectively and compared with retrospective audit data from prepandemic levels across 3 months. RESULTS: From 26 March 2020 to 2 July 381 patients were referred who were invited to provide FIT samples and underwent telephone consultations. Three hundred and fifty eight FIT samples were returned (94%). Onward referral for colonoscopy reduced from 62% to 34% (P < 0.001). There were 14 colorectal cancers (CRC) (3.7%) diagnosed, which was not statistically different from the prepandemic level of 3.9% (P = 0.995). Twelve of the 14 patients with a CRC diagnosis had provided samples; all 12 had FIT ≥10 µg/g and were offered fast-track investigations. CONCLUSIONS: The incorporation of FIT optimized the allocation of limited resources to triage those who required urgent colonic investigation for detecting CRC.

"My Voice Counts, Too": Voting Participation Among Individuals With Intellectual Disability.

Despite a strong societal commitment to ensuring that individuals with intellectual disability (ID) fully participate in their communities, few people with ID vote. Little is known about voting experiences from the perspective of people with ID. In-person, semistructured interviews were conducted with 28 adults with ID (Mage = 37 years) to obtain their input on voting. Constant comparison and content analysis methods were used to characterize themes. Results indicated that people with ID are interested in voting and desire to be included in the voting process yet receive little education on political issues or on how to make voting-related decisions. Support from family or service providers and self-advocacy facilitated their ability to vote. Implications of these findings and recommendations for future research are discussed.

A Direct Comparison of Self-Injurious and Stereotyped Motor Behavior Between Preschool-Aged Children With and Without Developmental Delays.

OBJECTIVE: To compare the prevalence of self-injurious behavior (SIB) and stereotyped motor behavior (STY) of preschool-aged children with developmental delays (DD group) and their peers without developmental delays (TD group) using a standardized caregiver report scale. METHODS: The Repetitive Behavior Scale-Revised was completed by caregivers of children with developmental delays and their peers without developmental delays. Frequency of occurrence and severity ratings for SIB and STY were compared between groups. RESULTS: SIB and STY were reported more often and at a greater level of severity in the DD group. Older chronological age was associated with more severe STY in the DD group but not the TD group. Gender was not related to STY or SIB for either group. CONCLUSIONS: Differences in STY and SIB were evident between preschoolers with and without DD. Findings are discussed from developmental and behavioral psychology perspectives regarding the expression of repetitive behavior in developmentally at-risk pediatric populations.

A practical approach to classifying and managing feeding difficulties.

Many young children are thought by their parents to eat poorly. Although the majority of these children are mildly affected, a small percentage have a serious feeding disorder. Nevertheless, even mildly affected children whose anxious parents adopt inappropriate feeding practices may experience consequences. Therefore, pediatricians must take all parental concerns seriously and offer appropriate guidance. This requires a workable classification of feeding problems and a systematic approach. The classification and approach we describe incorporate more recent considerations by specialists, both medical and psychological. In our model, children are categorized under the 3 principal eating behaviors that concern parents: limited appetite, selective intake, and fear of feeding. Each category includes a range from normal (misperceived) to severe (behavioral and organic). The feeding styles of caregivers (responsive, controlling, indulgent, and neglectful) are also incorporated. The objective is to allow the physician to efficiently sort out the wide variety of conditions, categorize them for therapy, and where necessary refer to specialists in the field.

Large gallstone impaction at a Meckel's diverticulum causing perforation and localized peritonitis: report of a case.

We are reporting a successful laparoscopic resection of a perforated Meckel's Diverticulum (MD) causing localized peritonitis due to an impacted gallstone. MD is a small benign pouch on the wall of the small intestine that is present in ∼2% of the population. It results from a failure of complete obliteration of the omphalomesenteric duct. MD is mainly lined by ileal mucosa; however, other ectopic tissue types can be found including gastric, duodenal, colonic, pancreatic, Brunner's glands, hepatobiliary tissue and endometrial mucosa. Most reported complications include bleeding, infection and obstruction. With relevance to this report, we can find no more than two reports of a large gallstone impacting the neck of the MD and causing ileus, and we were unable to find any reports that mention perforation due to impaction at the neck of an MD.

Assessment of the prerequisite skills for cognitive behavioral therapy in children with and without autism spectrum disorders.

The purpose of this study was to assess the cognitive skills of children with autism spectrum disorders (ASD) thought to be necessary for Cognitive Behavioral Therapy (CBT). Forty children with ASD and forty age-matched typically developing children between the ages of 7-12 years participated. Groups were comparable with regard to nonverbal IQ, but children with ASD had significantly lower verbal IQ. Children completed three CBT-related tasks requiring emotion recognition, discrimination among thoughts, feelings and behaviors, and cognitive mediation. With the exception of the emotion recognition task, children with ASD performed comparably to typically developing children and with a high rate of accuracy.

Self-injury among a community cohort of young children at risk for intellectual and developmental disabilities.

OBJECTIVE: To identify risk factors for self-injurious behavior in young children with developmental delay and to determine whether that group is also more likely to exhibit other challenging behaviors. STUDY DESIGN: A retrospective chart review of 196 children < 6 years of age referred for comprehensive neurodevelopmental evaluations. We analyzed child developmental level, receptive and expressive communication level, mobility, visual and auditory impairment, and co-morbid diagnoses of cerebral palsy, seizure disorders, and autism. RESULTS: Sixty-three children (32%; mean age = 42.7 mo, 63% male) were reported to engage in self-injurious behavior at the time of the evaluation. Children with and without self-injurious behavior did not differ on overall developmental level, expressive or receptive language level, mobility status or sensory functioning, or in rates of identification with cerebral palsy, seizure disorders, or autism. However, the self-injurious behavior group was rated significantly higher by parents on destructive behavior, hurting others, and unusual habits. CONCLUSIONS: Although self-injurious behavior was reported to occur in 32% of the cohort, the modal frequency was monthly/weekly and the severity was low. No significant differences were found for risk markers reported for adults, adolescents, and older children with intellectual and developmental disabilities. However, self-injurious behavior was comorbid with other behavior problems in this sample.

Stressful social interactions experienced by adults with mild intellectual disability.

Adults with intellectual disability are vulnerable to stressful social interactions. We determined frequency and severity of various stressful social interactions, identified the social partners in these interactions, and examined the specific interpersonal skill difficulties of 114 adults with mild intellectual disability. Participants' characteristic risk factors for stressful social interactions were also identified. Minor and unintentional negative actions of others had high frequency but low severity of stress. Serious and intentional negative actions of others had a low frequency but high severity of stress. Stressful social interactions with other people who have intellectual disability occurred frequently and had a high severity. Difficulty controlling aggression predicted stressful social interactions. Findings are beneficial to developers of interventions to decrease stressful social interactions.

Depression in adults with mild intellectual disability: role of stress, attributions, and coping.

The experience of stressful social interactions, negative causal attributions, and the use of maladaptive coping efforts help maintain depression over time in the general population. We investigated whether a similar experience occurs among adults with mild intellectual disability. We compared the frequency and stress impact of such interactions, identified causal attributions for these interactions, and determined the coping strategies of 47 depressed and 47 nondepressed adults with mild intellectual disability matched on subject characteristics. The depressed group reported a higher frequency and stress impact of stressful social interactions, more negative attribution style, and more avoidant and less active coping strategies did than the nondepressed group. Findings have implications for theory building and development of psychotherapies to treat depression.

Coping Strategies of Adults with Mild Intellectual Disability for Stressful Social Interactions.

Adults with mild intellectual disability (ID) experience stressful social interactions and often utilize maladaptive coping strategies to manage these interactions. We investigated the specific types of Active and Avoidant coping strategies reported by 114 adults with mild ID to deal with stressful social interactions. Open-ended responses to a sentence stem task were coded into five dimensions of Active and Avoidant coping. Adults with mild ID used Problem-Focused coping most frequently and this strategy was negatively correlated with psychological distress. Emotion-Focused coping was used infrequently but was also negatively related to psychological distress. Coping accounted for a significant portion of variance in psychological distress after controlling for perceptions of stressful social interactions. Findings have important implications for informing the development of interventions to enhance the ability of adults with mild ID to cope with stressful social interactions.