Predicting crystal form stability under real-world conditions.

The physicochemical properties of molecular crystals, such as solubility, stability, compactability, melting behaviour and bioavailability, depend on their crystal form1. In silico crystal form selection has recently come much closer to realization because of the development of accurate and affordable free-energy calculations2-4. Here we redefine the state of the art, primarily by improving the accuracy of free-energy calculations, constructing a reliable experimental benchmark for solid-solid free-energy differences, quantifying statistical errors for the computed free energies and placing both hydrate crystal structures of different stoichiometries and anhydrate crystal structures on the same energy landscape, with defined error bars, as a function of temperature and relative humidity. The calculated free energies have standard errors of 1-2 kJ mol-1 for industrially relevant compounds, and the method to place crystal structures with different hydrate stoichiometries on the same energy landscape can be extended to other multi-component systems, including solvates. These contributions reduce the gap between the needs of the experimentalist and the capabilities of modern computational tools, transforming crystal structure prediction into a more reliable and actionable procedure that can be used in combination with experimental evidence to direct crystal form selection and establish control5.

Transforming Computed Energy Landscapes into Experimental Realities: The Role of Structural Rugosity.

We exploit the possible link between structural surface roughness and difficulty of crystallisation. Polymorphs with smooth surfaces may nucleate and crystallise more readily than polymorphs with rough surfaces. The concept is applied to crystal structure prediction landscapes and reveals a promising complementary way of ranking putative crystal structures.

The importance of configurational disorder in crystal structure prediction: the case of loratadine.

Loratadine, an over-the-counter antihistamine medication, has two known monotropically related polymorphs, both of which feature disorder. A combined experimental and computational approach using variable temperature single crystal X-ray diffraction (VT-SCXRD) analysis and dispersion corrected density functional theory (DFT-D) reveals that the nature of the disorder in each form is markedly different and cannot be described by a simple isolated-site model with thermally populated conformations in either of the two cases. In Form I, the ethyl carbamate functionality adopts two different configurations, with adjacent moieties interacting along one-dimensional chains. The most stable arrangement features alternating configurations, but because of the low energetic cost of stacking faults, the domain sizes are short and an average crystal structure is observed experimentally. The configurational free energy of the disordered structure is lower than the energy of the two corresponding ordered crystal structures, but the energy decrease is dominated by the lower lattice energy of the alternating arrangement with a small entropic contribution. In Form II, the flexible cycloheptane bridge adopts two different configurations. The disorder is not an equilibrium property but is instead frozen-in during the crystallisation process. The configurational free energy of the disordered structure falls in between the lattice energies of the two corresponding ordered structures. The two ordered components of each disordered structure are all found in a crystal structure prediction (CSP) study with the GRACE programme. However, the experimentally observed stability relationship is only reproduced when the energy contribution of disorder is taken into account. The disordered model of Form I is found to be lower in energy than all the other predicted structures and there is no indication of a missing, thermodynamically more stable, form. The case of loratadine demonstrates that experimentally observed disorder close to 50/50 does not necessarily correspond to a free energy decrease by kT ln 2.

The association between Ehlers-Danlos syndrome-hypermobility type and gastrointestinal symptoms in university students: a cross-sectional study.

BACKGROUND: Patients with Ehlers-Danlos syndrome-hypermobility type (EDS-HT) have increased prevalence of gastrointestinal (GI) symptoms, particularly reflux and dyspepsia. EDS-HT is associated with dysautonomia, psychopathology, and chronic pain which can be associated with GI symptoms. The association between GI symptoms and EDS-HT in a 'non-patient' population and the effect of the above-mentioned factors has never been studied. METHODS: In a cross sectional study, a hypermobility questionnaire was used to screen university students; further clinical examination established the diagnosis of EDS-HT. Validated questionnaires assessed for GI, somatic, pain and autonomic symptoms, psychopathology and quality of life (QOL). These were compared in students with and without EDS-HT; logistic regression analysis examined associations between EDS-HT, GI symptoms and other variables. KEY RESULTS: Of 1998 students screened, 162 were included: 74 EDS-HT (21.0 years, 53% female) vs 88 Non-EDS-HT (21.5 years, 65% female). Compared to non-EDS-HT students, EDS-HT students were more likely to have multiple GI symptoms (41.9% vs 27.3% P=.05), particularly postprandial fullness (34.4% vs 15.9%, P=.01) and early satiety (32% vs 17%, P=.03), greater autonomic (P<.001) and somatic symptoms (P=.04) but not psychopathology (P>.8). The association between EDS-HT and postprandial symptoms was dependent on autonomic factors but independent of pain and psychopathology. Pain-related QOL scores were reduced in the EDS-HT group (80 vs 90, P=.03). CONCLUSIONS AND INFERENCES: The previously described association between EDS-HT, dyspepsia, pain and autonomic symptoms in patients is also present in non-patient groups. Future studies are necessary to explore the etiological role of connective tissue in GI and extra intestinal symptoms.

Ehlers-Danlos syndrome.

The Ehlers-Danlos syndromes (EDSs) were originally described by Ehlers in Denmark and Danlos in Paris in 1898 and 1908, respectively. They had both published individual case studies in which the common factor was laxity of ligaments leading to joint hypermobility and hyperextensibility of the skin. The choice of the name of this eponymous disease had been made by Dr Parkes Weber, an eminent London physician in the 1930s, who had a penchant for eponymous diseases, having had no less than seven attributed to himself, at least in part. Unfortunately, this was before the age of a computerised literature search, and Parkes Weber had inadvertently overlooked the very first description of EDS which had been made by Tchernabogov, a Russian dermatologist, whose description was published in 1891 and remains one of the best descriptions of EDS in the literature.

Functional gastrointestinal disorders are associated with the joint hypermobility syndrome in secondary care: a case-control study.

BACKGROUND: The overlap of unexplained gastrointestinal (GI) and somatic symptoms is well established in patients with functional gastrointestinal disorders (FGID). Joint hypermobility syndrome (JHS) is a non-inflammatory connective tissue disorder associated with GI and somatic symptoms. We aimed to determine whether there is an association between diagnosis of JHS and FGID and the impact of this association on comorbidities and quality of life (QOL). METHODS: Prospective case-control study in secondary care GI clinics over 2 years. JHS was assessed by the first author prior to consultation in 641 consecutive new patients. Diagnosis of FGID (cases, n = 336) or organic disorders (controls, n = 305) was established blind to JHS status. JHS prevalence was compared in cases (FGID patients) and controls (organic disorders patients). Extra-intestinal comorbidity and QOL were compared in FGID patients with and without JHS. KEY RESULTS: JHS prevalence was higher in FGID compared to organic GI disorders (39.0% vs 27.5%, ORadj: 1.51, CI: 1.07-2.12, p = 0.02), and particularly associated with functional gastroduodenal disorders (44.1%, ORadj: 2.08, CI: 1.25-3.46, p = 0.005), specifically postprandial distress syndrome (51%, ORadj: 1.99, CI: 1.06-3.76, p = 0.03). FGID patients with JHS had increased chronic pain (23.2% vs 11.9%, p = 0.01), fibromyalgia (10.5% vs 3.1%, p = 0.01), somatization scores (13 vs 10, p < 0.001), urinary autonomic scores (30.5 vs 20.7, p = 0.03), and worse pain-related QOL scores (45.0 vs 63.5, p = 0.004). CONCLUSIONS & INFERENCES: JHS is significantly associated with FGID, and this subgroup of patients have increased comorbidity and decreased QOL. Further research is required to understand the pathophysiological basis of this association.

Lower urinary tract symptoms in women with benign joint hypermobility syndrome: a case-control study.

INTRODUCTION AND HYPOTHESIS: Benign joint hypermobility syndrome (BJHS) is a connective tissue disorder associated with joint hypermobility. BJHS is under-recognised by medical professionals and is poorly managed. The aim of our study was to determine whether lower urinary tract symptoms (LUTS), including urinary incontinence (UI) and anterior compartment prolapse, are more common in women with BJHS than in the normal population. METHODS: This was a prospective case-control study. Women diagnosed with BJHS according to the Brighton criteria were recruited from a tertiary referral clinic. Controls were recruited from hospital personnel. Both groups completed the King's Health Questionnaire (KHQ) and the Prolapse Quality of Life Questionnaire (P-QoL). Objective assessment of pelvic organ prolapse (POP) was undertaken using the Pelvic Organ Prolapse Quantification (POP-Q) system. Analyses were performed using SPSS version 17.0. The statistical difference was analysed using McNemar's test. Comparison of QoL scores was performed with the Wilcoxon signed-rank test. RESULTS: Sixty individuals were recruited and matched with 60 healthy women. The prevalence of UI in those with BJHS was significantly higher than in controls(73.3 % vs. 48.3 %). The impact of UI on QoL was statistically significant in all domains of the KHQ. There was a significant difference between groups in most urinary-specific symptoms of the KHQ. A significant number of women with BJHS suffer from voiding difficulties. Prolapse of the anterior vaginal wall was objectively more severe in those with BJHS. CONCLUSIONS: Women with BJHS have LUTS and anterior compartment prolapse, which significantly impair their QoL. It is important to identify women who are symptomatic. The addition of a systematic active case-finding approach may be more effective in identifying these cases.

Prolapse and sexual function in women with benign joint hypermobility syndrome.

OBJECTIVE: To determine whether pelvic organ prolapse (POP) and sexual dysfunction are more severe in women with benign joint hypermobility syndrome (BJHS) than in the normal population. DESIGN: Case-control study. SETTING: King's College Hospital NHS Foundation Trust, London, UK and University College Hospital, London, UK. POPULATION: Women diagnosed with BJHS (n = 60) at University College Hospital. Control participants (n = 60) recruited from King's College Hospital NHS Foundation Trust. METHODS: Objective assessment of POP was undertaken using the Pelvic Organ Prolapse Quantification System (POP-Q). Both groups were asked to complete the Prolapse quality of life (P-QOL) and pelvic organ prolapse/urinary incontinence sexual (PISQ-12) questionnaires. MAIN OUTCOME MEASURES: Comparison of vaginal anatomy using POP-Q between the two groups. Comparison of P-QOL and PISQ-12 quality of life scores between the two groups. RESULTS: In all, 120 women (60 in Study group, 60 in Control group) were recruited. All women in the study group were matched with healthy control women according to age, parity and ethnicity. There was a statistically significant difference between points Aa, Ba, Ap, Bp and C in study and control groups showing that prolapse is objectively more severe in those with BJHS. Significantly more women with BJHS felt that POP interfered with sex and defecation compared with the control group. The impact of prolapse symptoms on quality of life was statistically different in almost all nine P-QOL domains. CONCLUSIONS: A large number of women with BJHS have prolapse symptoms, which significantly affect their quality of life. POP is more severe in women with BJHS.

Joint hypermobility and rectal evacuatory dysfunction: an etiological link in abnormal connective tissue?

BACKGROUND: Previous studies report an association between joint hypermobility (JHM), as a clinical feature of underlying connective tissue (CT) disorder, and pelvic organ prolapse. However, its association with rectal evacuatory dysfunction (RED) has not been evaluated. To investigate the prevalence of JHM in the general population and in patients with symptoms of RED referred for anorectal physiological investigation. METHODS: Bowel symptom and Rome III questionnaires to detect irritable bowel syndrome were sent to 273 patients with RED. Patients then underwent full investigation, including evacuation proctography. A validated 5-point self-reported questionnaire was used to assess JHM in both the patient group and 100 age- and sex-matched controls [87 female, median age 55 (range 28-87)]. KEY RESULTS: Seventy-three patients were excluded from analysis (incomplete questionnaire or investigation). Of 200, 65 patients [32%: 63 female, median age 52 (range 15-80)] and 14% of controls (P = 0.0005 vs patients) had features satisfying criteria for JHM. Overall constipation score (P < 0.0001), abdominal pain (P = 0.003), need for manual assistance (P = 0.009), and use of laxatives (P = 0.03) were greater in the JHM group than the non-JHM group. On proctography, 56 of JHM patients (86%) were found to have significant morphological abnormalities (e.g. functional rectocoele), compared with 64% of the non-JHM group (P = 0.001). CONCLUSIONS & INFERENCES: The greater prevalence of JHM in patients with symptoms of RED, and the demonstration of significantly higher frequencies of morphological abnormalities than those without JHM, raises the possibility of an important pathoaetiology residing in either an enteric or supporting pelvic floor abnormality of CT.

Unexplained gastrointestinal symptoms and joint hypermobility: is connective tissue the missing link?

BACKGROUND Unexplained gastrointestinal (GI) symptoms and joint hypermobility (JHM) are common in the general population, the latter described as benign joint hypermobility syndrome (BJHS) when associated with musculo-skeletal symptoms. Despite overlapping clinical features, the prevalence of JHM or BJHS in patients with functional gastrointestinal disorders has not been examined. METHODS The incidence of JHM was evaluated in 129 new unselected tertiary referrals (97 female, age range 16-78 years) to a neurogastroenterology clinic using a validated 5-point questionnaire. A rheumatologist further evaluated 25 patients with JHM to determine the presence of BJHS. Groups with or without JHM were compared for presentation, symptoms and outcomes of relevant functional GI tests. KEY RESULTS Sixty-three (49%) patients had evidence of generalized JHM. An unknown aetiology for GI symptoms was significantly more frequent in patients with JHM than in those without (P < 0.0001). The rheumatologist confirmed the clinical impression of JHM in 23 of 25 patients, 17 (68%) of whom were diagnosed with BJHS. Patients with co-existent BJHS and GI symptoms experienced abdominal pain (81%), bloating (57%), nausea (57%), reflux symptoms (48%), vomiting (43%), constipation (38%) and diarrhoea (14%). Twelve of 17 patients presenting with upper GI symptoms had delayed gastric emptying. One case is described in detail. CONCLUSIONS & INFERENCES In a preliminary retrospective study, we have found a high incidence of JHM in patients referred to tertiary neurogastroenterology care with unexplained GI symptoms and in a proportion of these a diagnosis of BJHS is made. Symptoms and functional tests suggest GI dysmotility in a number of these patients. The possibility that a proportion of patients with unexplained GI symptoms and JHM may share a common pathophysiological disorder of connective tissue warrants further investigation.

Joint hypermobility syndrome in childhood. A not so benign multisystem disorder?

OBJECTIVES: Joint hypermobility (JH) or "ligamentous laxity" is felt to be an underlying risk factor for many types of musculoskeletal presentation in paediatrics, and joint hypermobility syndrome (JHS) describes such disorders where symptoms become chronic, often more generalized and associated with functional impairment. Clinical features are felt to have much in common with more severe disorders, including Ehlers-Danlos syndrome (EDS), osteogenesis imperfecta and Marfan syndrome, although this has not been formally studied in children. We defined the clinical characteristics of all patients with joint hypermobility-related presentations seen from 1999 to 2002 in a tertiary referral paediatric rheumatology unit. METHODS: Patients were identified and recruited from paediatric rheumatology clinic and ward, and a dedicated paediatric rheumatology hypermobility clinic at Great Ormond Street Hospital. Data were collected retrospectively on the patients from the paediatric rheumatology clinics (1999-2002) and prospectively on patients seen in the hypermobility clinic (2000-2002). Specifically, historical details of developmental milestones, musculoskeletal or soft tissue diagnoses and symptoms, and significant past medical history were recorded. Examination features sought included measurements of joint and soft tissue laxity, and associated conditions such as scoliosis, dysmorphic features, cardiac murmurs and eye problems. RESULTS: One hundred and twenty-five children (64 females) were included on whom sufficient clinical data could be identified and who had clinical problems ascribed to JH present for longer than 3 months. Sixty-four were from the paediatric rheumatology clinic and 61 from the hypermobility clinic. No differences were found in any of the measures between the two populations and results are presented in a combined fashion. Three-quarters of referrals came from paediatricians and general practitioners but in only 10% was hypermobility recognized as a possible cause of joint complaint. The average age at onset of symptoms was 6.2 yr and age at diagnosis 9.0 yr, indicating a 2- to 3-yr delay in diagnosis. The major presenting complaint was arthralgia in 74%, abnormal gait in 10%, apparent joint deformity in 10% and back pain in 6%. Mean age at first walking was 15.0 months; 48% were considered "clumsy" and 36% as having poor coordination in early childhood. Twelve per cent had "clicky" hips at birth and 4% actual congenital dislocatable hip. Urinary tract infections were present in 13 and 6% of the female and male cases, respectively. Thirteen and 14%, respectively, had speech and learning difficulties diagnosed. A history of recurrent joint sprains was seen in 20% and actual subluxation/dislocation of joints in 10%. Forty per cent had experienced problems with handwriting tasks, 48% had major limitations of school-based physical education activities, 67% other physical activities and 41% had missed significant periods of schooling because of symptoms. Forty-three per cent described a history of easy bruising. Examination revealed that 94% scored > or =4/9 on the Beighton scale for generalized hypermobility, with knees (92%), elbows (87%), wrists (82%), hand metacarpophalangeal joints (79%), and ankles (75%) being most frequently involved. CONCLUSIONS: JHS is poorly recognized in children with a long delay in the time to diagnosis. Although there is a referral bias towards joint symptoms, a surprisingly large proportion is associated with significant neuromuscular and motor development problems. Our patients with JHS also show many overlap features with genetic disorders such as EDS and Marfan syndrome. The delay in diagnosis results in poor control of pain and disruption of normal home life, schooling and physical activities. Knowledge of the diagnosis and simple interventions are likely to be highly effective in reducing the morbidity and cost to the health and social services.

A simple questionnaire to detect hypermobility: an adjunct to the assessment of patients with diffuse musculoskeletal pain.

The aim of the study was to develop a simple and reproducible self-reporting questionnaire that identifies individuals with hypermobility. Two hundred and twelve consecutive hypermobile female new attendees to the hypermobility clinic at two London teaching hospitals and a random selection of 57 healthy volunteers completed a 10-part questionnaire. Questions were selected from clinical experience (RG), and assessed musculoskeletal symptoms and past and present physical agility. Of the 212 cases, 30 were hypermobile with no other underlying disorder and 182 fulfilled the 1998 Brighton criteria for benign joint hypermobility syndrome (BJHS). Odds ratios for the presence of hypermobility were calculated for each question. Six questions were found to be significant and the model of 'best fit' for sensitivity and specificity contained five of these. To demonstrate the reproducibility of the five-part questionnaire a second cohort of 170 hypermobile cases with BJHS and 50 controls was surveyed. Analysis demonstrated that a positive answer to any two questions in the five-part questionnaire gave the highest combined sensitivity and specificity for detecting hypermobility. The sensitivity and specificity was 84% and 89% respectively in the first cohort and reproduced with values of 84% and 80% in the second cohort. Overall the questionnaire correctly identified 84% of all cases and controls. This simple and reproducible questionnaire for detecting hypermobility could be of particular use as an adjunct in the clinical assessment of chronic, diffuse pain syndromes where hypermobility is often missed yet is potentially treatable.

British consultant rheumatologists' perceptions about the hypermobility syndrome: a national survey.

Three hundred and nineteen UK-based consultant rheumatologists, members of the British Society for Rheumatology (a response rate of 76%), responded to a questionnaire concerning their perceptions of the (benign joint) hypermobility syndrome (HMS). The questions were wide-ranging and covered the nature of the condition, its clinic prevalence, criteria for diagnosis, the efficacy of chosen treatments, the impact of the syndrome on affected individuals and the contribution that it makes to the overall burden of rheumatic disease morbidity. Ninety-two per cent of the respondents believed in the HMS as a distinct clinical entity but only 39% accepted it as a distinct pathological entity. Only 42% were prepared to comment on whether the HMS and Ehlers-Danlos syndrome, hypermobility type (formerly EDS type III) were one and the same entity. There was striking variability in estimated clinic prevalence and no consensus about the diagnostic criteria being used. There was little enthusiasm for treatments currently available. Nearly one-half of the respondents were sceptical about a significant impact of the HMS on people's lives and three-quarters about a significant contribution to the overall burden of rheumatic disease. There was little sign of awareness of findings in recent published studies. It seems unlikely, therefore, that evidence-based medicine is being practised in this area of rheumatology. An unexpected finding was a refreshing enthusiasm for joining regional interest groups on hypermobility (25% of all UK consultants expressed interest).

Hypermobility--not a circus act.

Joint hypermobility results from genetic variations in connective tissue matrix proteins resulting in stretchier tissues. For many it is an asset that confers greater facility for physical prowess. Others, less fortunate, fall prey to the associated effects of tissue fragility. The most frequently encountered constellation of traumatic and overuse injuries is termed the (benign joint) hypermobility syndrome (BJHS). This condition, poorly understood, frequently overlooked, misdiagnosed and inappropriately treated, is the cause of much needless suffering and anguish. Accumulating evidence suggests that BJHS represents a forme fruste of an heritable disorder of connective alongside Marfan syndrome, Ehlers-Danlos syndrome and osteogenesis imperfecta, with which it shares many overlapping features, but from which it can be phenotypically distinguished on the basis of clinical features and prognosis. The responsible gene defects have yet to be elucidated.

Heritable disorders of connective tissue.

This chapter seeks to draw readers' attention to the importance of the heritable disorders of connective tissue in clinical practice. It describes the principal features of the Marfan and Ehlers-Danlos syndromes, osteogenesis imperfecta and benign joint hypermobility syndrome, their clinical and prognostic similarities and differences, and their distinguishing features. Recently revised international classifications drawing on advances in molecular genetics are described in detail. Wherever possible, patients' symptoms are explained on the basis of the altered biomechanics of genetically aberrant connective tissue matrix proteins. Finally, the chapter draws attention to the often unrecognized burden of chronic pain borne by patients with these conditions, a feature of which many rheumatologists seem unaware, and sets out a rational and holistic approach to treatment and management that is based on the best currently available evidence.