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ABSTRACT: Faecal incontinence (FI) and constipation occur following corrective surgery for anorectal malformations (ARMs) and in children or adults with chronic constipation without a structural birth anomaly (chronic idiopathic constipation, CIC). Such symptoms may have profound effects on quality of life (QoL). This study systematically determined the burden of FI and constipation in these patients in adolescence and early adulthood, and their effect on QoL and psychosocial functioning in comparison with controls.
Patients with ARMs or CIC were compared with age- and sex-matched controls who had undergone appendicectomy more than 1 year previously and had no ongoing gastrointestinal symptoms. Constipation and FI were evaluated using validated Knowles-Eccersley-Scott Symptom (KESS) and Vaizey scores respectively. Standardized QoL and psychometric tests were performed in all groups.
The study included 49 patients with ARMs (30 male, aged 11-28 years), 45 with CIC (32 male, aged 11-30 years) and 39 controls (21 male, aged 11-30 years). The frequency of severe constipation among patients with ARMs was approximately half that seen in the CIC group (19 of 49 versus 31 of 45); however, frequencies of incontinence were similar (22 of 49 versus 21 of 45) (P < 0·001 versus controls for both symptoms). Physical and mental well-being were significantly reduced in both ARM and CIC groups compared with controls (P = 0·001 and P = 0·015 respectively), with generally worse scores among patients with CIC. Both were predicted by gastrointestinal symptom burden (P < 0·001). There were no statistically significant differences in state or trait psychiatric morbidity between groups.
FI and constipation are major determinants of poor QoL in adolescents and young adults with ARMs and in those with CIC.
British Journal of Surgery 05/2013; 100(6):832-9. · 4.61 Impact Factor
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ABSTRACT: Autoantibodies directed against specific neuronal antigens are found in a significant number of patients with gastrointestinal neuromuscular diseases (GINMDs) secondary to neoplasia. This study examined the presence of antineuronal antibodies in idiopathic GINMD and GINMD secondary to South American Trypanosomiasis. The GI distribution of voltage-gated potassium channels (VGKCs) was also investigated.
Seventy-three patients were included in the study with diagnoses of primary achalasia, enteric dysmotility, chronic intestinal pseudo-obstruction, esophageal or colonic dysmotility secondary to Chagas' disease. Sera were screened for specific antibodies to glutamic acid decarboxylase, voltage-gated calcium channels (VGCCs; P/Q subtype), nicotinic acetylcholine receptors (nAChRs; α3 subtype), and voltage-gated potassium channels (VGKCs, K(V) 1 subtype) using validated immunoprecipitation assays. The distribution of six VGKC subunits (K(V) 1.1-1.6), including those known to be antigenic targets of anti-VGKC antibodies was immunohistochemically investigated in all main human GI tract regions.
Three patients (14%) with chagasic GI dysmotility were found to have positive anti-VGKC antibody titers. No antibodies were detected in patients with idiopathic GINMD. The VGKCs were found in enteric neurons at every level of the gut in unique yet overlapping distributions. The VGKC expression in GI smooth muscle was found to be limited to the esophagus.
A small proportion of patients with GI dysfunction secondary to Chagas' disease have antibodies against VGKCs. The presence of these channels in the human enteric nervous system may have pathological relevance to the growing number of GINMDs with which anti-VGKC antibodies have been associated.
Neurogastroenterology and Motility 05/2012; 24(8):719-28, e344. · 3.41 Impact Factor
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ABSTRACT: Conflicting data exist on the contributions of advancing age and childbirth on the structure and function of the anal sphincter. This study aimed to examine the relative contributions of age and childbirth in a large cohort of women referred for investigation of symptoms of colorectal dysfunction (fecal incontinence and constipation).
This study was conducted at a specialist surgical colorectal investigation unit in a university teaching hospital.
Retrospective analysis was performed on prospectively collected demographic, symptom profile, and physiologic data from 3686 female patients. Strict exclusion criteria were applied, leaving 999 patients for univariate, multivariate, and logistic statistical modeling.
The effects of independent variables alone and in combination on anal sphincter pressures (resting and squeeze increment) and the presence of sphincter defects (internal and external) were expressed as regression coefficients and odds ratios.
Median age was 42 years (range, 16-88), and parity was 2 (range, 0-11); 16% were nulliparous. Three hundred sixty patients had fecal incontinence, 352 had constipation, and 287 had combined symptoms. Anal resting tone decreased with age by 0.66 cm H2O per year, and by 4.3 cm H2O per birth, and was associated with both internal and external anal sphincter defects (p = 0.0001 for both). Squeeze increment pressures decreased by 0.3 cm H2O per year, and by 3.8 cm H2O per birth; decreased pressures were, however, only significantly associated with external anal sphincter defects (p = 0.0001) as a result of childbirth. Cesarean delivery was protective against both reduced anal pressures and sphincter defects. Pudendal nerve terminal motor latencies increased bilaterally with age and with vaginal delivery; the impact of both was greater on the left nerve. Rectal sensation was unaffected by age or parity.
Aging predominantly affects anal resting pressures; childbirth, particularly instrumental delivery, is detrimental to the structure and function of the external sphincter.
Diseases of the Colon & Rectum 03/2012; 55(3):286-93. · 3.13 Impact Factor
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ABSTRACT: Acid infusion in humans induces primary and secondary oesophageal hypersensitivity. The effects of pregabalin, a centrally-acting modulator of voltage-sensitive calcium channels, on development of acid-induced oesophageal hypersensitivity remain unknown.
To study the effects of pregabalin on development of secondary oesophageal hypersensitivity in healthy humans.
Placebo-controlled, double-blind, randomised, cross-over study of 15 healthy volunteers (six women, age 21-56 years). After oesophageal manometry, baseline pain thresholds (PTs) to proximal oesophageal electrical stimulation were determined using bipolar ring electrodes. A 30-min infusion of HCl was performed in the distal oesophagus followed by PT measurements at 30 and 90 min. This protocol was repeated after administration of pregabalin (dosing schedule: 75 mg twice daily for 3 days then 150 mg twice daily for 1 day and then 150 mg on the morning of study) or placebo.
T0 PTs were similar in patients after receiving placebo or pregabalin [mean (s.d.) 32.9 mA (20.5) vs. 34.1 (15.7), P = 0.42]. Pregabalin reduced development of acid-induced hypersensitivity in the proximal oesophagus at 30 min [mean change in PT (C.I.) placebo -6.2 mA (-11.3 to +1.3) vs. pregabalin +0.20 mA (-2.7 to +3.3)] and 90 min [placebo -3.7 mA (-10.0 to +2.0) vs. pregabalin +0.7 mA (-4.7 to 7.3)] overall P = 0.001. Pregabalin reduced median visual analogue scale score for acid-induced pain (1/10 vs. placebo 3/10, P = 0.027).
Pregabalin attenuates development of secondary hypersensitivity in the proximal oesophagus after distal oesophageal acidification; it may thus have a role in treatment of patients with proven oesophageal pain hypersensitivity.
Alimentary Pharmacology & Therapeutics 12/2011; 35(3):319-26. · 3.77 Impact Factor
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ABSTRACT: Sacral nerve stimulation (SNS) has become an established option in the management of defaecatory disorders. There are many data on the end-organ effects of SNS, but limited consensus on its mechanism of action. The objective of this review was to determine the effect of sacral nerve stimulation (SNS) on anorectal function.
Systematic literature review of the effect of sacral nerve stimulation (SNS) on anorectal function.
There was significant heterogeneity of data pertaining to the effects of SNS on anorectal function, with no consistent change in physiological measures identified. Most data supported a mixed mechanism of action on anal motor and rectal sensory functioning.
To date, conflicting data exist on the mechanism of action of SNS as determined by end-organ changes in anorectal physiology. Nevertheless, the data as they stand best support a mixed mechanism of action on anal motor and rectal sensory functions.
Colorectal Disease 03/2011; 13 Suppl 2:5-9. · 2.93 Impact Factor
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C H Knowles,
B Veress,
R P Kapur,
T Wedel,
G Farrugia,
J-M Vanderwinden,
K Geboes,
V V Smith,
J E Martin,
G Lindberg,
P J Milla,
R De Giorgio
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ABSTRACT: BACKGROUND: Patients with gastrointestinal neuromuscular diseases may undergo operative procedures that yield tissue appropriate to diagnosis of underlying neuromuscular pathology. Critical to accurate diagnosis is the determination of limits of normality based on the study of control human tissues. Although robust diagnostic criteria exist for many qualitative alterations in the neuromuscular apparatus, these do not include quantitative values due to lack of adequate control data. PURPOSE: The aim of this report was to summarize all relevant available published quantitative data for elements of the human enteric nervous system (neuronal cell bodies, glial cells, and nerve fibers) from the perspective of the practicing pathologist. Forty studies meeting inclusion criteria were systematically reviewed with data tabulated in detail and discussed in the context of methodological variations and limitations. The results reveal a lack of concordance between observations of different investigators resulting in data insufficient to produce robust normal ranges. This diversity highlights the need to standardize the way pathologists collect, process, and quantitate neuronal and glial elements in enteric neuropathologic samples, as suggested by recent international guidelines on gastrointestinal neuromuscular pathology.
Neurogastroenterology and Motility 02/2011; 23(2):115-24. · 3.41 Impact Factor
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ABSTRACT: Stomal complications are prevalent and associated with considerable morbidity. This study examined the incidence and potential risk factors for their development.
The time of onset and presence of ten specific complications were recorded for patients with an intestinal stoma over 10 years at two urban hospitals. A database was established with 20 explanatory variables (such as common medical co-morbidities) derived from the stomatherapy and medical records. Univariable and multivariable analyses were performed to identify potential risk factors for the development of complications.
Some 1216 patients (mean age 64 years) with a minimum of 2 years' follow-up were included, of whom 544 (44·7 per cent) underwent surgery for malignancy and 647 (53·2 per cent) had a colostomy formed. There were 1219 complications in total; 807 major complications (excluding excoriation and slough) occurred in 564 patients (46·4 per cent), of which the commonest was parastomal hernia (171, 14·1 per cent). On multivariable analysis, musculoskeletal co-morbidity (odds ratio (OR) 1·79, 95 per cent confidence interval 1·05 to 3·07; P = 0·032), cancer (OR 1·48, 1·13 to 1·93; P = 0·004) and high American Association of Anesthesiologists score (OR = 3·80, 2·14 to 6·75; P < 0·001) were associated with an increased risk of complications. Preoperative siting was associated with a reduced risk (OR 0·59, 0·39 to 0·90; P = 0·014).
Intestinal stomal complications are common, occurring in almost half of patients. There are certain irremediable risk factors, allowing appropriate preoperative counselling.
British Journal of Surgery 12/2010; 97(12):1885-9. · 4.61 Impact Factor
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ABSTRACT: This review addresses the range of operations suggested to be of contemporary value in the treatment of constipation with critical evaluation of efficacy data, complications, patient selection, controversies and areas for future research.
Neurogastroenterology and Motility 12/2009; 21 Suppl 2:62-71. · 3.41 Impact Factor
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Gut 12/2009; 58(12):1703-5. · 10.11 Impact Factor
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ABSTRACT: 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.
Neurogastroenterology and Motility 10/2009; 22(3):252-e78. · 3.41 Impact Factor
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ABSTRACT: Acute colonic pseudo-obstruction is characterized by clinical and radiological evidence of acute large bowel obstruction in the absence of a mechanical cause. The condition usually affects elderly people with underlying co-morbidities, and early recognition and appropriate management are essential to reduce the occurrence of life-threatening complications.
A part-systematic review was conducted. This was based on key publications focusing on advances in management.
Although acute colonic dilatation has been suggested to result from a functional imbalance in autonomic nerve supply, there is little direct evidence for this. Other aetiologies derived from the evolving field of neurogastroenterology remain underexplored. The rationale of treatment is to achieve prompt and effective colonic decompression. Initial management includes supportive interventions that may be followed by pharmacological therapy. Controlled clinical trials have shown that the acetylcholinesterase inhibitor neostigmine is an effective treatment with initial response rates of 60-90 per cent; other drugs for use in this area are in evolution. Colonoscopic decompression is successful in approximately 80 per cent of patients, with other minimally invasive strategies continuing to be developed. Surgery has thus become largely limited to those in whom complications occur. A contemporary management algorithm is provided on this basis.
British Journal of Surgery 04/2009; 96(3):229-39. · 4.61 Impact Factor
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ABSTRACT: Advances in minimally invasive surgery have made laparoscopy and full-thickness bowel biopsy possible in the investigation of patients with suspected gastrointestinal neuromuscular disorders. The safety and diagnostic yield of this investigation have not been formally reported. A prospective study was undertaken of 124 patients with clinico-physiological diagnoses of chronic intestinal pseudo-obstruction, enteric dysmotility and severe irritable bowel syndrome undergoing LFTB in three European teaching centres with expertise in the management of gastrointestinal neuromuscular disorders. Perioperative data were collected including complications. Diagnostic yield was expressed as proportion with well-established specific neuromuscular abnormalities based on a protocol of routine and immunohistochemical techniques. The majority of patients underwent a laparoscopically assisted procedure with extracorporeal biopsy. Median operating time was 50 min, conversion rate 2% and length of stay 1 day. There was an 8% readmission rate for obstructive symptoms but minimal other morbidity and no mortality. Overall specific diagnostic yield was 81%, being high for jejunal biopsies (89%) but low for a small number of ileal and colonic biopsies. Laparoscopy and full-thickness biopsy of the bowel appears acceptable in terms of safety. It should be performed in a jejunal site to achieve a high diagnostic yield.
Neurogastroenterology and Motility 08/2008; 20(7):774-9. · 3.41 Impact Factor
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ABSTRACT: A proportion of patients with intractable constipation have persistent dilatation of the bowel, which in the absence of an organic cause is termed idiopathic megabowel (IMB). Whilst uncommon, this condition results in considerable morbidity. Traditional methods of identifying such patients are associated with inherent methodological limitations with anorectal manometry and contrast studies overestimating and underestimating the prevalence of the condition, respectively. Recently, controlled, pressure-based distension during fluoroscopic imaging has allowed more accurate identification of patients on the basis of a rectal diameter > 6.3 cm at the minimum distension pressure. Histopathological abnormalities of all three final effectors of sensorimotor function have been reported, although it remains unclear whether these changes are primary, secondary or epiphenomic. Physiological abnormalities of sensorimotor function, namely impaired perception of rectal distension and delayed colonic transit are well documented in patients with IMB. Further, the recent demonstration of two subgroups of patients, defined on the basis of rectal compliance, suggests the possibility that they differ pathophysiologically, although the clinical relevance of this distinction is uncertain. Surgery is performed when conservative therapy is ineffective or poorly tolerated. Numerous procedures have been attempted with variable success rates and significant mortality and morbidity. Surgery should preferably be performed in specialist centres given the relative infrequency with which such patients are encountered, and that they require comprehensive clinical, psychological and physiological evaluation preoperatively.
Colorectal Disease 07/2008; 10(6):531-8; discussion 538-40. · 2.93 Impact Factor
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Gut 06/2008; 57(5):674-83. · 10.11 Impact Factor
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ABSTRACT: Abnormalities of enteric nerves, interstitial cells of Cajal (ICC) and smooth muscle are often associated with severe gastrointestinal motility disorders. In this context, full-thickness biopsy of the gut may provide important diagnostic and prognostic clues as well as some possible therapeutic implications. Nonetheless, the unavoidable risk to further worsen prognosis evoked by laparotomy, and the unclear yield of histopathological analysis has hampered full-thickness gut sampling in patients with severe dysmotility. However, recent advances in minimally invasive surgery have refuelled enthusiasm in gastrointestinal neuromuscular pathology. In this issue of Neurogastroenterology and Motility, Miller et al. provide novel and exciting evidence that the appendix might be used as a surrogate tissue to analyse changes to enteric nerves, ICC and smooth muscle cells in patients with diabetic gastroenteropathy. The objective of this short review was to place this very important work in the context of current understanding of enteric neuromuscular dysfunction.
Neurogastroenterology and Motility 05/2008; 20(4):263-8. · 3.41 Impact Factor
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ABSTRACT: Sacral nerve stimulation (SNS) may improve faecal incontinence by modulating rectal sensation. This study measured changes in the peripheral expression of various neural epitopes in response to SNS.
Rectal mucosal biopsies were taken from 12 patients before and after temporary SNS, and from ten responders at 90 days after permanent stimulation. Sections were immunostained for substance P, transient receptor potential vanilloid (TRPV) 1, vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP). Levels were compared with those in nine continent controls.
Baseline levels of percentage area immunoreactivities of substance P (median 0.51 (95 per cent confidence interval 0.31 to 0.73) versus 0.13 (0.07 to 0.27) per cent; P < 0.001) and TRPV1 (0.76 (0.41 to 1.11) versus 0.09 (0.04 to 0.14) per cent; P < 0.001), but not of VIP (1.26 (0.37 to 2.15) versus 1.28 (0.39 to 2.17); P = 0.943), were significantly greater than in controls. Successful SNS resulted in a significant decrease in substance P immunostaining after temporary (0.15 (0.06 to 0.51) per cent; P = 0.051) and permanent (0.17 (0 to 0.46) per cent; P = 0.051) stimulation. Immunoreactivity of TRPV1, VIP, CGRP and neural markers showed no qualitative change.
Patients with faecal incontinence demonstrate normalization of raised rectal mucosal substance P levels following successful SNS.
British Journal of Surgery 04/2008; 95(4):477-83. · 4.61 Impact Factor
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ABSTRACT: Interdigestive human small bowel motility is characterized by the migrating motor complex (MMC). The aims of this study were to: (i) establish the normal range of variables of the nocturnal jejunal MMC and (ii) incorporate these data in a subsequent meta-analysis. Eighty-one recordings were performed by prolonged (24 h) ambulatory manometry in 51 subjects in two centres. Quantitative analysis was undertaken of 419 Phase III and 332 Phase II episodes. Adjusted mean values of seven variables were calculated using a mixed-effects model. Meta-analysis of pooled published data to generate a reliable 95% reference range was also performed. Adjusted mean values and confidence intervals are presented for all seven variables. Intrasubject variances were large in comparison with intersubject. Meta-analysis of 19 studies (356 pooled patients) meeting inclusion criteria produced wide reference ranges. At least five such ranges are useful for the detection of abnormality in the individual. This is the largest study of normal volunteers presented to date, with ranges for many variables produced using appropriate statistical methodology. A model for definition of abnormality has been proposed. We recommend that these data may be used by investigators in this field as a complement to other existing indicators of small bowel dysmotility.
Neurogastroenterology and Motility 11/2006; 18(10):927-35. · 3.41 Impact Factor
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ABSTRACT: To assess the short and intermediate outcomes of a modification of the traditional cutting seton technique, using a 'snug' silastic seton, to treat idiopathic anal fistulae.
Between August 1997 and December 2002, 35 patients with idiopathic fistulae (4 female; age 26-76 years) underwent insertion of a 'snugly' tied 1 mm silastic seton (silicone nerve vessel retractor, Medasil), as definitive treatment. Short-term assessment was performed by case note review. Patients were subsequently invited to participate in a medium-term review.
Twenty-nine patients' notes (3 female) were available for short-term analysis. Fistulae were classified as intersphincteric (9) and transsphincteric (20). The seton spontaneously cut out in 15/29 (52%) after a median of 24 weeks. In 14 patients the seton enclosed residual tissue (< 5 mm) required division as a day case procedure, at a median of 35 weeks. All fistulae healed but 10/29 (34%) patients (1 female; 8 transsphincteric) experienced minor incontinence. Sixteen patients participated in a medium-term review at a median of 42 months; 7 had experienced early continence disturbance. No patient suffered recurrence, but minor incontinence persisted in 4/16 (25%) patients (0 females; 3 transsphincteric). All patients were at least 'satisfied' with the outcome.
In the short and medium term, the 'snug' seton is a safe and effective addition to the fistula surgeon's armamentarium.
Colorectal Disease 05/2006; 8(4):328-37. · 2.93 Impact Factor
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ABSTRACT: Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a severe motility disorder associated with significant morbidity. Several histopathological (neuropathic and myopathic) phenotypes have been described but only a single adult with jejunal smooth (circular) muscle alpha-actin deficiency. We present a prospective multinational case series investigating smooth muscle alpha-actin deficiency as a biomarker of this disease.
A total of 115 fully clinically and physiologically (including prolonged (24 hour) ambulatory jejunal manometry) characterised CIIP patients from three European centres were studied. Immunohistochemical localisation of actins and other cytoskeletal proteins were performed on laparoscopic full thickness jejunal biopsies and compared with adult controls. Distribution of alpha-actin was also characterised in other gut regions and in the developing human alimentary tract.
Twenty eight of 115 (24%) CIIP patient biopsies had absent (n = 22) or partial (n = 6) jejunal smooth muscle alpha-actin immunostaining in the circular muscle layer. In contrast, smooth muscle alpha-actin staining was preserved in the longitudinal muscle and in adult jejunal controls (n = 20). Comparative study of other adult alimentary tract regions and fetal small intestine, suggested significant spatial and temporal variations in smooth muscle alpha-actin expression.
The ability to modulate alpha-smooth muscle actin expression, evident in development, is maintained in adult life and may be influenced by disease, rendering it a valuable biomarker even in the absence of other structural abnormalities.
Gut 12/2004; 53(11):1583-9. · 10.11 Impact Factor
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ABSTRACT: OBJECTIVE: Small bowel dysmotility has previously been demonstrated in some patients with slow transit constipation (STC), suggesting a generalized intestinal disorder. However, no study has addressed whether the incidence of small intestinal dysfunction differs between subgroups of patients in this heterogeneous population. Using appropriate methodology, we aimed to determine prospectively the proportion of individuals with abnormal small bowel motility, and to assess whether heterogeneity in terms of pattern of colonic transit delay (based on (111)In diethylene-triamine-pentaacetic acid (DTPA) isotope scintigraphy), or mode of onset (based on clinical history) is of importance. METHODS: Thirty-seven patients with STC underwent 24-h ambulatory jejunal manometry; data were compared with those obtained in 38 healthy controls. Automated quantitative analysis of seven variables of the nocturnal migrating motor complex was performed, to assess whether differences existed between groups, and whether individual patients had evidence of small intestinal dysmotility, defined as two or more measures of migrating motor complex variables outside the normal range. Four variables differed significantly between STC patients and controls: in phase III, propagation was slower, duration was longer, and contraction amplitude was higher; in phase II, contraction frequency was increased. Seven of 24 patients with a generalized pattern of colonic transit delay had abnormal small bowel motility compared with none of 13 with a left-sided delay (p < 0.04). These included four patients with chronic idiopathic symptoms and three with acquired symptoms. Approximately one third of patients with a generalized delay in colonic transit had evidence of jejunal enteric neuromuscular dysfunction. Individual patients with a left-sided colonic delay did not satisfy the criteria for nocturnal small bowel dysmotility, but as a group, some differences were noted from controls. In contrast to previous reports, evidence of generalized enteric dysmotility may be present irrespective of the mode of onset.
The American Journal of Gastroenterology 05/2003; 98(5):1123-34. · 7.28 Impact Factor
