Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer's disease and 5XFAD mice.

Approximately 22% of Alzheimer's disease (AD) patients suffer from seizures, and the co-occurrence of seizures and epileptiform activity exacerbates AD pathology and related cognitive deficits, suggesting that seizures may be a targetable component of AD progression. Given that alterations in neuronal excitatory:inhibitory (E:I) balance occur in epilepsy, we hypothesized that decreased markers of inhibition relative to those of excitation would be present in AD patients. We similarly hypothesized that in 5XFAD mice, the E:I imbalance would progress from an early stage (prodromal) to later symptomatic stages and be further exacerbated by pentylenetetrazol (PTZ) kindling. Post-mortem AD temporal cortical tissues from patients with or without seizure history were examined for changes in several markers of E:I balance, including levels of the inhibitory GABAA receptor, the sodium potassium chloride cotransporter 1 (NKCC1) and potassium chloride cotransporter 2 (KCC2) and the excitatory NMDA and AMPA type glutamate receptors. We performed patch-clamp electrophysiological recordings from CA1 neurons in hippocampal slices and examined the same markers of E:I balance in prodromal 5XFAD mice. We next examined 5XFAD mice at chronic stages, after PTZ or control protocols, and in response to chronic mTORC1 inhibitor rapamycin, administered following kindled seizures, for markers of E:I balance. We found that AD patients with comorbid seizures had worsened cognitive and functional scores and decreased GABAA receptor subunit expression, as well as increased NKCC1/KCC2 ratios, indicative of depolarizing GABA responses. Patch clamp recordings of prodromal 5XFAD CA1 neurons showed increased intrinsic excitability, along with decreased GABAergic inhibitory transmission and altered glutamatergic neurotransmission, indicating that E:I imbalance may occur in early disease stages. Furthermore, seizure induction in prodromal 5XFAD mice led to later dysregulation of NKCC1/KCC2 and a reduction in GluA2 AMPA glutamate receptor subunit expression, indicative of depolarizing GABA receptors and calcium permeable AMPA receptors. Finally, we found that chronic treatment with the mTORC1 inhibitor, rapamycin, at doses we have previously shown to attenuate seizure-induced amyloid-ß pathology and cognitive deficits, could also reverse elevations of the NKCC1/KCC2 ratio in these mice. Our data demonstrate novel mechanisms of interaction between AD and epilepsy and indicate that targeting E:I balance, potentially with US Food and Drug Administration-approved mTOR inhibitors, hold therapeutic promise for AD patients with a seizure history.

The role of mTORC1 activation in seizure-induced exacerbation of Alzheimer's disease.

The risk of seizures is 10-fold higher in patients with Alzheimer's disease than the general population, yet the mechanisms underlying this susceptibility and the effects of these seizures are poorly understood. To elucidate the proposed bidirectional relationship between Alzheimer's disease and seizures, we studied human brain samples (n = 34) from patients with Alzheimer's disease and found that those with a history of seizures (n = 14) had increased amyloid-ß and tau pathology, with upregulation of the mechanistic target of rapamycin (mTOR) pathway, compared with patients without a known history of seizures (n = 20). To establish whether seizures accelerate the progression of Alzheimer's disease, we induced chronic hyperexcitability in the five times familial Alzheimer's disease mouse model by kindling with the chemoconvulsant pentylenetetrazol and observed that the mouse model exhibited more severe seizures than the wild-type. Furthermore, kindled seizures exacerbated later cognitive impairment, Alzheimer's disease neuropathology and mTOR complex 1 activation. Finally, we demonstrated that the administration of the mTOR inhibitor rapamycin following kindled seizures rescued enhanced remote and long-term memory deficits associated with earlier kindling and prevented seizure-induced increases in Alzheimer's disease neuropathology. These data demonstrated an important link between chronic hyperexcitability and progressive Alzheimer's disease pathology and suggest a mechanism whereby rapamycin may serve as an adjunct therapy to attenuate progression of the disease.

Weekend Admissions for Somatic Symptom and Related Disorders and Length of Stay.

OBJECTIVES: To evaluate whether admission on weekends affects the length of stay (LOS) for patients hospitalized with somatic symptom and related disorders (SSRDs). METHODS: Data from 2012-2018 was obtained for all patients aged 4 to 21 years (N = 5459) with a primary discharge diagnosis of SSRDs from 52 tertiary care pediatric hospitals in the United States. We obtained patient demographics, admission date and/or time, LOS, procedure count, and comorbid conditions. We defined a weekend as 3 pm Friday to 3 pm Sunday. The Wilcoxon rank test was used for unadjusted analysis. Multiple logistic regression was used to estimate the odds of having LOS >1 day, >2 days, >3 days, and >4 days in weekend versus weekday groups. RESULTS: Weekend admission significantly correlated with increased LOS (P < .001). Compared with weekdays, a weekend admission was associated with increased odds of having LOS >1, >2, and >3 days. This remained statistically significant while adjusting for the number of chronic conditions, procedures, and individuals with Black or Hispanic ethnicity compared with White ethnicity. LOS was not associated with sex or age of the patients. CONCLUSIONS: Patients with SSRDs admitted on the weekend have an increased LOS compared with those admitted on a weekday. This may be due to a decrease in multidisciplinary care available during weekends. In future studies, researchers should aim to better understand the specific factors that contribute to this disparity and test interventions that may close the gap in care, including expanding to 7-day services, increasing mental health resources, and working to decrease the need for inpatient admissions.

The Medial Metaphyseal Periosteal Artery (MMPA): An Alternate Pedicle for the Medial Femoral Trochlea Flap.

We report a case of medial femoral trochlea flap used for scaphoid proximal pole reconstruction, in which the transverse branch of the descending genicular artery was vestigial. The medial metaphyseal periosteal artery was clearly the dominant pedicle supplying the trochlear region. The flap was safely raised on the medial metaphyseal periosteal artery pedicle. The incidence of this uncommon presentation remains unknown and this anatomical variant is newly described.

New Mosquitocide Derived From Volcanic Rock.

Malaria, dengue, yellow fever, and the Zika and West Nile Viruses are major vector-borne diseases of humans transmitted by mosquitoes. According to the World Health Organization, over 80% of the world's population is at risk of contacting these diseases. Insecticides are critical for mosquito control and disease prevention, and insect insecticide resistance is on the increase; new alternatives with potentially different modes of action from current chemistry are needed. During laboratory screening of industrial minerals for insecticide activity against Anopheles gambiae (Giles) (Diptera: Culicidae) we discovered a novel mechanical insecticide derived from volcanic rock (MIVR) with potential use as a residual spray. In modified WHO cone tests, the time to 50% mortality was 5 h under high-humidity conditions. MIVR treated surfaces demonstrated no mosquito repellency. In field studies where the mechanical insecticide was applied to wood using standard spray equipment and then placed under stilt homes in New Orleans, LA, the residual activity was >80% after 9 wk against Aedes aegypti (L.) (Diptera: Culicidae), Aedes albopictus (Skuse) (Diptera: Culicidae) and Culex quinquefasciatus (Say) (Diptera: Culicidae) (with similar efficacy to a positive chemical insecticide control). In scanning electron microcopy studies, the MIVR was transferred as particles mostly to the legs of the mosquito. This wettable powder made from volcanic rock is a mechanical insecticide representing a potential new mode of action different from current chemistry for mosquito control and is in commercial development under the trade name Imergard™WP as an indoor and outdoor residual spray.

Vertebral osteomyelitis due to Salmonella Poona in a healthy adolescent female.

We present a case of vertebral osteomyelitis in a previously healthy, adolescent Caucasian female athlete. After months of lower back pain, spinal imaging demonstrated phlegmon and suspected osteomyelitis of the L4 vertebral body. A bone biopsy was obtained, and microbiologic cultures yielded pure growth of Salmonella enterica subsp. enterica serovar Poona (S. Poona), a member of the nontyphoid Salmonella group associated with food-borne gastroenteritis in the United States. This case represents the first reported association of S. Poona with osteomyelitis and is interesting in that the infection developed in a patient without traditional risk factors for invasive Salmonella disease (i.e. sickle cell disease). This case highlights the importance of keeping a broad differential diagnosis for lower back pain and emphasizes the value of obtaining specimens for microbiologic culture to aid in diagnosing non-traditional and potentially emerging bacterial pathogens.

ImergardTMWP: A Non-Chemical Alternative for an Indoor Residual Spray, Effective against Pyrethroid-Resistant Anopheles gambiae (s.l.) in Africa.

Malaria is the deadliest mosquito-borne disease and kills predominantly people in sub-Saharan Africa (SSA). The now widespread mosquito resistance to pyrethroids, with rapidly growing resistance to other insecticide classes recommended by the World Health Organization (WHO), may overturn the successes gained in mosquito control in recent years. It is of utmost importance to search for new, inexpensive, and safe alternatives, with new modes of action, that might improve the efficacy of current insecticides. The efficacy of a novel mechanical insecticidal mineral derived from volcanic rock, ImergardTMWP, was investigated to determine its efficacy as a stand-alone residual wall spray and as a mixture with deltamethrin (K-Othrine® Polyzone) in experimental huts in Cove, Benin. The evaluation was conducted with susceptible (Kisumu) and wild-type Anopheles gambiae (s.l.). Deltamethrin applied alone demonstrated 40-45% mortality (at 72 h post-exposure) during the first four months, which declined to 25% at six months for wild An. gambiae from Cove. ImergardTMWP alone and mixed with deltamethrin, under the same assay conditions, produced 79-82% and 73-81% mortality, respectively, during the same six-month period. ImergardTMWP met the 80% WHO bio-efficacy threshold for residual activity for the first five months with 78% residual activity at six months. ImergardTMWP can be used as a mixture with chemical insecticides or as a stand-alone pesticide for mosquito control in Africa.

Surgical Treatment and Outcomes of Syndactyly: A Systematic Review.

Background: Different techniques are used to release simple and complex congenital syndactyly in order to create an adequate web space, and to separate the fingers to allow independent function. Methods: This article is a systematic review of the literature, aiming to evaluate the evidence for the different techniques and outcome measures utilised. Results: The studies consisted mainly of retrospective, non-controlled descriptive series and a few retrospective cohort studies. The level of evidence is predominantly poor. Conclusions: Although recommendations in favour of any particular surgical technique cannot be given based on evidence, a number of conclusions can be drawn out of the existing literature with regards to the design of the incisions for finger separation, use of pulp flaps and grafts.

Iatrogenic Femur Fracture Following Medial Femoral Condyle Flap Harvest.

A case of iatrogenic femoral fracture after harvest of a medial femoral condyle flap is presented. The procedure was performed for a recalcitrant nonunion of the clavicle that required a flap of 6 × 1 × 1 cm. The patient suffered a supracondylar fracture at the proximal extent of the flap harvest site 3 weeks after surgery, requiring surgical fixation of the femur.

Bio-Efficacy of Diatomaceous Earth, Household Soaps, and Neem Oil against Spodoptera frugiperda (Lepidoptera: Noctuidae) Larvae in Benin.

Spodoptera frugiperda was first reported in Africa in 2016 and has since become a serious threat to maize/cereal production on the continent. Current control of the pest relies on synthetic chemical insecticides, which can negatively impact the environment and promote the development of resistance when used indiscriminately. Therefore, great attention is being paid to the development of safer alternatives. In this study, several biorational products and a semi-synthetic insecticide were evaluated. Two household soaps ("Palmida" and "Koto") and a detergent ("So Klin") were first tested for their efficacy against the larvae under laboratory conditions. Then, the efficacy of the most effective soap was evaluated in field conditions, along with PlantNeem (neem oil), Dezone (diatomaceous earth), and Emacot 19 EC (emamectin benzoate), in two districts, N'Dali and Adjohoun, located, respectively, in northern and southern Benin. The soaps and the detergent were highly toxic t second-instar larvae with 24 h lethal concentrations (LC50) of 0.46%, 0.44%, and 0.37% for So Klin, Koto, and Palmida, respectively. In field conditions, the biorational insecticides produced similar or better control than Emacot 19 EC. However, the highest maize grain yields of 7387 and 5308 kg/ha were recorded, respectively, with Dezone (N'Dali) and Emacot 19 EC (Adjohoun). A cost-benefit analysis showed that, compared to an untreated control, profits increased by up to 90% with the biorational insecticides and 166% with Emacot 19 EC. Therefore, the use of Palmida soap at 0.5% concentration, neem oil at 4.5 L/ha, and Dezone at 7.5 kg/ha could provide an effective, environmentally friendly, and sustainable management of S. frugiperda in maize.

Implementing Resident Team Assistant Programs at Academic Medical Centers: Lessons Learned.

BACKGROUND: Excessive inpatient administrative tasks can lead to adverse consequences for residents and their patients. Furthermore, this burden has been linked to depersonalization, a major component of physician burnout. OBJECTIVE: To describe the development, implementation, feasibility, acceptability, and early outcomes of Resident Team Assistant (RTA) programs. METHODS: Three large academic medical centers created RTA programs in which administrative assistants are incorporated into inpatient medical teams. First steps included a needs assessment and driver diagram creation to identify key issues and to solidify goals. Program directors were assigned, and RTAs were hired, trained, and incorporated into inpatient teams at each institution (2003, 2016, 2018). Program leadership and institutional stakeholders met regularly to discuss development and quality assurance. Surveys and direct interviews were performed to evaluate impact and acceptability. Institutional goals in accordance to RTAs tasks were also investigated. RESULTS: Resident surveys and interviews have shown acceptability with RTAs completing a large percentage of resident administrative tasks while promoting time spent in direct clinical care and job satisfaction. Hospital-specific improvements have included increase in referring physician communication rate and decrease in work hour violations. The programs have maintained high feasibility and sustainability with a relatively low time commitment from leadership and cost for the institutions. CONCLUSIONS: The RTA programs at the 3 institutions have continued to be sustained over time with perceived improvements in administrative task burden and job satisfaction for the residents. They have maintained high acceptability and feasibility in terms of effort and costs for the hospitals.

Cadaveric Dissection of the Axillary Nerve: An Investigation of Extra-Muscular and Intra-Muscular Branching Patterns.

BACKGROUND: Variations in the axillary nerve branching patterns have been reported. The aim of the study is to investigate the extra- and intra-muscular course of the axillary nerve and quantify the regional innervation of the deltoid. METHODS: In fresh frozen specimens, the origin of the axillary nerve from the posterior cord of the brachial plexus and its extra- and intra-muscular course were identified. Muscle dimensions, branching patterns and the distance from the axillary nerve origin to major branches were measured. The weights of muscle segments supplied by major branches of the axillary nerve were recorded. RESULTS: Twenty-three cadaveric dissections were completed. The axillary nerve bifurcated within the quadrangular space in all cases. The mean distance from the origin to bifurcation of the axillary nerve was 39 ± 13 mm; from axillary nerve bifurcation to the teres minor branch was 13 ± 6 mm; and from axillary nerve bifurcation to the middle branch of anterior division was 26 ± 11 mm. The nerve to teres minor and superior lateral brachial cutaneous nerve originated from the posterior division or common trunk in all cases. No fibrous raphe were identified separating anterior, middle and posterior deltoid segments. The anterior division of axillary nerve supplied 85 ± 4% of the deltoid muscle (by weight). The posterior division supplied 15 ± 4% of the deltoid muscle (by weight). The posterior deltoid was supplied by both anterior and posterior divisions in 91.3% of cases. CONCLUSIONS: This study demonstrates a consistent branching pattern of the axillary nerve. The anterior division of the axillary nerve innervates all three deltoid segments in most instances (85% of the deltoid by weight). This study supports the concept of re-innervation of the anterior division alone in isolated axillary nerve injuries.

Cost Comparison of Collagenase Clostridium Histolyticum and Fasciectomy for Treatment of Dupuytren's Contracture in the Australian Health System.

BACKGROUND: Dupuytren's disease results in contracted cords in the hand that lead to deformity and disability. Current treatment options include fasciectomy and an injectable, collagenase clostridium histolyticum. No cost comparison studies have been published within the Australian health care environment. METHODS: A retrospective review of all patients treated for Dupuytren's disease in a major teaching hospital was undertaken to compare the costs of treatment by fasciectomy or collagenase injection. RESULTS: Eighteen patients underwent fasciectomy and 21 collagenase clostridium histolyticum injections were performed during the study period and were eligible for inclusion under the review criteria. Of the 39 patients, 36 were male and 3 were female with an average age 66.4 years (50-85). Twenty-five digits were treated by fasciectomy in 18 patients, and 23 digits were treated by collagenase in 21 patients. The fasciectomy group attended an average 9.2 visits (5-22), incurring an average costing of US$5738.12 per patient ($3181.18-$9618.10). The collagenase group attended an average 3.8 visits (3-8), incurring an average costing of US$2076.83 per patient ($1842.24-$3929.57). CONCLUSIONS: Collagenase treatment of Dupuytren's contracture represents a significant reduction in cost relative to fasciectomy, with 64% savings, length of follow up and number of visits. This is a similar finding to studies in other countries.

Neutrophilic Dermatosis of the Hands: A Review of 17 Cases.

PURPOSE: Neutrophilic dermatosis of the hands is an inflammatory skin condition related to Sweet syndrome that responds to corticosteroids. It commonly affects the dorsum of the hand and often mimics infection, with violaceous inflammatory papules and plaques that may ulcerate. The aim of this study was to review the clinical presentation of neutrophilic dermatosis of the hands. METHODS: A retrospective review was undertaken of all cases of neutrophilic dermatosis of the hands seen at a tertiary hospital in New South Wales, Australia, over a 5-year period. RESULTS: Seventeen cases were identified. The mean time to diagnosis was 9 days after lesion onset. Most cases were older adults (mean age, 71 years). The most common referral diagnoses were infection or a nonhealing wound and 65% of cases reported a history of trauma. The dorsal index finger was the site of involvement in 41% of cases. One case involved the palm. Histopathology reports were available for skin punch biopsy for 14 of 17 cases, which showed dermal neutrophilic infiltrate (93%) and epidermal involvement with necrosis, ulceration, or pustulation (64%). Six cases were treated surgically prior to the correct diagnosis and management being introduced. CONCLUSIONS: Neutrophilic dermatosis of the hands was often misdiagnosed as infection. A history of trauma is common and may be misleading. Dermatological consultation and skin punch biopsy are useful in confirming the diagnosis, ideally prior to surgical management. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV.

House Staff Participation in Patient Safety Reporting: Identification of Predominant Barriers and Implementation of a Pilot Program.

OBJECTIVES: Patient safety event (PSE) reporting is a critical element for healthcare organizations that are striving for continuous quality improvement. Although resident physicians routinely provide the majority of direct patient care, the level of their participation in PSE reporting historically has been low. In addition, as part of the Accreditation Council for Graduate Medical Education's Next Accreditation System, the Clinical Learning Environment Review site visit assesses residents' engagement in PSE reporting at each accredited academic institution. The objective of this study was to understand the common barriers to PSE reporting and design an intervention to increase the number of PSE reports by resident physicians. METHODS: We surveyed 304 residents and fellows to assess attitudes toward the PSE reporting system and identify barriers to submitting online PSE reports. Based on this analysis of barriers, we piloted interventions with the internal medicine residency program and measured their effect on resident PSE reporting. RESULTS: Of the survey respondents, 58% had never submitted a PSE report. The most commonly identified barriers were too much time required to submit a report (38% of all respondents), lack of education on how or what to report (37%), lack of feedback or change after reporting (19%), and concern for repercussions or lack of anonymity (13%). Based on this analysis of barriers, we piloted interventions with the internal medicine residency program to educate residents about PSE reporting through a reminder message in their orientation e-mail, informational slides at the end of conferences that described what and how to report, a pocket card with reporting instructions, and leadership encouragement during walk rounds by chief medical residents and the program director. Compared with the 10 weeks before the start of the intervention, the number of PSE reports submitted by internal medicine residents more than doubled, from 16 to 37 reports (P < 0.01). This increase in resident PSE reporting was sustained for 20 weeks despite the interventions lasting only 8 weeks. CONCLUSIONS: A resident-driven intervention that fostered a culture of encouragement for PSE reporting through leadership support and targeted education increased the number of PSE reports submitted by internal medicine residents at our health system. Hospitals and health systems should seek to understand the common barriers to PSE reporting from this important group of direct patient care providers and administer structured educational programs to encourage their participation.

Improving Interdisciplinary Provider Communication Through a Unified Paging System.

OBJECTIVES: Interdisciplinary communication at a Veterans Affairs (VA) academic teaching hospital is largely dependent on alphanumeric paging, which has limitations as a result of one-way communication and lack of reliable physician identification. Adverse patient outcomes related to difficulty contacting the correct consulting provider in a timely manner have been reported. METHODS: House officers were surveyed on the level of satisfaction with the current VA communication system and the rate of perceived adverse patient outcomes caused by potential delays within this system. Respondents were then asked to identify the ideal paging system. These results were used to develop and deploy a new Web site. A postimplementation survey was repeated 1 year later. This study was conducted as a quality improvement project. RESULTS: House officer satisfaction with the preintervention system was 3%. The majority used more than four modalities to identify consultants, with 59% stating that word of mouth was a typical source. The preferred mode of paging was the university hospital paging system, a Web-based program that is used at the partnering academic institution. Following integration of VA consulting services within the university hospital paging system, the level of satisfaction improved to 87%. Significant decreases were seen in perceived adverse patient outcomes (from 16% to 2%), delays in patient care (from 90% to 16%), and extended hospitalizations (from 46% to 4%). CONCLUSIONS: Our study demonstrates significant improvement in physician satisfaction with a newly implemented paging system that was associated with a decreased perceived number of adverse patient events and delays in care.

Stevens-Johnson syndrome and HIV in children in Swaziland.

BACKGROUND: Stevens-Johnson syndrome (SJS) can be a severe and life-threatening reaction with many potential causes, including multiple medications used in HIV care and treatment. Specific risk factors, especially in children, are not currently well-understood. METHODS: We describe a series of cases of SJS that occurred from 2006 to 2010 in an HIV-focused clinic in Mbabane, Swaziland. The electronic medical and pharmacy records of all pediatric patients <20 years old were reviewed to identify cases of SJS. Patient demographic, immunosuppression and outcome data were also collected. RESULTS: A total of 19 cases of SJS were documented. Eighty-four percent of cases were attributed to nevirapine (NVP) exposure whereas the remaining cases were caused by cotrimoxazole (11%) and efavirenz (5%). Median symptom onset was 22 days after initiation of the offending medication (interquartile range = 14-25 days). At time of SJS, 84% had advanced or severe immunosuppression. Forty-two percent of patients required hospitalization, and no SJS-associated deaths were known to occur. Use of efavirenz was attempted in 8 NVP-associated cases after SJS resolution and was successful in all except 1. CONCLUSIONS: SJS occurrence was rare in this population, with the majority of cases being associated with NVP. All occurred within 32 days of medication initiation, providing a target window for intensified monitoring and anticipatory guidance. SJS can occur in children at any age, with any level of immunosuppression, and can occur during the lead-in dosing period of NVP.

The use of V-Y advancement flaps for closure of pretibial skin defects after excision of cutaneous lesions.

METHODS: We retrospectively analyzed 88 consecutive V-Y flap closures of pretibial surgical defects of up to 45 mm in diameter. RESULTS: Eight percent of patients developed wound infection, which showed a significant association with antihypertensive use. No bleeding complications were experienced in any of the patients, including 40 patients on antiplatelet or anticoagulation therapy. Health care costs were calculated as far less than those for patients treated with split skin grafting because of shorter hospital stay and fewer dressing visits. CONCLUSION: V-Y flap closure is a safe and reliable technique and is a superior alternative to split skin grafting in appropriate defects in the pretibial area.