Management of Seymour Fractures in Children and Adolescents: A Systematic Review and Meta-Analysis.

PURPOSE: Seymour fractures are injuries with a potentially high risk of infection and osteomyelitis. The optimal management of this pediatric open fracture is unknown. We performed a systematic review and meta-analysis to summarize the best evidence for these fractures and determine their optional management based on primary clinical studies. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review and meta-analysis was performed. A comprehensive search strategy was applied to the MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, and gray literature databases (from May 1966 to April 15, 2020). Studies describing patients under the age of 18 years with Seymour fractures were included. Treatment was grouped based on debridement and antibiotic status as well as the timing of these interventions. The primary outcome was infection. The secondary outcomes included malunion, physeal disturbance, and nail dystrophy. RESULTS: The searches helped identify 56 records, of which 10 nonrandomized studies met our inclusion criteria, comprising 352 patients and 355 fractures. Early (<48 hours) debridement was associated with significantly less risk of infection (risk ratio [RR] = 0.28 [95% CI, 0.12-0.64]) and malunion (RR = 0.25 [95% CI, 0.07-0.99]). Prophylactic (<24 hours) antibiotics significantly reduced the risk of infection (RR = 0.21 [95% CI, 0.10-0.43]). In addition, prophylactic antibiotics and debridement were associated with a 70% reduction in the risk of infection (RR = 0.30 [95% CI, 0.11-0.83]). Over one-third of patients with delayed presentation (median 8.5 days) were infected at presentation. CONCLUSIONS: The high-risk nature of Seymour fractures may be mitigated by prompt recognition and early, basic interventions, which can usually be performed in any setting. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

The optimal management of Seymour fractures in children and adolescents: a systematic review protocol.

BACKGROUND: Seymour fractures are open, displaced juxta-epiphyseal fractures of the distal phalanx, with an overlying nail bed laceration that occur in children and adolescents with an open physis. This fracture occurs rarely, but its potential consequences are clinically significant. Due to anatomical particulars and proximity to the growth plate, this open fracture may result in soft tissue infection and osteomyelitis, leading to growth arrest and persistent mallet deformity. At present, there is no consensus as to the optimal management of Seymour fractures. The objective of this study will be to systematically evaluate the existing evidence on the management of Seymour fractures in children and adolescents and to establish what are the most important factors pertaining to an uncomplicated recovery. METHODS: We designed and registered a study protocol for a systematic review of randomised controlled trials and observational studies. A comprehensive literature search will be conducted (from inception to present) in MEDLINE, EMBASE, CINAHL and Cochrane Library databases. Grey literature will be identified through searching Open Grey and dissertation databases using an exhaustive search strategy. All clinical studies examining the management of Seymour fractures will be included. The interventions (irrigation and debridement; prophylactic antibiotics) and their timings (early vs late) will be compared to no antibiotics and no debridement. Primary outcome measures will be the incidence of superficial and deep infection. Secondary outcomes will include other adverse events such mal-union, non-union, need for re-operation, physeal disturbance and nail dystrophy/atrophy. Two independent reviewers will screen all citations, full-text articles, and abstract data. Conflicts will be resolved through discussion. The study methodological quality (or bias) will be appraised using an appropriate tool. A narrative synthesis will be performed. If data permits, we will conduct random-effects meta-analysis where appropriate. DISCUSSION: This review will provide evidence for the management of Seymour fractures, based on a cumulation of existing smaller studies. Due to the rarity of this fracture pattern, included studies are expected to be mainly observational and prone to bias; however, there is value in summarising the evidence to guide clinicians. SYSTEMATIC REVIEW REGISTRATION: Systematic review registration: PROSPERO CRD42020153726.

Defining Normal Parameters for the Male Nipple-Areola Complex: A Prospective Observational Study and Recommendations for Placement on the Chest Wall.

BACKGROUND: The nipple-areola complex (NAC) is important aesthetically and functionally for both sexes. Methods for positioning the NAC in males are less well established in the literature compared to females but are just as important. OBJECTIVES: This study aims to determine the normal parameters for the male NAC, to review literature, and to present a reliable method for preoperative placement. METHODS: Normal male patients, with no prior chest wall conditions, were prospectively recruited to participate. General demographics and chest wall dimensions were recorded-sternal notch to nipple (SNND), internipple (IND), anterior axillary folds distances (AFD), NAC, and chest circumference were measured. Comparisons were made using t test and ANOVA. RESULTS: One hundred and fifty-eight patients were recruited (age range, 18-90 years); mostly (86.7%) with normal or overweight BMI. The IND averaged 249.4 mm, the SNND averaged 204.2 mm, and the AFD averaged 383.8 mm. Areola diameter averaged 26.6 mm and for the nipple, 6.9 mm. The IND:AFD ratio was 0.65. There was no statistical difference in the IND:AFD ratio, SNND, or NAC parameters comparing different ethnic groups. The SNND increased with greater BMI (P ≤ 0.001). Using these data, we suggest ideal NAC dimensions and devised a simple method for positioning of the NAC on the male chest wall. CONCLUSIONS: This is the largest study, with the widest range in age and BMI, to date on this topic. Although fewer men than women undergo surgery to the breast, there is a growing awareness for enhancing the appearance of the male chest wall.

Learning from lawsuits: Ten-years of NHS litigation authority claims against 11 surgical specialities in England.

INTRODUCTION: Medico-legal claims are a drain on NHS resources and promote defencive practice. The litigious burden of surgery in England has not been previously described. This paper describes trends over ten years of claims made against the NHS across 11 surgical specialities. MATERIALS AND METHODS: Data were requested for all claims received by the NHS Litigation Authority (NHSLA) from 2004 to 2014. Surgical specialities included cardiothoracic, general, neurosurgery, obstetric, oral and maxillofacial (OMFS), orthopaedic, otorhinolaryngology, paediatric, plastic, urology and vascular surgery. A literature review of peer-reviewed publications was performed with search terms 'NHSLA' and 'Surgery'. RESULTS: The NHS paid out approximately £1.5 billion across 11 surgical specialities from 2004 to 2014. Orthopaedic, obstetric and general surgery received the largest number of claims per year, and paediatric surgery the least. The mean time from registration of claim with the NHSLA to settlement was 25.5 months (range 17.8 months-35 months). Neurosurgery was responsible for the highest average amount paid per claim, and OMFS the lowest. Failure/delay in treatment and/or diagnosis and failure to warn/adequately consent were the three leading types of claim. 806 never events were successfully claimed for during the ten-year period. DISCUSSION AND CONCLUSION: Sharing information and good practice should be a priority for surgical professionals. Lessons learnt from medico-legal claims are transferrable in strategic planning. This pan-speciality report has demonstrated considerable burden on the NHS and should promote improvement in practice on an individual level in addition to providing systems based recommendations to NHS and international organisations.

Growth in children with choledochal malformations: effect of the Roux loop.

PURPOSE: Excision and biliary reconstruction using a Roux loop is the current standard for choledochal malformation (CM). This is un-physiological, delivering bile beyond the duodenum and excluding a significant length of the jejunum from intestinal absorption. We investigated whether this had an effect on post-operative growth. METHODS: Retrospective case-note analysis of children surgically treated for CM. Growth variables were converted to standard deviation scores (SDS) and compared against population norms. P < 0.05 was significant. RESULTS: From 1994 to 2014, 135 children (<16 years) were identified. Median age at surgery was 3.3 (IQR 1.5-7) years. Morphology included: type 1 Cystic (n = 54, 40%), type 1 Fusiform (n = 58, 43%) and type 4 (intra and extra-hepatic) (n = 22, 16%). There was pre-operative growth failure [median weight SDS = -0.4 (-1.2 - 0.4), P = 0.0004] with a similar trend for height [SDS = -0.38 (-1.2 - 0.5), P = 0.08)]. This correlated with presentation bilirubin (r s = -0.24, P = 0.004), GGT (r s = -0.27, P = 0.002) and AST (r s = -0.27, P = 0.002) but not morphology (P = 0.82) or presentation (P = 0.4). Median follow-up was 1.9 (0.6-4.7) years, during which time both height (P = 0.73) and weight (P = 0.45) reverted to normal. CONCLUSION: This is the first report of growth in children with CM following a Roux-loop reconstruction and showed pre-operative growth failure probably attributed to a period of biliary obstruction but catch-up growth when corrected.

Excess of allele1 for alpha3 subunit GABA receptor gene (GABRA3) in bipolar patients: a multicentric association study.

The available data from preclinical and pharmacological studies on the role of gamma amino butyric acid (GABA) support the hypothesis that a dysfunction in brain GABAergic system activity contributes to the vulnerability to bipolar affective disorders (BPAD). Moreover, the localization of the alpha3 subunit GABA receptor GABRA3 gene on the Xq28, a region of interest in certain forms of bipolar illness, suggests that GABRA3 may be a candidate gene in BPAD. In the present study, we tested the genetic contribution of the GABRA3 dinucleotide polymorphism in a European multicentric case-control sample, matched for sex and ethnogeographical origin. Allele and genotype (in females) frequencies were compared in 185 BPAD patients and 370 controls. A significant increase of genotype 1-1 was observed in BPAD females compared to controls (P=0.0004). Furthermore, when considering recessivity of allele 1 (females with genotype 1-1 and males carrying allele 1), results were even more significant (P= 0.00002). Our findings suggest that the GABRA3 polymorphism may confer susceptibility to or may be in linkage disequilibrium with another gene involved in the genetic etiology of BPAD.

Serotonin transporter gene (5-HTTLPR) and major psychoses.

Serotoninergic neurotransmitter systems have been implicated in the pathogenesis of major psychoses. A functional polymorphism (5-HTTLPR) in the upstream regulatory region of the gene (SLC6A4) has been associated with a number of psychiatric disturbances, but conflicting replication followed. The aim of this study was to investigate the possibility that the 5-HTTLPR might be associated with major psychoses. One thousand, eight hundred and twenty inpatients (789 bipolars, 667 major depressives, 66 delusionals, 261 schizophrenics, 37 psychotics not otherwise specified-NOS) and 457 control subjects were included in this study. A subsample of 1235 patients (523 bipolars, 359 major depressives, 259 schizophrenics, 66 delusionals, 28 psychotic NOS) were evaluated for lifetime psychotic symptomatology using the Operational Criteria for Psychotic illness (OPCRIT) checklist. The subjects were also typed for 5-HTTLPR variants using PCR techniques. 5-HTTLPR allele frequencies were not significantly different between controls and bipolars, major depressives, schizophrenics, delusionals and psychotic NOS; genotype analysis also did not show any association. The analysis of symptomatology did not show significant differences. Consideration of possible stratification factors such as sex and age of onset did not significantly influence results. 5-HTTLPR variants are not therefore a liability factor for major psychoses or for major psychoses symptomatology.

No association between dopamine D(2) and D(4) receptor gene variants and antidepressant activity of two selective serotonin reuptake inhibitors.

The possible association of the dopamine receptor D(2) (Ser 311Cys) and D(4) exon 3 (48 base pair repeat) gene variants with the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) was investigated in a sample of 364 inpatients affected by a major depressive episode treated with fluvoxamine, 300 mg/day (n=266), or paroxetine, 20-40 mg/day (n=98). The severity of depressive symptoms was assessed weekly with the Hamilton Rating Scale for Depression. Dopamine receptor D(2) (DRD2) and dopamine receptor D(4) (DRD4) allelic variants were determined in each subject by polymerase chain reaction. We observed that DRD2 and DRD4 variants were not associated with response to SSRI treatment. Possible stratification factors, such as sex, diagnosis, presence of psychotic features, depressive symptoms at baseline, paroxetine and fluvoxamine plasma levels, and pindolol augmentation did not significantly influence the observed results. The investigated DRD2 and DRD4 gene variants therefore do not seem to play a major role in the antidepressant activity of SSRIs, at least in the present sample.

Influence of 5-HTTLPR and TPH variants on illness time course in mood disorders.

The aim of our study was to investigate gene variants in the long-term outcome of mood disorders. We retrospectively studied a sample of inpatients affected by recurrent and rapid cycling mood disorders. The serotonin transporter gene-linked functional polymorphic region (5-HTTLPR) and the A218C tryptophan hydroxylase (TPH) gene variant were determined using a PCR-based technique. For 5-HTTLPR polymorphism we genotyped 435 inpatients affected by major depressive (n=153), bipolar (n=213) and rapid cycling (n=69) mood disorders and 456 controls; for TPH we genotyped 399 inpatients (MD, n=132; BP, n=203; rapid cycling n=64) and 259 controls. Random Regression Model analysis was used to investigate the longitudinal time course of the illness. 5-HTTLPR and TPH polymorphisms were not associated with mood disorders time course. However we observed an excess of 5-HTTLPR*long alleles among rapid cycling subjects compared to both controls (P=0.018) and remitting mood disorders (P=0.006). TPH frequencies did not differ between mood disorders subtypes. Our results suggest that 5-HTTLPR variants may confer a susceptibility toward rapid cycling mood disorders.

Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder.

Substantial evidence supports a role for dysfunction of brain serotonergic (5-HT) systems in the pathogenesis of major affective disorder, both unipolar (recurrent major depression) and bipolar.(1) Modification of serotonergic neurotransmission is pivotally implicated in the mechanism of action of antidepressant drugs(2) and also in the action of mood stabilizing agents, particularly lithium carbonate.(3) Accordingly, genes that code for the multiple subtypes of serotonin receptors that have been cloned and are expressed in brain,(4) are strong candidates for a role in the genetic etiology of affective illness. We examined a structural variant of the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine to serine substitution in the N terminal extracellular domain of the receptor protein (cys23ser),(5) in 513 patients with recurrent major depression (MDD-R), 649 patients with bipolar (BP) affective disorder and 901 normal controls. The subjects were drawn from nine European countries participating in the European Collaborative Project on Affective Disorders. There was significant variation in the frequency of the HT2CR ser23 allele among the 10 population groups included in the sample (from 24.6% in Greek control subjects to 9.2% in Scots, chi(2) = 20.9, df 9, P = 0.01). Logistic regression analysis demonstrated that over and above this inter-population variability, there was a significant excess of HT2CR ser23 allele carriers in patients compared to normal controls that was demonstrable for both the MDD (chi(2) = 7.34, df 1, P = 0.006) and BP (chi(2) = 5.45, df 1, P = 0.02) patients. These findings support a possible role for genetically based structural variation in 5-HT2C receptors in the pathogenesis of major affective disorder.

Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity.

The aim of the present study was to test a possible effect of the A218C tryptophan hydroxylase (TPH) gene variant on the antidepressant activity of fluvoxamine in a sample of major and bipolar depressives, with or without psychotic features. Two hundred and seventeen inpatients were treated with fluvoxamine 300 mg and either placebo or pindolol in a double blind design for 6 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression. TPH allelic variants were determined in each subject by using a PCR-based technique. No significant finding was observed in the overall sample as well as in the pindolol group, while TPH*A/A was associated with a slower response to fluvoxamine treatment in subjects not taking pindolol (P = 0.001). This effect was independent from the previously reported influence of 5-HTTLPR polymorphism. If confirmed, these results may shed further light on the genetically determined component of the response to pharmacological treatments, thus helping the clinician to individualize each patient's therapy according to their genetic pattern.

Tryptophan hydroxylase gene and major psychoses.

Disturbances of the serotoninergic neurotransmitter system have been implicated in the pathogenesis of mood disorders. The tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme of serotonin biosynthesis, has been recently reported to be associated with bipolar disorder. In this study, we investigated TPH A218C gene variants in a sample of subjects affected by major psychoses. One thousand four hundred and twenty-four inpatients affected by bipolar (n=627), major depressive (n=511), schizophrenic (n=210), delusional (n=48) disorder and psychotic disorder not otherwise specified (n=27) (DSM-IV) were included; all patients and 380 controls were typed for the TPH variants using PCR techniques. A sub-sample of 963 patients was assessed using the Operational Criteria for Psychotic Illness (OPCRIT). TPH variants were not associated with major psychoses, but a trend was observed toward an excess of TPH*A/A in bipolar disorder. The analysis of symptomatology factors did not show any significant difference either; however, a trend was observed for males with the TPH*A genotype to have lower depressive symptoms compared with TPH*C subjects. Possible stratification factors such as current age and age of onset did not affect the observed results. TPH A218C variants are not, therefore, a major liability factor for the symptoms of major psychoses to have in the present sample. TPH*A containing variants may be a protective factor for depressive symptoms among male subjects with mood disorders or for a subtype of mood disorders characterized by a mainly manic form of symptomatology.

DRD4 exon 3 variants associated with delusional symptomatology in major psychoses: a study on 2,011 affected subjects.

We previously reported an association of DRD4 exon3 long allele variants with delusional symptomatology independently from diagnoses. The aim of this investigation was to study DRD4 in major psychoses and to test the association in a larger sample. We studied 2,011 inpatients affected by bipolar disorder (n = 811), major depressive disorder (n = 635), schizophrenia (n = 419), delusional disorder (n = 104), psychotic disorder not otherwise specified (n = 42), and 601 healthy controls. A subsample of 1,264 patients were evaluated using the OPCRIT checklist and differences of symptomatology factor scores among genetic variants were assessed using one-way analysis of variance (ANOVA). DRD4 allele and genotype frequencies in bipolars, schizophrenics, delusionals, and psychotic NOS were not significantly different from controls; major depressives showed a trend toward an excess of DRD4*Short and DRD4*Short/Short variants versus controls. The ANOVA on factor scores in the whole subsample of 1,264 subjects showed a significant difference on delusion factor in allele analysis (P = 0.007), and in genotype one (P = 0.018), with DRD4*Long containing variants associated with severe symptomatology. The analysis in the replication subjects only (n = 803) showed a trend in the same direction, though not reaching the significance level. This analysis in an enlarged sample suggests that DRD4*Long alleles exert a small but significant influence on the delusional symptomatology in subjects affected by major psychoses.

Tryptophan hydroxylase polymorphism and suicidality in unipolar and bipolar affective disorders: a multicenter association study.

BACKGROUND: Being the rate-limiting enzyme in the biosynthesis of serotonin, the tryptophan hydroxylase gene (TPH) has been considered a possible candidate gene in bipolar and unipolar affective disorders (BPAD and UPAD). Several studies have investigated the possible role of TPH polymorphisms in affective disorders and suicidal behavior. METHODS: The TPH A218C polymorphism has been investigated in 927 patients (527 BPAD and 400 UPAD) and their matched healthy control subjects collected within the European Collaborative Project on Affective Disorders. RESULTS: No difference of genotype distribution or allele distribution was found in BPAD or UPAD. No statistically significant difference was observed for allele frequency and genotypes counts. In a genotype per genotype analysis in UPAD patients with a personal history of suicide attempt, the frequency of the C-C genotype (homozygosity for the short allele) was lower in UPAD patients (24%) than in control subjects (43%) (chi(2) = 4.67, p =.03). There was no difference in allele or genotype frequency between patients presenting violent suicidal behavior (n = 48) and their matched control subjects. CONCLUSIONS: We failed to detect an association between the A218C polymorphism of the TPH gene and BPAD and UPAD in a large European sample. Homozygosity for the short allele is significantly less frequent in a subgroup of UPAD patients with a history of suicide attempt than in control subjects.

Serotonin transporter gene associated with lithium prophylaxis in mood disorders.

The aim of this study was to investigate the possible association between the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the prophylactic efficacy of lithium in mood disorders. Two hundred and one subjects affected by bipolar (n = 167) and major depressive (n = 34) disorder were followed prospectively for an average of 58.2 months and were typed for their 5-HTTLPR variant using polymerase chain reaction techniques. 5-HTTLPR variants were associated with lithium outcome (F = 5.35; df = 2,198; P = 0.005). Subjects with the s/s variant showed a worse response compared to both l/s and l/l variants. Consideration of possible stratification effects such as sex, polarity, age at onset, duration of lithium treatment and previous episodes did not influence the observed association. 5-HTTLPR variants may be a possible influencing factor for the prophylactic efficacy of lithium in mood disorders.

Serotonin-2C and serotonin-1A receptor genes are not associated with psychotic symptomatology of mood disorders.

The serotonergic system is involved in both pathophysiology and treatment of mood disorders. In the present study we investigated the possible influence of the polymorphisms of the serotonin-1A and 2C receptor genes on the symptomatology of mood disorders. Eighty-four inpatients affected by mood disorders (72 bipolar and 12 major depressive disorder) were assessed by the Operational Criteria Checklist for Psychotic Illness to score their lifetime psychotic symptomatology. The subjects were also typed for 5HT1A and 5HT2C variants using polymerase chain reaction techniques. No association was found between 5HT2C and psychopathology as defined by the four symptomatologic factors used as phenotype definition (mania, depression, delusion, and disorganization) even when bipolar subjects were analyzed separately. Only one subject with the 5HT1A variant was observed. Genetic variation at the 5HT1A and 5HT2C receptor genes does not, therefore, play a major role in the pathogenesis of mood disorders symptomatology. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:161-166, 2000.

Dopamine receptor D2 Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses.

The D2 receptor (DRD2) is a binding site of many psychoactive drugs and it has been proposed as a genetic risk factor for psychiatric disorders. The aim of this investigation was to study the DRD2 S311C variant in major psychoses. We studied 1182 inpatients with diagnoses of bipolar disorder (n = 480), major depressive disorder (n = 269), schizophrenia (n = 366), delusional disorder (n = 44), psychotic disorder not otherwise specified (n = 23) and 267 healthy controls. Eight hundred and eighty-seven subjects were also scored for their lifetime symptomatology using the the Operational Criteria checklist for psychotic illness (OPCRIT). DRD2 variants were not associated with affected subjects even when possible confounders like gender and onset were considered. When we considered the 887 subjects with the symptomatologic analysis, we observed a significant association of the DRD2 S311C variant with both delusion and disorganization features. The association was present independently from diagnoses. Our results do not show that coding variants of the DRD2 S311C play a major role in conferring susceptibility to major psychoses, but they may be connected with disorganized and delusional symptomatology independently from diagnoses.

Serotonin receptor 2A, 2C, 1A genes and response to lithium prophylaxis in mood disorders.

The aim of this study was to investigate the influence of serotonin receptors 2A, 2C and 1A gene variants on lithium prophylactic efficacy in mood disorders. One hundred and twenty-four subjects affected by bipolar (n=102) and major depressive (n=22) disorder were followed prospectively for an average of 52 months and were typed for 5-HT2A (T102C: n=111, HTP: n=104), 5-HT2C (n=110) and 5-HT1A (n=61) variants. Both 5-HT2A and 5-HT2C variants were not associated with lithium outcome. Consideration of possible stratification effects like gender, polarity, family history, age at onset and duration of lithium treatment did not influence results. No 5-HT1A gene variant was identified. 5-HT2A and 2C variants are not, therefore, associated with lithium prophylactic efficacy in mood disorders.

Serotonin-2A receptor gene is not associated with symptomatology of schizophrenia.

The serotonin receptor type 2A (5-HT2A) is a primary candidate for involvement in major psychoses. Polymorphisms within the 5-HT2A gene have recently been reported to be associated with a variety of psychopathological conditions. In the present study, we investigated the potential influence of the T102C polymorphism on the psychopathology of schizophrenia. One hundred eighty-eight inpatients affected by schizophrenia (DSM-III-R) were assessed by the Operational Criteria checklist for psychotic illness (OPCRIT) and were typed for their 5-HT2A variants by PCR techniques. Mania, depression, delusion and disorganization were the four symptomatologic factors previously derived from our psychotic population that were used to define phenotype in our sample. Genetic variants of the polymorphism under study were not associated with these symptomatologic factors, and consideration of possible stratification effects such as sex and age of onset did not reveal any association either. Our results do not, therefore, support the hypothesis that the serotonin receptor 2A gene is a liability factor for the symptomatology of schizophrenia as defined by the OPCRIT checklist. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:84-87, 2000.