Individuals with attention-deficit/hyperactivity disorder (ADHD) have difficulties navigating dynamic everyday situations that contain multiple sensory inputs that need to either be attended to or ...ignored. As conventional experimental tasks lack this type of everyday complexity, we administered a film-based multi-talker condition with auditory distractors in the background. ADHD-related aberrant brain responses to this naturalistic stimulus were identified using intersubject correlations (ISCs) in functional magnetic resonance imaging (fMRI) data collected from 51 adults with ADHD and 29 healthy controls. A novel permutation-based approach introducing studentized statistics and subject-wise voxel-level null-distributions revealed that several areas in cerebral attention networks and sensory cortices were desynchronized in participants with ADHD (n = 20) relative to healthy controls (n = 20). Specifically, desynchronization of the posterior parietal cortex occurred when irrelevant speech or music was presented in the background, but not when irrelevant white noise was presented, or when there were no distractors. We also show regionally distinct ISC signatures for inattention and impulsivity. Finally, post-scan recall of the film contents was associated with stronger ISCs in the default-mode network for the ADHD and in the dorsal attention network for healthy controls. The present study shows that ISCs can further our understanding of how a complex environment influences brain states in ADHD.
•We used a naturalistic multi-talker condition to reveal aberrant brain synchronization in ADHD.•Intersubject correlations (ISCs) in attention-related brain areas were decreased in ADHD.•ISCs in the parietal cortex were weaker in ADHD during irrelevant speech or music.•ISCs in different regions were associated with symptoms and with recall of the film content.•We demonstrate the advantages of using naturalistic conditions when studying the neural underpinnings of ADHD.
In clinical trials with oncolytic adenoviruses, there has been no mortality associated with treatment vectors. Likewise, in the Advanced Therapy Access Program (ATAP), where 290 patients were treated ...with 10 different viruses, no vector-related mortality was observed. However, as the patient population who received adenovirus treatments in ATAP represented heavily pretreated patients, often with very advanced disease, some patients died relatively soon after receiving their virus treatment mandating autopsy to investigate cause of death. Eleven such autopsies were performed and confirmed disease progression as the cause of death in each case. The regulatory requirement for investigating the safety of advanced therapy medical products presented a unique opportunity to study tissue samples collected as a routine part of the autopsies. Oncolytic adenoviral DNA was recovered in a wide range of tissues, including injected and noninjected tumors and various normal tissues, demonstrating the ability of the vector to disseminate through the vascular route. Furthermore, we recovered and cultured viable virus from samples of noninjected brain metastases of an intravenously treated patient, confirming that oncolytic adenovirus can reach tumors through the intravascular route. Data presented here give mechanistic insight into mode of action and biodistribution of oncolytic adenoviruses in cancer patients.
With the emergence of effective immunotherapeutics, which nevertheless harbor the potential for toxicity and are expensive to use, biomarkers are urgently needed for identification of cancer patients ...who respond to treatment. In this clinical-epidemiological study of 202 cancer patients treated with oncolytic adenoviruses, we address the biomarker value of serum high-mobility group box 1 (HMGB1) protein. Overall survival and imaging responses were studied as primary endpoints and adjusted for confounding factors in two multivariate analyses (Cox and logistic regression). Mechanistic studies included assessment of circulating tumor-specific T-cells by ELISPOT, virus replication by quantitative PCR, and inflammatory cytokines by cytometric bead array. Patients with low HMGB1 baseline levels (below median concentration) showed significantly improved survival (p = 0.008, Log-Rank test) and radiological disease control rate (49.2% vs. 30.0%, p = 0.038, χ
2
test) as compared to high-baseline patients. In multivariate analyses, the low HMGB1 baseline status was a strong prognostic (HR 0.638, 95% CI 0.462-0.881) and the best predictive factor for disease control (OR 2.618, 95% CI 1.004-6.827). Indicative of an immune-mediated mechanism, antitumor T-cell activity in blood and response to immunogenic-transgene coding viruses associated with improved outcome only in HMGB1-low patients. Our results suggest that serum HMGB1 baseline is a useful prognostic and predictive biomarker for oncolytic immunotherapy with adenoviruses, setting the stage for prospective clinical studies.
Background
Previous lumbar spine surgery is a frequent exclusion criterion for studies evaluating lumbar surgery outcomes. In real-life clinical settings, this patient population is important, as a ...notable proportion of patients evaluated for lumbar spine surgery have undergone prior lumbar surgery already previously. Knowledge about the long-term outcomes after microdiscectomy on patients with previous lumbar surgery and how they compare to those of first-time surgery is lacking.
Methods
The original patient cohort for screening included 615 consecutive patients who underwent surgery for lumbar disc herniation, with a median follow-up time of 18.1 years. Of these patients, 89 (19%) had undergone lumbar spine surgery prior to the index surgery. Propensity score matching (based on age, sex, and follow-up time) was utilized to match two patients without prior surgery with each patient with a previous surgery. The primary outcome measure was the need for further lumbar spine surgery during the follow-up period, and the secondary outcome measures consisted of present-time patient-reported outcome measures (Oswestry Disability Index, EuroQol-5D) and present-time ability to carry out employment.
Results
Patients who received previous lumbar surgeries had a higher need for further surgery (44% vs. 28%,
p
= 0.009) and had a shorter time to further surgery than the propensity score-matched cohort (mean Kaplan–Meier estimate, 15.7 years vs. 19.8 years,
p
= 0.008). Patients with prior surgery reported inferior Oswestry Disability Index scores (13.7 vs. 8.0,
p
= 0.036). and EQ-5D scores (0.77 vs. 0.86,
p
= 0.01). In addition, they had a higher frequency of receiving lumbar spine-related disability pensions than the other patients (12% vs. 1.9%,
p
= 0.01).
Conclusions
Patients with previous lumbar surgery had inferior long-term outcomes compared to patients without prior surgery. However, the vast majority of these patients improved quickly after the index surgery. Furthermore, the difference in the patients’ reported outcomes was small at the long-term follow-up, and they reported high satisfaction with the results of the study surgery. Hence, surgery for these patients should be considered if surgical indications are met, but special care needs must be accounted for when deliberating upon their indications for surgery.
Background
Lumbar disc herniation is often managed conservatively; nevertheless, surgical intervention can be required. Majority of patients experience a drastic relief of symptoms after surgery, but ...previous studies have reported that their health-related quality of life remains inferior compared to the general population for several years. There may be a major cumulative loss of health-related quality of life for young patients as they have long expected life ahead of them.
Methods
A total of 526 eligible adult patients under the age of 40 underwent surgery for lumbar disc herniation from 1990 to 2005. Patients’ baseline characteristics were acquired by chart review to confirm eligibility to the study. Follow-up quality of life data was acquired by sending patients EQ-5D questionnaire at median 18 years after index surgery, and those 316 patients responding to the questionnaire (60%) were included in the study. Propensity score matching was utilized to match every study patient with two general population sample participants from a large Finnish population health study. Primary objective was to compare the quality of life to that of the control population. Secondary objective was to explore which patient characteristics lead to inferior outcome.
Results
The mean EQ-index for the patient cohort was 0.86, while it was 0.84 for the age and gender–matched general population sample (difference 0.02, 95% CI − 0.0004 to 0.049). Within the patient cohort, an increasing number of lifetime lumbar surgeries was associated with progressively deteriorating EQ-index scores (
p
= 0.049) and longer duration of symptoms prior to the surgery correlated with lower score (
p
= 0.013).
Conclusion
Patients who underwent surgery for lumbar disc herniation nearly two decades ago reported quality of life comparable to the age and gender–matched general population. However, patients who had undergone numerous lumbar surgeries had significantly worse outcome. Therefore, possible ways to prevent cumulation of lumbar surgeries could improve long-term health-related quality of life.
Hydrocephalic patients with abdominal pathologies often need a ventriculo-atrial (VA) shunt placement. Cut-down on the internal jugular vein has historically been used to insert a VA shunt. This ...technique is more time consuming and has greater complications. Less invasive methods, such as ultrasound-guided percutaneous VA shunt placement provides greater comfort for surgeon, is more rapid, and has fewer complications. However, this technique has not been demonstrated on video. Here we demonstrate ultrasound-guided and ECG-aided VA shunt catheter placement in a 70-year-old patient with normal pressure hydrocephalus. The internal jugular vein is punctured under ultrasound guidance with an 18-gauge needle. A guidewire is introduced through the needle, the needle is removed, and a small skin incision is placed at the entry point of the guidewire. A skin dilator with a sheath introducer is advanced to the vein using the guidewire and the guidewire is thereafter removed. An atrial shunt catheter (e.g. Codman® Medos® Atrial catheter) filled with sterile water is inserted through the sheath. The sheath is removed and a syringe filled with sterile aqua is connected to the catheter with a metal tip. The ECG connection of the right upper limb is connected to the tip of syringe to adjust for the optimal depth of the catheter under ECG guidance (point of highest p-wave amplitude). The catheter is clamped and tunneled to reach the site for the valve on the scalp. The ventricle catheter is placed at the Kocher point and connected to the valve (Video 1).
Ultrasound-guided VA shunt placement is safe, comfortable, rapid, and has a reduced rate of complications.
•Ventriculo-atrial shunt•Ultrasound guidance•Video demonstration•Ultrasound guided and ECG aided VA-shunt implantation is a fast and safe method
Purpose
The purpose of the study was to evaluate the long-term outcome after surgery for lumbar disc herniation in a young adult population.
Methods
A total of 526 consecutive patients between 18 and ...40 years of age who underwent surgery for lumbar disc between 1990 and 2005 were included in the study. The primary outcomes were the need for new lumbar spine surgery during the follow-up and secondary outcomes were short-term subjective outcome, the Oswestry Disability Index (ODI) score, and the ability to carry out employment at the end of the long-term follow-up.
Results
A total of 96% of the patients had a reduction in their symptoms at the clinical follow-up (median of 50 days post-surgery). Twenty-one patients (4.0%) had a reoperation within 28 days. Excluding these early reoperations, 136 patients (26%) had additional lumbar spine surgery and 18 patients (3.4%) underwent lumbar fusion during the follow-up of median 18 years. The annual risk for new surgery was 1.4%. In total, 316 patients (60%) returned the ODI questionnaire, and their mean score was 8.1. Patients with a higher number of additional lumbar spine surgeries (
p
< 0.001) reported deteriorating ODI scores.
Conclusion
Patients showed excellent short-term recovery from their symptoms. In the long term, the mean ODI score for the patients was comparable to the normative population. However, a notable proportion of the patients required additional lumbar surgery during the follow-up period, and a higher number of lumbar surgeries was associated with poor ODI scores.
Anterior cervical discectomy and fusion (ACDF) procedures is thought to lead to accelerated degeneration of the adjacent cervical discs and in some cases can be symptomatic (adjacent segment disease, ...or ASD). The occurrence of ASD is of particular interest when treating young individuals, as the cumulative disease burden may become increasingly significant during their expectedly long lifetime. However, the overall impact of a surgical intervention on the lifetime prognosis of ASD remains unclear.
Our goal was to study the long-term outcomes of ACDF surgery among those members of the young adult population who have been operated on between the ages of 18 and 40.
Retrospective study.
All patients between 18 and 40 years of age at the time of surgery who underwent ACDF due to degenerative cervical disorders at Helsinki University Hospital between the years of 1990 and 2005 (476 patients).
Cervical reoperation rate, satisfaction with the surgery, employment status, Neck Disability Index (NDI).
We retrospectively analyzed the medical records of all patients between 18 and 40 years of age at the time of surgery who underwent ACDF due to degenerative cervical disorders at Helsinki University Hospital between the years of 1990 and 2005. We sent questionnaires to all available patients at the end of the follow-up (median 17.5 years) to assess their current neck symptoms, general situations, and levels of satisfaction with the surgery. Furthermore, we compared the results for different types of ACDF surgeries (ie, discectomy only vs. synthetic cage or bone autograft implantation for fusion) in propensity-score-matched groups.
Of the 476 patients who were included in the study, surgery was performed in 72% of the cases due to intervertebral disc herniation and in 28% due to spondylotic changes. The total reoperation rate during the entire follow-up (median 17.5 years) was 24%, and 19.5% if early reoperations (<28 days from index surgery) were excluded. At 10 years postsurgery, the total reoperation rate was 16.8% and 12.8% with early reoperations excluded. The probability of surgery for adjacent level disease was 10.3% at 10 years and 16.8% for the duration of the entire follow-up, with the annual incidence rate of 1.1% for those with ASD requiring surgery. Statistically significant risk factors leading to the need for further cervical surgery included central spinal cord compression and smoking at the time of the index operation. After propensity score matching, there was no significant difference found between the outcomes of different types of surgery. A total of 443 patients were still able to be contacted 12–28 years after the surgery. Of the 281 patients responding to the questionnaires, 92% were still satisfied with the results. With respect to employment, 67% of patients were working, 7% were unemployed, and 7% were on disability due to cervical problems. The median NDI score was 12%, with 56% of patients having an NDI score lower than 15%; it has been suggested that this latter NDI score serves as a cut-off value for significant neck morbidity. The NDI scores were significantly higher among female patients, patients with spondylosis, and patients having undergone further cervical surgeries during the follow-up.
Long-term satisfaction with the surgery was very high, and the employment rate among patients resembled that of the general population in Finland. Thus, the long-term prognosis after having ACDF surgery at a younger age seems to be good, even though nearly half of the patients experienced some persistent neck symptoms later in life.
Natural tropism to the liver is a major obstacle in systemic delivery of adenoviruses in cancer gene therapy. Adenovirus binding to soluble coagulation factors and to cellular heparan sulphate ...proteoglycans via the fiber shaft KKTK domain are suggested to cause liver tropism. Serotype 5 adenovirus constructs with mutated KKTK regions exhibit liver detargeting, but they also transduce tumors less efficiently, possibly due to altered fiber conformation. We constructed Ad5/3lucS*, a 5/3 chimeric adenovirus with a mutated KKTK region. The fiber knob swap was hypothesized to facilitate tumor transduction. This construct was studied with or without additional coagulation factor ablation. Ad5/3lucS* exhibited significantly reduced transduction of human hepatic cells in vitro and mouse livers in vivo. Combination of coagulation factor ablation by warfarinization to Ad5/3lucS* seemed to further enhance liver detargeting. Cancer cell transduction by Ad5/3lucS* was retained in vitro. In vivo, viral particle accumulation in M4A4-LM3 xenograft tumors was comparable to controls, but Ad5/3lucS* transgene expression was nearly abolished. Coagulation factor ablation did not affect tumor transduction. These studies set the stage for further investigations into the effects of the KKTK mutation and coagulation factor ablation in the context of 5/3 serotype chimerism. Of note, the putative disconnect between tumor transduction and transgene expression could prove useful in further understanding of adenovirus biology.
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