Adjuvanted Vaccine Induces Functional Antibodies against Pseudomonas aeruginosa Filamentous Bacteriophages.

Pseudomonas aeruginosa (Pa), a WHO priority 1 pathogen, resulted in approximately 559,000 deaths globally in 2019. Pa has a multitude of host-immune evasion strategies that enhance Pa virulence. Most clinical isolates of Pa are infected by a phage called Pf that has the ability to misdirect the host-immune response and provide structural integrity to biofilms. Previous studies demonstrate that vaccination against the coat protein (CoaB) of Pf4 virions can assist in the clearance of Pa from the dorsal wound model in mice. Here, a consensus peptide was derived from CoaB and conjugated to cross-reacting material 197 (CRM197). This conjugate was adjuvanted with a novel synthetic Toll-like receptor agonist (TLR) 4 agonist, INI-2002, and used to vaccinate mice. Mice vaccinated with CoaB-CRM conjugate and INI-2002 developed high anti-CoaB peptide-specific IgG antibody titers. Direct binding of the peptide-specific antibodies to whole-phage virus particles was demonstrated by ELISA. Furthermore, a functional assay demonstrated that antibodies generated from vaccinated mice disrupted the replicative cycle of Pf phages. The use of an adjuvanted phage vaccine targeting Pa is an innovative vaccine strategy with the potential to become a new tool targeting multi-drug-resistant Pa infections in high-risk populations.

Long duration of immunotherapy before radiosurgery might improve intracranial control of melanoma brain metastases.

PURPOSE: Despite significant advances that have been made in management of metastatic melanoma with immune checkpoint therapy, optimal timing of combination immune checkpoint therapy and stereotactic radiosurgery is unknown. We have reported toxicity and efficiency outcomes of patients treated with concurrent immune checkpoint therapy and stereotactic radiosurgery. PATIENTS AND METHODS: From January 2014 to December 2016, we analyzed 62 consecutive patients presenting 296 melanoma brain metastases, treated with gamma-knife and receiving concurrent immune checkpoint therapy with anti-CTLA4 or anti-PD1 within the 12 weeks of SRS procedure. Median follow-up time was 18 months (mo) (13-22). Minimal median dose delivered was 18 gray (Gy), with a median volume per lesion of 0.219 cm3. RESULTS: The 1-year control rate per irradiated lesion was 89% (CI 95%: 80.41-98.97). Twenty-seven patients (43.5%) developed distant brain metastases after a median time of 7.6 months (CI 95% 1.8-13.3) after gamma-knife. In multivariate analysis, positive predictive factors for intracranial tumor control were: delay since the initiation of immunotherapy exceeding 2 months before gamma-knife procedure (P=0.003) and use of anti-PD1 (P=0.006). Median overall survival (OS) was 14 months (CI 95%: 11-NR). Total irradiated tumor volume<2.1 cm3 was a positive predictive factor for overall survival (P=0.003). Ten patients (16.13%) had adverse events following irradiation, with four grade≥3. Predictive factors of all grade toxicity were: female gender (P=0.001) and previous treatment with MAPK (P=0.05). CONCLUSION: A long duration of immune checkpoint therapy before stereotactic radiosurgery might improve intracranial tumor control, but this relationship and its ideal timing need to be assessed in prospective trials.

The effect of climate change on avian offspring production: A global meta-analysis.

Climate change affects timing of reproduction in many bird species, but few studies have investigated its influence on annual reproductive output. Here, we assess changes in the annual production of young by female breeders in 201 populations of 104 bird species (N = 745,962 clutches) covering all continents between 1970 and 2019. Overall, average offspring production has declined in recent decades, but considerable differences were found among species and populations. A total of 56.7% of populations showed a declining trend in offspring production (significant in 17.4%), whereas 43.3% exhibited an increase (significant in 10.4%). The results show that climatic changes affect offspring production through compounded effects on ecological and life history traits of species. Migratory and larger-bodied species experienced reduced offspring production with increasing temperatures during the chick-rearing period, whereas smaller-bodied, sedentary species tended to produce more offspring. Likewise, multi-brooded species showed increased breeding success with increasing temperatures, whereas rising temperatures were unrelated to reproductive success in single-brooded species. Our study suggests that rapid declines in size of bird populations reported by many studies from different parts of the world are driven only to a small degree by changes in the production of young.

Applying objective metrics to neurosurgical skill development with simulation and spaced repetition learning.

OBJECTIVE: Surgical skills laboratories augment educational training by deepening one's understanding of anatomy and allowing the safe practice of technical skills. Novel, high-fidelity, cadaver-free simulators provide an opportunity to increase access to skills laboratory training. The neurosurgical field has historically evaluated skill by subjective assessment or outcome measures, as opposed to process measures with objective, quantitative indicators of technical skill and progression. The authors conducted a pilot training module with spaced repetition learning concepts to evaluate its feasibility and impact on proficiency. METHODS: The 6-week module used a simulator of a pterional approach representing skull, dura mater, cranial nerves, and arteries (UpSurgeOn S.r.l.). Neurosurgery residents at an academic tertiary hospital completed a video-recorded baseline examination, performing supraorbital and pterional craniotomies, dural opening, suturing, and anatomical identification under a microscope. Participation in the full 6-week module was voluntary, which precluded randomizing by class year. The intervention group participated in four additional faculty-guided trainings. In the 6th week, all residents (intervention and control) repeated the initial examination with video recording. Videos were evaluated by three neurosurgical attendings who were not affiliated with the institution and who were blinded to participant grouping and year. Scores were assigned via Global Rating Scales (GRSs) and Task-based Specific Checklists (TSCs) previously built for craniotomy (cGRS, cTSC) and microsurgical exploration (mGRS, mTSC). RESULTS: Fifteen residents participated (8 intervention, 7 control). The intervention group included a greater number of junior residents (postgraduate years 1-3; 7/8) compared to the control group (1/7). External evaluators had internal consistency within 0.5% (kappa probability > Z of 0.00001). The total average time improved by 5:42 minutes (p < 0.003; intervention, 6:05, p = 0.07; control, 5:15, p = 0.001). The intervention group began with lower scores in all categories and surpassed the comparison group in cGRS (10.93 to 13.6/16) and cTSC (4.0 to 7.4/10). Percent improvements for the intervention group were cGRS 25% (p = 0.02), cTSC 84% (p = 0.002), mGRS 18% (p = 0.003), and mTSC 52% (p = 0.037). For controls, improvements were cGRS 4% (p = 0.19), cTSC 0.0% (p > 0.99), mGRS 6% (p = 0.07), and mTSC 31% (p = 0.029). CONCLUSIONS: Participants who underwent a 6-week simulation course showed significant objective improvement in technical indicators, particularly individuals who were early in their training. Small, nonrandomized grouping limits generalizability regarding degree of impact; however, introducing objective performance metrics during spaced repetition simulation would undoubtedly improve training. A larger multiinstitutional randomized controlled study will help elucidate the value of this educational method.

Hypofractionated postoperative stereotactic radiotherapy for large resected brain metastases.

PURPOSE: The aim of the present retrospective study was to report outcomes after hypofractionated stereotactic radiotherapy (HSRT) for resected brain metastases (BM). PATIENTS AND METHODS: We reviewed results of patients with resected BM treated with postoperative HSRT (3×7.7Gy to the prescription isodose 70%) between May 2013 and June 2020. Local control (LC), distant brain control (DBC), overall survival (OS), leptomeningeal disease relapse (LMDR), and radiation necrosis (RN) occurrence were reported. RESULTS: Twenty-two patients with 23 brain cavities were included. Karnofsky Performance status (KPS) was≥70 in 77.3%. Median preoperative diameter was 37mm [21.0-75.0] and median planning target volume (PTV) was 23 cm3 [9.9-61.6]. Median time from surgery to SRT was 69 days [7-101] and 48% of patients had a local relapse on pre-SRT imaging. Median follow-up was 17.5 months [1.6-95.9]. One and two-year LC rates were 60.9 and 52.2% respectively. One and 2-year DBC rates were 45.5 and 40.9%. Median OS was 16.5 months. Four patients (18.2%) presented LMDR during follow-up. RN occurred in 6 patients (27.2%). Three factors were associated with OS: ECOG-PS (P=0.009), KPS (P=0.04), cystic or solid nature of the metastasis before surgery (P=0.037). Several factors were related to RN occurrence: PTV diameter and volume, Normal brain V21, V21 and V24 isodoses volumes. CONCLUSION: HSRT is the most widely used scheme for larger brain cavities after surgery. The optimal dose and scheme remain to be defined as well as the optimal delay between postoperative SRT and surgery. Dose escalation may be necessary, especially in case of subtotal resection.

Radiotherapy of non-tumoral refractory neurological pathologies.

Intracranial radiotherapy has been improved, primarily because of the development of stereotactic approaches. While intracranial stereotactic body radiotherapy is mainly indicated for treatment of benign or malignant tumors, this procedure is also effective in the management of other neurological pathologies; it is delivered using GammaKnife® and linear accelerators. Thus, brain arteriovenous malformations in patients who are likely to experience permanent neurological sequelae can be managed by single session intracranial stereotactic body radiotherapy, or radiosurgery, in specific situations, with an advantageous benefit/risk ratio. Radiosurgery can be recommended for patients with disabling symptoms, which are poorly controlled by medication, such as trigeminal neuralgia, and tremors, whether they are essential or secondary to Parkinson's disease. This literature review aims at defining the place of intracranial stereotactic body radiotherapy in the management of patients suffering from non-tumoral refractory neurological pathologies. It is clear that the multidisciplinary collaboration of experienced teams from Neurosurgery, Neurology, Neuroradiology, Radiation Oncology and Medical Physics is needed for the procedures using high precision radiotherapy techniques, which deliver high doses to locations near functional brain areas.

Multidisciplinary approaches to complication reduction in complex spine surgery: a systematic review.

BACKGROUND CONTEXT: Complex spine surgery carries a high complication rate that can produce suboptimal outcomes for patients undergoing these extensive operations. However, multidisciplinary pathways introduced at multiple institutions have demonstrated a promising potential toward reducing the burden of complications in patients being treated for spinal deformities. To date, there has been no effort to systematically collate the multidisciplinary approaches in use at various institutions. PURPOSE: The present study aims to determine effective multidisciplinary strategies for reducing the complication rate in complex spine surgery by analyzing existing institutional multidisciplinary approaches and delineating common themes across multiple practice settings. STUDY DESIGN: Systematic review. METHODS: We followed guidelines established under the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The studies reported on data from PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science and Cochrane. We included articles that described either approaches to, or results from, the implementation of multidisciplinary paradigms during the preoperative, perioperative, and postoperative phases of care for patients undergoing complex spine surgery. We excluded studies that only targeted one complication unless such an approach was in coordination with more extensive multidisciplinary planning at the same institution. RESULTS: A total of 406 unique articles were identified. Following an initial determination based on title and abstract, 22 articles met criteria for full-text review, and 10 met the inclusion criteria to be included in the review. Key aspects of multidisciplinary approaches to complex spine surgery included extensive preoperative workup and interdisciplinary conferencing, intraoperative communication and monitoring, and postoperative floor management and discharge planning. These strategies produced decreases in surgical duration and complication rates. CONCLUSIONS: This study represents the first to systematically analyze multidisciplinary approaches to reduce complications in complex spine surgery. This review provides a roadmap toward reducing the elevated complication rate for patients undergoing complex spine surgery.

Laminectomy plus Fusion versus Laminectomy Alone for Lumbar Spondylolisthesis.

BACKGROUND: The comparative effectiveness of performing instrumented (rigid pedicle screws affixed to titanium alloy rods) lumbar spinal fusion in addition to decompressive laminectomy in patients with symptomatic lumbar grade I degenerative spondylolisthesis with spinal stenosis is unknown. METHODS: In this randomized, controlled trial, we assigned patients, 50 to 80 years of age, who had stable degenerative spondylolisthesis (degree of spondylolisthesis, 3 to 14 mm) and symptomatic lumbar spinal stenosis to undergo either decompressive laminectomy alone (decompression-alone group) or laminectomy with posterolateral instrumented fusion (fusion group). The primary outcome measure was the change in the physical-component summary score of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36; range, 0 to 100, with higher scores indicating better quality of life) 2 years after surgery. The secondary outcome measure was the score on the Oswestry Disability Index (range, 0 to 100, with higher scores indicating more disability related to back pain). Patients were followed for 4 years. RESULTS: A total of 66 patients (mean age, 67 years; 80% women) underwent randomization. The rate of follow-up was 89% at 1 year, 86% at 2 years, and 68% at 4 years. The fusion group had a greater increase in SF-36 physical-component summary scores at 2 years after surgery than did the decompression-alone group (15.2 vs. 9.5, for a difference of 5.7; 95% confidence interval, 0.1 to 11.3; P=0.046). The increases in the SF-36 physical-component summary scores in the fusion group remained greater than those in the decompression-alone group at 3 years and at 4 years (P=0.02 for both years). With respect to reductions in disability related to back pain, the changes in the Oswestry Disability Index scores at 2 years after surgery did not differ significantly between the study groups (-17.9 in the decompression-alone group and -26.3 in the fusion group, P=0.06). More blood loss and longer hospital stays occurred in the fusion group than in the decompression-alone group (P<0.001 for both comparisons). The cumulative rate of reoperation was 14% in the fusion group and 34% in the decompression-alone group (P=0.05). CONCLUSIONS: Among patients with degenerative grade I spondylolisthesis, the addition of lumbar spinal fusion to laminectomy was associated with slightly greater but clinically meaningful improvement in overall physical health-related quality of life than laminectomy alone. (Funded by the Jean and David Wallace Foundation and others; SLIP ClinicalTrials.gov number, NCT00109213.).

Development of a Breast Cancer Treatment Program in Port-au-Prince, Haiti: Experiences From the Field.

PURPOSE: The nonprofit Project Medishare launched a breast cancer treatment program in Port-au-Prince in July 2013 to address the demand for breast cancer care in Haiti. We outline the development of the program, highlight specific challenges, and discuss key considerations for others working in global oncology. METHODS: We reflected on our experiences in the key areas of developing partnerships, building laboratory capacity, conducting medical training, using treatment algorithms, and ensuring access to safe, low-cost chemotherapy drugs. We also critically reviewed our costs and quality measures. RESULTS: The program has treated a total of 139 patients with breast cancer with strong adherence to treatment regimens in 85% of patients. In 273 chemotherapy administrations, no serious exposure or adverse safety events were reported by staff. The mortality rate for 94 patients for whom we have complete data was 24% with a median survival time of 53 months. Our outcome data were likely influenced by stage at presentation, with more than half of patients presenting more than 12 months after first noticing a tumor. Future efforts will therefore focus on continuing to improve the level of care, while working with local partners to spread awareness, increase screening, and get more women into care earlier in the course of their disease. CONCLUSION: Our experiences may inform others working to implement protocol-based cancer treatment programs in resource-poor settings and can provide valuable lessons learned for future global oncology efforts.

Giant thoracic osteophyte: a distinct clinical entity.

Calcified lesions described within the neural axis are classified as either an ossification of the posterior longitudinal ligament, diffuse idiopathic skeletal hyperostosis, or ossification of the ligamentum flavum. We aim to describe a unique pathologic entity: the giant thoracic osteophyte. We identified four patients who were surgically treated at the Massachusetts General Hospital from 2006 to 2012 with unusual calcified lesions in the ventral aspect of the spinal canal. In order to differentiate giant thoracic osteophytes from calcified extruded disc material, disc volumetrics were performed on actual and simulated disc spaces. All patients underwent operative resection of the calcific lesion as they had signs and/or symptoms of spinal cord compression. The lesions were found to be isolated, large calcific masses that originated from the posterior aspect of adjacent thoracic vertebral bodies. Pathological examination was negative for tumor. Adjacent disc volumes were not significantly different from the index disc (p=0.91). A simulated calculation hypothesizing that the calcific mass was extruded disc material demonstrated a significant difference (p=0.01), making this scenario unlikely. In conclusion, giant thoracic osteophyte is a unique and rare entity that can be found in the thoracic spine. The central tenant of surgical treatment is resection to relieve spinal cord compression.

Stereotactic radiotherapy for large solitary brain metastases.

PURPOSE: To assess effectiveness and toxicity levels of stereotactic radiation therapy without whole brain radiation therapy in patients with solitary brain metastases larger than 3cm. PATIENTS AND METHODS: Between June 2007 and March 2009, 12 patients received fractionated stereotactic radiation therapy and 24 patients underwent stereotactic radiosurgery. For the fractionated stereotactic radiation therapy group, 3×7.7Gy were delivered to the planning target volume (PTV); median volume and diameter were 29.4 cm(3) and 4.4cm, respectively. For the stereotactic radiosurgery group, 14Gy were delivered to the PTV; median volume and diameter were 15.6 cm(3) and 3.7cm, respectively. RESULTS: Median follow-up was 218 days. For the fractionated stereotactic radiation therapy group, local control rates were 100% at 360 days and 64% at 720 days; for the stereotactic radiosurgery group, rates were 58% at 360 days and 48% at 720 days (P=0.06). Median survival time was 504 days for the fractionated stereotactic radiation therapy group and 164 days for the stereotactic radiosurgery group (P=0.049). Two cases of grade 2 toxicity were observed in the fractionated stereotactic radiation therapy group, and 6 cases of grade 1-2 toxicity, in the stereotactic radiosurgery group. CONCLUSIONS: This study provides data to support that fractionated stereotactic radiation therapy without whole brain radiation therapy with a margin dose of 3 fractions of 7.7Gy for treatment of solitary large brain metastases is efficient and well-tolerated. Because of the significant improvement in overall survival, this schedule should be assessed in a randomized trial.

Surgical treatment options and management strategies of metastatic renal cell carcinoma to the lumbar spinal nerve roots.

Spinal nerve root metastasis of renal cell carcinoma is a rare occurrence. In addition to treatment of the primary lesion, surgical resection of the nerve root metastasis, occasionally with sacrifice of the involved nerve, is the accepted standard of treatment. Resection often resolves presenting motor and pain symptoms due to relief of neural compression. We describe two patients with nerve root metastasis of renal cell carcinoma and their management. While locally advanced and metastatic renal cell carcinoma has been shown to be chemo- and radio-resistant, immunotherapy is a promising treatment. Given the high prevalence of systemic disease in patients with intradural metastases, systemic (and possibly intracranial) imaging can be used to identify other potential areas of disease.

Induced and sustained hypernatremia for the prevention and treatment of cerebral edema following brain injury.

Cerebral edema develops in response to and as a result of a variety of neurologic insults such as ischemic stroke, traumatic brain injury, and tumor. It deforms brain tissue, resulting in localized mass effect and increase in intracranial pressure (ICP) that are associated with a high rate of morbidity and mortality. When administered in bolus form, hyperosmolar agents such as mannitol and hypertonic saline have been shown to reduce total brain water content and decrease ICP, and are currently the mainstays of pharmacological treatment. However, surprisingly, little is known about the increasingly common clinical practice of inducing a state of sustained hypernatremia. Herein, we review the available studies employing sustained hyperosmolar therapy to induce hypernatremia for the prevention and/or treatment of cerebral edema. Insufficient evidence exists to recommend pharmacologic induction of hypernatremia as a treatment for cerebral edema. The strategy of vigilant avoidance of hyponatremia is currently a safer, potentially more efficacious paradigm.

Neurological surgery: the influence of physical and mental demands on humans performing complex operations.

Performing neurological surgery is an inherently demanding task on the human body, both physically and mentally. Neurosurgeons routinely perform "high stakes" operations in the setting of mental and physical fatigue. These conditions may be not only the result of demanding operations, but also influential to their outcome. Similar to other performance-based endurance activities, training is paramount to successful outcomes. The inflection point, where training reaches the point of diminishing returns, is intensely debated. For the neurosurgeon, this point must be exploited to the maximum, as patients require both the best-trained and best-performing surgeon. In this review, we explore the delicate balance of training and performance, as well as some routinely used adjuncts to improve human performance.

Infection following operations on the central nervous system: deconstructing the myth of the sterile field.

Neurosurgical patients are at a high risk for infectious sequelae following operations. For neurosurgery in particular, the risk of surgical site infection has a unique implication given the proximity of the CSF and the CNS. Patient factors contribute to some degree; for example, cancer and trauma are often associated with impaired nutritional status, known risk factors for infection. Additionally, care-based factors for infection must also be considered, such as the length of surgery, the administration of steroids, and tissue devascularization (such as a craniotomy bone flap). When postoperative infection does occur, attention is commonly focused on potential lapses in surgical "sterility." Evidence suggests that the surgical field is not free of microorganisms. The authors propose a paradigm shift in the nomenclature of the surgical field from "sterile" to "clean." Continued efforts aimed at optimizing immune capacity and host defenses to combat potential infection are warranted.

Socioeconomic status correlates with the prevalence of advanced coronary artery disease in the United States.

BACKGROUND: Increasingly studies have identified socioeconomic factors adversely affecting healthcare outcomes for a multitude of diseases. To date, however, there has not been a study correlating socioeconomic details from nationwide databases on the prevalence of advanced coronary artery disease. We seek to identify whether socioeconomic factors contribute to advanced coronary artery disease prevalence in the United States. METHODS AND FINDINGS: State specific prevalence data was queried form the United States Nationwide Inpatient Sample for 2009. Patients undergoing percutaneous coronary angioplasty and coronary artery bypass graft were identified as principal procedures. Non-cardiac related procedures, lung lobectomy and hip replacement (partial and total) were identified and used as control groups. Information regarding prevalence was then merged with data from the Behavioral Risk Factor Surveillance System, the largest, on-going telephone health survey system tracking health conditions and risk behaviors in the United States. Pearson's correlation coefficient was calculated for individual socioeconomic variables including employment status, level of education, and household income. Household income and education level were inversely correlated with the prevalence of percutaneous coronary angioplasty (-0.717; -0.787) and coronary artery bypass graft surgery (-0.541; -0.618). This phenomenon was not seen in the non-cardiac procedure control groups. In multiple linear regression analysis, socioeconomic factors were significant predictors of coronary artery bypass graft and percutaneous transluminal coronary angioplasty (p<0.001 and p=0.005, respectively). CONCLUSIONS: Socioeconomic status is related to the prevalence of advanced coronary artery disease as measured by the prevalence of percutaneous coronary angioplasty and coronary artery bypass graft surgery.

[Medical devices needed for stereotactic radiosurgery and intracranial stereotactic radiotherapy]. / Équipements requis pour la mise en œuvre de la radiochirurgie et de la radiothérapie en conditions stéréotaxiques intracrânienne.

Since the previous special issue of Cancer Radiothérapie dedicated to radiosurgery in 1998, many important technological and computer developments have improved external beam radiotherapy treatment device performances. Whereas the Gamma Knife(®) was the gold standard for intracranial radiosurgery, new linear accelerator developments have led to new possibilities for the clinicians. This article describes quickly the different devices available for cranial radiosurgery or fractionated stereotactic radiotherapy.

[History of radiosurgery]. / Historique de la radiochirurgie.

Within the last decades, radiosurgery, also known as stereotactic radiotherapy, has become more and more popular as a non-invasive treatment of small benign tumours, arteriovenous malformations, metastases, and also some functional neurological structures, such as the fifth cranial nerve for trigeminal neuralgesia. It allows precisely delivering very high dose in a small volume under stereotactic conditions with minimal irradiation of tissue around the area. The first equipment devoted to radiosurgery was the Leksell Gamma Knife®. It is now challenged by some linear accelerators providing radiosurgery technology, such as the CyberKnife®, the Novalis Tx® radiosurgery platform, and the True Beam® linear accelerator.

Delayed post-traumatic bilateral abducens nerve palsy with complete recovery.

Isolated bilateral abducens (sixth) nerve palsy is rare in the setting of trauma. To date, most cases have been reported in patients who sustain cranial fractures or have other acute intracranial pathologies, including acute hemorrhage. We describe the case of a 41-year-old man who presented with bilateral abducens nerve palsy in the setting of acute head trauma without evidence of cranial fractures or other acute intracranial pathology. Six months after the initial injury, he regained bilateral function of his abducens nerves with intact extraocular muscle movements. Full recovery is the natural history in the majority of traumatic abducens nerve palsies, and this is an important consideration when counseling patients with such injuries.