Rethinking drug design in the artificial intelligence era

Artificial intelligence (AI) tools are increasingly being applied in drug discovery. While some protagonists point to vast opportunities potentially offered by such tools, others remain sceptical, waiting for a clear impact to be shown in drug discovery projects. The reality is probably somewhere in-between these extremes, yet it is clear that AI is providing new challenges not only for the scientists involved but also for the biopharma industry and its established processes for discovering and developing new medicines. This article presents the views of a diverse group of international experts on the 'grand challenges' in small-molecule drug discovery with AI and the approaches to address them

Surveillance biopsies in children post-kidney transplant

Surveillance biopsies are increasingly used in the post-transplant monitoring of pediatric renal allograft recipients. The main justification for this procedure is to diagnose early and presumably modifiable acute and chronic renal allograft injury. Pediatric recipients are theoretically at increased risk for subclinical renal allograft injury due to their relatively large adult-sized kidneys and their higher degree of immunological responsiveness. The safety profile of this procedure has been well investigated. Patient morbidity is low, with macroscopic hematuria being the most common adverse event. No patient deaths have been attributed to this procedure. Longitudinal surveillance biopsy studies have revealed a substantial burden of subclinical immunological and non-immunological injury, including acute cellular rejection, interstitial fibrosis and tubular atrophy, microvascular lesions and transplant glomerulopathy. The main impediment to the implementation of surveillance biopsies as the standard of care is the lack of demonstrable benefit of early histological detection on long-term outcome. The considerable debate surrounding this issue highlights the need for multicenter, prospective, and randomized studies

Leading through agonistic conflict: Contested sense-making in national political arenas

This article examines the social processes of political leadership in situations of contest and conflict, taking place within a key and long-established democratic institution, the UK Parliament. The empirical focus is on leadership in House of Commons select committees, which are concerned with holding the government to account. Headlines and media scrutiny, combined with internal challenge from the cross-party mix of politicians on the committees and a range of external stakeholders, create leadership challenges for committee chairs. The study is of two committee inquiries led by the same committee chair, which occurred concurrently and in real time, thereby providing a rare comparative study of leadership through the same leader at the same time but with different leadership challenges. Rather than shying away from conflict, as does much of the leadership literature, this research highlights how leaders who actively engage in challenge and conflict can build a degree of shared purpose among diverse groups of stakeholders. It examines and combines, in theory elaboration, two theories relevant to understanding these leadership processes: agonistic pluralism with its role in creating respectful conflictual consensus, and the theory of sense-making and sense-giving. The two cases (the two inquiries) had different trajectories and reveal how the chair recognised and dealt with conflict to achieve sense-making outcomes across divergent interests and across political parties. There are implications not only for understanding political leadership but also more widely for leadership where there are diverse and sometimes conflicting interests

Anchoring of proteins to lactic acid bacteria

The anchoring of proteins to the cell surface of lactic acid bacteria (LAB) using genetic techniques is an exciting and emerging research area that holds great promise for a wide variety of biotechnological applications. This paper reviews five different types of anchoring domains that have been explored for their efficiency in attaching hybrid proteins to the cell membrane or cell wall of LAB. The most exploited anchoring regions are those with the LPXTG box that bind the proteins in a covalent way to the cell wall. In recent years, two new modes of cell wall protein anchoring have been studied and these may provide new approaches in surface display. The important progress that is being made with cell surface display of chimaeric proteins in the areas of vaccine development and enzyme- or whole-cell immobilisation is highlighted.

Utilization of a mobile medical van for delivering pediatric care in the bateys of the Dominican Republic

Background Bateys are impoverished areas of housing for migrant Haitian sugar cane workers in the Dominican Republic (DR). In these regions, preventative health care is almost non-existent, public service accessibility is limited, and geographic isolation prevents utilization of care even by those families with resources. Consequently, the development of a viable mobile system is vital to the delivery of acute and preventative health care in this region. Aims This study evaluated an existing mobile medical system. The primary goal was to describe the population served, diseases treated, and resources utilized. A secondary goal was to determine qualitatively an optimal infrastructure for sustainable health care delivery within the bateys. Methods Information on basic demographic data, diagnosis, chronicity of disease, and medications dispensed was collected on all pediatric patients seen in conjunction with an existing mobile medical system over a 3-month period in the DR. Health statistics for the region were collected and interviews were conducted with health care workers (HCWs) and community members on existing and optimal health care infrastructure. Results Five hundred eighty-four pediatric patients were evaluated and treated. Median age was 5 years (range 2 weeks to 20 years), and 53.7% of patients seen were 5 years of age or younger. The mean number of complaints per patient was 2.8 (range 0 to 6). Thirty-six percent (373) of all diagnoses were for acute complaints, and 64% (657) were chronic medical problems. The most common pediatric illnesses diagnosed clinically were gastrointestinal parasitic infection (56.6%), skin/fungal infection (46.2%), upper respiratory tract infections (URIs) (22.8%), previously undiagnosed asthma and allergies (8.2%), and symptomatic anemia (7.2%). Thirty HCWs and community members were interviewed, and all cited the need for similar resources: a community clinic and hospital referral site, health promoters within each community, and the initiation of pediatric training for community HCWs. Conclusion A mobile medical system is a sustainable, efficient mechanism for delivering acute and preventive care in the Haitian bateys of the Dominican Republic. The majority of patients served were 8 years of age or younger with multiple presenting symptoms. A pediatric protocol for identifying the most appropriate drugs and supplies for mobile units in the DR can be created based upon diseases evaluated. Qualitative data from HCWs and community members identified the need for an integrative health care delivery infrastructure and community health promoters versed in pediatric care who can aid in education of batey members and monitor chronic and acute illnesses. We are planning follow-up visits to implement these programs

An evaluation of alcohol attendances to an inner city emergency department before and after the introduction of the UK Licensing Act 2003

Background: The Licensing Act 2003 (The Act) was implemented on the 24th November 2005 across England and Wales. The Act allowed more flexible and longer opening hours for licensed premises. We investigated the effect of The Act on alcohol related attendances to an inner city emergency department in Birmingham, UK. \ud \ud Methods: We compared the proportion and time of alcohol related emergency department attendances in one week periods in January 2005 and 2006, before and after the implementation of The Licensing Act 2003. An alcohol related attendance was defined as any attendance where there was any documentation of the patient having consumed alcohol before presenting to the emergency department, if they appeared intoxicated on examination, or if alcohol attributed to their final diagnosis. \ud \ud Results: The total weekly attendances increased slightly from 1,912 in 2005 to 2,146 in 2006. There was non-significant reduction in the proportion of alcohol related attendances between 2005 (3.6%) and 2006 (2.9%). A significantly greater proportion of attendances occurred at the weekend between 18.00 and 23.59 in 2005 (61.4%) than in 2006 (17.2%). There was a corresponding significant increase in the weekend proportion of attendances occurring between 03.00 to 05.59 in 2006. \ud \ud Conclusion: Our findings show that there was a change in the pattern of alcohol related attendances to the emergency department around the time of implementation of the Licensing Act 2003, which has implications for delivery of emergency department services

Insulin Resistance and Body Fat Distribution in South Asian Men Compared to Caucasian Men

South Asians are susceptible to insulin resistance even without obesity. We examined the characteristics of body fat content, distribution and function in South Asian men and their relationships to insulin resistance compared to Caucasians.Twenty-nine South Asian and 18 Caucasian non-diabetic men (age 27+/-3 and 27+/-3 years, respectively) underwent euglycemic-hyperinsulinemic clamp for insulin sensitivity, underwater weighing for total body fat, MRI of entire abdomen for intraperitoneal (IP) and subcutaneous abdominal (SA) fat and biopsy of SA fat for adipocyte size.Compared to Caucasians, in spite of similar BMI, South Asians had higher total body fat (22+/-6 and 15+/-4% of body weight; p-value<0.0001), higher SA fat (3.5+/-1.9 and 2.2+/-1.3 kg, respectively; p-value = 0.004), but no differences in IP fat (1.0+/-0.5 and 1.0+/-0.7 kg, respectively; p-value = 0.4). SA adipocyte cell size was significantly higher in South Asians (3491+/-1393 and 1648+/-864 microm2; p-value = 0.0001) and was inversely correlated with both glucose disposal rate (r-value = -0.57; p-value = 0.0008) and plasma adiponectin concentrations (r-value = -0.71; p-value<0.0001). Adipocyte size differences persisted even when SA was matched between South Asians and Caucasians.Insulin resistance in young South Asian men can be observed even without increase in IP fat mass and is related to large SA adipocytes size. Hence ethnic excess in insulin resistance in South Asians appears to be related more to excess truncal fat and dysfunctional adipose tissue than to excess visceral fat

Quality of Life in Men With Prostate Cancer Randomly Allocated to Receive Docetaxel or Abiraterone in the STAMPEDE Trial

PURPOSE: Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices. METHODS: A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints. RESULTS: Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2; P = .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5; P < .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0; P = .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6; P < .001). CONCLUSION: Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment

Seasonality in depressive and anxiety symptoms among primary care patients and in patients with depressive and anxiety disorders; results from the Netherlands Study of Depression and Anxiety

<p>Abstract</p> <p>Background</p> <p>Little is known about seasonality of specific depressive symptoms and anxiety symptoms in different patient populations. This study aims to assess seasonal variation of depressive and anxiety symptoms in a primary care population and across participants who were classified in diagnostic groups 1) healthy controls 2) patients with a major depressive disorder, 3) patients with any anxiety disorder and 4) patients with a major depression and any anxiety disorder.</p> <p>Methods</p> <p>Data were used from the Netherlands Study of Depression and Anxiety (NESDA). First, in 5549 patients from the NESDA primary care recruitment population the Kessler-10 screening questionnaire was used and data were analyzed across season in a multilevel linear model. Second, in 1090 subjects classified into four groups according to psychiatric status according to the Composite International Diagnostic Interview, overall depressive symptoms and atypical versus melancholic features were assessed with the Inventory of Depressive Symptoms. Anxiety and fear were assessed with the Beck Anxiety Inventory and the Fear questionnaire. Symptom levels across season were analyzed in a linear regression model.</p> <p>Results</p> <p>In the primary care population the severity of depressive and anxiety symptoms did not show a seasonal pattern. In the diagnostic groups healthy controls and patients with any anxiety disorder, but not patients with a major depressive disorder, showed a small rise in depressive symptoms in winter. Atypical and melancholic symptoms were both elevated in winter. No seasonal pattern for anxiety symptoms was found. There was a small gender related seasonal effect for fear symptoms.</p> <p>Conclusions</p> <p>Seasonal differences in severity or type of depressive and anxiety symptoms, as measured with a general screening instrument and symptom questionnaires, were absent or small in effect size in a primary care population and in patient populations with a major depressive disorder and anxiety disorders.</p

Clinical characteristics of cyclodeviation

PURPOSE: To retrospectively evaluate the incidence of cyclodeviation among patients with diplopia and analyse the causative diseases and clinical manifestations of cyclodeviation. METHODS: The medical records of 266 consecutive patients of 15 years of age or older presenting with diplopia, who had undergone the Lancaster red-green test (LRGT) from January 2001 to December 2002, were retrospectively reviewed. The presence of cyclodeviation on LRGT, predisposing conditions, causative diseases, and clinical manifestations of cyclotropia were analysed. Cyclodeviation on the LRGT were compared with those from the Maddox double-rod test (MDRT) and fundus photography. RESULTS: A total of 63 (24%) out of 266 patients exhibited cyclodeviation on LRGT. Eight out of 63 patients with cyclodeviation on the LRGT complained of torsional diplopia. Superior oblique palsy (SOP) was the most common causative disease (42 patients), followed by skew deviation (six) and thyroid orbitopathy (three). Excyclodeviation was found in 57 patients and incyclodeviation in four patients on the LRGT. The spontaneous recovery rate was 83% in patients of vascular origin and 17% of traumatic origin. Cyclodeviation with the MDRT and fundus photography showed good correlation with those obtained from the LRGT. There was no association of the amount of cyclotropia with the presence of torsional diplopia as well as with its recovery. CONCLUSION: In spite of the rare complaint of torsional diplopia, 24% of the patients with diplopia showed cyclodeviation on the LRGT. SOP was the most common causative disease. Most of the patients with cyclodeviation of a vascular origin showed spontaneous improvement