A prospective pilot study to assess for histologic changes on vulvar biopsies in postmenopausal women with lichen sclerosus treated with fractionated CO2 laser therapy.

OBJECTIVES: To investigate the histologic characteristics of vulvar tissues before and after completion of fractionated carbon dioxide (CO2 ) laser therapy (FxCO2) for vulvar lichen sclerosus (LS). The secondary objective was to assess subjective improvement in symptoms via the Skindex-16 questionnaire. METHODS: This prospective single-arm study was conducted from April 2021 to August 2022 at one academic medical center. Ten postmenopausal women with biopsy-proven LS planning FxCO2 laser treatment were enrolled. Exclusion criteria included prior transvaginal mesh for prolapse, topical corticosteroid use within 8 weeks, prior pelvic radiation, malignancy, active genital infection, or pregnancy. The vulvovaginal SmartXide2-V2-LR laser system fractionated CO2 laser (DEKA) was utilized to treat visually affected areas of vulvar and perianal LS with a single pass. Subjects underwent three treatments 4-6 weeks apart. Subjects completed the Skindex-16 questionnaire and had vulvar biopsy at baseline and at 4 weeks after completion of fractionated CO2 laser therapy. Blinded histologic slides were scored by one dermatopathologist (Michael A. Cardis) rating from 1 to 5 the degree of dermal sclerosis, inflammation, and epidermal atrophy. Change scores were calculated as the difference between pre- and post-treatment scores for each subject. RESULTS: The 10 subjects enrolled had a mean age of 61 and most were white, privately insured, and had a college/graduate-level education. Post-fractionated CO2 laser treatment vulvar biopsies showed significant improvement in sclerosis and epidermal atrophy compared with pretreatment baseline biopsy specimens (p < 0.05) with no statistically significant change found in inflammation score. Skindex-16 and FSFI scores showed a trend towards improvement (p > 0.05 for both). A statistically significant correlation was found between change in sclerosis and Skindex-16 symptoms scores with an average change of 21.4 units in Skindex-16 symptoms score for every one-point change in histologic sclerosis score (p = 0.03). CONCLUSIONS: In postmenopausal women with vulvar LS undergoing fractionated CO2 laser, symptomatic improvements correlated with histologic change in degree of sclerosis on vulvar biopsy. These results demonstrate FxCO2 laser therapy as a promising option for the treatment of LS and suggest that further studies should assess degree of sclerosis on histopathology.

COVID-19 therapeutics and outcomes among solid organ transplant recipients during the Omicron BA.1 era.

Treatment outcomes associated with the use of novel COVID-19 therapeutics in solid organ transplant recipients (SOTR) are not well described in the literature. The objective of this analysis was to characterize 30-day hospitalization and other key secondary endpoints experienced by outpatient SOTR with mild-moderate COVID-19 treated with nirmatrelvir/ritonavir (NR), sotrovimab, or no SARS-CoV-2 specific treatment. This IRB-approved, retrospective study included 154 SOTR with a documented positive SARS-CoV-2 infection between December 16, 2021 and January 19, 2022 (a predominant Omicron BA.1 period in New York City). Patients who received NR (N = 28) or sotrovimab (N = 51) experienced a lower rate of 30-day hospitalization or death as compared to those who received no specific treatment (N = 75) (p = .009). A total of three deaths occurred, all among patients who initially received no specific treatment prior to hospitalization. These results suggest a role for SARS-CoV-2 specific agents in the treatment of SOTR with COVID-19, and that there does not appear to be any difference in effectiveness when comparing NR versus sotrovimab.

Interplay between a Mental Disorder Risk Gene and Developmental Polarity Switch of GABA Action Leads to Excitation-Inhibition Imbalance.

Excitation-inhibition (E-I) imbalance is considered a hallmark of various neurodevelopmental disorders, including schizophrenia and autism. How genetic risk factors disrupt coordinated glutamatergic and GABAergic synapse formation to cause an E-I imbalance is not well understood. Here, we show that knockdown of Disrupted-in-schizophrenia 1 (DISC1), a risk gene for major mental disorders, leads to E-I imbalance in mature dentate granule neurons. We found that excessive GABAergic inputs from parvalbumin-, but not somatostatin-, expressing interneurons enhance the formation of both glutamatergic and GABAergic synapses in immature mutant neurons. Following the switch in GABAergic signaling polarity from depolarizing to hyperpolarizing during neuronal maturation, heightened inhibition from excessive parvalbumin+ GABAergic inputs causes loss of excitatory glutamatergic synapses in mature mutant neurons, resulting in an E-I imbalance. Our findings provide insights into the developmental role of depolarizing GABA in establishing E-I balance and how it can be influenced by genetic risk factors for mental disorders.

Antibiotic prophylaxis for ureteral stent removal after kidney transplantation.

There are no guidelines for antibiotic prophylaxis for ureteral stent removal after kidney transplantation. We reviewed the charts of 277 adult kidney transplant recipients with ureteral stents transplanted at our center between September 2014 and December 2015 and investigated whether antibiotic prophylaxis for stent removal was associated with reduced incidence of urinary tract infections (UTI). We defined UTI as a urine culture ≥104  CFU/mL of bacterial isolates irrespective of symptoms. Primary outcome was the incidence of UTI within four weeks of stent removal. Among the 277 recipients, 199 (72%) were on sulfamethoxazole/trimethoprim (SMZ/TMP) as Pneumocystis jirovecii prophylaxis. At the time of ureteral stent removal, 56 recipients (20%) received additional antibiotic prophylaxis (ABX+) and 221 (80%) did not (ABX-). The difference in the incidence of UTI in the ABX(+) group (16%) and ABX(-) group (19%) was not statistically significant (P = 0.85). Variables independently associated with the development of UTI were recipient age (odds ratio [OR] 1.04, [95% confidence interval 1.01-1.07]) and UTI while stents were in situ (OR 3.9 [2.00-7.62]). Use of SMZ/TMP was protective (OR 0.35 [0.18-0.7]). Our study does not show a statistically significant benefit for additional antibiotic prophylaxis for ureteral stent removal. Antibiotic prophylaxis may be beneficial for recipients not on SMZ/TMP at the time of stent removal.

Routine prophylaxis with proton pump inhibitors and post-transplant complications in kidney transplant recipients undergoing early corticosteroid withdrawal.

Surgical stress, corticosteroids, and mycophenolate may contribute to gastrointestinal ulcers/bleeding after kidney transplantation. Prophylactic acid suppression with H2RAs or PPIs is often utilized after transplantation, although unclear if truly indicated after early corticosteroid withdrawal (CSWD). PPIs have been associated with increased risks of Clostridium difficile infection (CDI), pneumonia, and acute rejection. This retrospective cohort study investigated benefits and risks of prolonged PPI use following kidney transplantation and included 286 kidney recipients undergoing CSWD within five d of transplant who were maintained on tacrolimus and mycophenolate mofetil/sodium. Patients on PPI before transplant, H2RA before/after transplant, and/or those with pre-transplant GI complications were excluded. A total of 171 patients received PPI>30 d, mean duration 287 ± 120 d (PPI group); 115 patients were not maintained on acid suppression (No-PPI group). GI ulceration and bleeding events were rare in PPI group (1.2% and 2.3%, respectively) and not observed in No-PPI group (p = NS). The incidence of infectious or hematological complications was not significantly different between groups. The PPI group experienced more biopsy-proven acute rejection (9.4% vs. 2.6%, p = 0.03). No direct benefit was observed with PPI in reducing the incidence of GI ulcers and bleeding events in kidney transplant recipients undergoing early CSWD. Further studies are needed to investigate the association of PPI and acute rejection.

Insulin-associated neuroinflammatory pathways as therapeutic targets for traumatic brain injury.

Traumatic brain injury (TBI) is characterized by an abrupt blow or exchange of force against the head and can be categorized as mild, moderate, and severe. The secondary cell death after TBI displays ischemic-like patterns including neuroinflammation. The scavenger receptor cluster of differentiation (CD) 36 is a lipid-associated protein capable of transducing intracellular signals to promote inflammatory mechanisms within different cell types. Expression and activation of CD36 is closely related to dyslipidemia secondary to diabetes. Diabetes mellitus (DM) has been documented as a co-morbidity factor in TBI, in that patients with a history of diabetes present with more severe brain damage and slower recovery from TBI than non-diabetic patients. Indeed, a strict regulation of blood serum glucose by the use of insulin promotes a better outcome for TBI patients. Based on these recent findings, we now advance the hypothesis that CD36 via DM insulin-associated pathways is closely involved in TBI chronic pathology.

Oceanographic lidar profiles compared with estimates from in situ optical measurements.

Oceanographic lidar profiles measured in an aerial survey were compared with in situ measurements of water optical properties made from a surface vessel. Experimental data were collected over a two-week period in May 2010 in East Sound, Washington. Measured absorption and backscatter coefficients were used with the volume-scattering function in a quasi-single-scattering model to simulate an idealized lidar return, and this was convolved with the measured instrument response to accurately reproduce the measured temporal behavior. Linear depth-dependent depolarization from the water column and localized depolarization from scattering layers are varied to fine tune the simulated lidar return. Sixty in situ measurements of optical properties were correlated with nearly collocated and coincident lidar profiles; our model yielded good matches (±3 dB to a depth of 12 m) between simulated and measured lidar profiles for both uniform and stratified waters. Measured attenuation was slightly higher (5%) than diffuse attenuation for the copolarized channel and slightly lower (8%) for the cross-polarized channel.

International shortfall inequality in life expectancy in women and in men, 1950-2010.

OBJECTIVE: To assess international shortfall inequality in life expectancy at birth among women and men and the influence of geography and country income group. METHODS: The authors used estimates of life expectancy at birth, by sex, for 12 five-year periods between 1950-1955 and 2005-2010 and estimates of population for the midpoints of each period from the World population prospects, 2008 revision. Shortfall inequality was defined as the weighted average of the deviations of each country's average life expectancy by sex from the highest attained life expectancy by sex for each period. FINDINGS: International shortfall inequalities in life expectancy among men and among women decreased between 1950 and 1975 but stagnated thereafter. International shortfall inequality in life expectancy has been higher in women than in men, ranging from 1.9 to 2.9 years. Women in low-income countries have the biggest shortfall, currently at around 26.7 years. CONCLUSION: International shortfall inequality is higher among women than men primarily because women in low-income and lower-middle-income country groups show larger differences in life expectancy than men. Further investigation is needed to determine the pathways causing these inequalities.

A longitudinal MRI study of muscle atrophy during lower leg immobilization following ankle fracture.

PURPOSE: To investigate MRI biomarkers of muscle atrophy during cast immobilization of the lower leg. MATERIALS AND METHODS: Eighteen patients (8 male, 10 female), who had one lower leg immobilized in a cast, underwent 3.0 Tesla (T) MR imaging 5, 8, 15, 29, and 43 days after casting. Measurements were made on both lower legs of total muscle volume. Cross-sectional area (CSA), fractional water content, and T(2) were measured in tibialis anterior (TA), gastrocnemius medialis (GM) and lateralis (GL) and soleus (SOL). Fiber pennation angle was measured in GM. RESULTS: Total muscle volume decreased by 17% (P < 0.001) over the 6 weeks of immobilization. The greatest loss in CSA (mean[SD]) was seen in GM (-23.3(8.7)%), followed by SOL (-19.0(9.8)%), GL (-17.1(6.5)%), and TA (-10.7(5.9)%). Significant reductions of CSA were also detectable in the contra-lateral leg. T(2) increased in all muscles: TA 27.0(2.5) ms to 29.6(2.8) ms (P < 0.001), GM 34.6(2.9) ms to 39.8(5.4) ms (P < 0.001) and SOL 34.4 (2.9) ms to 44.9(5.9) ms (P < 0.001). Small reductions were found in fractional water content. Pennation angle decreased in the cast leg (P < 0.001). CONCLUSION: Quantitative MR imaging can detect and monitor progressive biochemical and biophysical changes in muscle during immobilization.

Generation of Cerenkov radiation at 850 nm in higher-order-mode fiber.

We demonstrate generation of Cerenkov radiation at 850 nm in a higher-order-mode (HOM) fiber. The LP02 mode in this solid, silica-based fiber has anomalous dispersion from 690 nm to 810 nm. Cerenkov radiation with 3 nJ pulse energy is generated in this module, exhibiting 60% energy conversion efficiency from the input. The HOM fiber provides a valuable fiber platform for nonlinear wavelength conversion with pulse energies in-between index-guided silica-core photonic crystal fibers and air-core photonic bandgap fibers.

Rates of change and sensitivity to change in cartilage morphology in healthy knees and in knees with mild, moderate, and end-stage radiographic osteoarthritis: results from 831 participants from the Osteoarthritis Initiative.

OBJECTIVE: To study the longitudinal rate of (and sensitivity to) change of knee cartilage thickness across defined stages of radiographic osteoarthritis (OA), specifically healthy knees and knees with end-stage radiographic OA. METHODS: One knee of 831 Osteoarthritis Initiative participants was examined: 112 healthy knees, without radiographic OA or risk factors for knee OA, and 719 radiographic OA knees (310 calculated Kellgren/Lawrence [K/L] grade 2, 300 calculated K/L grade 3, and 109 calculated K/L grade 4). Subregional change in thickness was assessed after segmentation of weight-bearing femorotibial cartilage at baseline and 1 year from coronal magnetic resonance imaging (MRI). Regional and ordered values (OVs) of change were compared by baseline radiographic OA status. RESULTS: Healthy knees displayed small changes in plates and subregions (±0.7%; standardized response mean [SRM] ±0.15), with OVs being symmetrically distributed close to zero. In calculated K/L grade 2 knees, changes in cartilage thickness were small (<1%; minimal SRM -0.22) and not significantly different from healthy knees. Knees with calculated K/L grade 3 showed substantial loss of cartilage thickness (up to -2.5%; minimal SRM -0.35), with OV1 changes being significantly (P < 0.05) greater than those in healthy knees. Calculated K/L grade 4 knees displayed the largest rate of loss across radiographic OA grades (up to -3.9%; minimal SRM -0.51), with OV1 changes also significantly (P < 0.05) greater than in healthy knees. CONCLUSION: MRI-based cartilage thickness showed high rates of loss in knees with moderate and end-stage radiographic OA, and small rates (indistinguishable from healthy knees) in mild radiographic OA. From the perspective of sensitivity to change, end-stage radiographic OA knees need not be excluded from longitudinal studies using MRI cartilage morphology as an end point.