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Biomedical subjects

John Dean

Publications and source records attributed to John Dean.

12 recordsLinked to original sources
PubMed2025

Utility of genome sequencing and group-enrichment to support splice variant interpretation in Marfan syndrome.

PURPOSE: To quantify the impact of noncanonical FBN1 splice site variants in undiagnosed Marfan syndrome (MFS), a connective tissue disorder associated with skeletal abnormalities and familial thoracic aortic aneurysm disease (FTAAD). METHODS: A systematic analysis of ultrarare FBN1 variants was performed using genome sequencing data from the 100,000 Genomes Project. Variants were annotated with SpliceAI and the significance of enrichment among individuals with FTAAD was assessed using Fisher's exact test. Experimental validation used RNA sequencing, reverse transcriptase polymerase chain reaction, minigene constructs, and replication analysis was with data from UK Biobank. RESULTS: Using aggregate data for 78,195 individuals, we identified 13,864 singleton single-nucleotide variants in FBN1 of which 21 were predicted to affect splicing (SpliceAI > 0.5). Incidence of candidate splice variants in individuals recruited with FTAAD (9/703) was significantly elevated compared with that seen in non-FTAAD participants (12/77,492; odds ratio = 84, P = 9.7 × 10-14). Additional analysis uncovered a further 14 families harboring 11 different FBN1 splice variants. A total of 20 candidate splice variants in 23 families were identified, of which 70% lay beyond the ±8 splice regions. RNA testing confirmed the predicted splice aberration in 16 of 20 and for 9 of 20, pseudoexonization was the likely splicing anomaly. CONCLUSION: Our findings indicate that noncanonical splice variants may account for approximately 3% of families with undiagnosed FTAAD, highlighting the importance of incorporating analysis of introns and confirmatory RNA testing into genetic testing for Marfan syndrome.

Humans↗
PubMed2006

Topical eutectic mixture for premature ejaculation (TEMPE): a novel aerosol-delivery form of lidocaine-prilocaine for treating premature ejaculation.

OBJECTIVE: To evaluate, in a phase II study, the efficacy and safety of a topical eutectic mixture for premature ejaculation (TEMPE), a metered-dose aerosol spray containing a eutectic mixture of lidocaine and prilocaine, as a treatment for PE. PATIENTS AND METHODS: Men with PE (Diagnostic and Statistical Manual-IV definition) aged 18-75 years were randomized into a double-blind, placebo-controlled study in the UK and the Netherlands. Efficacy variables included the mean change in intravaginal ejaculatory latency time (IELT) from baseline and the proportion of patients who achieved an IELT of > or = 4, > or = 3 or > or = 2 min on two occasions, and the effect of TEMPE on the index of ejaculatory control (IEC) and sexual quality-of-life (SQoL) scores of patients and their partners. Safety and adverse event data were also collected. Fifty-four patients were randomized and received study treatment. RESULTS: The observed mean change in IELT from baseline to the end of the treatment period was 3.8 min in the TEMPE group and 0.7 min in the placebo group, and when adjusted for baseline and centre was 2.4 times higher in the TEMPE than the placebo group (P < 0.01). The efficacy of TEMPE in increasing IELT was further supported by positive trends in the other efficacy endpoints. The proportion of men who had an IELT time > or = 2, > or = 3 or > or = 4 min on two occasions after treatment was 11/20 (55%), 8/20 (40%) and 5/25 (20%) in the TEMPE group, and 8/23 (35%), 3/23 (13%) and 3/23 (13%) in the placebo group, respectively, although these differences were not statistically significant. Improvements in IEC and SQoL (male and female) scores also showed trends towards greater efficacy for TEMPE than placebo. In all, 35 of 42 (83%) patients considered the spray easy to use. Mild to moderate local numbness occurred in three (12%) of the TEMPE-treated patients but did not lead to discontinuation. CONCLUSION: Topical treatment with TEMPE produced a statistically and clinically significant increase in IELT compared with placebo, and resulted in positive trends in ejaculatory control and SQoL. TEMPE was considered easy to use and was well tolerated. The data support the conduct of further large-scale studies to establish the utility of TEMPE as a first-line treatment for PE.

Administration, Topical↗
PubMed2006

Psychosocial outcomes and drug attributes affecting treatment choice in men receiving sildenafil citrate and tadalafil for the treatment of erectile dysfunction: results of a multicenter, randomized, open-label, crossover study.

INTRODUCTION: Although sildenafil citrate (sildenafil) and tadalafil are efficacious and well-tolerated treatments for erectile dysfunction (ED), preference studies have shown that patients may favor one medication over the other. AIM: To determine whether psychosocial outcomes differed when men with ED received tadalafil compared with sildenafil. MAIN OUTCOME MEASURES: Measures included a treatment preference question, Psychological and Interpersonal Relationship Scales (PAIRS), and Drug Attribute Questionnaire. METHODS: Randomized, open-label, crossover study. After a 4-week baseline, men with ED (N = 367; mean age = 54 years; naïve to type 5 phosphodiesterase inhibitor therapy) were randomized: tadalafil for 12 weeks then sildenafil for 12 weeks or vice versa (8-week dose optimization/4-week assessment phases). During dose optimization, patients started with 10 mg tadalafil, or 25 or 50 mg sildenafil and could titrate to their optimal dose (10 or 20 mg tadalafil; 25, 50, or 100 mg sildenafil). Medications were taken as needed. Patients completing both 12-week periods chose which medication to continue during an 8-week extension. RESULTS: Of 291 men completing both treatment periods, 71% (N = 206) chose tadalafil and 29% (N = 85) chose sildenafil (P < 0.001) for the 8-week extension. When taking tadalafil compared with sildenafil men had higher mean endpoint scores on PAIRS Sexual Self-Confidence (tadalafil = 2.91 vs. sildenafil = 2.75; P < 0.001) and Spontaneity (tadalafil = 3.32 vs. sildenafil = 3.17; P < 0.001) Domains and a lower mean endpoint score on Time Concerns Domain (tadalafil = 2.2 vs. sildenafil = 2.59; P < 0.001). The two most frequently chosen drug attributes to explain treatment preference were ability to get an erection long after taking the medication and firmness of erections. Tadalafil and sildenafil were well tolerated with 12 (3.3%) patients discontinuing for an adverse event. CONCLUSIONS: As measured with PAIRS, men with ED had higher sexual self-confidence and spontaneity and less time concerns related to sexual encounters when treated with tadalafil compared with sildenafil. These psychosocial outcomes may help explain why more men (71%) preferred tadalafil for the treatment of ED in this clinical trial.

Adult↗
PubMed2005

Characterisation, prevalence, and consultation rates of erectile dysfunction.

Erectile dysfunction (ED), assessed clinically by tools such as the International Index of Erectile Function (IIEF), affects millions of men across the world. Around 10-25% of men of all ages are affected rising to 20-45% in older age groups. Different definitions of ED and selection of different patient populations account for much of the variability reported in epidemiological surveys. Ageing populations in the developed world and growing populations in the developing world make it likely that the prevalence of ED will increase in the future. ED affects quality of life, and the condition may result in outcomes such as anxiety and withdrawal from a relationship. The condition remains a source of embarrassment for many men and health professionals, and it remains under-reported, under-recognized, and undertreated. Adequate medical assessment and intervention are needed to address ED.

Age Factors↗
PubMed2005

Current perspectives on the clinical assessment and diagnosis of female sexual dysfunction and clinical studies of potential therapies: a statement of concern.

INTRODUCTION: The assessment and diagnosis of female sexual dysfunction (FSD) are in a state of transition because of evolving concepts of female sexuality and suggested changes to the FSD diagnostic framework. AIM: To review the problems with current FSD diagnosis. METHODS: Multidisciplinary experts from five countries were assembled to convene a "Postmenopausal FSD Roundtable on specific topics related to FSD." MAIN OUTCOME MEASURE: Expert opinion was based on a review of evidence-based medical literature, presentation, and internal discussion. RESULTS: Current FSD diagnosis is challenging because of poorly defined distinctions between normal and abnormal, a limited ability to integrate subjective and objective findings and an inability to incorporate contextual factors that play a significant role in sexual behavior. The availability of self-administered questionnaires (SAQs) that assess various domains of female sexual function, as well as those developed specifically for postmenopausal women, suggests that a more structured approach to assessment and diagnosis may be possible. Several SAQs reflecting proposed changes to the FSD diagnostic framework by the American Foundation for Urologic Disease (AFUD), including the Sexual Function Questionnaire (SFQ) and the Female Sexual Distress Scale (FSDS), have been introduced and recently incorporated into a Structured Diagnostic Method (SDM). Recent regulatory decisions and events affecting the development of FSD interventions have highlighted the lack of consensus with regard to clinically meaningful FSD outcomes, as well as shortcomings in a U.S. Food and Drug Administration draft document that provides the primary guidance for conducting FSD clinical studies in the United States. CONCLUSIONS: Given the high cost and inherent risk of clinical studies, continued development efforts toward FSD therapies are unlikely to proceed in the absence of significant changes in regulatory guidance that reflect the current understanding of FSD and incorporate validated assessment tools.

Clinical Trials as Topic↗
PubMed2005

Ethical aspects of sexual medicine.

INTRODUCTION: Ethics describe the ways in which moral life is understood. Morality comprises norms for human conduct, and addresses what is right and what is wrong. AIM: To provide a consensus-based summary of the ethical aspects of sexual medicine. METHODS: Over 200 multidisciplinary specialists from 60 countries were divided into 17 consultation committees as part of a process organized by an international consultation on sexual medicine held in Paris, June 28-July 1, 2003 in close alliance with several sexual medicine organizations. Embarking on a study on ethics in sexual medicine, 10 experts from eight countries assembled over a two-year period to develop this consensus-based summary. MAIN OUTCOME MEASURE: Although ethics are recognized as subjective, expert opinion was based on grading of evidence-based medical literature, in addition to cultural and ethical considerations. The process also involved extensive internal committee discussion, public presentation, and debate. RESULTS: Contemporary medical practitioners provide health care for patients from many different cultures from all around the world. Thus, it is recommended that all health professionals working in sexual medicine should above all be able to demonstrate respect, understanding, and tolerance toward the differing moral worldviews of their patients and colleagues, and the societies they represent. In sexual medicine, health professionals have an obligation to respect the autonomy of any individual that they treat, regardless of that individual's religious or socio-cultural tradition, race, gender, or sexual orientation. Sexual rights are a necessary condition for sexual health. Sexual health requires a positive and respectful approach to sexuality and sexual relationships as well as the possibility of having pleasurable and safe sexual experiences, free of coercion, discrimination, and violence. For sexual health to be attained and maintained, the sexual rights of all persons must be respected, protected, and fulfilled. CONCLUSIONS: Additional discussion and research on ethics in sexual medicine is needed.

Cultural Diversity↗
PubMed2004

Canadian 2003 International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema.

C1 inhibitor deficiency (hereditary angioedema [HAE]) is a rare disorder for which there is a lack of consensus concerning diagnosis, therapy, and management, particularly in Canada. European initiatives have driven the approach to managing HAE with 3 C1-INH Deficiency Workshops held every 2 years in Hungary starting in 1999, with the third Workshop having recently been held in May 2003. The European Contact Board has established a European HAE Registry that will hopefully advance our knowledge of this disorder. The Canadian Hereditary Angioedema Society/Société d'Angioédème Héréditaire du Canada organized a Canadian International Consensus Conference held in Toronto, Ontario, Canada, on October 24 to 26, 2003, to foster consensus between major European and North American HAE treatment centers. Papers were presented by investigators from Europe and North America, and this consensus algorithm approach was discussed. There is a paucity of double-blind placebo-controlled trials in the treatment of HAE, making levels of evidence to support the algorithm less than optimal. Enclosed is the consensus algorithm approach recommended for the diagnosis, therapy, and management of HAE and agreed to by the authors of this article. This document is only a consensus algorithm approach and requires validation. As such, participants agreed to make this a living 2003 algorithm (ie, a work in progress) and agreed to review its content at future international HAE meetings. The consensus, however, has strength in that it was arrived at by the meeting of patient-care providers along with patient group representatives and individual patients reviewing information available to date and reaching agreement on how to approach the diagnosis, therapy, and management of HAE circa 2003. Hopefully evidence to support approaches to the management of HAE will approach the level of meta-analysis of randomized controlled trials in the near future.

Algorithms↗
PubMed2004

Intensive insulin therapy in type 1 and type 2 diabetes.

Intensive insulin regimens can produce substantial clinical benefits for patients with type 1 and type 2 diabetes, but they are associated with an increased incidence of hypoglycaemia. This article discusses such regimens and whether the risk of hypoglycaemia can be reduced by using the new basal insulin analogue, insulin glargine.

Diabetes Mellitus, Type 1↗
PubMed2004

Subantimicrobial dose doxycycline enhances the efficacy of scaling and root planing in chronic periodontitis: a multicenter trial.

BACKGROUND: Previous studies have shown that subantimicrobial dose doxycycline (SDD) is of clinical benefit in the treatment of chronic periodontitis (CP). The aim of this study was to further assess the role of SDD as an adjunct to scaling and root planing (SRP) in the treatment of CP. METHODS: A double-blind, randomized, placebo-controlled, multicenter clinical study was conducted to test the efficacy of SDD (20 mg doxycycline B.I.D.) in combination with SRP in subjects with moderate to severe CP. Two-hundred ten subjects were treated with a standardized episode of SRP and randomized to receive either adjunctive SDD or placebo for 9 months. Efficacy parameters included per-subject mean changes in clinical attachment level (CAL) and probing depth (PD) from baseline, and the total number of sites with attachment gains and probing depth reductions > or = 2 mm and > or = 3 mm from baseline. RESULTS: In periodontal sites with PD 4 to 6 mm and > or = 7 mm (N = 209, intent-to-treat population), mean improvements in CAL and PD were greater following SRP with adjunctive SDD than SRP with placebo, achieving statistical significance in all baseline disease categories at month 9 (P < 0.05). At month 9, 42.3% of sites in the SDD group demonstrated CAL gain > or = 2 mm compared to 32.0% of sites in the placebo group (P < 0.01). CAL gain > or = 3 mm was seen in 15.4% of sites in the SDD group compared to 10.6% of sites in the placebo group (P < 0.05). When considering the same thresholds of change in PD, 42.9% of sites in the SDD group compared to 31.1% of sites in the placebo group demonstrated PD reduction > or = 2 mm (P < 0.01), and 15.4% of sites in the SDD group compared to 9.1% of sites in the placebo group demonstrated PD reduction > or = 3 mm (P < 0.01). CONCLUSION: Adjunctive subantimicrobial dose doxycycline enhances scaling and root planing. It results in statistically significant attachment gains and probing depth reductions over and above those achieved by scaling and root planing with placebo.

Adult↗