The impact of wait time on patient outcomes in knee and hip replacement surgery: a scoping review protocol.

BACKGROUND: Total hip and total knee replacement surgery are in high demand, leading to long wait times for many patients. While on the waiting list, patients may experience worsening pain, reduced mobility, and deteriorating health. Given that long wait times are common for lower joint replacement surgery, it is important to understand how patient health changes during the wait period and whether this impacts patient outcomes after surgery. The aim of this scoping review will be to identify and describe the evidence regarding the impact of wait time on patient outcomes for patients who undergo total knee and total hip replacement surgery. METHODS: This scoping review was designed with guidance from the Joanna Briggs Institute Manual for Evidence Synthesis, and results will be reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews. EMBASE, Medline, PubMed, Scopus, CINAHL, and Cochrane electronic databases will be searched for English language articles published after 1999. Studies of adult patients with osteoarthritis undergoing primary knee or hip replacement surgery, which measure patient outcomes over the wait period for surgery, will be included. Two independent reviewers will screen titles and abstracts followed by full article review. Data will be extracted by two reviewers using a standardized form. Outcomes assessed during the wait period will be identified and described in tables. Factors associated with changes in health status during the wait period will be qualitatively described. DISCUSSION: This review will map the evidence regarding wait times for lower extremity joint replacement surgery. Better understanding of how the impact of wait times on patient health status is measured over the perioperative period will inform future research on wait times. SCOPING REVIEW REGISTRATION: Registered with Open Science Framework, Feb 14, 2021 DOI: https://doi.org/10.17605/OSF.IO/MV4FS.

Low dose novel PARP-PI3K inhibition via nanoformulation improves colorectal cancer immunoradiotherapy.

Multimodal therapy is often used in oncology to overcome dosing limitations and chemoresistance. Recently, combination immunoradiotherapy has shown great promise in a select subset of patients with colorectal cancer (CRC). Furthermore, molecularly targeted agents delivered in tandem with immunotherapy regimens have been suggested to improve treatment outcomes and expand the population of responding patients. In this study, radiation-sensitizing small molecules niraparib (PARP inhibitor) and HS-173 (PI3K inhibitor) are identified as a novel combination that synergistically enhance toxicity and induce immunogenic cell death both in vitro and in vivo in a CRC model. These inhibitors were co-encapsulated in a polymer micelle to overcome solubility limitations while minimizing off-target toxicity. Mice bearing syngeneic colorectal tumors (CT26) were administered these therapeutic micelles in combination with X-ray irradiation and anti-CTLA-4 immunotherapy. This combination led to enhanced efficacy demonstrated by improved tumor control and increased tumor infiltrating lymphocytes. This report represents the first investigation of DNA damage repair inhibition combined with radiation to potentiate anti-CTLA-4 immunotherapy in a CRC model.

Can the Oxford Knee and Hip Score identify patients who do not require total knee or hip arthroplasty?

AIMS: The aim of this study was to determine if the Oxford Knee and Hip Score (OKHS) can accurately predict when a primary knee or hip referral is deemed nonsurgical versus surgical by the surgeon during their first consultation, and to identify nonsurgical OKHS screening thresholds. PATIENTS AND METHODS: We retrospectively reviewed pre-consultation OKHS for all consecutive primary total knee arthroplasty (TKA) and total hip arthroplasty (THA) consultations of a single surgeon over three years. The 1436 knees (1016 patients) and 478 hips (388 patients) included were categorized based on the surgeon's decision into those offered surgery during the first consultation versus those not (nonsurgical). Spearman's rank correlation coefficients and receiver operating characteristic (ROC) curve analysis were performed. RESULTS: Oxford Scores were better for the nonsurgical cohorts (p < 0.001) and correlated with the surgical decision (p < 0.001). ROC area under the curve values for knees (0.83, 95% confidence intervals (CI) 0.81 to 0.85) and hips (0.87, 95% CI 0.84 to 0.91) were excellent. A conservative and effective threshold for knees is Oxford Knee Score (OKS) > 32 points (sensitivity = 0.997, negative predictive value (NPV) = 0.992) and for hips is Oxford Hip Score (OHS) > 34 points (sensitivity = 0.997, NPV = 0.978). Severable potential lower OKHS thresholds were identified. CONCLUSION: Pre-consultation OKHS demonstrate good ability to predict when a primary TKA or THA referral will be deemed nonsurgical in a single surgeon's practice. Multiple OKHS thresholds can effectively screen out nonsurgical referrals. Cite this article: Bone Joint J 2019;101-B(6 Supple B):23-30.

[Scleromyxedema]. / Skleromyxödem.

Scleromyxedema is a rare disorder that frequently affects multiple extracutaneous organ systems and is usually associated with monoclonal gammopathy. The pathogenesis of scleromyxedema is unknown. The clinical course is chronic and progressive and can lead to marked morbidity or death. The skin findings consist of multiple waxy papules and indurated plaques. Progressive skin involvement can lead to decreased mobility of the mouth and joints. Extracutaneous manifestations occur in the musculoskeletal or cardiovascular system, in the gastrointestinal or respiratory tract, or in the kidneys. There are no approved or evidence-based treatment options available for scleromyxedema. High-dose immunoglobulins are considered the treatment of choice, followed by lenalidomide (or thalidomide) and systemic glucocorticosteroids, or in severe cases even autologous hematopoetic stem cell transplantation. Long-term maintenance treatment is usually required and close clinical follow-up is necessary as recurrence of scleromyxedema is common after withdrawal of an effective therapy.

Gait instability in valproate-treated patients: Call to measure ammonia levels.

OBJECTIVE: Hyperammonemia induced by valproate (VPA) treatment may lead to several neurological and systemic symptoms as well as to seizure exacerbation. Gait instability and recurrent falls are rarely mentioned as symptoms, especially not as predominant ones. METHODS: We report five adult patients with frontal lobe epilepsy (FLE) who were treated with VPA and in whom a primary adverse effect was unstable gait and falls. RESULTS: There were four males and one female patients with FLE, 25-42-year-old, three following epilepsy surgery. All of them were treated with antiepileptic drug polytherapy. Gait instability with falls was one of the principal sequelae of the treatment. Patients also exhibited mild encephalopathy (all patients) and flapping tremor (three patients) that developed following the addition of VPA (three patients) and with chronic VPA treatment (two patients). VPA levels were within the reference range. Serum ammonia levels were significantly elevated (291-407 µmole/L, normal 20-85) with normal or slightly elevated liver enzymes. VPA dose reduction or discontinuation led to the return of ammonia levels to normal and resolution of the clinical symptoms, including seizures, which disappeared in two patients and either decreased in frequency or became shorter in duration in the other three. CONCLUSIONS: Gait instability due to hyperammonemia and VPA treatment is probably under-recognized in many patients. It can develop when the VPA levels are within the reference range and with normal or slightly elevated liver enzymes.

Psychogenic seizures: long-term outcome in patients with and without epilepsy.

OBJECTIVES: Psychogenic non-epileptic seizures (PNES) may resemble epileptic events. Epileptic and non-epileptic seizures are not mutually exclusive phenomena and may coexist in the same patient. The aim of this study was to evaluate the long-term outcome of psychogenic events in patients with PNES alone and those with both PNES and epilepsy (PNES + EPI) as diagnosed by video-EEG (vEEG) monitoring. MATERIALS AND METHODS: All adult admissions to the Tel-Aviv Medical Center's vEEG unit between 2004 and 2009 were screened for the presence of PNES. We retrospectively retrieved data from their medical files and supplemented the follow-up by a telephonic questionnaire. RESULTS: Eligible patients (n = 51) were divided into those with PNES + EPI (n = 24) and those with PNES alone (n = 27). The follow-up period was 4.8 ± 0.3 and 4.3 ± 0.3 years, respectively. Both groups had similar female predominance and similar age at admission to the vEEG unit. Time from PNES onset to hospitalization was longer in PNES patients compared to those with PNES + EPI. The majority of subjects in each group reported a history of at least one major stressful life event. Opisthotonus was significantly more frequently observed in PNES patients, and they had more events during vEEG hospitalization. Psychogenic events ceased during the follow-up period in 22% of the PNES patients and in 58% of the PNES + EPI patients (P > 0.001). CONCLUSION: Our results indicate that following vEEG-based diagnosis of PNES, the long-term outcome of PNES cessation may be more favorable for patients with concomitant epilepsy than for patients without epilepsy.

The prognosis of refractory epilepsy patients rejected from epilepsy surgery.

OBJECTIVE: Up to one-third of individuals diagnosed as having epilepsy continue to have seizures despite appropriate anti-epileptic drug treatment. These patients are often referred for presurgical evaluation, and many are rejected from focal resective surgery due to medical reasons or, alternatively, they choose not to undergo it. We compared the outcomes and characteristics of the non-operated patients who continued on medical therapy alone with those who underwent vagus nerve stimulator (VNS) implantation in addition to medical therapy. METHODS: The medical records of consecutive adult patients referred for presurgical evaluation for suitability for epilepsy surgery in the Tel-Aviv Sourasky Medical Center between 2007 and 2011 and were rejected from or decided against surgery were reviewed. Updated information on seizure frequency was supplemented by telephone interviews between April and July, 2013. RESULTS: Fifty-two patients who continued solely on medical therapy and 35 patients who additionally underwent VNS implantation were included in the study. Forty-seven of the former and 33 of the latter agreed to be interviewed. There was a significant improvement in the seizure frequency between the time of the presurgical evaluation and the time of the interview in both groups. Eight medically treated patients (17%) and 2 patients who also underwent VNS implantation (6%) reported being seizure-free during the preceding 3 months. CONCLUSIONS: A considerable minority of patients with refractory epilepsy who were rejected or chose not to undergo epilepsy surgery may improve over time and even become seizure-free following adjustment of anti-epileptic drugs with or without concomitant VNS.

Utility of hospitalization following a first unprovoked seizure.

OBJECTIVES: Hospital admission in otherwise healthy patients following a first unprovoked seizure is controversial. We aimed to evaluate the influence of admission in a neurology department on the identification of risk factors for seizure recurrence in patients with a first unprovoked seizure. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients with a first unprovoked seizure, who were admitted to the neurology departments at two medical centers between 2007 and 2009. Risk factors for seizure recurrence included the following: abnormal neurological examination, abnormal brain CT scan, and epileptiform discharges on the EEG. RESULTS: The study group included 97 patients (52 men) aged 18-85 years (mean 42). Eighty-seven (90%) patients were admitted following a generalized tonic-clonic seizure. Risk factors were identified in the emergency room (ER) in 36 (37%) patients, mainly including abnormalities of the neurological examination and brain CT scan. Nineteen (20%) patients had a risk factor which was not apparent during ER evaluation, consisting of epileptiform activity on the EEG. Five (5%) patients had recurrent seizures during admission, three of them without risk factors during the ER evaluation. CONCLUSIONS: Risk factors for seizure recurrence were detected during admission in nearly a quarter of the patients who presented to the emergency room with a first unprovoked seizure. Because the main advantage of admission is the EEG recording, we suggest that an early EEG should be obtained in these patients either during admission or through a special accelerated outpatient arrangement.

A revised intracarotid etomidate memory (Wada) procedure.

OBJECTIVES: To evaluate unilateral memory function by the means of a modified Montreal etomidate speech and memory procedure (e-SAM) in epilepsy patients who were candidates for standard anterior temporal lobectomy involving resection of mesial temporal lobe structures. MATERIALS AND METHODS: After the first three patients experienced significant side effects with the e-SAM procedure, we modified the procedure to a single bolus injection. The neuropsychological data of all 21 patients who underwent unilateral memory testing by means of intracarotid injection of etomidate were analyzed. RESULTS: There was a significant difference in memory scores when injections were on the side ipsilateral to the epileptogenic focus compared with when the injections were on the contralateral side (P < 0.01), supposedly reflecting unilateral hippocampal memory function and dysfunction. In addition, the procedural modification resulted in eradication of all major side effects in the ensuing 18 patients. CONCLUSIONS: The technical modification of the Montreal procedure from continuous to bolus injection effectively enabled the demonstration of the relative weakness of the memory function of the epileptogenic hemisphere. The revised etomidate procedure provided the clinical information on unilateral hippocampal memory function necessary for surgical decision.

Long-term video-EEG in patients with frontal seizures.

The interictal epileptiform discharge (IED) yield of long-term video-EEG (LTVEEG) monitoring is increased compared to a single out-patient EEG, but was not studied specifically in frontal lobe epilepsy. Since IED recording can influence the length of monitoring when seizures are not recorded during LTVEEG, we aimed to assess the IED yield of LTVEEG recording in patients with frontal seizures. We retrospectively reviewed the medical records of 20 patients with frontal seizures during non-invasive LTVEEG in Tel Aviv Medical Center between 2003 and 2008 and compared them with the results of out-patient EEG. The study group included 11 (55%) men and 9 women aged 15-82 years (mean: 27 years). LTVEEG duration ranged between 4 and 29 days (mean: 14 days). IEDs were detected by each of the tests in eight (40%) patients. We conclude that non-invasive LTVEEG and out-patient EEG have a similar diagnostic yield for IEDs in patients with frontal seizures. Therefore, seizures remain the most relevant clinical outcome of LTVEEG.

Postponing the morning dose of AEDs: effect on the epileptiform EEG activity.

BACKGROUND: The effects of postponing the morning dose of antiepileptic drugs (AEDs) before undergoing an electroencephalogram (EEG) on the likelihood of recording interictal epileptiform activity (IEA) in patients with epilepsy are unclear. METHODS: This was a prospective study on patients undergoing video-EEG monitoring. The 3-h recordings used for evaluation started at 08:00 am. Each subject received the usual AED dosage at 08:00 am on the first full day of recording but not until 11:00 am on the following day. IEA (spikes, sharp waves, and spike and wave complexes) was counted at 1-h intervals on each day and compared. Each subject served as his/her own control. The measureable serum drug levels were obtained at 10:00 am on both days. RESULTS: Fifty patients (age 32 ± 11.7 years, 22 women) were enrolled. Forty-seven had focal epilepsy, and three had generalized epilepsy. Six were on monotherapy, and 44 were on polytherapy. The number of IEAs w/wo medication was similar throughout each hour. Twenty-five patients had IEA on the 1st day, and 28 had IEA on the 2nd day. Twenty-one had IEA on both days, while 18 had none on either day. Seven of the 25 without IEA on the 1st day had IEA on the 2nd day, and 4 of the 25 with IEA had no IEA on the 2nd day. Age, gender, epilepsy type, disease duration, seizure frequency, and AED type did not influence IEA. CONCLUSIONS: Delaying the morning dose of AEDs prior to an EEG tracing was not associated with increased IEA in patients with epilepsy.

Epilepsy syndrome-associated balance dysfunction assessed by static posturography.

PURPOSE: To compare subclinical balance dysfunction in patients with various epilepsy syndromes with apparently healthy subjects. METHODS: Twenty-seven patients with localization-related epilepsy (LRE), 19 with primary generalized epilepsy (PGE), who had no subjective complaints of impaired balance and no abnormal neurologic findings on examination, and 22 apparently healthy subjects, underwent static posturography using the Posture Scale Analyzer (PSA) system. RESULTS: Sway index was higher in patients compared to healthy subjects in all tests, significant for single leg stance (p=0.005). Patients with PGE had a higher sway index compared to patients with LRE in six of the tests, also significant for single leg stance (p=0.027). This difference was not affected by the type of AED treatment or disease duration. CONCLUSION: Posturography can improve balance function assessment in patients with epilepsy, demonstrate subclinical impairment in seemingly asymptomatic patients, and further characterize balance deficits in different epilepsy syndromes.

Possible remote functional reorganization in left temporal lobe epilepsy.

OBJECTIVE: To provide functional magnetic resonance imaging-based insight into the impact of left temporal lobe epilepsy (TLE) on language-related functional re-organization. MATERIALS AND METHODS: Ten right-handed patients with left TLE were compared with 10 matched healthy controls. Regional brain activation during the language task was measured in the inferior frontal gyrus (IFG) and in the superior temporal gyrus (STG), and the regional inter-hemispheric lateralization index (LI) was calculated. RESULTS: Left language lateralization was documented in all the patients and controls. Reduced lateralization in the IFG was due to decreased activity in the left frontal region rather than to increased activity in the right frontal region. The LI values in the STG correlated with the LI values in the IFG in the controls but not in the patients. CONCLUSIONS: The left IFG was most probably involved in the epileptogenesis and concomitant language-related cortical plasticity in patients with left TLE.

Long-term tetrahydroaminoacridine treatment and quantitative EEG in Alzheimer's disease.

The development of therapies for Alzheimer's disease (AD) has focused on drugs designed to correct the loss of cholinergic function within the central nervous system. Quantitative EEG (qEEG) changes associated with AD consist of background slowing. One way to study the effects of cholinergic drugs may be through assessment of their qEEG effects. The aim of the current work was to evaluate the effect of long-term treatment with tetrahydroaminoacridine (THA) on qEEG in AD patients.

Video-EEG monitoring of paroxysmal events in the elderly.

OBJECTIVES: To determine the importance of video-EEG monitoring (VEM) in elderly patients with various paroxysmal events. MATERIAL AND METHODS: We retrospectively identified 16 subjects > or = 60 years old out of 834 (1.9%; 7 females, mean age 67.8 +/- 7.7 years), who were admitted to the Video-EEG Unit between 1997 and 2005 and compared data between those with and without epileptic events. RESULTS: Epilepsy was confirmed in six patients, psychogenic non-epileptic seizures (NES) were diagnosed in seven, one patient had NES and epilepsy whereas the recorded events were non-conclusive in two. NES patients had a higher predisposition to psychiatric disturbances (P<0.02). Following VEM and management alteration, the frequency of monthly events decreased significantly for the cohort as a whole (P<0.001). VEM directly influenced the diagnosis, treatment and outcome of 14 of 16 (88%) patients. CONCLUSION: Video-EEM plays a vital role in the evaluation of paroxysmal events in the elderly, but is vastly underutilized in this population group.

Levels of evidence available for techniques in antireflux surgery.

The objective of this study was to determine the levels of evidence and grades of recommendations available for techniques in antireflux surgery. Areas of technical controversy in antireflux surgery were identified and developed into eight answerable questions. The external evidence was surveyed using the databases Medline and EMBASE. Abstracts and appropriate articles were identified from January 1966 to December 2005. A set of search strategies was systematically employed to determine the levels of evidence available for each clinical question. Primary outcome measures included the determination of levels of evidence and grade of recommendation based on The Oxford Center for Evidence-Based Medicine. Secondary outcome measures included for randomized controlled trials were Jadad scores, noting the presence of a sample size calculation, and the determination of an effect estimate and the reporting of a confidence interval. Higher quality randomized controlled trials (mostly level 2b, occasional level 1b) existed to answer three questions: whether to complete a 360 degrees or partial wrap; whether or not to divide the short gastric vessels; and whether to perform laparoscopic or open surgery. Lower quality randomized controlled trials were available to determine whether the use of mesh was helpful, whether or not to use a bougie catheter for calibration of the wrap, and whether an anterior or posterior wrap results in a superior outcome. This was deemed to be of inferior grade of recommendation due to the lack (< 2) of trials available and the sole presence of level 2b evidence. The final two questions: whether to complete fundoplication using a thoracic or abdominal approach and whether to use intraoperative manometry relied exclusively upon level 4 evidence and thus received a lower grade of recommendation. A higher Jadad score seemed to be associated with studies having a higher level of evidence available to answer the question. Sample size calculations were given to answer three questions. Effect estimate was difficult to interpret given inconsistent findings, composite outcomes and lack of reported confidence intervals. In conclusion, antireflux surgery has many randomized controlled trials available upon which to base clinical practice. Unfortunately, these are generally of poor quality. We recommend that esophageal surgeons determine consistent outcome measures and endeavor to improve the quality of randomized controlled trials they perform.

Is there any correlation between severity of epilepsy and cognitive abilities in patients with temporal lobe epilepsy?

Frequent refractory seizures may cause cognitive deterioration when they present at an early age, especially in infants. The findings of previous studies designed to examine the impact of repetitive seizures on cognition in adolescents and adults, however, have shown wide variation. We analyzed the data of neuropsychological evaluations of patients before they underwent temporal lobe resection because of refractory seizure disorder in our institution from 1998 to 2001. Forty-four consecutive patients aged 12-48 years underwent a comprehensive neuropsychological evaluation that included a battery of selected visual and verbal memory tests. Statistical analysis revealed no significant correlation between disease-related parameters, such as age of onset, duration of active disease, estimated cumulative number of complex partial seizures and secondarily generalized seizures, and the results of neuropsychological tests. These findings support the hypothesis that factors other than repetitive seizures are responsible for cognitive dysfunction among adolescents and adults.

LGI1 mutations in temporal lobe epilepsies.

BACKGROUND AND OBJECTIVES: A number of familial temporal lobe epilepsies (TLE) have been recently recognized. Mutations in LGI1 (leucine-rich, glioma-inactivated 1 gene) have been found in a few families with the syndrome of autosomal dominant partial epilepsy with auditory features (ADPEAF). The authors aimed to determine the spectrum of TLE phenotypes with LGI1 mutations, to study the frequency of mutations in ADPEAF, and to examine the role of LGI1 paralogs in ADPEAF without LGI1 mutations. METHODS: The authors performed a clinical and molecular analysis on 75 pedigrees comprising 54 with a variety of familial epilepsies associated with TLE and 21 sporadic TLE cases. All were studied for mutations in LGI1. ADPEAF families negative for LGI1 mutations were screened for mutations in LGI2, LGI3, and LGI4. RESULTS: Four families had ADPEAF, 22 had mesial TLE, 11 had TLE with febrile seizures, two had TLE with developmental abnormalities, and 15 had various other TLE syndromes. LGI1 mutations were found in two of four ADPEAF families, but in none of the other 50 families nor in the 21 individuals with sporadic TLE. The mutations were novel missense mutations in exons 1 (c.124T-->G; C42G) and 8 (c.1418C-->T; S473L). No mutations in LGI2, LGI3, or LGI4 were found in the other two ADPEAF families. CONCLUSION: In TLE, mutations in LGI1 are specific for ADPEAF but do not occur in all families. ADPEAF is genetically heterogeneous, but mutations in LGI2, LGI3, or LGI4 did not account for families without LGI1 mutations.

Cortical lesions associated with transient neurological symptoms - not always a matter of cause and effect.

The occurrence of transient recurrent stereotypical neurological events mandates the exclusion of an underlying brain lesion. When imaging studies demonstrate the presence of a structural brain lesion, a cause and effect relationship between the two entities is assumed, and the decision for surgical intervention may then follow almost automatically. We describe five patients with transient neurological events suspected as being seizures that were referred for surgery because of an associated structural brain lesion. Video electroencephalographic recordings revealed that the events that brought these patients to neurosurgical attention were non-epileptic seizures. None of these patients underwent surgical intervention, and all were referred for behavioral therapy. Therefore, even in the presence of a confirmed brain lesion, the presenting paroxysmal events may be of a non-organic origin and should not necessarily be assumed to be caused by the concomitantly existing structural abnormality.