Characterising benign fibrous soft-tissue tumours in adults: why is it so difficult and what do we need to know?

Fibrous, myofibroblastic, and fibrohistiocytic soft-tissue tumours are amongst the most common benign soft-tissue lesions encountered in clinical practice. They demonstrate varied biological behaviour and imaging characteristics. Benign fibroblastic lesions, such as nodular fasciitis, are small, have a self-limited course, and rarely recur after excision, whereas deep fibromatosis and plexiform fibrohistiocytic tumours tend to exhibit more aggressive features and often have high recurrence rates. MRI with its superior tissue contrast, multiplanar imaging capability, and lack of ionising radiation is regarded as the preferred method of tumour evaluation, tissue characterisation, and assessment of treatment response. Histopathological features are depicted at MRI, reflecting the amount and distribution of the cellular and fibrous matrix. Cellular tumours tend to show higher T2 signal intensity and post-contrast enhancement as compared to tumours with greater collagenous content, which appear dark and show less enhancement. Awareness of MR characteristics, pathological behaviour, and common sites of occurrence of fibrous soft-tissue tumours will help radiologists to determine the appropriate differential diagnosis and guide patient management.

The impact of parent socio-economic status on executive functioning and cortical morphology in individuals with schizophrenia and healthy controls.

BACKGROUND: Relatively lower executive functioning is characteristic of individuals with schizophrenia. As low socio-economic status (SES) early in life (i.e. parent SES) has been linked with lower executive skills in healthy children, we hypothesized that parental SES (pSES) would be more strongly related to executive functioning in individuals with schizophrenia than in controls and have a greater impact on prefrontal cortical morphology. METHOD: Healthy controls (n = 125) and individuals with schizophrenia (n = 102) completed tests assessing executive functioning and intelligence. The groups were matched on pSES, which was evaluated with the Hollingshead-Redlich scale. A principal components analysis (PCA) was conducted on 10 variables from six executive tests, yielding three specific components (fluency, planning and response inhibition). Voxel-based morphometry (VBM) was used to evaluate effects of pSES on gray matter (GM) concentration. RESULTS: Lower pSES was associated with lower scores across the three executive functioning components, and a significant group by pSES interaction was observed such that low pSES, in particular, affected individuals with schizophrenia. These effects remained significant when intellectual ability, education and self-SES (sSES) were added as covariates. VBM revealed that lower pSES was associated with reduced GM volume in several anterior brain regions, especially the superior frontal gyrus, in patients but not in controls. CONCLUSIONS: These findings suggest that individuals with schizophrenia may be particularly vulnerable to the adverse impact of low pSES, in terms of both lower executive skills and reduced anterior GM volumes.

MRI features of soft-tissue lumps and bumps.

Superficial soft-tissue lesions are frequently encountered by radiologists in everyday practice. Characterization of these soft-tissue lesions remains problematic, despite advances in imaging. By systematically using clinical history, anatomical location, and signal intensity characteristics on MRI images, one can determine the diagnosis for the subset of determinate lesions that have characteristic clinical and imaging features as well as narrow the differential diagnoses for lesions with non-specific or indeterminate characteristics. In this review, a spectrum of histologically proven benign and malignant superficial soft-tissue lesions from a single institution will be presented. In addition, a few tumour-like conditions will be included as they can be encountered during imaging of soft-tissue masses.

MAPK14 and CNR1 gene variant interactions: effects on brain volume deficits in schizophrenia patients with marijuana misuse.

BACKGROUND: Adolescent marijuana use is associated with increased risk for schizophrenia. We previously reported that marijuana misuse in conjunction with specific cannabinoid receptor 1 (CNR1) genetic variants (rs12720071-G-allele carriers) contributed to white-matter (WM) brain volume deficits in schizophrenia patients. In this study, we assessed the influence of another cannabinoid-related gene, mitogen-activated protein kinase 14 (MAPK14), and potential MAPK14-CNR1 gene-gene interactions in conferring brain volume abnormalities among schizophrenia patients with marijuana abuse/dependence. MAPK14 encodes a member of the MAPK family involved in diverse cellular processes, including CNR1-induced apoptosis. METHOD: We genotyped 235 schizophrenia patients on nine MAPK14 tag single nucleotide polymorphisms (tSNPs). Approximately one quarter of the sample had marijuana abuse or dependence. Differential effects of MAPK14 tSNPs on brain volumes across patients with versus without marijuana abuse/dependence were examined using ANCOVA. RESULTS: Of the MAPK14 tSNPs, only rs12199654 had significant genotype effects and genotype × marijuana misuse interaction effects on WM volumes. rs12199654-A homozygotes with marijuana abuse/dependence had significantly smaller total cerebral and lobar WM volumes. The effects of MAPK14 rs12199654 on WM volume deficits remained significant even after controlling for the CNR1 rs12720071 genotype. There were significant main effects of the MAPK14 CNR1 diplotype and diplotype × marijuana interaction on WM brain volumes, with both genetic variants having additive contributions to WM volume deficits only in patients with marijuana misuse. CONCLUSIONS: Given that CNR1-induced apoptosis is preceded by increased MAPK phosphorylation, our study suggests that potential MAPK14-CNR1 gene-gene interactions may mediate brain morphometric features in schizophrenia patients with heavy marijuana use.

Statistical epistasis and progressive brain change in schizophrenia: an approach for examining the relationships between multiple genes.

Although schizophrenia is generally considered to occur as a consequence of multiple genes that interact with one another, very few methods have been developed to model epistasis. Phenotype definition has also been a major challenge for research on the genetics of schizophrenia. In this report, we use novel statistical techniques to address the high dimensionality of genomic data, and we apply a refinement in phenotype definition by basing it on the occurrence of brain changes during the early course of the illness, as measured by repeated magnetic resonance scans (i.e., an 'intermediate phenotype.') The method combines a machine-learning algorithm, the ensemble method using stochastic gradient boosting, with traditional general linear model statistics. We began with 14 genes that are relevant to schizophrenia, based on association studies or their role in neurodevelopment, and then used statistical techniques to reduce them to five genes and 17 single nucleotide polymorphisms (SNPs) that had a significant statistical interaction: five for PDE4B, four for RELN, four for ERBB4, three for DISC1 and one for NRG1. Five of the SNPs involved in these interactions replicate previous research in that, these five SNPs have previously been identified as schizophrenia vulnerability markers or implicate cognitive processes relevant to schizophrenia. This ability to replicate previous work suggests that our method has potential for detecting a meaningful epistatic relationship among the genes that influence brain abnormalities in schizophrenia.

Phylogenetic analyses of morphological evolution in the gametophyte and sporophyte generations of the moss order Hookeriales (Bryopsida).

Morphological characters from the gametophyte and sporophyte generations have been used in land plants to infer relationships and construct classifications, but sporophytes provide the vast majority of data for the systematics of vascular plants. In bryophytes both generations are well developed and characters from both are commonly used to classify these organisms. However, because morphological traits of gametophytes and sporophytes can have different genetic bases and experience different selective pressures, taxonomic emphasis on one generation or the other may yield incongruent classifications. The moss order Hookeriales has a controversial taxonomic history because previous classifications have focused almost exclusively on either gametophytes or sporophytes. The Hookeriales provide a model for comparing morphological evolution in gametophytes and sporophytes, and its impact on alternative classification systems. In this study we reconstruct relationships among mosses that are or have been included in the Hookeriales based on sequences from five gene regions, and reconstruct morphological evolution of six sporophyte and gametophyte traits that have been used to differentiate families and genera. We found that the Hookeriales, as currently circumscribed, are monophyletic and that both sporophyte and gametophyte characters are labile. We documented parallel changes and reversals in traits from both generations. This study addresses the general issue of morphological reversals to ancestral states, and resolves novel relationships in the Hookeriales.

Striatal function in relation to negative symptoms in schizophrenia.

BACKGROUND: Previous studies have suggested that motivational aspects of executive functioning, which may be disrupted in schizophrenia patients with negative symptoms, are mediated in part by the striatum. Negative symptoms have been linked to impaired recruitment of both the striatum and the dorsolateral prefrontal cortex (DLPFC). Here we tested the hypothesis that negative symptoms are associated primarily with striatal dysfunction, using functional magnetic resonance imaging (fMRI). METHOD: Working-memory load-dependent activation and gray matter volumes of the striatum and DLPFC were measured using a region-of-interest (ROI) approach, in 147 schizophrenia patients and 160 healthy controls. In addition to testing for a linear relationships between striatal function and negative symptoms, we chose a second, categorical analytic strategy in which we compared three demographically and behaviorally matched subgroups: patients with a high burden of negative symptoms, patients with minimal negative symptoms, and healthy subjects. RESULTS: There were no differences in striatal response magnitudes between schizophrenia patients and healthy controls, but right DLPFC activity was higher in patients than in controls. Negative symptoms were inversely associated with striatal, but not DLPFC, activity. In addition, patients with a high burden of negative symptoms exhibited significantly lower bilateral striatal, but not DLPFC, activation than schizophrenia patients with minimal negative symptoms. Working memory performance, antipsychotic exposure and changes in gray matter volumes did not account for these differences. CONCLUSIONS: These data provide further evidence for a robust association between negative symptoms and diminished striatal activity. Future work will determine whether low striatal activity in schizophrenia patients could serve as a reliable biomarker for negative symptoms.

Nuclear morphometry in columnar cell lesions of the breast: is it useful?

AIMS: To evaluate the nuclear morphometric features of breast columnar cell lesions (CCLs) observed on mammotome core biopsies, to determine if there are significant measurable differences between those with atypia and those without. Correlation with follow-up open excision specimens was made. METHODS: Mammotome core biopsies performed on patients that contained CCLs were derived from the departmental case files. Histological material was reviewed and foci of CCLs demarcated for nuclear morphometric assessment, which was accomplished using an imaging system. Nuclear parameters studied were nuclear area and perimeter, circularity factor and feret's diameter. Statistical analysis used the GraphPad Prism software, with p<0.05 indicating significance. RESULTS: On examination of core biopsies of 40 patients with CCLs, 8 lesions were benign, 4 showed atypical lobular hyperplasia, 8 showed CCLs with nuclear atypia, 19 disclosed atypical ductal hyperplasia (ADH) and 1 showed ductal carcinoma in situ (DCIS). The nuclear area, perimeter and feret's diameter of CCLs with atypia were significantly greater than those without (p = 0.04, 0.03 and 0.019, respectively), whereas no difference was observed in the circularity factor. Follow-up open excision biopsy specimens in 24 patients showed upgrading to DCIS in 40% of cases diagnosed initially with ADH on core biopsy compared with 20% of CCLs with atypia. CONCLUSIONS: Nuclear morphometry in CCLs confirms nuclear size as the key parameter in the assessment of nuclear atypia. Whether it can be potentially used as an adjunctive tool depends on the establishment of appropriate cut-offs.

Pathological diagnosis of columnar cell lesions of the breast: are there issues of reproducibility?

AIMS: To assess inter/intraobserver variability in the interpretation of a series of digitised images of columnar cell lesions (CCLs) of the breast. METHODS: After a tutorial on breast CCL, 39 images were presented to seven staff pathologists, who were instructed to categorize the lesions as follows: 0, no columnar cell change (CCC) or ductal carcinoma in situ (DCIS); 1, CCC; 2, columnar cell hyperplasia; 3, CCC with architectural atypia; 4, CCC with cytological atypia; 5, DCIS. Concordance with the tutor's diagnosis and degree of agreement among pathologists for each image were determined. The same set of images was re-presented to the pathologists one week later, their diagnoses collated, and inter/intraobservor reproducibility and level of agreement for individual images analysed. RESULTS: Diagnostic reproducibility with the tutor ranged from moderate to substantial (kappa values, 0.439-0.697) in the first exercise. At repeat evaluation, intraobserver agreement was fair to perfect (kappa values, 0.271-0.832), whereas concordance with the tutor varied from fair to substantial (kappa values, 0.334-0.669). There was unanimous agreement on more images during the second exercise, mainly because of agreement on the diagnosis of DCIS. The lowest agreement was seen for CCC with cytological atypia. CONCLUSIONS: Interobserver and intraobserver agreement is good for DCIS, but more effort is needed to improve diagnostic consistency in the category of CCC with cytological atypia. Continued awareness and study of these lesions are necessary to enhance recognition and understanding.

Untreated initial psychosis: its relation to quality of life and symptom remission in first-episode schizophrenia.

OBJECTIVE: Previous studies have suggested that there may be an association between longer duration of untreated psychosis and poor outcome in schizophrenia. These studies have been interpreted as providing evidence that untreated psychosis may constitute an "active morbid process" that is "toxic" to the brain. If untreated psychosis is neurotoxic, this would form a strong basis for early intervention in schizophrenia. METHOD: Seventy-four neuroleptic-naive patients with DSM-IV schizophrenia were evaluated 6 months after their first inpatient hospitalization. The authors examined the relationship between untreated initial psychosis duration (measured from onset of first symptom as well as from onset of full positive syndrome) and quality of life, symptom severity, and time to remission of positive symptoms. RESULTS: Earlier age at illness onset was associated with longer duration of untreated prodromal psychotic symptoms. There were no significant gender differences in duration of untreated initial psychosis, nor were there any significant associations between untreated initial psychosis duration and premorbid functioning. After controlling for the effects of age at onset, the duration of untreated initial psychosis did not significantly impair subsequent quality of life, symptom severity, or remission of positive symptoms. CONCLUSIONS: Duration of untreated initial psychosis was not prognostic of poor outcome early in the course of schizophrenia. Biological measures of neurotoxicity are needed to examine the "toxic psychosis" hypothesis more directly.

Impaired glucose tolerance and abnormal movements in patients with schizophrenia.

OBJECTIVE: Diabetes mellitus has been implicated as a risk factor for tardive dyskinesia. The authors examined the association between abnormal movements and impaired glucose metabolism, which often precedes the development of overt diabetes, in patients with schizophrenia. METHOD: Twenty-one patients with DSM-IV schizophrenia receiving neuroleptic medication were given oral glucose tolerance tests involving serial glucose and insulin levels. These values were analyzed in relationship to abnormal involuntary movement ratings. RESULTS: Patients with impaired glucose tolerance had higher mean abnormal movement scores than those without glucose intolerance, but this difference was not statistically significant. There was, however, an association between the magnitude of the fasting insulin level and abnormal movements after the authors controlled for fasting glucose level. Additionally, the fasting glucose level predicted abnormal movements after the authors controlled for age. CONCLUSIONS: Hyperinsulinemia and hyperglycemia associated with insulin resistance may potentially contribute to the pathogenesis of tardive dyskinesia. Findings from this small cross-sectional study suggest a possible relationship that requires clarification through larger, longitudinal studies.

Two-year outcome in first-episode schizophrenia: predictive value of symptoms for quality of life.

OBJECTIVE: Many studies have validated the grouping of schizophrenic symptoms into three independent dimensions: negative, psychotic, and disorganized. Negative symptoms are considered to be an important prognostic indicator, but this clinical observation requires further empirical study, especially with respect to psychosocial functioning. When present at the onset of the first episode, negative symptoms suggest that the patient will develop significant psychosocial impairment. The predictive values of the psychotic and disorganized symptom dimensions, on the other hand, have been less certain. METHOD: In this study of 50 first-episode schizophrenic patients, who were mostly neuroleptic-naive at intake, the authors examined the relationship between the severity of these three symptom dimensions (measured by using the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms) at index hospitalization and quality of life at 2-year follow-up. RESULTS: Negative symptom severity was positively and significantly correlated with later occupational impairment, financial dependence on others, impaired relationships with friends, impaired ability to enjoy recreational activities, and global assessment of functioning. The magnitudes of correlation between the levels of psychotic symptoms or disorganized symptoms and 2-year quality of life measures were comparatively lower. Analyses using multivariate regression statistics also revealed similar findings. CONCLUSIONS: Severity of negative symptoms at index hospitalization may be a portent of poor outcome. In general, severity of psychotic or disorganized symptoms at intake does not appear to predict subsequent quality of life.

Potential inhibitors of polyamine biosynthesis. 2. alpha-Alkyl- and benzyl-(+/-)-ornithine.

Alpha-Methyl-(+/-)-ornithine hydrochloride was not a substrate for ornithine decarboxylase from rat prostate glands. It produced equal inhibition of ornithine decarboxylase obtained from rat prostate glands, spleens of mice inoculated with L1210 leukemic cells, and regenerating rat liver indicating its lack of selectivity for any of these tissues. In these three tissues the inhibition was competitive with L-ornithine. A number of alpha-alkyl- and alpha-aralkyl-substituted analogs of (+/-)-ornithine were synthesized and evaluated in vitro as inhibitors of the enzyme L-ornithine decarboxylase obtained from prostate glands of rats. These compounds were obtained by the reaction of alkyl iodide or benzyl bromide with the anion obtained by treatment of 3-(benzalimino)piperidin-2-one with sodium hydride. The following alpha-substituted analogs of (+/-)-ornithine were obtained: ethyl, n-propyl, n-butyl, n-hexyl, n-octyl, and benzyl. The synthesized compounds were found to be much less active than alpha-methyl-(+/-)-ornithine as competitive inhibitors of ornithine decarboxylase in vitro. The most active compound in the series was alpha-n-octyl-(+/-)-ornithine which was 60-fold less active than alpha-methyl-(+/-)-ornithine and the least active analog was alpha-n-butyl-(+/-)-ornithine which was 270-fold less active than the alpha-methyl-(+/-)-ornithine.

A comparative effectiveness study of risperidone and olanzapine in the treatment of schizophrenia.

BACKGROUND: Risperidone and olanzapine have each been demonstrated to be efficacious and safe in the treatment of patients with chronic schizophrenia. To evaluate their relative effectiveness, and to better understand the advantages and limitations of each neuroleptic during actual clinical use, we compared one directly against the other. METHOD: Forty-two subjects with DSM-IV schizophrenia had received open-label treatment with either risperidone or olanzapine. Symptoms, global functioning, and extrapyramidal side effects before and after acute treatment were compared within and across groups. At 6-month follow-up, the relative effectiveness of these 2 atypical neuroleptics on symptoms and quality of life were further evaluated. RESULTS: Following an average of 4 weeks of acute treatment, both risperidone and olanzapine were effective in reducing negative, psychotic, and disorganized symptoms. Although both neuroleptics were associated with low occurrence of treatment-emergent parkinsonism, risperidone was more likely to induce akathisia. The measures for parkinsonism were no different across treatment groups, even after taking into account the higher rate of anticholinergic use in the risperidone group. Following 6 months of treatment with these 2 atypical neuroleptics, there was a significantly greater reduction in psychotic symptoms among risperidone-treated subjects. Otherwise, risperidone and olanzapine appear to be equally effective in reducing disorganized and negative symptoms and in improving the quality of life. CONCLUSION: Risperidone and olanzapine were equally effective as acute treatments. Risperidone was more effective for treatment of psychotic symptoms at 6 months, but otherwise the 2 medications were equally effective in the routine clinical care of patients with schizophrenia. If low (<6 mg/day) doses of risperidone are used, the 2 medications have comparable rates of parkinsonian side effects.

Studies on human filariasis in Malaysia: the application of an indirect hemagglutination technique for immunodiagnosis.

The indirect hemagglutination (IHA) test done with turkey red cells was applied to 173 serum samples obtained from patients and persons exposed to Wuchereria bancrofti and Brugia malayi in endemic areas of Peninsular Malaysia. A crude extract of adult worms of the rat filaria, Breinlia booliati, was used as the antigen. When a titer of 1:16 was taken as negative, positive IHA test rates in sera from microfilaria-negative persons in endemic areas, microfilaremic cases, and patients with clinical filariasis were 13%, 75%, and 80%, respectively. Results of the IHA test correlated well with results obtained with the indirect fluorescent technique.

Studies on human filariasis in Malaysia: immunoglobulin and complement levels in persons infected with Brugia malayi and Wuchereria bancrofti.

Levels of immunoglobulins G, A, M and E as well as complement components C3c and C4 have been determined in populations in various endemic areas in Peninsular Malaysia and also in filariasis patients. High immunoglobulin levels were seen. In the microfilarial-negative group IgG was 2009 mg% while IgE was 3967 I.U./ml. In the filariasis group, Wuchereria bancrofti patients had significantly higher levels of IgG, IgM and IgE, namely, 3314 mg%, 804 mg% and 18400 I.U./ml respectively. The significance of these levels is discussed.

Interspecific competition among Aedes aegypti, Ae. albopictus, and Ae. triseriatus (Diptera: Culicidae): larval development in mixed cultures.

Interactions among the larvae of Aedes aegypti (L.), Ae. albopictus (Skuse), and Ae. triseriatus (Say) were studied in trispecific and bispecific mixed populations under laboratory and field conditions. Competitive stress (as evidenced by the average time to first, 50, and 75% pupation and the total pupation periods for mixed populations of each species in comparison with their single species controls) was more pronounced in mixed cultures reared in glass jars in the laboratory than in tires under field conditions. In the laboratory, the larval development of Ae. aegypti reared together with Ae. albopictus or Ae. triseriatus, or both, larvae was accelerated significantly. Conversely, the time to pupation for Ae. albopictus and Ae. triseriatus was delayed when reared with Ae. aegypti. However, the average wing length of female Ae. albopictus and Ae. triseriatus was greater in the mixed cultures than in single species cultures. These data indicated that the effect of intraspecific competition was greater than interspecific competition. Adequate food and higher temperature appeared to promote rapid development and higher survival of the immature stages of the three Aedes species in tires placed in the field. In general, Ae. triseriatus larvae required a longer period for larval development and had greater larval mortality than either Ae. aegypti or Ae. albopictus. In mixed populations of Ae, albopictus and Ae. aegypti in the jars and food-rich tires, the periods needed to attain first, 50, and 75% cumulative pupation were not significantly different than in single species controls. We conclude that no clear-cut displacement occurred in mixed experimental populations of Ae. aegypti and Ae. albopictus.

Food ingestion and digestive enzymes in larval Aedes aegypti and Ae. albopictus (Diptera: Culicidae).

Frequency of the labral brush movements of first, second, and fourth instars of Aedes aegypti (L.) and Aedes albopictus (Skuse) was studied comparatively in the laboratory. A frequency of 197 strokes per min for the first and second instars was observed in the former species compared to 118 strokes per min in the latter species. A faster ingestion rate of algal cells also was observed in first and second instars of Ae. aegypti (mean 57.5 cells per s) compared with first and second instars of Ae. albopictus (mean 22.4 cells per s). The digestive enzymes chymotrypsin (EC 3.4.21.1) and trypsin (EC 3.4.21.4) were more active in the peritrophic membrane (including food contents) than in the midgut epithelium of both species. Chymotrypsin activity in 11-d-old third and fourth instars of Ae. albopictus was 28 times higher than in the corresponding stadia of Ae. aegypti, indicating that the former species may have a superior enzymatic process for digesting food proteins.

Dependence on public financial support early in the course of schizophrenia.

Although most patients with schizophrenia rely on public financial support, little is known about how soon after the onset of illness such dependence occurs. Forty-eight patients with schizophrenia were followed for a mean of five years after their first hospitalization to examine their reliance on public support. At one year after their first hospitalization, 27 subjects (56 percent) were primarily supported by social service agencies. Once such support was initiated, it was maintained throughout the entire follow-up period for all patients except two. The findings indicate that dependence on public financial assistance begins very early in the course of illness for most hospitalized patients with schizophrenia.

Epidemiology, presentation and management of congenital muscular torticollis.

AIM OF STUDY: Congenital muscular torticollis is a condition of debatable aetiology and management. Untreated, cervical function and facial cosmesis may be severely compromised. The aim of this study was to establish the epidemiology, presentation and management of congenital muscular torticollis in Singapore. PATIENTS: Ninety-one patients with torticollis were seen at the National University Hospital (NUH) from January 1994 to December 1997. Torticollis was first noted at a median age of 2 months with the median age of presentation being 6 months. At presentation, a sternomastoid tumour was noted in 33 patients and 62 patients had facial asymmetry. Thirteen of 22 patients with neonatal records available had mandibular hypoplasia at birth on the side where the sternomastoid was affected. Half of the patients (45) had a right sided lesion, with 46 being left sided. The rates of assisted breech delivery, instrumental deliveries (forceps and vacuum) and Caesarean section were higher in the study group. Nine (59.1%) of 13 patients with vertex presentation, had a lesion on the side of the presenting shoulder. Forty-eight of 72 patients responded well to therapy with improvement; 20 underwent surgery and the median age of presentation of 19.5 months in this group was significantly later than that of 4 months in the group which responded to physiotherapy alone. CONCLUSION: Birth trauma appears to be the main aetiological factor in congenital muscular torticollis. Patients generally respond well to physiotherapy. This study revealed 2 findings hitherto unreported: (1) mandibular hypoplasia may be an useful early sign of this condition, and (2) the side affected may depend on the side of shoulder delivered first. More studies, however, are required to confirm these findings.