Early, On-Treatment Levels and Dynamic Changes of Genomic Instability in Circulating Tumor DNA Predict Response to Treatment and Outcome in Metastatic Breast Cancer Patients.

BACKGROUND: Circulating tumor DNA (ctDNA) offers high sensitivity and specificity in metastatic cancer. However, many ctDNA assays rely on specific mutations in recurrent genes or require the sequencing of tumor tissue, difficult to do in a metastatic disease. The purpose of this study was to define the predictive and prognostic values of the whole-genome sequencing (WGS) of ctDNA in metastatic breast cancer (MBC). METHODS: Plasma from 25 patients with MBC were taken at the baseline, prior to treatment (T0), one week (T1) and two weeks (T2) after treatment initiation and subjected to low-pass WGS. DNA copy number changes were used to calculate a Genomic Instability Number (GIN). A minimum predefined GIN value of 170 indicated detectable ctDNA. GIN values were correlated with the treatment response at three and six months by Response Evaluation Criteria in Solid Tumours assessed by imaging (RECIST) criteria and with overall survival (OS). RESULTS: GIN values were detectable (>170) in 64% of patients at the baseline and were significantly prognostic (41 vs. 18 months OS for nondetectable vs. detectable GIN). Detectable GIN values at T1 and T2 were significantly associated with poor OS. Declines in GIN at T1 and T2 of > 50% compared to the baseline were associated with three-month response and, in the case of T1, with OS. On the other hand, a rise in GIN at T2 was associated with a poor response at three months. CONCLUSIONS: Very early measurements using WGS of cell-free DNA (cfDNA) from the plasma of MBC patients provided a tumor biopsy-free approach to ctDNA measurement that was both predictive of the early tumor response at three months and prognostic.

Variations in AP and frog-leg pelvic radiographs in a pediatric population.

INTRODUCTION: It is common for pediatric patients with a history of hip dysplasia to undergo anteroposterior (AP) and frog-leg (FL) lateral radiographs to monitor development of the hip. Because of sensitivity of pediatric tissues to ionizing radiation, we sought to document the relationship between AP and FL radiographs and to determine which image was better to assess acetabular dysplasia. METHODS: An Institutional Review Board-approved, retrospective review was conducted on 33 patients screened for hip dysplasia at a single institution. We sought to determine whether either film was more likely to be qualitatively better in position and whether there were differences in acetabular measures between the 2 radiographs. Standard measurements on AP and FL radiographs were made by 5 observers on 2 different occasions to assess interobserver and intraobserver variability. RESULTS: The mean age was 23+1 months, and 80% were female; none of the children had hip dysplasia. There was no statistical significance in the quotient of pelvic rotation (AP 1.2 + 0.1 degrees and FL 1.1 + 0.1 degrees; P = 0.84). There was a statistical difference in obturator height in mm (AP 16.0 + 0.3 and FL 17.8 + 0.2; P = 7.2E-10). The mean intraobserver variability for the acetabular index was 1.8 + 0.2 and 1.7 + 0.2 degrees for AP and FL alignments, respectively (P = 0.58), and the mean interobserver variability was 1.7 + 0.1 and 1.7 + 0.1 degrees, respectively (P = 0.75). The measurements of linear variability between the AP and FL showed no statistical significant difference with the exception of the left Hilgenreiner distance in mm (AP 1.00 + 0.08 and FL 0.81 + 0.08; P = 0.02). DISCUSSION: These results demonstrate that there is little clinical difference in variability of positioning and rotational variables between AP and FL radiographs for hip dysplasia. These results indicate that either image could be used assess to acetabular dysplasia thus decreasing risks of ionizing radiation. LEVEL OF EVIDENCE: Level III.

Does active referral by a doctor or 12-Step peer improve 12-Step meeting attendance? Results from a pilot randomised control trial.

BACKGROUND: Active engagement in 12-Step self-help groups (SHG) is associated with improvements in substance use outcomes during and after treatment, yet levels of participation in SHG meetings in the U.K. remain low. METHOD: An RCT investigating the impact of active referral to SHG, delivered by doctors or 12-Step peers during inpatient treatment on both inpatient and post-treatment meeting attendance was conducted. 151 inpatients with alcohol, opiate, crack-cocaine or benzodiazepine dependence undergoing detoxification, received one of two active referral interventions: 12-Step peer intervention (PI), doctor intervention (DI), or no intervention (NI). 83% of the sample was followed up, 2-3 months following discharge. RESULTS: Active referral interventions significantly increased attendance at 12-Step meetings during inpatient treatment (88% versus 73%, p<.05). Rates of post-discharge meeting attendance were PI=64%, DI=48%, NI=33%, with those in the PI group significantly (OR=3.6; CI=1.3, 9.8) more likely to have attended. Inpatient meeting attenders were three times as likely to have attended meetings post-discharge (59% versus 20%, p<.01), and post-discharge meeting attenders reported significantly higher abstinence rates (60.8% versus 39.2%, p<.05) at follow-up. However, abstinence rates did not differ significantly across intervention groups (44% [PI], 41% [DI] and 36% [NI]). CONCLUSION: Attendance at 12-Step SHGs is associated with greater rates of abstinence and active referral, especially by 12-Step peers, increases 12-Step SHG attendance rates. However, improved clinical outcomes among attendees might not occur until stronger recovery peer support networks are established. These results show promise for the benefit of incorporating Twelve Step Facilitation into U.K. treatment settings.

Hydrostatic comparison of nonpenetrating titanium clips versus conventional suture for repair of spinal durotomies.

STUDY DESIGN: Biomechanics. OBJECTIVE: To compare the hydrostatic strength of suture and nonpenetrating titanium clip repairs of standard spinal durotomies. SUMMARY OF BACKGROUND DATA: Dural tears are a frequent complication of spine surgery and can be associated with significant morbidity. Primary repair of durotomies with suture typically is attempted, but a true watertight closure can be difficult to obtain because of leakage through suture tracts. Nonpenetrating titanium clips have been developed for vascular anastomoses and provide a close apposition of the tissues without the creation of a suture tract. METHODS: Twenty-four calf spines were prepared with laminectomies and the spinal cord was evacuated leaving an intact dura. After Foley catheters were inserted from each end and inflated adjacent to a planned dural defect, the basal flow rate was measured and a 1-cm longitudinal durotomy was made with a scalpel. Eight repairs were performed for each material, which included monofilament suture, braided suture, and nonpenetrating titanium clips. The flow rate at 30, 60, and 90 cm of water and the time needed for each closure were measured. RESULTS: There was no statistically significant difference in the baseline leak rate for all 3 groups. There was no difference in the leakage rate of durotomies repaired with clips and intact specimens at any pressure. Monofilament and braided suture repairs allowed significantly more leakage than both intact and clip-repaired specimens at all pressures. The difference in leak rate increased as the pressure increased. Closing the durotomy with clips took less than half the time of closure with suture. CONCLUSION: Nonpenetrating titanium clips provide a durotomy closure with immediate hydrostatic strength similar to intact dura whereas suture repair with either suture was significantly less robust. The use of titanium clips was more rapid than that of suture repair.

Love, eye contact and the developmental origins of empathy v. psychopathy.

BACKGROUND: A propensity to attend to other people's emotions is a necessary condition for human empathy. AIMS: To test our hypothesis that psychopathic disorder begins as a failure to attend to the eyes of attachment figures, using a `love' scenario in young children. METHOD: Children with oppositional defiant disorder, assessed for callous-unemotional traits, and a control group were observed in a love interaction with mothers. Eye contact and affection were measured for each dyad. RESULTS: There was no group difference in affection and eye contact expressed by the mothers. Compared with controls, children with oppositional defiant disorder expressed lower levels of affection back towards their mothers; those with high levels of callous-unemotional traits showed significantly lower levels of affection than the children lacking these traits. As predicted, the former group showed low levels of eye contact toward their mothers. Low eye contact was not correlated with maternal coercive parenting or feelings toward the child, but was correlated with psychopathic fearlessness in their fathers. CONCLUSIONS: Impairments in eye contact are characteristic of children with callous-unemotional traits, and these impairments are independent of maternal behaviour.

Spinal duraplasty materials and hydrostasis: a biomechanical study: laboratory investigation.

OBJECT: Dural tears are a frequent complication of spinal surgery and contribute to significant morbidity. Occasionally, dural tears cannot be closed primarily and dural patch grafts must be utilized. No data exist on the comparative immediate hydrostatic strength of various patch materials used alone or with a biological adhesive in a spinal dural tear model. Thus, the authors conducted this study to determine the comparative effectiveness of various patch materials used with and without biological adhesive. METHODS: Twenty-four thoracic spines from calves were prepared with laminectomies and spinal cord evacuation, leaving the dura intact. Foley catheters were inflated on either side of a planned dural defect, and baseline hydrostasis was measured using a fluid column at 30, 60, and 90 cm of H(2)O. A standard dural defect (1 × 2 cm) was created, and 8 patches of each material (human fascia lata, Duragen, and Preclude) were sutured in place using 5-0 Prolene hemo-seal running sutures. Hydrostasis was again tested at the same pressures. Finally, a hydrogel sealant (Duraseal) was placed over the defect and hydrostasis was again tested. Results were analyzed with repeated measures ANOVA. RESULTS: The leakage rate increased significantly at each pressure tested for all conditions. There was no difference in leakage among the 3 patch materials at any of the pressures or for either condition (with or without sealant). All patch materials allowed significantly greater leakage than the intact condition at all pressures. The use of sealant reduced leakage significantly at the 30 and 60 mm Hg pressures to levels similar to the intact condition. At 90 mm Hg, leakage of the sealed construct was greater than at the intact condition but significantly less than without the use of sealant. CONCLUSIONS: All 3 dural patch materials were of similar hydrostatic strength and allowed greater leakage than at the intact condition. The use of sealant reduced the amount of leakage at all pressures compared with patching alone but allowed more leakage than the intact state at a high hydrostatic pressure (90 mm Hg).

New estimates of the number of children living with substance misusing parents: results from UK national household surveys.

BACKGROUND: The existing estimates of there being 250,000 - 350,000 children of problem drug users in the UK (ACMD, 2003) and 780,000 - 1.3 million children of adults with an alcohol problem (AHRSE, 2004) are extrapolations of treatment data alone or estimates from other countries, hence updated, local and broader estimates are needed. METHODS: The current work identifies profiles where the risk of harm to children could be increased by patterns of parental substance use and generates new estimates following secondary analysis of five UK national household surveys. RESULTS: The Health Survey for England (HSfE) and General Household Survey (GHS) (both 2004) generated consistent estimates - around 30% of children under-16 years (3.3 - 3.5 million) in the UK lived with at least one binge drinking parent, 8% with at least two binge drinkers and 4% with a lone (binge drinking) parent. The National Psychiatric Morbidity Survey (NPMS) indicated that in 2000, 22% (2.6 million) lived with a hazardous drinker and 6% (705,000) with a dependent drinker. The British Crime Survey (2004) and NPMS (2000) indicated that 8% (up to 978,000) of children lived with an adult who had used illicit drugs within that year, 2% (up to 256,000) with a class A drug user and 7% (up to 873,000) with a class C drug user. Around 335,000 children lived with a drug dependent user, 72,000 with an injecting drug user, 72,000 with a drug user in treatment and 108,000 with an adult who had overdosed. Elevated or cumulative risk of harm may have existed for the 3.6% (around 430,000) children in the UK who lived with a problem drinker who also used drugs and 4% (half a million) where problem drinking co-existed with mental health problems. Stronger indicators of harm emerged from the Scottish Crime Survey (2000), according to which 1% of children (around 12,000 children) had witnessed force being used against an adult in the household by their partner whilst drinking alcohol and 0.6% (almost 6000 children) whilst using drugs. CONCLUSION: Whilst harm from parental substance use is not inevitable, the number of children living with substance misusing parents exceeds earlier estimates. Widespread patterns of binge drinking and recreational drug use may expose children to sub-optimal care and substance-using role models. Implications for policy, practice and research are discussed.

Involvement of the spine in patients with multiple hereditary exostoses.

BACKGROUND: Extension of a vertebral exostosis into the spinal canal is rare, but many isolated cases have been reported in the literature. Three existing patients with multiple hereditary exostoses at our institution had development of neurologic findings and were found to have exostoses in the spinal canal. These findings led us to perform magnetic resonance imaging or computed tomographic scans for the remaining patients with multiple hereditary exostoses at our institution. METHODS: Forty-four patients at our institution (including twenty-six male patients and eighteen female patients) had multiple hereditary exostoses. Forty-three patients were evaluated with magnetic resonance imaging and one was evaluated with computed tomography to look for spinal column involvement. RESULTS: Thirty (68%) of the forty-four patients had exostoses arising from the spinal column, and twelve (27%) had lesions encroaching into the spinal canal. Thirty-six of the forty-four patients also had plain radiographs, but only six had radiographs that accurately identified the lesions and another six had radiographs that mistakenly identified lesions that were not confirmed with magnetic resonance imaging or computed tomography. Patients with lesions inside the spinal canal were typically asymptomatic and neurologically normal, with radiographs that did not demonstrate the lesion. Compared with female patients, male patients were more likely to have spinal lesions and more likely to have lesions encroaching into the spinal canal (p = 0.014). CONCLUSIONS: The risk that a patient with multiple hereditary exostoses has a lesion within the spinal canal is much higher than previously suspected (27%). Because the potential exists for serious neurologic injury to occur, we have begun to use magnetic resonance imaging to screen all patients who have multiple hereditary exostoses at least once during the growing years.

It ain't what you do, it's the way that you do it: a qualitative study of advice for young cannabis users.

INTRODUCTION: Advice is a widely recommended and practised intervention with young drug users. Study of precisely how advice is given and received in any setting has, however, been limited. DESIGN AND METHODS: We qualitatively analysed 106 audio-recordings of advice sessions on cannabis use for young people within a randomised trial. Inductive data analysis was guided by a focus on practitioner behaviour which served to engage the active participation of the young drug user in the session. RESULTS: A cluster of 'Information Management' activities was identified together with an 'Interactive Orientation' evident in a series of specific behaviours. Participants were most successfully engaged when both were combined, understood here as 'Personalised Advice-giving'. DISCUSSION AND CONCLUSIONS: These components identified in this exploratory study might assist further research in rectifying the absence of a solid empirical basis for effective practice in advice giving with young drug users and more widely.

Glistenings in the single-piece, hydrophobic, acrylic intraocular lenses.

PURPOSE: To study glistenings in single-piece AcrySof (models SA60 and SN60; Alcon, Fort Worth, Texas, USA) intraocular lenses (IOLs). DESIGN: Observational, longitudinal study. METHODS: Consecutive patients with the SA60 were examined at 12, 24, and 36 months after surgery; those with the SN60 were examined 12 months after surgery. Best-corrected logarithm of the minimum angle of resolution visual acuity, glare testing, contrast sensitivity, and wavefront analysis were performed. Any patient with pathologic features likely to impact visual quality was eliminated. All IOLs were photographed, and glistenings were analyzed for size and density by a computer program. RESULTS: All IOLs had glistenings, and neither size, density, nor severity index (size x density) correlated with acuity, glare testing, or wavefront analysis results. High spatial resolution contrast acuity (patch D) had a borderline correlation (P = .06) with severity index, as did progress over time (P = .04). CONCLUSIONS: All IOLs studied had glistenings. High spatial resolution contrast sensitivity impact and severity progression over time deserve further study.

Autosomal dominant cone dystrophy caused by a novel mutation in the GCAP1 gene (GUCA1A).

PURPOSE: To describe the clinical features and genetic analysis of a family with an autosomal dominant cone dystrophy (adCD). METHODS: Selected members of a family with an autosomal dominant cone dystrophy underwent ophthalmic evaluation. Blood samples were obtained, genomic DNA was isolated, and genomic fragments were amplified by PCR. Linkage to locus D6S1017 was established. DHPLC mutational analysis and direct sequencing were used to identify a mutation in GUCA1A, the gene encoding the guanylate cyclase activating protein 1 (GCAP1). RESULTS: Of 24 individuals who are at risk of the disease in a five generation family, 11 members were affected. Clinical presentations included photophobia, color vision defects, central acuity loss, and legal blindness with advanced age. The disease phenotype was observed in the second and third decades of life and segregated in an autosomal dominant fashion. An electroretinogram performed on one proband revealed profoundly subnormal and prolonged photopic and flicker responses, but preserved scotopic ERGs, consistent with a cone dystrophy. Mutational analysis and direct sequencing revealed a C451T transition in GUCA1A, corresponding to a novel L151F mutation in GCAP1. Like the E155G mutation, this mutation occurs in the EF4 hand domain, a region of GCAP1 critical in conferring calcium sensitivity to the protein. The leucine at this position is highly conserved among vertebrate guanylate cyclase activating proteins. CONCLUSIONS: A novel L151F missense mutation in the EF4 high affinity Ca2+ binding site of GCAP1 is linked to adCD in a large pedigree. The cone dystrophy in this family shares clinical and electrophysiologic characteristics with other previously described adCD caused by mutations in GUCA1A.