Search

Background The differential risk of incident dementia associated with receiving various overactive bladder (OAB) drugs is unknown. Objective To estimate the association of antimuscarinic OAB drug (exposure), compared with a β-3 agonist (mirabegron), and incident dementia. Design, setting, and participants A population-based nested case-control study was conducted in patients treated with OAB medications in Ontario, Canada. A total of 11 392 patients aged ≥66 yr with a new diagnosis of dementia between 2010 and 2017, and 29 881 age- and sex-matched controls without dementia were included in the study. Intervention Receipt of an antimuscarinic OAB drug or receipt of mirabegron, within the previous 6–12 mo. Outcome measurements and statistical analysis Cases developed dementia and Alzheimer’s disease. Controls were derived from the general population and matched to cases based on important baseline characteristics. Odds ratios (ORs) for incident dementia, adjusted for demographic and health-related characteristics, were determined. Results and limitations Patients receiving solifenacin (OR 1.24; 95% confidence interval 1.08–1.43) and darifenacin (OR 1.30; 95% CI 1.08–1.56) in the prior 6 mo had increased odds of incident dementia compared with those receiving mirabegron. In the 6 mo to 1 yr prior to diagnosis, receipt of solifenacin (OR 1.34; 95% CI 1.11–1.60), darifenacin (OR 1.49; 95% CI 1.19–1.86), tolterodine (OR 1.21; 95% CI 1.02–1.45), and fesoterodine (OR 1.39; 95% CI 1.14–1.71) was associated with increased odds of incident dementia compared with receipt of mirabegron. No effect was seen with oxybutynin or trospium. Limitations included misclassification of the outcome and residual confounding associated with the use of health administrative databases. Conclusions Older adults receiving solifenacin and darifenacin in the 6 mo prior to diagnosis, and those receiving solifenacin, darifenacin, tolterodine, or fesoterodine in the year prior to diagnosis, have increased odds of incident dementia, compared with those receiving mirabegron. Oxybutynin and trospium were not associated with dementia, likely due to a protopathic bias. Careful drug selection is warranted when treating patients with OAB. Patient summary In a large Canadian cohort of patients who developed dementia after starting an overactive bladder (OAB) medication, those taking some anticholinergic medications for OAB have an increased risk of dementia compared with those taking mirabegron.

OBJECTIVE Traditional surgery for adult spinal deformity (ASD) is effective but may result in exposure-related morbidity. Minimally invasive surgery (MIS) can potentially minimize this morbidity; however, high-level evidence is lacking. This study presents the first prospective multicenter investigation of MIS approaches for ASD. METHODS A prospective multicenter study was conducted. Inclusion criteria were age ≥ 18 years, with at least one of the following radiographic criteria: coronal Cobb (CC) angle ≥ 20°, sagittal vertical axis (SVA) > 5 cm, pelvic tilt (PT) > 25°, and thoracic kyphosis > 60°. Additional inclusion criteria were circumferential MIS, including interbody fusion (transforaminal lumbar interbody fusion [TLIF], lateral lumbar interbody fusion [LLIF], or anterior lumbar interbody fusion [ALIF]) with percutaneous posterior fixation on a minimum of 4 intervertebral levels. Radiographic and clinical outcomes (visual analog scale [VAS], Oswestry Disability Index [ODI], and Scoliosis Research Society–22 [SRS-22]) were collected preoperatively and at 12 months postoperatively; preoperative and postoperative values were compared using paired Student t-tests. RESULTS Seventy-five patients with a minimum 1-year follow-up were identified (75 of 111; 67.6%). The mean ± SD age was 68.8 ± 9.0 years, and 48 patients (64%) were female. Patients underwent a mean of 6.7 ± 2.9 levels of fusion with LLIF (85%), ALIF (55%), and TLIF (9%); the mean estimated blood loss was 547.6 ± 567.2 mL, and the mean length of stay was 7.0 ± 3.7 days. Significant improvements were observed in ODI (−19 ± 12.9, p < 0.001), SRS-22 (0.8 ± 0.66, p < 0.001), VAS back (−4.3 ± 2.8, p < 0.001), and VAS leg (−3.0 ± 3.2, p < 0.001) scores. Significant decreases in SVA (−26.4 ± 53.6 mm; p < 0.001), pelvic incidence–lumbar lordosis (−11.3° ± 14.9°, p < 0.001), and CC angle (−12.1° ± 11.8°, p < 0.001) were also observed. Complications occurred in 39 patients (52%); 11 patients (15%) experienced major complications, and 16 patients (21%) required reoperation. CONCLUSIONS MIS approaches for ASD resulted in meaningful symptomatic improvement. The complication rates were similar to historic norms, with a fairly high reoperation rate at 1 year. Longer follow-up will be necessary to evaluate the durability of this approach in the treatment of ASD.

OBJECTIVE Previous studies have demonstrated the short-term radiographic and clinical benefits of circumferential minimally invasive surgery (cMIS) and hybrid (i.e., minimally invasive anterior or lateral interbody fusion with an open posterior approach) techniques to correct adult spinal deformity (ASD). However, it is not known if these benefits are maintained over longer periods of time. This study evaluated the 2- and 3-year outcomes of cMIS and hybrid correction of ASD. METHODS A multicenter database was retrospectively reviewed for patients undergoing cMIS or hybrid surgery for ASD. Patients were ≥ 18 years of age and had one of the following: maximum coronal Cobb angle (CC) ≥ 20°, sagittal vertical axis (SVA) > 5 cm, pelvic incidence–lumbar lordosis mismatch (PI-LL) ≥ 10°, or pelvic tilt (PT) > 20°. Radiographic parameters were evaluated at the latest follow-up. Clinical outcomes were compared at 2- and 3-year time points and adjusted for age, preoperative CC, levels operated, levels with interbody fusion, presence of L5–S1 anterior lumbar interbody fusion, and upper and lower instrumented vertebral level. RESULTS Overall, 197 (108 cMIS, 89 hybrid) patients were included with 187 (99 cMIS, 88 hybrid) and 111 (60 cMIS, 51 hybrid) patients evaluated at 2 and 3 years, respectively. The mean (± SD) follow-up duration for cMIS (39.0 ± 13.3 months, range 22–74 months) and hybrid correction (39.9 ± 16.8 months, range 22–94 months) were similar for both cohorts. Hybrid procedures corrected the CC greater than the cMIS technique (adjusted p = 0.022). There were no significant differences in postoperative SVA, PI-LL, PT, and sacral slope (SS). At 2 years, cMIS had lower Oswestry Disability Index (ODI) scores (adjusted p < 0.001), greater ODI change as a percentage of baseline (adjusted p = 0.006), less visual analog scale (VAS) back pain (adjusted p = 0.006), and greater VAS back pain change as a percentage of baseline (adjusted p = 0.001) compared to hybrid techniques. These differences were no longer significant at 3 years. At 3 years, but not 2 years, VAS leg pain was lower for cMIS compared to hybrid techniques (adjusted p = 0.032). Those undergoing cMIS had fewer overall complications compared to hybrid techniques (adjusted p = 0.006), but a higher odds of pseudarthrosis (adjusted p = 0.039). CONCLUSIONS In this review of a multicenter database for patients undergoing cMIS and hybrid surgery for ASD, hybrid procedures were associated with a greater CC improvement compared to cMIS techniques. cMIS was associated with superior ODI and back pain at 2 years, but this difference was no longer evident at 3 years. However, cMIS was associated with superior leg pain at 3 years. There were fewer complications following cMIS, with the exception of pseudarthrosis.

Background: Morton neuroma is a common, painful disorder of the foot with multiple treatment options of varying cost and effectiveness. Objective: The aim of this study was to determine the most co...

Gut dysbiosis, defined as pathogenic alterations in the distribution and abundance of different microbial species, is associated with neuropathic pain in a variety of clinical conditions, but this has not been explored in the context of neuropathy in people with HIV (PWH). We assessed gut microbial diversity and dysbiosis in PWH and people without HIV (PWoH), some of whom reported distal neuropathic pain (DNP). DNP was graded on a standardized, validated severity scale. The gut microbiome was characterized using 16S rRNA sequencing and diversity was assessed using phylogenetic tree construction. Songbird analysis (https://github.com/mortonjt/songbird) was used to produce a multinomial regression model predicting counts of specific microbial taxa through metadata covariate columns. Participants were 226 PWH and 101 PWoH, mean (SD) age 52.0 (13.5), 21.1% female, 54.7% men who have sex with men, 44.7% non-white. Among PWH, median (interquartile range, IQR) nadir and current CD4 were 174 (21, 302) and 618 (448, 822), respectively; 90% were virally suppressed on antiretroviral therapy. PWH and PWoH did not differ with respect to microbiome diversity as indexed by Faith's phylogenetic diversity (PD). More severe DNP was associated with lower alpha diversity as indexed by Faith's phylogenetic diversity in PWH (Spearman's ρ=.224, P=0.0007), but not in PWoH (Spearman's ρ=.032, P=.748). These relationships were not confounded by demographics or disease factors. In addition, the log-ratio of features identified at the genus level as Blautia to Lachnospira was statistically significantly higher in PWH with DNP than in PWH without DNP (t-test, P=1.01e-3). Furthermore, the log-ratio of Clostridium features to Lachnospira features also was higher in PWH with DNP than in those without (t-test, P=6.24e-5). Our results, in combination with previous findings in other neuropathic pain conditions, suggest that gut dysbiosis, particularly reductions in diversity and relative increases in the ratios of Blautia and Clostridium to Lachnospira, may contribute to prevalent DNP in PWH. Two candidate pathways for these associations, involving microbial pro-inflammatory components and microbially-produced anti-inflammatory short chain fatty acids, are discussed. Future studies might test interventions to re-establish a healthy gut microbiota and determine if this prevents or improves DNP. PERSPECTIVE: The association of neuropathic pain in people with HIV with reduced gut microbial diversity and dysbiosis raises the possibility that re-establishing a healthy gut microbiota might ameliorate neuropathic pain in HIV by reducing proinflammatory and increasing anti-inflammatory microbial products.

Background Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant condition that predisposes to emphysema, cirrhosis, panniculitis, and vasculitis. Under-recognition has prompted efforts to enhance early detection and testing of at-risk individuals. Direct-to-consumer (DTC) genetic testing represents an additional method of detection. Research Question The study addressed three questions: 1) Does a DTC testing service identify previously undetected individuals with AATD? 2) What was the time interval between initial AATD-related symptoms and initial diagnosis of AATD in such individuals? and 3) What was the behavioral impact of learning about a new diagnosis of AATD through a DTC test? Study Design and Methods In this cross-sectional study, 195,014 individuals responded to a survey within the 23andMe, Inc. research platform. Results Among 195,014 study participants, the allele frequency for either the PI*S and PI*Z AATD variants was 21.6% (6.5% for PI*Z and 15.1% for PI*S); 0.63% were PI*ZZ, half of whom reported having a physician confirm the diagnosis. Approximately 27% of those with physician-diagnosed AATD reported first becoming aware of AATD through the DTC test. Among those newly-aware participants, the diagnostic delay interval was 22.3 years. Participants frequently shared their DTC test results with healthcare providers (HCPs) and the reported impact of learning a diagnosis of AATD was high. For example, 51.1% of PI*ZZ individuals shared their DTC result with an HCP. The odds ratio for PI*ZZ smokers to report smoking reduction as a result of receiving the DTC result was 1.7 [CI 1.4, 2.2] compared to those without a Z allele and for reduced alcohol consumption was 4.0 [CI 2.6, 5.9]. Interpretation In this largest available report on DTC testing for AATD, this test, in combination with clinical follow-up, can help to identify previously undiagnosed AATD patients. Moreover, receipt of the DTC AATD report was associated with positive behavior change, especially among those with risk variants.

BackgroundMethamphetamine use, sexual risk behaviors, and depression contribute to ongoing human immunodeficiency virus (HIV) and sexually transmitted infection (STI) disparities among men who have sex with men (MSM). The relative contributions of these effects longitudinally are not well understood.MethodsThis analysis used visit-level data from a longitudinal cohort of MSM, half with HIV, in Los Angeles, CA. From August 2014 to March 2020, participants completed follow-up visits every 6 months and underwent testing for rectal gonorrhea/chlamydia (GC/CT) and completed questionnaires including depressive symptoms, number of receptive anal intercourse (RAI) partners, and methamphetamine use. Path analysis with structural equation modeling using concurrent and lagged covariates was used to identify relative contributions of methamphetamine use and depression on number of RAI partners and rectal GC/CT across time.ResultsFive hundred fifty-seven MSM with up to 6 visits (3 years) were included for a total of 2437 observations. Methamphetamine use and depressive symptoms were positively associated with number of RAI partners (β = 0.28, P < 0.001; β = 0.33, P = 0.018, respectively), which was positively associated with rectal GC/CT (β = 0.02, P < 0.001). When stratified by HIV status, depressive symptoms were positively associated with RAI partners for HIV-negative MSM (β = 0.50, P = 0.007) but were not associated for MSM living with HIV (β = 0.12, P = 0.57). Methamphetamine use was positively associated with RAI partners in both strata.ConclusionsFactors and patterns, which contribute to risk behaviors associated with rectal GC/CT, may differ by HIV status. Our findings demonstrate the importance of combined treatment and prevention efforts that link screening and treatment of stimulant use and depression with STI prevention and treatment.

Context Insulin resistance (IR) is associated with polycystic ovaries and hyperandrogenism, but underpinning mechanisms are poorly understood and therapeutic options are limited. Objective To characterize hyperandrogenemia and ovarian pathology in primary severe IR (SIR), using IR of defined molecular etiology to interrogate disease mechanism. To extend evaluation of gonadotropin-releasing hormone (GnRH) analogue therapy in SIR. Methods Retrospective case note review in 2 SIR national referral centers. Female patients with SIR with documented serum total testosterone (TT) concentration. Results Among 185 patients with lipodystrophy, 65 with primary insulin signaling disorders, and 29 with idiopathic SIR, serum TT ranged from undetectable to 1562 ng/dL (54.2 nmol/L; median 40.3 ng/dL [1.40 nmol/L]; n = 279) and free testosterone (FT) from undetectable to 18.0 ng/dL (0.625 nmol/L; median 0.705 ng/dL [0.0244 nmol/L]; n = 233). Higher TT but not FT in the insulin signaling subgroup was attributable to higher serum sex hormone–binding globulin (SHBG) concentration. Insulin correlated positively with SHBG in the insulin signaling subgroup, but negatively in lipodystrophy. In 8/9 patients with available ovarian tissue, histology was consistent with polycystic ovary syndrome (PCOS). In 6/6 patients treated with GnRH analogue therapy, gonadotropin suppression improved hyperandrogenic symptoms and reduced serum TT irrespective of SIR etiology. Conclusion SIR causes severe hyperandrogenemia and PCOS-like ovarian changes whether due to proximal insulin signaling or adipose development defects. A distinct relationship between IR and FT between the groups is mediated by SHBG. GnRH analogues are beneficial in a range of SIR subphenotypes.

Objectives: Omadacycline was tested against 7000 bacterial isolates collected prospectively from medical centres in the USA during 2019. Methods: Antimicrobial susceptibility testing was performed according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Results: Omadacycline was active against: Staphylococcus aureus (MIC50/90, 0.12/0.25 mg/L; 98.3% susceptible), including methicillin-resistant S. aureus (MRSA); Enterococcus faecalis (MIC50/90, 0.06/0.25 mg/L; 100.0% susceptible), including vancomycin-resistant enterococci (VRE); Streptococcus pneumoniae (MIC50/90, 0.06/0.06 mg/L; 99.8% susceptible); viridans group streptococci, including Streptococcus anginosus group (MIC50/90, 0.03/0.06 mg/L; 100.0% susceptible); β-haemolytic streptococci, including Streptococcus pyogenes (MIC50/90, 0.06/0.12 mg/L; 99.2% susceptible); Enterobacterales (MIC50/90, 1/8 mg/L; 86.9% inhibited at ≤4 mg/L), including Escherichia coli (MIC50/90, 0.5/2 mg/L; 99.6% inhibited at ≤4 mg/L); Enterobacter cloacae (MIC50/90, 2/4 mg/L; 98.5% susceptible); Klebsiella pneumoniae (MIC50/90, 1/4 mg/L; 93.2% susceptible); Acinetobacter baumannii (MIC50/90, 0.5/4 mg/L; 90.8% inhibited at ≤4 mg/L); Haemophilus influenzae (MIC50/90, 0.5/1 mg/L; 100.0% susceptible); and Moraxella catarrhalis (MIC50/90, ≤0.12/0.25 mg/L). Conclusion: The 2019 in vitro activity of omadacycline against key Gram-positive and Gram-negative pathogens has not changed compared with the prior 3 years of surveillance in the SENTRY Antimicrobial Surveillance Program. Omadacycline merits further study in serious infections where resistant pathogens may be encountered.

OBJECTIVE Few studies have compared fractional curve correction after long fusion between transforaminal lumbar interbody fusion (TLIF) and anterior lumbar interbody fusion (ALIF) for adult symptomatic thoracolumbar/lumbar scoliosis (ASLS). The objective of this study was to compare fractional correction, health-related quality of life (HRQL), and complications associated with L4–S1 TLIF versus those of ALIF as an operative treatment of ASLS. METHODS The authors retrospectively analyzed a prospective multicenter adult spinal deformity database. Inclusion required a fractional curve ≥ 10°, a thoracolumbar/lumbar curve ≥ 30°, index TLIF or ALIF performed at L4–5 and/or L5–S1, and a minimum 2-year follow-up. TLIF and ALIF patients were propensity matched according to the number and type of interbody fusion at L4–S1. RESULTS Of 135 potentially eligible consecutive patients, 106 (78.5%) achieved the minimum 2-year follow-up (mean ± SD age 60.6 ± 9.3 years, 85% women, 44.3% underwent TLIF, and 55.7% underwent ALIF). Index operations had mean ± SD 12.2 ± 3.6 posterior levels, 86.6% of patients underwent iliac fixation, 67.0% underwent TLIF/ALIF at L4–5, and 84.0% underwent TLIF/ALIF at L5–S1. Compared with TLIF patients, ALIF patients had greater cage height (10.9 ± 2.1 mm for TLIF patients vs 14.5 ± 3.0 mm for ALIF patients, p = 0.001) and lordosis (6.3° ± 1.6° for TLIF patients vs 17.0° ± 9.9° for ALIF patients, p = 0.001) and longer operative duration (6.7 ± 1.5 hours for TLIF patients vs 8.9 ± 2.5 hours for ALIF patients, p < 0.001). In all patients, final alignment improved significantly in terms of the fractional curve (20.2° ± 7.0° to 6.9° ± 5.2°), maximum coronal Cobb angle (55.0° ± 14.8° to 23.9° ± 14.3°), C7 sagittal vertical axis (5.1 ± 6.2 cm to 2.3 ± 5.4 cm), pelvic tilt (24.6° ± 8.1° to 22.7° ± 9.5°), and lumbar lordosis (32.3° ± 18.8° to 51.4° ± 14.1°) (all p < 0.05). Matched analysis demonstrated comparable fractional correction (−13.6° ± 6.7° for TLIF patients vs −13.6° ± 8.1° for ALIF patients, p = 0.982). In all patients, final HRQL improved significantly in terms of Oswestry Disability Index (ODI) score (42.4 ± 16.3 to 24.2 ± 19.9), physical component summary (PCS) score of the 36-item Short-Form Health Survey (32.6 ± 9.3 to 41.3 ± 11.7), and Scoliosis Research Society–22r score (2.9 ± 0.6 to 3.7 ± 0.7) (all p < 0.05). Matched analysis demonstrated worse ODI (30.9 ± 21.1 for TLIF patients vs 17.9 ± 17.1 for ALIF patients, p = 0.017) and PCS (38.3 ± 12.0 for TLIF patients vs 45.3 ± 10.1 for ALIF patients, p = 0.020) scores for TLIF patients at the last follow-up (despite no differences in these parameters at baseline). The rates of total complications were similar (76.6% for TLIF patients vs 71.2% for ALIF patients, p = 0.530), but significantly more TLIF patients had rod fracture (28.6% of TLIF patients vs 7.1% of ALIF patients, p = 0.036). Multiple regression analysis demonstrated that a 1-mm increase in L4–5 TLIF cage height led to a 2.2° reduction in L4 coronal tilt (p = 0.011), and a 1° increase in L5–S1 ALIF cage lordosis led to a 0.4° increase in L5–S1 segmental lordosis (p = 0.045). CONCLUSIONS Operative treatment of ASLS with L4–S1 TLIF versus ALIF demonstrated comparable mean fractional curve correction (66.7% vs 64.8%), despite use of significantly larger, more lordotic ALIF cages. TLIF cage height had a significant impact on leveling L4 coronal tilt, whereas ALIF cage lordosis had a significant impact on restoration of lumbosacral lordosis. The advantages of TLIF may include reduced operative duration and hospitalization; however, associated HRQL was inferior and more rod fractures were detected in the TLIF patients included in this study.

International audience; ABSTRACT Purpose PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients. Methods Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes. Results Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort ( n = 6). No significant reduction in affected tissue volume was observed (mean −4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement). Conclusion Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use.

Purpose In the midst of a pandemic, residency interviews transitioned to a virtual format for the first time. Little is known about the effect this will have on the match process. The study aim is to evaluate resident application processes and perceived outcomes. Methods An electronic survey was distributed to 142 colon and rectal surgery residency applicants (95% of total). Results A total of 77 applicants responded to the survey (54% response rate). Applicants reported high levels of satisfaction with virtual interviews but less comfort. Utilizing the mute button and using notes in a different way from face-to-face interviews were significantly associated with applicant confidence that they ranked the right program highest. A majority of applicants (73%) would recommend virtual interviews next year even if COVID-19 is not a factor. Conclusion While applicants appear generally satisfied with virtual interviews, they also reported less comfort. Applicant confidence was predicted by utilizing the unique technological affordances offered by the virtual platform.

OBJECTIVE Deterioration of global coronal alignment (GCA) may be associated with worse outcomes after adult spinal deformity (ASD) surgery. The impact of fusion length and upper instrumented vertebra (UIV) selection on patients with this complication is unclear. The authors’ objective was to compare outcomes between long sacropelvic fusion with upper-thoracic (UT) UIV and those with lower-thoracic (LT) UIV in patients with worsening GCA ≥ 1 cm. METHODS This was a retrospective analysis of a prospective multicenter database of consecutive ASD patients. Index operations involved instrumented fusion from sacropelvis to thoracic spine. Global coronal deterioration was defined as worsening GCA ≥ 1 cm from preoperation to 2-year follow-up. RESULTS Of 875 potentially eligible patients, 560 (64%) had complete 2-year follow-up data, of which 144 (25.7%) demonstrated worse GCA at 2-year postoperative follow-up (35.4% of UT patients vs 64.6% of LT patients). At baseline, UT patients were younger (61.6 ± 9.9 vs 64.5 ± 8.6 years, p = 0.008), a greater percentage of UT patients had osteoporosis (35.3% vs 16.1%, p = 0.009), and UT patients had worse scoliosis (51.9° ± 22.5° vs 32.5° ± 16.3°, p < 0.001). Index operations were comparable, except UT patients had longer fusions (16.4 ± 0.9 vs 9.7 ± 1.2 levels, p < 0.001) and operative duration (8.6 ± 3.2 vs 7.6 ± 3.0 hours, p = 0.023). At 2-year follow-up, global coronal deterioration averaged 2.7 ± 1.4 cm (1.9 to 4.6 cm, p < 0.001), scoliosis improved (39.3° ± 20.8° to 18.0° ± 14.8°, p < 0.001), and sagittal spinopelvic alignment improved significantly in all patients. UT patients maintained smaller positive C7 sagittal vertical axis (2.7 ± 5.7 vs 4.7 ± 5.7 cm, p = 0.014). Postoperative 2-year health-related quality of life (HRQL) significantly improved from baseline for all patients. HRQL comparisons demonstrated that UT patients had worse Scoliosis Research Society–22r (SRS-22r) Activity (3.2 ± 1.0 vs 3.6 ± 0.8, p = 0.040) and SRS-22r Satisfaction (3.9 ± 1.1 vs 4.3 ± 0.8, p = 0.021) scores. Also, fewer UT patients improved by ≥ 1 minimal clinically important difference in numerical rating scale scores for leg pain (41.3% vs 62.7%, p = 0.020). Comparable percentages of UT and LT patients had complications (208 total, including 53 reoperations, 77 major complications, and 78 minor complications), but the percentage of reoperated patients was higher among UT patients (35.3% vs 18.3%, p = 0.023). UT patients had higher reoperation rates of rod fracture (13.7% vs 2.2%, p = 0.006) and pseudarthrosis (7.8% vs 1.1%, p = 0.006) but not proximal junctional kyphosis (9.8% vs 8.6%, p = 0.810). CONCLUSIONS In ASD patients with worse 2-year GCA after long sacropelvic fusion, UT UIV was associated with worse 2-year HRQL compared with LT UIV. This may suggest that residual global coronal malalignment is clinically less tolerated in ASD patients with longer fusion to the proximal thoracic spine. These results may inform operative planning and improve patient counseling.

Photovoltaic solar power generating facilities are proliferating rapidly in California and elsewhere. While this trend is welcomed for many reasons (e.g., reducing greenhouse gas emissions), these facilities also can have profound environmental impacts, particularly to local species populations. These impacts become more significant when species of conservation concern are affected. In the San Joaquin Desert region in central California, a number of conservation measures have been routinely implemented on solar facilities, and these measures have facilitated continued use of the facilities by a number of species of conservation concern. Some of the more significant measures include permeable security fences, vegetation management, movement corridors, avoiding critical features such as dens and burrows, and vehicle speed limits. Detailed studies have been conducted on San Joaquin kit foxes (Vulpes macrotis mutica) using solar facilities in the San Joaquin Desert. Demographic and ecological attributes of foxes are similar between foxes using the facilities and foxes on nearby reference sites, and values for foxes on solar sites are within the ranges of values for foxes reported from sites within core population areas. Facilitated by the conservation measures, kit foxes are using at least six facilities in the San Joaquin Desert as are a variety of other species of conservation concern. This successful model also potentially could be adapted to other ecosystems and applied to facilities in regions outside of the San Joaquin Desert, such as the Mojave Desert. Determining whether species in other regions can use photovoltaic solar facilities and identifying the most efficacious conservation measures will require time and testing, and these efforts would benefit from collaborative efforts among landowners, solar developers, natural resources agencies, researchers, and others. The San Joaquin Desert facilities and a recent demonstration facility in the Mojave Desert provide strong evidence that solar facilities can be constructed and operated in a manner that also accommodates continued use of the facilities by some species of conservation concern.

Plastics are ubiquitous in the modern world with both positive and negative consequences. Students will benefit from understanding how plastics are manufactured. They will be more aware of the material and have a better appreciation for the need to recycle. Injection molding is one of the primary plastics manufacturing methods and hobby scale injection molding machines can be used to educate students about plastics and polymers. Furthermore, it is possible to create custom injection molds from aluminum using similar hobby scale tools. In this article, experiences introducing injection molding in the classroom and experiences with mold making as a senior design project are presented. Suggestions and procedures for using the injection molding machine and for creating custom aluminum molds are covered.

Background The development of anti-drug antibodies, also termed inhibitors, against administered Factor FVIII (FVIII) is one of the major complications in the clinical management of Hemophilia A. Once formed, these inhibitory antibodies abrogate the activity of FVIII, resulting in loss of hemostatic efficacy and patients are subjected to increased risk of bleeding tendencies. Current treatment options after inhibitor development are expensive and ineffective in some cases. Therefore, treatment strategies that can prevent inhibitor formation is an effective approach in the management of Hemophilia A. Objectives We aimed to evaluate and discuss the use of a tolerogenic form of FVIII as an immunotherapy strategy to prevent inhibitor risk. Methods FVIII was associated with nanoparticles containing lysophosphatidylserine (Lyso-PS) and administered to Hemophilia A mice via intravenous route. These animals then received weekly re-challenge injections with free FVIII, and plasma was collected at the end of the study to evaluate for inhibitor development. To investigate whether Lyso-PS nanoparticles influence the plasma survival of FVIII, a pharmacokinetic study following a single intravenous administration of FVIII in the presence and absence of Lyso-PS nanoparticles was performed. For dosing convenience, the tolerogenic effect of Lyso-PS nanoparticles following oral administration was also examined. Results and conclusions The results demonstrated that FVIII associated with Lyso-PS nanoparticles significantly reduced inhibitor development while improving plasma survival of FVIII following intravenous administration, suggesting a multifunctional FVIII form to improve clinical utility. Additionally, reduction in inhibitor formation can also be achieved using Lyso-PS nanoparticles through the user-friendly oral route of administration.

Objective While adjuvant treatment regimens have been modified for older patients with glioblastoma (GBM), surgical strategies have not been tailored. Methods Clinical data of 48 consecutive patients aged 70 years or older, who underwent surgical resection for GBM with intraoperative ultrasonography (IoUS) alone or combination with intraoperative MRI (IoMRI) at Yale New Haven Hospital were retrospectively reviewed. Variables were analyzed, and comparative analyses were performed. Results The addition of IoMRI was not superior to IoUS alone in terms of overall survival (OS) (P = 0.306), Karnofsky Performance Score (KPS) at postoperative 6 weeks (P = 0.704) or extent of resection (P = 0.263). Length of surgery (LOSx), however, was significantly longer (P = 0.0002) in the IoMRI group. LOSx (P = 0.015) and hospital stay (P = 0.025) were predictors of postoperative complications. Increased EOR (GTR or NTR) (P = 0.030), postoperative adjuvant treatment (P < 0.0001) and postoperative complications (P = 0.006) were predictive for OS. Patients with relatively lower preoperative KPS scores ( Conclusions Aggressive management with surgical resection should be considered in older patients with GBM, even those with relatively poor KPS. The use of ioMRI in this population does not appear to confer any measurable benefit over ioUS in experienced hands, but prolongs the length of surgery significantly, which is a preventable prognostic factor for impeding care.

AimTo compare the frequently used CD138 immunohistochemistry-based method of plasma cell quantitation, to a proposed new method, using interobserver and intraobserver concordance parameters.MethodsArchival CD138 immunohistochemically stained slides made from paraffin-embedded bone marrow biopsies of 33 patients with a confirmed diagnosis of multiple myeloma were used. Light microscopic examination was performed using low magnification lenses (10×) for both the overview estimation method (method A) and the new method (method B), and high magnification lenses (50×), for method B only. For method B, reviewers selected three areas with low, intermediate and high plasma cell densities using 10× lenses. Using a well-defined technique, the 50× lens was then used to count plasma cells as a percentage of all nucleated cells. After blinded relabelling of all the slides, the nine reviewers repeated the plasma cell quantitation using both methods. The plasma cell counts were obtained, and the review times were recorded.ResultsOverall intraobserver concordance was comparable for method A (concordance correlation coefficient (CCC)=0.840) and method B (CCC=0.733). Interobserver concordance for method A (intraclass correlation coefficient (ICC)=0.793 and 0.713) and method B (ICC=0.657 and 0.658) indicated high similarity between reviewers. Method A showed poor interobserver concordance (ICC=0.105) at low plasma cell densities.ConclusionsThe new method is comparable to the frequently used overview estimation method in terms of intraobserver and interobserver concordance, and cost. The new method has superior interobserver concordance at low plasma cell densities. The new method appears more amenable to digital scanning and analysis.

The paper presents a performance analysis of a selected few rough set–based classification systems. They are hybrid solutions designed to process information with missing values. Rough set-–based classification systems combine various classification methods, such as support vector machines, k–nearest neighbour, fuzzy systems, and neural networks with the rough set theory. When all input values take the form of real numbers, and they are available, the structure of the classifier returns to a non–rough set version. The performance of the four systems has been analysed based on the classification results obtained for benchmark databases downloaded from the machine learning repository of the University of California at Irvine.

Background Atrioventricular (AV)-synchronous single-chamber leadless pacing using a mechanical atrial sensing algorithm produced high AV synchrony in clinical trials, but clinical practice experience with these devices has not yet been described. Objective To describe pacing outcomes and programming changes with AV-synchronous leadless pacemakers in clinical practice. Methods Consecutive patients without persistent atrial fibrillation who received an AV-synchronous leadless pacemaker and completed follow-up between February 2020 and April 2021 were included. We evaluated tracking index (atrial mechanical sense followed by ventricular pace [AM-VP] divided by total VP), total AV synchrony (sum of AM-ventricular sense [AM-VS], AM-VP, and AV conduction mode switch), use of programming optimization, and improvement in AV synchrony after optimization. Results Fifty patients met the inclusion criteria. Mean age was 69 ± 16.8 years, 24 (48%) were women, 24 (48%) had complete heart block, and 17 (34%) required ≥50% pacing. Mean tracking index was 41% ± 34%. Thirty-five patients (70%) received ≥1 programming change. In 36 patients with 2 follow-up visits, tracking improved by +9% ± 28% (P value for improvement = .09) and +18% ± 19% (P = .02) among 15 patients with complete heart block. Average total AV synchrony increased from 89% [67%, 99%] to 93% [78%, 100%] in all patients (P = .22), from 86% [52%, 98%] to 97% [82%, 99%] in those with complete heart block (P = .04), and from 73% [52%, 80%] to 78% [70%, 85%] in those with ≥50% pacing (P = .09). Conclusion In patients with AV-synchronous leadless pacemakers, programming changes are frequent and are associated with increased atrial tracking and increased AV synchrony in patients with complete heart block., Graphical abstract

Current clinical guidelines by both American Association for the Study of Liver Disease and European Association for the Study of the Liver recommend endoscopy in all patients admitted with acute variceal bleeding within 12 hours of admission. Transjugular intrahepatic portosystemic shunt (TIPS) creation may be considered in patients at high risk if hemorrhage cannot be controlled endoscopically. We conducted a cross‐sectional observational study to assess how frequently TIPS is created for acute variceal bleeding in the United States without preceding endoscopy. Adult patients undergoing TIPS creation for acute variceal bleeding in the United States (n = 6,297) were identified in the last 10 available years (2007‐2016) of the National Inpatient Sample. Hierarchical logistic regression was used to examine the relationship between endoscopy nonutilization and hospital characteristics, controlling for patient demographics, income level, insurance type, and disease severity. Of 6,297 discharges following TIPS creation for acute variceal bleeding in the United States, 31% (n = 1,924) did not receive first‐line endoscopy during the same encounter. Rates of “no endoscopy” decreased with increasing population density of the hospital county (nonmicropolitan counties 43%, n = 114; mid‐size metropolitan county 35%, n = 513; and central county with >1 million population 23%, n = 527) but not by hospital teaching status (n = 1,465, 32% teaching vs. n = 430, 26% nonteaching; P = 0.10). Higher disease mortality risk (odds ratio, 0.42; 95% confidence interval, 0.22‐0.80; P = 0.02) was associated with lower odds of noncompliance. Conclusion: One third of all patients undergoing TIPS creation for acute variceal bleeding in the United States do not receive first‐line endoscopy during the same encounter. Patients admitted to urban hospitals are more likely to receive guideline‐concordant care., In this cross‐sectional, population‐based study we examined how often TIPS was created among patients for acute variceal bleeding without use of first‐line endoscopy as recommended by both American Association for the Study of Liver Disease (AASLD) and The European Association for the Study of the Liver (EASL) guidelines. We report endoscopy non‐utilization in nearly a third (n = 1924/6297, 31%) of such encounters nationally. We also found that endoscopy non‐utilization was more prevalent among hospitals in less densely populated counties.

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

INTRODUCTION Spinal anesthesia is utilized as an alternative to general anesthesia in infants for some surgeries. After spinal anesthesia, infants often become less conscious without administration of sedative medications. The aim of this study was to assess electroencephalographic (EEG) correlates after spinal anesthesia in a cohort of infants. PATIENTS AND METHODS This pilot study included 12 infants who underwent spinal anesthesia. Unprocessed electroencephalography was recorded. The electroencephalogram was interpreted by four neurologists. Processed analyses compared electroencephalogram changes 30 min after spinal anesthesia to baseline. RESULTS Following spinal anesthesia, all 12 infants became sedated. Electroencephalography in all 12 demonstrated Stage 2 sleep with the appearance of sleep spindles (12-14 Hz) in the frontal and central leads in 8/12 (67%) of subjects. The median time to onset of sleep spindles was 24.7 interquartile range (21.2, 29.9) min. The duration of sleep spindles was 25.1 interquartile range (5.8, 99.8) min. Voltage attenuation and background slowing were the most common initial changes. Compared to baseline, the electroencephalogram 30 min after spinal anesthesia showed significantly increased absolute delta power (p = 0.02) and gamma power (p

OBJECTIVE We aimed to evaluate the implementation of a dedicated surgical critical care service (SCCS) on failure to rescue (FTR) rates in rural Kenya. SUMMARY BACKGROUND DATA FTR adversely impacts perioperative outcomes. In the resource-limited contexts of low- and middle-income countries, emergency gastrointestinal surgery carries high morbidity and mortality rates. Quality improvement initiatives that decrease FTR rates are essential for improving perioperative care. METHODS All patients who underwent emergency gastrointestinal surgery between January 2016 and June 2019 at Tenwek Hospital in rural Kenya were reviewed. Critical care capabilities were constant throughout the study period. A supervised surgical resident was dedicated to the daily care of critically ill surgical patients beginning in January 2018. The impact of the SCCS initiation on the outcome of FTR was evaluated, controlling for patient complexity via the African Surgical Outcomes Study (ASOS) Surgical Risk Score. RESULTS A total of 484 patients were identified, consisting of 278 without and 206 with an active SCCS. A total of 165 (34.1%) patients experienced postoperative complications, including 49 mortalities (10.1%) yielding an FTR rate of 29.7%. The FTR rate decreased after SCCS implementation from 36.8% (95% CI 26.7-47.8%) to 21.8% (95% CI 13.2-32.6%) (p = 0.035) despite an increase in the average patient ASOS score from 14.5 (95% CI 14.1-14.9) to 15.2 (95% CI 14.7-15.7) (p = 0.03). CONCLUSIONS The implementation of an SCCS in rural Kenya resulted in decreased rates of FTR despite an increase in patient complexity and severity of critical illness.

Despite public administration’s growing interest in personnel diversity and ethical leadership, little is known about the effectiveness of ethical leadership in managing diverse public workforces. Can ethical leadership moderate the relationships between demographic diversity and key organizational outcomes? To answer, we synthesize four theories about demographic diversity, ethical leadership, and inclusion: social categorization theory, social exchange theory, social learning theory, and optimal distinctiveness theory. These theories illuminate the interrelationships between diversity, ethical leadership, and two types of collective organizational outcomes: affective commitment climate and race-based employment discrimination. Using panel data from the US federal government, feasible generalized least squares models indicate that racial diversity is negatively related to affective commitment climate and positively related to race-based employment discrimination. The results also show that ethical leadership beneficially moderates the associations of racial diversity with the two organizational outcomes. These findings suggest that ethical leadership aids public managers and personnel in racially diverse public agencies.

OBJECTIVE Circumferential minimally invasive spine surgery (cMIS) for adult scoliosis has become more advanced and powerful, but direct comparison with traditional open correction using prospectively collected data is limited. The authors performed a retrospective review of prospectively collected, multicenter adult spinal deformity data. The authors directly compared cMIS for adult scoliosis with open correction in propensity-matched cohorts using health-related quality-of-life (HRQOL) measures and surgical parameters. METHODS Data from a prospective, multicenter adult spinal deformity database were retrospectively reviewed. Inclusion criteria were age > 18 years, minimum 1-year follow-up, and one of the following characteristics: pelvic tilt (PT) > 25°, pelvic incidence minus lumbar lordosis (PI-LL) > 10°, Cobb angle > 20°, or sagittal vertical axis (SVA) > 5 cm. Patients were categorized as undergoing cMIS (percutaneous screws with minimally invasive anterior interbody fusion) or open correction (traditional open deformity correction). Propensity matching was used to create two equal groups and to control for age, BMI, preoperative PI-LL, pelvic incidence (PI), T1 pelvic angle (T1PA), SVA, PT, and number of posterior levels fused. RESULTS A total of 154 patients (77 underwent open procedures and 77 underwent cMIS) were included after matching for age, BMI, PI-LL (mean 15° vs 17°, respectively), PI (54° vs 54°), T1PA (21° vs 22°), and mean number of levels fused (6.3 vs 6). Patients who underwent three-column osteotomy were excluded. Follow-up was 1 year for all patients. Postoperative Oswestry Disability Index (ODI) (p = 0.50), Scoliosis Research Society–total (p = 0.45), and EQ-5D (p = 0.33) scores were not different between cMIS and open patients. Maximum Cobb angles were similar for open and cMIS patients at baseline (25.9° vs 26.3°, p = 0.85) and at 1 year postoperation (15.0° vs 17.5°, p = 0.17). In total, 58.3% of open patients and 64.4% of cMIS patients (p = 0.31) reached the minimal clinically important difference (MCID) in ODI at 1 year. At 1 year, no differences were observed in terms of PI-LL (p = 0.71), SVA (p = 0.46), PT (p = 0.9), or Cobb angle (p = 0.20). Open patients had greater estimated blood loss compared with cMIS patients (1.36 L vs 0.524 L, p < 0.05) and fewer levels of interbody fusion (1.87 vs 3.46, p < 0.05), but shorter operative times (356 minutes vs 452 minutes, p = 0.003). Revision surgery rates between the two cohorts were similar (p = 0.97). CONCLUSIONS When cMIS was compared with open adult scoliosis correction with propensity matching, HRQOL improvement, spinopelvic parameters, revision surgery rates, and proportions of patients who reached MCID were similar between cohorts. However, well-selected cMIS patients had less blood loss, comparable results, and longer operative times in comparison with open patients.

High- $\kappa $ insulators have allowed MOSFETs to obtain extremely high gate capacitances while still suppressing gate leakage. However, using high- $\kappa $ gate insulators increases the strength of lateral fringing fields throughout MOSFETs, thus causing fringe-induced barrier lowering (FIBL), an electrostatic short-channel effect. The use of high- $\kappa $ insulators in place of thin low- $\kappa $ insulators with the same equivalent oxide thicknesses (EOTs) has, therefore, been associated with a tradeoff between a device’s electrostatic control and gate leakage. In this study, we use nonequilibrium Green’s function (NEGF) simulations to demonstrate that FIBL can be exploited to improve the performance of ultrascaled 2-D-material-based MOSFETs by reducing the impact of source-to-drain tunneling currents that are pervasive in extremely scaled MOSFETs, especially at low currents. As a result, we find that MOSFETs with high- $\kappa $ gate insulators offer improved performances for low-power applications compared to MOSFETs with low- $\kappa $ gate insulators at identical EOTs, even before considering the effect of gate leakage.

Although innate immunity is linked to metabolic health, the effect of leptin signaling in cells from the innate immune system on glucose homeostasis has not been thoroughly investigated. We generated two mouse models using Cre-lox methodology to determine the effect of myeloid cell-specific leptin receptor (Lepr) reconstitution and Lepr knockdown on in vivo glucose metabolism. Male mice with myeloid cell-specific Lepr reconstitution (Lyz2Cre+LeprloxTB/loxTB) had better glycemic control as they aged compared to male mice with whole-body transcriptional blockade of Lepr (Lyz2Cre−LeprloxTB/loxTB). In contrast, Lyz2Cre+LeprloxTB/loxTB females only had a trend for diminished hyperglycemia after a prolonged fast. During glucose tolerance tests, Lyz2Cre+LeprloxTB/loxTB males had a mildly improved plasma glucose profile compared to Cre− controls while Lyz2Cre+LeprloxTB/loxTB females had a similar glucose excursion to their Cre− controls. Myeloid cell-specific Lepr knockdown (Lyz2Cre+Leprflox/flox) did not significantly alter body weight, blood glucose, insulin sensitivity, or glucose tolerance in males or females. Expression of the cytokine interleukin 10 (anti-inflammatory) tended to be higher in adipose tissue of male Lyz2Cre+LeprloxTB/loxTB mice (p = 0.0774) while interleukin 6 (pro-inflammatory) was lower in male Lyz2Cre+Leprflox/flox mice (p Lepr in cells of myeloid lineage has beneficial effects on glucose metabolism in male mice.

INTRODUCTION: Mood disorders are associated with fronto-limbic structural and functional abnormalities and deficits in omega-3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Emerging evidence also suggests that n-3 PUFA, which are enriched in fish oil, promote cortical plasticity and connectivity. The present study performed a graph-based connectome analysis to investigate the role of n-3 PUFA in emotion-related network organization in medication-free depressed adolescent bipolar offspring. METHODS: At baseline patients (n=53) were compared with healthy controls (n=53), and patients were then randomized to 12-week double-blind treatment with placebo or fish oil. At baseline and endpoint, erythrocyte EPA+DHA levels were measured and fMRI scans (4 Tesla) were obtained while performing a continuous performance task with emotional and neutral distractors (CPT-END). Graph-based analysis was used to characterize topological properties of large-scale brain network organization. RESULTS: Compared with healthy controls, patients exhibited lower erythrocyte EPA+DHA levels (p=0.0001), lower network clustering coefficients (p=0.029), global efficiency (p=0.042), and lower node centrality and connectivity strengths in frontal-limbic regions (p

OBJECTIVE The association of seizures with meningiomas is poorly understood. Moreover, any relationship between seizures and the underlying meningioma genomic subgroup has not been studied. Herein, the authors report on their experience with identifying clinical and genomic factors associated with preoperative and postoperative seizure presentation in meningioma patients. METHODS Clinical and genomic sequencing data on 394 patients surgically treated for meningioma at Yale New Haven Hospital were reviewed. Correlations between clinical, histological, or genomic variables and the occurrence of preoperative and postoperative seizures were analyzed. Logistic regression models were developed for assessing multiple risk factors for pre- and postoperative seizures. Mediation analyses were also conducted to investigate the causal pathways between genomic subgroups and seizures. RESULTS Seventeen percent of the cohort had presented with preoperative seizures. In a univariate analysis, patients with preoperative seizures were more likely to have tumors with a somatic NF2 mutation (p = 0.020), WHO grade II or III tumor (p = 0.029), atypical histology (p = 0.004), edema (p < 0.001), brain invasion (p = 0.009), and worse progression-free survival (HR 2.68, 95% CI 1.30–5.50). In a multivariate analysis, edema (OR 3.11, 95% CI 1.46–6.65, p = 0.003) and atypical histology (OR 2.00, 95% CI 1.03–3.90, p = 0.041) were positive predictors of preoperative seizures, while genomic subgroup was not, such that the effect of an NF2 mutation was indirectly mediated through atypical histology and edema (p = 0.012). Seizure freedom was achieved in 83.3% of the cohort, and only 20.8% of the seizure-free patients, who were more likely to have undergone gross-total resection (p = 0.031), were able to discontinue antiepileptic drug use postoperatively. Preoperative seizures (OR 3.54, 95% CI 1.37–9.12, p = 0.009), recurrent tumors (OR 2.89, 95% CI 1.08–7.74, p = 0.035), and tumors requiring postoperative radiation (OR 2.82, 95% CI 1.09–7.33, p = 0.033) were significant predictors of postoperative seizures in a multivariate analysis. CONCLUSIONS Seizures are relatively common at meningioma presentation. While NF2-mutated tumors are significantly associated with preoperative seizures, the association appears to be mediated through edema and atypical histology. Patients who undergo radiation and/or have a recurrence are at risk for postoperative seizures, regardless of the extent of resection. Preoperative seizures may indeed portend a more potentially aggressive molecular entity and challenging clinical course with a higher risk of recurrence.

Background Higher educational attainment predicts lower hypertension. Yet, associations between nontraditional educational trajectories (eg, interrupted degree programs) and hypertension are less well understood, particularly among structurally marginalized groups who are more likely to experience these non-traditional trajectories. Methods In National Longitudinal Survey of Youth 1979 cohort data (N = 6 317), we used sequence and cluster analyses to identify groups of similar educational sequences—characterized by timing and type of terminal credential—that participants followed from age 14–48 years. Using logistic regression, we estimated associations between the resulting 10 educational sequences and hypertension at age 50. We evaluated effect modification by individual-level indicators of structural marginalization (race, gender, race and gender, and childhood socioeconomic status [cSES]). Results Compared to terminal high school (HS) diploma completed at traditional age, terminal GED (OR: 1.32; 95%CI: 1.04, 1.66) or Associate degree after Conclusions Both type and timing to terminal credential matter for hypertension but effects may vary by experiences of structural marginalization. Documenting the nuanced ways in which complex educational trajectories are associated with health could elucidate underlying mechanisms and inform systems-level interventions for health equity.

As sphenoid wing meningiomas (SWMs) are associated with varying degrees of bony involvement, we sought to understand potential relationships between genomic subgroup and this feature. Patients treated at Yale-New Haven Hospital for SWM were reviewed. Genomic subgroup was determined via whole exome sequencing, while the extent of bony involvement was radiographically classified as no bone invasion (Type I), hyperostosis only (Type II), tumor invasion only (Type III), or both hyperostosis and tumor invasion (Type IV). Among additional clinical variables collected, a subset of tumors was identified as spheno-orbital meningiomas (SOMs). Machine-learning approaches were used to predict genomic subgroups based on pre-operative clinical features. Among 64 SWMs, 53% had Type-II, 9% had Type-III, and 14% had Type-IV bone involvement; nine SOMs were identified. Tumors with invasion (i.e., Type III or IV) were more likely to be WHO grade II (p: 0.028). Additionally, tumors with invasion were nearly 30 times more likely to harbor NF2 mutations (OR 27.6; p: 0.004), while hyperostosis only were over 4 times more likely to have a TRAF7 mutation (OR 4.5; p: 0.023). SOMs were a significant predictor of underlying TRAF7 mutation (OR 10.21; p: 0.004). SWMs with invasion into bone tend to be higher grade and are more likely to be NF2 mutated, while SOMs and those with hyperostosis are associated with TRAF7 variants. Pre-operative prediction of molecular subtypes based on radiographic bony characteristics may have significant biological and clinical implications based on known recurrence patterns associated with genomic drivers and grade.

BACKGROUND To better counsel vestibular schwannoma patients, it is necessary to understand the tumor control rates of stereotactic radiosurgery (SRS). OBJECTIVES To determine tumor control rates, factors determining control and complication rates following SRS. METHODS Tertiary hospital retrospective cohort. RESULTS 579 tumors (576 patients) were treated with SRS. 477 tumors (474 patients, 82%) had ≥1 year follow up and 60% (344) ≥3 years follow up. 88% of tumors had primary SRS and 6.7% salvage SRS. Median follow up time was 4.6 years. At 3 years, the tumor control rate of primary SRS was 89% (258 of 290) in sporadic tumors compared to 43% in Neurofibromatosis type II (3 of 17) (p

Graphical Plain Language Summary COVID-19 vaccines are safe for people living with MS on or off disease-modifying therapies and are important for the prevention of COVID-19. Antibody responses for individuals on certain DMTs may be diminished, however, T-cell responses may be preserved in those individuals. Data are lacking regarding optimal timing of vaccinations, and delaying disease-modifying therapies may increase the risk of disease activity and progression. In this perspective podcast, the authors recommend COVID-19 vaccination as soon as possible, regardless of timing considerations, in most cases. Electronic supplementary material The online version of this article (10.1007/s40120-021-00266-z) contains supplementary material, which is available to authorized users.

Systemic inhibition of Notch with γ-secretase inhibitors (GSI) decreases multiple myeloma tumor growth, but the clinical use of GSI is limited due to its severe gastrointestinal toxicity. In this study, we generated a GSI Notch inhibitor specifically directed to the bone (BT-GSI). BT-GSI administration decreased Notch target gene expression in the bone marrow, but it did not alter Notch signaling in intestinal tissue or induce gut toxicity. In mice with established human or murine multiple myeloma, treatment with BT-GSI decreased tumor burden and prevented the progression of multiple myeloma-induced osteolytic disease by inhibiting bone resorption more effectively than unconjugated GSI at equimolar doses. These findings show that BT-GSI has dual anti-myeloma and anti-resorptive properties, supporting the therapeutic approach of bone-targeted Notch inhibition for the treatment of multiple myeloma and associated bone disease. Significance: Development of a bone-targeted Notch inhibitor reduces multiple myeloma growth and mitigates cancer-induced bone destruction without inducing the gastrointestinal toxicity typically associated with inhibition of Notch.

Objectives Two pilot studies of AR‐42, a pan‐histone deacetylase inhibitor, in human neurofibromatosis type 2 (NF2), vestibular schwannomas (VS), and meningiomas are presented. Primary endpoints included safety, and intra‐tumoral pharmacokinetics (PK) and pharmacodynamics (PD). Methods Pilot 1 is a subset analysis of a phase 1 study of AR‐42 in solid tumors, which included NF2 or sporadic meningiomas. Tumor volumes and treatment‐related adverse events (TRAEs) are reported (NCT01129193). Pilot 2 is a phase 0 surgical study of AR‐42 assessing intra‐tumoral PK and PD. AR‐42 was administered for 3 weeks pre‐operatively. Plasma and tumor drug concentrations and p‐AKT expression were measured (NCT02282917). Results Pilot 1: Five patients with NF2 and two with sporadic meningiomas experienced a similar incidence of TRAEs to the overall phase I trial. The six evaluable patients had 15 tumors (8 VS, 7 meningiomas). On AR‐42, tumor volume increased in six, remained stable in eight, and decreased in one tumor. The annual percent growth rate decreased in eight, remained stable in three, and increased in four tumors. Pilot 2: Four patients with sporadic VS and one patient with meningioma experienced no grade 3/4 toxicities. Expression of p‐AKT decreased in three of four VS. All tumors had higher AR‐42 concentrations than plasma. Conclusions AR‐42 is safe. Tumor volumes showed a mixed response, but most slowed growth. On a 40‐mg regimen, drug concentrated in tumors and growth pathways were suppressed in most tumors, suggesting this may be a well‐tolerated and effective dose. A phase 2 study of AR‐42 for NF2‐associated tumors appears warranted. Level of Evidence 1b, 4.

Objective To evaluate medical and surgical complication rates between robotic-assisted versus conventional elective posterior lumbar fusions. Methods The Symphony Integrated DataVerse was queried using International Classification of Diseases, 10th Edition, Clinical Modification procedure codes to identify patients undergoing elective posterior lumbar fusions for degenerative spine pathologies between 2015 and 2018. International Classification of Diseases, 10th Edition, Clinical Modification procedure codes (8E0W4CZ, 8E0W0CZ, 8E0W3CZ) were used to identify patients undergoing a robotic-assisted spinal fusion. Outcome measures were 90-day medical and surgical complications, 1-year pseudarthrosis, and 1-year revision surgery rates. Multivariate logistic regression analyses were used to assess whether undergoing a robotic-assisted fusion (vs. conventional fusion) was associated with differences in wound complications, medical complications, pseudarthrosis, revision surgery, and readmissions within 90 days of surgery. Results A total of 39,387 patients undergoing elective posterior lumbar fusions were included in the cohort—of whom 245 (0.62%) patients underwent a robotic-assisted fusion. Multivariate analysis showed that robotic-assisted fusion (vs. conventional fusion) was not associated with significant differences in 90-day rates of wound complications (P = 0.299), urinary tract infections (P = 0.648), acute myocardial infarctions (P = 0.209), acute renal failure (P = 0.461), pneumonia (P = 0.214), stroke (P = 0.917), deep venous thrombosis (P = 0.562), pulmonary embolism (P = 0.401), and readmissions (P = 0.985). In addition, there were no significant differences in the 1-year rates of revision fusions (P = 0.316) and pseudarthrosis (P = 0.695). Conclusions Patients who underwent a robotic-assisted fusion had similar rates of surgical and medical complications compared with those who underwent a conventional fusion. Further studies are warranted to better understand the future role of robots in spine surgery.

OBJECTIVE To evaluate the effects of fish oil (FO), a source of the omega-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on emotion-generated corticolimbic functional connectivity in depressed youth at high risk for developing bipolar I disorder. METHODS Thirty-nine antidepressant-free youth with a current depressive disorder diagnosis and a biological parent with bipolar I disorder were randomized to 12-week double-blind treatment with FO or placebo. At baseline and endpoint, fMRI (4 Tesla) scans were obtained while performing a continuous performance task with emotional and neutral distractors (CPT-END). Seed-to-voxel functional connectivity analyses were performed using bilateral orbitofrontal cortex (OFC) and amygdala (AMY) seeds. Measures of depression, mania, global symptom severity, and erythrocyte fatty acids were obtained. RESULTS Erythrocyte EPA+DHA composition increased significantly in the FO group (+47%, p ≤ 0.0001) but not in the placebo group (-10%, p = 0.11). Significant group by time interactions were found for functional connectivity between the left OFC and the left superior temporal gyrus (STG) and between the right AMY and right inferior temporal gyrus (ITG). OFC-STG connectivity increased in the FO group (p = 0.0001) and decreased in the placebo group (p = 0.0019), and AMY-ITG connectivity decreased in the FO group (p = 0.0014) and increased in the placebo group (p

BACKGROUND. Neuroinflammation is a well-known feature of early Alzheimer disease (AD) yet astrocyte activation has not been extensively evaluated with in vivo imaging in Mild Cognitive Impairment (MCI) due to amyloid plaque pathology. Unlike neurons, astrocytes metabolize acetate, which has potential as a glial biomarker in neurodegeneration in response to AD pathologic features. Since the medial temporal lobe (MTL) is a hotspot for AD neurodegeneration and inflammation, we assessed astrocyte activity in the MTL and compared to amyloid and cognition. METHODS. We evaluate spatial patterns of in vivo astrocyte activation and their relationships to amyloid deposition and cognition in a cross-sectional pilot study of 6 participants with MCI and 5 cognitively normal (CN) participants. We measure (11)C-acetate and (18)F-florbetaben amyloid standardized uptake values ratios (SUVRs) and kinetic flux compared to cerebellum on positron emission tomography (PET), with magnetic resonance imaging and neurocognitive testing. RESULTS. Medial temporal lobe (MTL) (11)C-acetate SUVR was significantly elevated in MCI compared to CN participants (P = 0.03; Cohen d = 1.76). Moreover, MTL (11)C-acetate SUVR displayed significant associations with global and regional amyloid burden in MCI. Greater MTL (11)C-acetate retention was significantly related with worse neurocognitive measures including the Montreal Cognitive Assessment (P = 0.001), Word List Recall memory (P = 0.03), Boston Naming Test (P = 0.04) and Trails B test (P = 0.04). CONCLUSIONS. While further validation is required, this exploratory pilot study suggests a potential role for (11)C-acetate PET as a neuroinflammatory biomarker in MCI and early AD to provide clinical and translational insights into astrocyte activation as a pathological response to amyloid.

This article examines the state of public service motivation research and associated big questions from the shared perspective of participants who gathered for a 20-year retrospective conference en...

Overexpression of B-cell leukemia/lymphoma 2 (BCL2) renders acute myeloid leukemia (AML) cells resistant to chemotherapy and has been associated with unfavorable outcomes. Oblimersen (G3139) is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 BCL2 codons. In a phase 1 study of AML patients treated with G3139, cytarabine, and daunorubicin induction with cytarabine consolidation, no antisense-related toxicity was reported, and BCL2 downregulation occurred in patients achieving complete remission. In this phase 3 trial, untreated older AML patients were randomized to cytarabine (100 mg/m2 per day on days 4-10) and daunorubicin (60 mg/m2 per day on days 4-6) followed by cytarabine consolidation (2000 mg/m2 per day on days 4-8) with (arm A) or without (arm B) G3139 (7 mg/m2 per day on days 1-10 [induction] or days 1-8 [consolidation]). A total of 506 patients were enrolled. No differences in toxicity were observed between arms. Estimated overall survival (OS) at 1 year was 43% for arm A and 40% for arm B (1-sided log rank P = .13), with no differences in disease-free (DFS; P = .26) or event-free survival (P = .80). Subgroup analyses showed patients age

Purpose To evaluate visual, refractive, aberrometric and patient-reported outcomes of wavefront-guided (WFG) myopic laser in situ keratomileusis (LASIK) using a high-resolution Hartmann-Shack aberrometer (iDesign Advanced WaveScan system, Johnson & Johnson Vision, Santa Ana, CA) with a new nomogram. The study was designed to determine if the new nomogram resolved the mild undercorrection that occurs with the manufacturer's default settings. Setting Three private LASIK practices. Design Prospective, open label, non-comparative, multicenter study. Methods One hundred ninety eyes of 95 patients underwent bilateral WFG LASIK for the correction of myopia or myopic astigmatism. A new nomogram was used, which effectively adjusted the wavefront-measured refraction sphere up or down to equal the manifest refraction sphere. Patients were followed for six months. Results Eighty-four patients completed final follow up. At 6 months, 96.4% (162/168) of eyes achieved monocular uncorrected distance visual acuity of 20/20 or better. No eye lost two or more lines of corrected distance visual acuity. The safety and efficacy indices were 1.12 and 1.09, respectively. 98% of eyes (164/168) had manifest refraction spherical equivalent within ±0.5 D of emmetropia and 92% (154/168) had residual manifest refractive astigmatism ≤0.5 D. Fewer patients experienced burning, stinging, soreness and irritation postoperatively than preoperatively. 96% (81/84) of patients reported improved quality of life. Conclusions WFG myopic LASIK using a high-resolution Hartmann Shack aberrometer and a new nomogram resolved the undercorrection with the manufacturer's default settings. The treatment was safe and effective with excellent visual and refractive outcomes, high patient satisfaction and improved quality of life.

Objective:Recent cannabis exposure has been associated with lower rates of neurocognitive impairment in people with HIV (PWH). Cannabis’s anti-inflammatory properties may underlie this relationship by reducing chronic neuroinflammation in PWH. This study examined relations between cannabis use and inflammatory biomarkers in cerebrospinal fluid (CSF) and plasma, and cognitive correlates of these biomarkers within a community-based sample of PWH.Methods:263 individuals were categorized into four groups: HIV− non-cannabis users (n= 65), HIV+ non-cannabis users (n= 105), HIV+ moderate cannabis users (n= 62), and HIV+ daily cannabis users (n= 31). Differences in pro-inflammatory biomarkers (IL-6, MCP-1/CCL2, IP-10/CXCL10, sCD14, sTNFR-II, TNF-α) by study group were determined by Kruskal–Wallis tests. Multivariable linear regressions examined relationships between biomarkers and seven cognitive domains, adjusting for age, sex/gender, race, education, and current CD4 count.Results:HIV+ daily cannabis users showed lower MCP-1 and IP-10 levels in CSF compared to HIV+ non-cannabis users (p= .015;p= .039) and were similar to HIV− non-cannabis users. Plasma biomarkers showed no differences by cannabis use. Among PWH, lower CSF MCP-1 and lower CSF IP-10 were associated with better learning performance (allps < .05).Conclusions:Current daily cannabis use was associated with lower levels of pro-inflammatory chemokines implicated in HIV pathogenesis and these chemokines were linked to the cognitive domain of learning which is commonly impaired in PWH. Cannabinoid-related reductions of MCP-1 and IP-10, if confirmed, suggest a role for medicinal cannabis in the mitigation of persistent inflammation and cognitive impacts of HIV.

To quantify overall CT repeat and reject rates at five institutions and investigate repeat and reject rates for CT pulmonary angiography (CTPA).In this retrospective study, we apply an automated repeat rate analysis algorithm to 103,752 patient examinations performed at five institutions from July 2017 to August 2019. The algorithm identifies repeated scans for specific scanner and protocol combinations. For each institution, we compared repeat rates for CTPA to all other CT protocols. We used logistic regression and analysis of deviance to compare CTPA repeat rates across institutions and size-based protocols.Of 103,752 examinations, 1,447 contained repeated helical scans (1.4%). Overall repeat rates differed across institutions (P .001) ranging from 0.8% to 1.8%. Large-patient CTPA repeat rates ranged from 3.0% to 11.2% with the odds (95% confidence intervals) of a repeat being 4.8 (3.5-6.6) times higher for large- relative to medium-patient CTPA protocols. CTPA repeat rates were elevated relative to all other CT protocols at four of five institutions, with strong evidence of an effect at two institutions (P.001 for each; odds ratios: 2.0 [1.6-2.6] and 6.2 [4.4-8.9]) and somewhat weaker evidence at the others (P = .005 and P = 0.011; odds ratios: 2.2 [1.3-3.8] and 3.7 [1.5-9.1], respectively). Accounting for size-based protocols, CTPA repeat rates differed across institutions (P .001).The results indicate low overall repeat rates (2%) with CTPA rates elevated relative to other protocols. Large-patient CTPA rates were highest (eg, 11.2% at one institution). Differences in repeat rates across institutions suggest the potential for quality improvement.

Summary Background Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Primary analysis of the phase 3 trial in adults aged 60–75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia provided support for approval of CPX-351 by the US Food and Drug Administration and European Medicines Agency. We describe the prospectively planned final 5-year follow-up results. Methods This randomised, open-label, multicentre, phase 3 trial was done across 39 academic and regional cancer centres in the USA and Canada. Eligible patients were aged 60–75 years and had a pathological diagnosis of acute myeloid leukaemia according to WHO 2008 criteria, no previous induction therapy for acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned 1:1 (stratified by age and acute myeloid leukaemia subtype) to receive up to two induction cycles of CPX-351 (100 units/m2 administered as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the second induction) or standard chemotherapy (cytarabine 100 mg/m2 per day continuous intravenous infusion for 7 days plus intravenous daunorubicin 60 mg/m2 on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the second induction [5+2]). Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery could receive up to tw cycles of consolidation therapy with CPX-351 (65 units/m2 90-min infusion on days 1 and 3) or chemotherapy (5+2, same dosage as in the second induction cycle). The primary outcome was overall survival analysed in all randomly assigned patients. No additional adverse events were collected with long-term follow-up, except data for deaths. This trial is registered with ClinicalTrials.gov , NCT01696084 , and is complete. Findings Between Dec 20, 2012, and Nov 11, 2014, 309 patients with newly diagnosed high-risk or secondary acute myeloid leukaemia were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients). At a median follow-up of 60·91 months (IQR 60·06–62·98) in the CPX-351 group and 59·93 months (59·73–60·50) in the 7+3 group, median overall survival was 9·33 months (95% CI 6·37–11·86) with CPX-351 and 5·95 months (4·99–7·75) with 7+3 (HR 0·70, 95% CI 0·55–0·91). 5-year overall survival was 18% (95% CI 12–25%) in the CPX-351 group and 8% (4–13%) in the 7+3 group. The most common cause of death in both groups was progressive leukaemia (70 [56%] of 124 deaths in the CPX-351 group and 74 [53%] of 140 deaths in the 7+3 group). Six (5%) of 124 deaths in the CPX-351 group and seven (5%) of 140 deaths in the 7+3 group were considered related to study treatment. Interpretation After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall survival in patients aged 60–75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia. Funding Jazz Pharmaceuticals.

PURPOSE OF REVIEW Substantial progress has been made recently on the development of new therapeutics for cryptosporidiosis, an infection by the protozoan parasite Cryptosporidium that is associated with diarrhea, malnutrition, growth stunting, cognitive deficits, and oral vaccine failure in children living in low-resource settings. RECENT FINDINGS Various drug discovery approaches have generated promising lead candidates. The repurposed antimycobacterial drug clofazimine was tested in Malawian HIV patients with cryptosporidiosis but was ineffective. Target-based screens identified inhibitors of lysyl-tRNA synthetase, phenylalanyl-tRNA synthetase, methionyl-tRNA synthetase, and calcium-dependent protein kinase 1. Phenotypic screens led to discovery of a phosphatidylinositol 4-kinase inhibitor, the piperazine MMV665917, and the benzoxaborole AN7973. The relationship between pharmacokinetic properties and in-vivo efficacy is gradually emerging. A pathway to clinical trials, regulatory approval, and introduction has been proposed but additional work is needed to strengthen the route. SUMMARY Several lead compounds with potent activity in animal models and a favorable safety profile have been identified. A sustained effort will be required to advance at least one to clinical proof-of-concept studies. The demonstrated risk of resistance indicates multiple candidates should be advanced as potential components of a combination therapy.

In the US, methadone treatment can only be provided to patients with opioid use disorder (OUD) through federal and state-regulated opioid treatment programs (OTPs). There is a shortage of OTPs, and racial and geographic inequities exist in access to methadone treatment. The National Institute on Drug Abuse Clinical Trials Network convened the Methadone Access Research Task Force to develop a research agenda to expand and create more equitable access to methadone treatment for OUD. This research agenda included mechanisms that are available within and outside the current regulations. The task force identified 6 areas where research is needed: (1) access to methadone in general medical and other outpatient settings; (2) the impact of methadone treatment setting on patient outcomes; (3) impact of treatment structure on outcomes in patients receiving methadone; (4) comparative effectiveness of different medications to treat OUD; (5) optimal educational and support structure for provision of methadone by medical providers; and (6) benefits and harms of expanded methadone access. In addition to outlining these research priorities, the task force identified important cross-cutting issues, including the impact of patient characteristics, treatment, and treatment system characteristics such as methadone formulation and dose, concurrent behavioral treatment, frequency of dispensing, urine or oral fluid testing, and methods of measuring clinical outcomes. Together, the research priorities and cross-cutting issues represent a compelling research agenda to expand access to methadone in the US.

Objective:Given the aging population of people with HIV (PWH), along with increasing rates of binge drinking among both PWH and the general older adult population, this study examined the independent and interactive effects of HIV, binge drinking, and age on neurocognition.Method:Participants were 146 drinkers stratified by HIV and binge drinking status (i.e., ≥4 drinks for women and ≥5 drinks for men within approximately 2 h): HIV+/Binge+ (n = 30), HIV−/Binge+ (n = 23), HIV+/Binge− (n = 55), HIV−/Binge− (n = 38). All participants completed a comprehensive neuropsychological battery measuring demographically-corrected global and domain-specific neurocognitive T scores. ANCOVA models examined independent and interactive effects of HIV and binge drinking on neurocognitive outcomes, adjusting for overall alcohol consumption, lifetime substance use, sex, and age. Subsequent multiple linear regressions examined whether HIV/Binge group moderated the relationship between age and neurocognition.Results:HIV+/Binge+ participants had worse global neurocognition, processing speed, delayed recall, and working memory than HIV−/Binge− participants (p’s < .05). While there were significant main effects of HIV and binge drinking, their interaction did not predict any of those neurocognitive outcomes (p’s > .05). Significant interactions between age and HIV/Binge group showed that HIV+/Binge+ participants demonstrated steeper negative relationships between age and neurocognitive outcomes of learning, delayed recall, and motor skills compared to HIV−/Binge− participants (p’s < .05).Conclusions:Results showed adverse additive effects of HIV and binge drinking on neurocognitive functioning, with older adults demonstrating the most vulnerability to these effects. Findings support the need for interventions to reduce binge drinking, especially among older PWH.

Objective This study examined the in vitro activity of iclaprim and comparators against 40 Listeria monocytogenes clinical isolates mostly (95%) from patients with bloodstream infections (BSI) from the United States, Australia/New Zealand, Latin America, and Europe collected between 2012-2018 were tested. Methods Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI criteria. Results The iclaprim MIC90 value for all L. monocytogenes was 0.015 µg/ml. The MIC50/90 values for iclaprim were 4-fold lower than trimethoprim, the only FDA approved dihydrofolate reductase inhibitor, against all L. monocytogenes. Conclusions Iclaprim demonstrated lower MIC values than trimethoprim against a collection (2012-2018) of L. monocytogenes clinical isolates mostly from patients with blood stream infections from the United States, Australia/New Zealand, Latin America, and Europe.