Efficacy and safety of two incobotulinumtoxinA injection intervals in cervical dystonia patients with inadequate benefit from standard injection intervals of botulinum toxin: Phase 4, open-label, randomized, noninferiority study.

IntroductionSome patients with cervical dystonia (CD) receiving long-term botulinum neurotoxin (BoNT) therapy report early waning of treatment benefit before the typical 12-week reinjection interval. Methods: This phase 4, open-label, randomized, noninferiority study (CD Flex; NCT01486264) compared 2 incobotulinumtoxinA injection schedules (Short Flex: 8 ± 2 weeks; Long Flex: 14 ± 2 weeks) in CD patients. Previous BoNT-responsive subjects who reported acceptable clinical benefit lasting < 10 weeks were recruited. Efficacy and safety were evaluated after 8 injection cycles. The primary endpoint was change in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) severity subscale 4 weeks after the eighth injection. Secondary endpoints included TWSTRS total and subscale scores. Immunogenicity was assessed in a subset of patients. Results: Two hundred eighty-two CD patients were randomized and treated (Short Flex, N = 142; Long Flex, N = 140), and 207 completed the study. Significant improvements in TWSTRS severity from study baseline to 4 weeks after cycle 8 were observed in both the Short Flex (4.1 points; P < 0.0001) and Long Flex (2.4 points; P = 0.002) groups; Short Flex was noninferior to Long Flex (LS mean difference = 1.4 points; 95% CI = [-2.9, 0.1] < Δ = 2.0). Key secondary endpoints favored Short Flex intervals. Adverse events (AEs) were comparable between groups. There was no secondary loss of treatment effect. Conclusion: Injection cycles < 10 weeks for incobotulinumtoxinA are effective (and noninferior to longer intervals) for treating CD patients with early waning of clinical benefit. Shorter injection intervals did not increase AEs or lead to loss of treatment effect.

Cognitive effects of theta frequency bilateral subthalamic nucleus stimulation in Parkinson's disease: A pilot study.

BACKGROUND: There is significant evidence for cognitive decline following deep brain stimulation (DBS). Current stimulation paradigms utilize gamma frequency stimulation for optimal motor benefits; however, little has been done to optimize stimulation parameters for cognition. Recent evidence implicates subthalamic nucleus (STN) theta oscillations in executive function, and theta oscillations are well-known to relate to episodic memory, suggesting that theta frequency stimulation could potentially improve cognition in Parkinson's disease (PD). OBJECTIVE: To evaluate the acute effects of theta frequency bilateral STN stimulation on executive function in PD versus gamma frequency and off, as well as investigate the differential effects on episodic versus nonepisodic verbal fluency. METHODS: Twelve patients (all males, mean age 60.8) with bilateral STN DBS for PD underwent a double-blinded, randomized cognitive testing during stimulation at (1) 130-135 Hz (gamma), (2) 10 Hz (theta) and (3) off. Executive functions and processing speed were evaluated using verbal fluency tasks (letter, episodic category, nonepisodic category, and category switching), color-word interference task, and random number generation task. Performance at each stimulation frequency was compared within subjects. RESULTS: Theta frequency significantly improved episodic category fluency compared to gamma, but not compared to off. There were no significant differences between stimulation frequencies in other tests. CONCLUSION: In this pilot trial, our results corroborate the role of theta oscillations in episodic retrieval, although it is unclear whether this reflects direct modulation of the medial temporal lobe and whether similar effects can be found with more canonical memory paradigms. Further work is necessary to corroborate our findings and investigate the possibility of interleaving theta and gamma frequency stimulation for concomitant motor and cognitive effects.

Open-label titration of apomorphine sublingual film in patients with Parkinson's disease and "OFF" episodes.

INTRODUCTION: The efficacy and safety of apomorphine sublingual film (APL-130277; APL) for the on-demand treatment of "OFF" episodes associated with Parkinson's disease (PD) was demonstrated in a double-blind trial. Herein we describe the ability of patients to receive effective and tolerable APL dose titration during the open-label titration phase. METHODS: Adult patients with levodopa-responsive PD and "OFF" episodes were enrolled. In practically defined "OFF," patients were observed for a FULL "ON" after their usual morning carbidopa/levodopa (CD/LD) dose and then after titration with APL following each increasing dose (10-35 mg). Antiemetic medication was administered for 3 days before initiation of titration and was continued throughout titration. Motor responses were evaluated predose and postdose using Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score. Safety outcomes were evaluated. RESULTS: Among 141 patients who enrolled in the study and received APL during open-label titration, 109 (77.3%) achieved a FULL "ON" (66.1% at 10-20 mg) and 10 did not. Patients who successfully completed APL dose titration tended to be younger, had a longer mean time since PD diagnosis, and had lower levodopa requirements than those who discontinued during titration for any reason. Change in MDS-UPDRS Part III scores from predose to 30 min postdose after titration with the effective dose of APL (n = 109) was similar across all dose groups. In a post hoc analysis, the magnitude of motor response with APL was ~2-fold higher than with CD/LD 15 min postdose, and the observed peak response occurred earlier with APL than with the trend seen for CD/LD (45 vs 90 min, respectively). Overall, the most common (≥10%) treatment-emergent adverse events (TEAEs) during APL dose titration were nausea (20.6%), yawning (12.1%), dizziness (11.3%), and somnolence (11.3%). Twelve patients discontinued due to TEAEs during APL dose titration, most commonly (≥2%) because of dizziness (2.8%), nausea (2.1%), and somnolence (2.1%). CONCLUSION: Among eligible patients with PD and "OFF" episodes who had their APL dose successfully titrated to an effective and tolerable level, most were able to do so within the first 3 titrated doses but some required further dose escalations. The use of APL can provide benefit for the treatment of "OFF" episodes.

Alcohol and the Hospitalized Patient.

Alcohol use is a common social and recreational activity in our society. Misuse of alcohol can lead to significant medical comorbidities that can affect essentially every organ system and lead to high health care costs and utilization. Heavy alcohol use across the spectrum from binge drinking and intoxication to chronic alcohol use disorder can lead to high morbidity and mortality both in the long and short term. Recognizing and treating common neurologic, gastrointestinal, and hematological manifestations of excess alcohol intake are essential for those who care for hospitalized patients. Withdrawal is among the most common and dangerous sequela associated with alcohol use disorder.

Evaluating the cost-effectiveness of a sequential pneumococcal vaccination compared to single-dose vaccination strategy for adults in Hong Kong.

Two vaccines, 23-valent pneumococcal polysaccharide vaccine (PPSV23) and 13-valent pneumococcal conjugate vaccine (PCV13), are widely available for the prevention of pneumococcal disease in adults. However, it is unclear how cost-effective these pneumococcal vaccine choices are in the Hong Kong healthcare environment. We aimed to assess the cost-effectiveness of a sequential administration of PCV13 followed by PPSV23 compared to a single dose of PPSV23 vaccination for pneumococcal disease control in Hong Kong adults aged ≥65 years and individuals aged 20-64 years with immunocompromising and chronic conditions. A previously developed deterministic cohort sequential model was applied to compare the outcomes of two vaccination strategies from a societal perspective. Population-specific model input, including incidence, mortality, case-fatality, risk group distribution, vaccination costs, disease management, and productivity loss, was estimated from a Hong Kong-wide electronic medical database. Costs were valued in US$ in 2017. Vaccination strategies with an incremental cost-effectiveness ratio (ICER, defined as incremental cost per QALY saved) less than one local GDP per capita ($46,193 in 2017) were defined as highly cost-effective. Deterministic sensitivity analyses (SA) were conducted. Compared with single-dose PPSV23, sequential vaccination of PCV13 followed by PPSV23 was cost-saving for adults aged ≥20 years. In the deterministic SA, the base-case results were robust for tested parameter uncertainties. Future vaccination policies should consider the cost-effectiveness of a sequential vaccination strategy as a measure to reduce the vaccine-preventable pneumococcal disease burden in Hong Kong.

Mild cognitive impairment, psychiatric symptoms, and executive functioning in patients with Parkinson's disease.

OBJECTIVE: Mild cognitive impairment (MCI) and psychiatric symptoms (anxiety, depression, and apathy) are common in Parkinson's disease (PD). While studies have supported the association between psychiatric symptoms and cognitive performance in PD, it is unclear if the magnitude of link between psychiatric symptoms and cognitive health is stronger by MCI status. The purpose of this study was to examine the association between cognitive performance and psychiatric symptoms in PD and whether MCI status moderates this association. METHODS/DESIGN: Participants (N = 187) completed a comprehensive neuropsychological assessment that included measures of attention, language, executive function (EF), visuospatial ability, episodic memory, and psychiatric symptoms. Participants were classified as PD-MCI (N = 73) or PD-normal cognition (NC; N = 114). Linear regression analyses were conducted to examine the association between psychiatric symptoms and cognitive performance and the moderating effect of PD-MCI status. RESULTS: There were no differences in mean psychiatric symptoms between PD-MCI and PD-NC. Psychiatric symptoms were predominantly associated with worse EF. The magnitude of the association between anxiety and worse EF was larger in participants with PD-MCI compared with PD-NC. A multivariable regression analysis examining the independent contributions of each symptom demonstrated the most robust association between EF and anxiety. CONCLUSIONS: Symptoms of anxiety, depression, and apathy are associated with worse executive functioning in individuals with PD. PD-MCI may be important in moderating the association between cognitive performance, specifically anxiety, and EF. Factors that promote cognitive resilience may serve as key therapeutic modalities in managing neuropsychiatric symptoms in PD.

Treadmill exercise elevates striatal dopamine D2 receptor binding potential in patients with early Parkinson's disease.

We have previously demonstrated changes in dopaminergic neurotransmission after intensive exercise in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of Parkinson's disease (PD), including an increase in the dopamine D2 receptor (DA-D2R), using noninvasive PET imaging with the radioligand [18F]fallypride. The purpose of this feasibility and translational study was to examine whether intensive exercise leads to similar alterations in DA-D2R expression using PET imaging with [18F]fallypride in individuals with early-stage PD. In this pilot study, four patients with early-stage PD were randomized to receive intensive exercise (treadmill training sessions three times/week for 8 weeks) or no exercise. Two healthy age-matched individuals participated in treadmill training. Alterations in the DA-D2R binding potential (BP) as a marker for receptor expression were determined using PET imaging with [18F]fallypride. Turning performance in the patients with PD as a measure of postural control and the Unified Parkinson's Disease Rating Scale scores pre-exercise and postexercise were determined. Our data showed an exercise-induced increase in [18F]fallypride BP as well as improved postural control in patients with PD who exercised. Changes in DA-D2R BP were not observed in patients with PD who did not exercise. These results suggest that exercise can lead to neuroplasticity in dopaminergic signaling and contribute to improved function that may be task specific (postural control) in early-stage PD.

A high-throughput screening system for Arabidopsis transcription factors and its application to Med25-dependent transcriptional regulation.

The activities of transcription factors (TFs) require interactions with specific DNA sequences and other regulatory proteins. To detect such interactions in Arabidopsis, we developed a high-throughput screening system with a Gateway-compatible Gal4-AD-TF library of 1589 Arabidopsis TFs, which can be easily screened by mating-based yeast-one-hybrid (Y1H) and yeast-two-hybrid (Y2H) methods. The efficiency of the system was validated by examining two well-characterized TF-DNA and TF-protein interactions: the CHE-CCA1 promoter interaction by Y1H and NPR1-TGAs interactions by Y2H. We used this system to identify eight TFs that interact with a Mediator subunit, Med25, a key regulator in JA signaling. We identified five TFs that interacted with the GCC-box cis-element in the promoter of PDF1.2, a downstream gene of Med25. We found that three of these TFs, all from the AP2-EREBP family, interact directly both with Med25 and the GCC-box of PDF1.2, suggesting that Med25 regulates PDF1.2 expression through these three TFs. These results demonstrate that this high-throughput Y1H/Y2H screening system is an efficient tool for studying transcriptional regulation networks in Arabidopsis. This system will be available for other Arabidopsis researchers, and thus it provides a vital resource for the Arabidopsis community.

Primary eyelid leiomyoma.

A 10-year-old white male presented with a recurrent painful nodule of the left lateral lower eyelid margin with associated madarosis. The initial pathologic diagnosis at an outside institution was reported as chalazion. The lesion was re-excised, and histopathologic examination with immunohistochemical evaluation confirmed the diagnosis of leiomyoma. This is the first reported case of primary leiomyoma originating in the eyelid.

Intubation of the ostium and nasolacrimal duct with a single self-linking silicone stent in external dacryocystorhinostomy.

PURPOSE: To describe a stent placement method that eliminates stent prolapse in external dacryocystorhinostomy. METHODS: A retrospective, institutional review board- approved case series of patients undergoing external dacryocystorhinostomy with an alternative stenting method. Following anastomosis of the posterior flaps, one arm of a Crawford silicone stent is passed through each canaliculus. Both arms are then passed through the nasolacrimal duct and retrieved in the inferior meatus. The 2 distal arms are redirected in the nose; one arm is looped around the proximal portions within the lacrimal sac and tied to the second arm. The stent is self-linked around the inferior turbinate. RESULTS: Nine patients underwent external dacryocystorhinostomy with alternative stenting. None experienced postoperative stent prolapse. At last follow-up (average, 38 months; range, 5-102 months), 8 patients reported resolution of tearing and exhibited normal dye clearance. On compression of the lacrimal sac, none of these 8 patients exhibited reflux of stagnant tears or dye through the canaliculi. CONCLUSIONS: This alternative method improves stent retention by using the inferior turbinate as a stopper to eliminate stent prolapse. The self-linking nature obviates the need and expense of additional biomedical devices.

Outcomes of orbital implants after evisceration and enucleation in patients with endophthalmitis.

PURPOSE OF REVIEW: This manuscript reviews enucleation and evisceration and primary versus secondary orbital implant placement in patients with endophthalmitis. A brief discussion of sympathetic ophthalmia is included as well. RECENT FINDINGS: Opinions remain variable when considering enucleation versus evisceration and primary versus secondary orbital implant placement in patients with endophthalmitis. Although rare, sympathetic ophthalmia remains a concern among surgeons. SUMMARY: Recent findings indicate enucleation and evisceration are performed for blind eyes with endophthalmitis and both porous and nonporous implants may be placed primarily with acceptable outcomes in these patients.

Quantitation of Staphylococcus aureus in seawater using CHROMagar SA.

A microbiological algorithm has been developed to analyze beach water samples for the determination of viable colony forming units (CFU) of Staphylococcus aureus (S. aureus). Membrane filtration enumeration of S. aureus from recreational beach waters using the chromogenic media CHROMagar SA alone yields a positive predictive value (PPV) of 70%. Presumptive CHROMagar SA colonies were confirmed as S. aureus by 24-hour tube coagulase test. Combined, these two tests yield a PPV of 100%. This algorithm enables accurate quantitation of S. aureus in seawater in 72 hours and could support risk-prediction processes for recreational waters. A more rapid protocol, utilizing a 4-hour tube coagulase confirmatory test, enables a 48-hour turnaround time with a modest false negative rate of less than 10%.

Congenital eyelid eversion.

Congenital bilateral upper eyelid eversion is a rare, benign condition that often resolves spontaneously without permanent sequelae. The authors present an unusual case requiring multiple surgical interventions in a newborn child. A previously undescribed method that restored anatomic eyelid position in this patient is also outlined.

Asymptomatic nephrolithiasis detected by ultrasound.

BACKGROUND AND OBJECTIVES: Data from several countries suggest a recent world-wide increase in the prevalence of stone disease. However, these studies have not analyzed the effect that increases in utilization of imaging modalities have had on detection of asymptomatic stones. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A retrospective chart review of all patients who had an abdominal or retroperitoneal ultrasound in 2005 at a Department of Veterans' Affairs Medical Center was conducted. The charts of patients who had ultrasounds demonstrating kidney stones were further reviewed. Patients were classified into symptomatic and asymptomatic groups on the basis of their clinical history. Age and sex for all patients were recorded. For those patients with stones, additional data were recorded. Of all patients in the study, the percentage of those with asymptomatic stones was calculated. Taking into account uncertainty about symptomaticity in some patients, a sensitivity analysis for the presence or absence of gross and microhematuria was performed to determine a range for the percent of asymptomatic stones. Appropriate statistical tests were used to determine significance. RESULTS: The prevalence of all kidney stones in the study group was 8.6 %. Using the sensitivity analysis, 29.8 to 45.7% of all stones were asymptomatic. Of stones found on abdominal ultrasounds, 71.4% were asymptomatic, whereas 36.8% of stones found on retroperitoneal ultrasound were asymptomatic. CONCLUSIONS: Asymptomatic stones have a relatively high prevalence on ultrasound. Epidemiologic estimates of prevalence of nephrolithiasis need to account for increases in utilization of imaging modalities and the resulting detection bias.

Efficacy of fresh versus refrigerated botulinum toxin in the treatment of lateral periorbital rhytids.

PURPOSE: To determine if there is a difference in the efficacy of refrigerated (previously reconstituted) versus freshly reconstituted botulinum toxin (Botox Cosmetic, Allergan, Irvine, CA, U.S.A.) in the treatment of lateral periorbital rhytids. METHODS: This is a randomized, double-blind, controlled, prospective study. Participants included individuals who were interested in the treatment of their lateral periorbital rhytids (crow's feet) and responded to signs posted in ophthalmology clinics at our institution. Patients were randomized to receive fresh botulinum toxin on 1 side and refrigerated (reconstituted 2 weeks prior) botulinum toxin on the other. Photographs were taken at the pretreatment visit and at the 2-week, 6-week, and 3-month post-treatment visits. Patients were asked to describe any improvement in the appearance of the rhytids at the 2-week visit, the appearance of the rhytids at the 6-week visit, the appearance of the rhytids at the 3-month visit, and finally, the duration of effect at the 3-month visit as well as whether any intervening loss of efficacy had been noted subjectively. The subjective information was recorded by 1 investigator (JIH) at each of the follow-up visits. At the conclusion of the study, the photographs were shown to an ophthalmic plastic and reconstructive surgery fellow, who did not participate in the interventional portion of the study, to determine the response to treatment. This physician was masked to the study protocol and purpose and looked at each photograph without knowledge of treatment arm or timeline. The physician used the Wrinkle Assessment Scale developed by Lemperle et al. to grade the lateral periorbital rhytids on a 0 to 5 scale. RESULTS: Forty-five patients were included in the final analysis. One patient felt there was a difference in the time of onset with the refrigerated toxin taking effect on day 3 versus day 4 for the fresh toxin. Unmasking revealed the following: 5 patients felt there was a greater effect on the freshly reconstituted side while 6 patients felt there was a greater effect on the refrigerated side. The independent physician evaluator determined there was a difference in effect between sides in 4 patients with the greater effect on the fresh side in 2 patients and the refrigerated side in 2 patients. CONCLUSIONS: This study demonstrates that 2 weeks of refrigeration does not appear to significantly affect the time of onset or efficacy of botulinum toxin in the treatment of lateral periorbital rhytids.

Retained nuclear fragments in the anterior chamber after phacoemulsification with an intact posterior capsule.

OBJECTIVE: To review the clinical features and treatment of patients with retained nuclear fragments in the anterior chamber (AC). DESIGN: Single-center, retrospective, noncomparative, consecutive case series. PARTICIPANTS: Sixteen patients with a diagnosis of retained nuclear fragments in the AC. METHODS: Retrospective review of the medical records at Bascom Palmer Eye Institute in Miami, Florida, to identify all patients with a diagnosis of retained nuclear fragments in the AC after phacoemulsification surgery without rupture of the posterior capsule. Charts were reviewed and patient characteristics, ocular history, clinical findings, treatment (medical and surgical), and visual outcomes were recorded. MAIN OUTCOME MEASURES: Visual outcome and visual acuity at last follow-up visit. RESULTS: Most patients presented with corneal edema and anterior segment inflammation. All patients proved refractory to medical management, and surgical extraction of the retained lens fragment was required. Ten patients were myopic or had long axial lengths and/or steep keratometry readings. Three patients underwent penetrating keratoplasty for intractable corneal edema. One patient required a second surgery for fragment removal after a previous unsuccessful attempt at removal. Visual outcomes for the patients without macular disease who had lens fragment removal alone ranged from 20/20 to 20/40. Of the 2 patients without macular disease who underwent penetrating keratoplasty, the visual outcomes were 20/50 and 20/30. CONCLUSIONS: Retention of nuclear fragments in the AC may occur after phacoemulsification. This complication was associated with myopia in a majority of patients in this series, and we hypothesize that small fragments may hide in the posterior chamber in these larger eyes. Surgical removal was associated with a good visual outcome in patients without macular disease.

Desmoplastic malignant melanoma of the lip: a report of 6 cases and review of the literature.

Desmoplastic malignant melanoma is a rare neoplasm consisting primarily of spindle-shaped melanoma cells embedded in a fibrous stroma, with approximately 6% of cases occurring in the lip. A literature search revealed that most reported cases occur in sun-exposed areas in older men. Few cases of desmoplastic malignant melanoma of the lip in young people (in their mid-twenties) have been described. We report 6 previously undocumented cases of labial desmoplastic malignant melanoma occurring in young individuals and review 20 cases from the literature. Physicians should consider the possibility of desmoplastic malignant melanoma in young people who present with atypical lip lesions, which on histopathologic analysis demonstrate spindle-cell hyperplasia. Although this diagnosis is rare and there have not been reports of such patients in the literature thus far, our findings should alert clinicians to the possibility of desmoplastic malignant melanoma as a diagnosis for lip lesions in young people.