Nevin Manimala

J Int AIDS Soc. 2022 Apr;25(4):e25895. doi: 10.1002/jia2.25895.

ABSTRACT

INTRODUCTION: HIV reservoirs and infected cells may persist in tissues with low concentrations of antiretrovirals (ARVs). Traditional pharmacology methods cannot assess variability in ARV concentrations within morphologically complex tissues, such as lymph nodes (LNs). We evaluated the distribution of six ARVs into LNs and the proximity of these ARVs to CD4⁺ T cells and cell-associated RT-SHIV viral RNA.

METHODS: Between December 2014 and April 2017, RT-SHIV infected (SHIV+; N = 6) and healthy (SHIV-; N = 6) male rhesus macaques received two selected four-drug combinations of six ARVs over 10 days to attain steady-state conditions. Serial cryosections of axillary LN were analysed by a multimodal imaging approach that combined mass spectrometry imaging (MSI) for ARV disposition, RNAscope in situ hybridization for viral RNA (vRNA) and immunohistochemistry for CD4⁺ T cell and collagen expression. Spatial relationships across these four imaging domains were investigated by nearest neighbour search on co-registered images using MATLAB.

RESULTS: Through MSI, ARV-dependent, heterogeneous concentrations were observed in different morphological LN regions, such as the follicles and medullary sinuses. After 5-6 weeks of infection, more limited ARV penetration into LN tissue relative to the blood marker heme was found in SHIV+ animals (SHIV+: 0.7 [0.2-1.4] mm; SHIV-: 1.3 [0.5-1.7] mm), suggesting alterations in the microcirculation. However, we found no detectable increase in collagen deposition. Regimen-wide maps of composite ARV distribution indicated that up to 27% of SHIV+ LN tissue area was not exposed to detectable ARVs. Regions associated with B cell follicles had median 1.15 [0.94-2.69] -fold reduction in areas with measurable drug, though differences were only statistically significant for tenofovir (p = 0.03). Median co-localization of drug with CD4⁺ target cells and vRNA varied widely by ARV (5.1-100%), but nearest neighbour analysis indicated that up to 10% of target cells and cell-associated vRNA were not directly contiguous to at least one drug at concentrations greater than the IC50 value.

CONCLUSIONS: Our investigation of the spatial distributions of drug, virus and target cells underscores the influence of location and microenvironment within LN, where a small population of T cells may remain vulnerable to infection and low-level viral replication during suppressive ART.

PMID:35441468 | DOI:10.1002/jia2.25895

Pediatr Blood Cancer. 2022 Apr 19:e29691. doi: 10.1002/pbc.29691. Online ahead of print.

ABSTRACT

BACKGROUND: CWS/RMS-96 was an international multicenter trial with randomization between two therapy arms of the standard four-drug therapy (vincristine, ifosfamide, adriamycin, dactinomycin [VAIA]) versus an intensified six-drug regimen (carboplatin, epirubicin, vincristine, dactinomycin, ifosfamide, and etoposide [CEVAIE]) for high-risk rhabdomyosarcoma (RMS), extraskeletal Ewing sarcoma (EES), and undifferentiated sarcoma (UDS) in children, adolescents, and young adults aiming to improve their survival. Intensified chemotherapy with CEVAIE did not improve outcome.

METHODS: Patients younger than 21 years with a previously untreated localized HR-RMS, EES, and UDS were enrolled from Cooperative Weichteilsarkom Studiengruppe (CWS) centers in Germany, Austria, Poland, Switzerland, and from Italian Soft Tissue Sarcoma Committee (STSC) centers. Randomization (1:1) to receive either 9 × 21 days cycles of VAIA or CEVAIE was performed separately in CWS and STSC. Hyperfractionated accelerated radiotherapy (32-44.8 Gy) was added at week 9-12 according to histology and response to chemotherapy. A secondary microscopically complete nonmutilating resection was performed if possible. Primary endpoints were response to chemotherapy, event-free (EFS) and overall survival (OS).

RESULTS: Five hundred fifty-seven patients (HR-RMS: n = 416, EES and UDS: n = 141) underwent randomization: VAIA (n = 273) or CEVAIE (n = 284). Radiotherapy was given to 70% of patients in both groups. A secondary resection was performed in 47% and 48% patients, respectively. The 5-year EFS and OS for the VAIA and CEVAIE treatment arms were 59.8% and 60.8% (p = .89), and 74.2% and 68.3% (p = .16), respectively. No differences in response, toxicity, or second malignancies emerged in the two groups.

CONCLUSION: The use of an intensified regimen failed to show a significant improvement in tumor response and outcome of patients with localized HR-RMS, EES, and UDS.

PMID:35441463 | DOI:10.1002/pbc.29691

Orthop Surg. 2022 Apr 19. doi: 10.1111/os.13237. Online ahead of print.

ABSTRACT

OBJECTIVE: To compare the clinical efficacy of posterior percutaneous endoscopic unilateral laminotomy (PPEUL) and anterior cervical decompression and fusion (ACDF) in the treatment of single-segment spondylotic myelopathy (CSM).

METHODS: This is a retrospective research, from January 2017 to December 2019, 30 cases were included in the PPEUL group and 32 cases were included in the ACDF group. The operative duration, blood loss, length of stay, complications, Japanese Orthopaedic Association (JOA) score, visual analogue scale (VAS) score, MacNab classification and imaging data were collected preoperatively, postoperative 1-week, final follow-up and statistically analyzed.

RESULTS: The surgery was completed successfully on all patients, and there were no serious complications, such as nerve or spinal cord injury or infection. In the PPEUL and ACDF groups, the operative duration were 56.63 ± 1.40 and 65.21 ± 2.45 min, the intraoperative blood loss were 51.69 ± 3.23 and 50.51 ± 5.48 mL, and the hospitalization duration was 5.75 ± 1.43 and 6.38 ± 2.16 days. The follow-up period in the PPEUL and ACDF groups was 24.96 ± 1.12 months and 25.65 ± 1.45 months, respectively. There was no significant difference in intraoperative blood loss between the two groups, but the hospitalization and operative durations in the PPEUL group were significantly shorter than those in the ACDF group (P < 0.05). The VAS scores at postoperative 1 week and final follow-up were significantly improved compared with those before surgery. The JOA scores at postoperative 1 week and final follow-up were significantly improved compared with those before surgery, but there was no significant difference between the two groups at the last follow-up. The intervertebral disc height of the adjacent segment at the last follow-up was significantly lower in the ACDF group than in the PPEUL group (P < 0.05), but there was no significant difference between the two groups in the intervertebral disc height of the surgical segment (P > 0.05). The rate of excellent and good results was 90.0% and 87.5%, respectively. Postoperative cervical CT and MRI showed that the spinal canal was fully decompressed and spinal cord compression was relieved.

CONCLUSION: PPEUL has the advantages of reduced trauma, rapid recovery and remarkable curative efficacy, so it is a new choice for the treatment of CSM.

PMID:35441460 | DOI:10.1111/os.13237

Ecol Appl. 2022 Apr 19:e2638. doi: 10.1002/eap.2638. Online ahead of print.

ABSTRACT

Information about how animal abundance varies across landscapes is needed to inform management action but is costly and time-consuming to obtain; surveys of a single population distributed over a large area can take years to complete. Surveys employing small, spatially replicated sampling units improve efficiency, but statistical estimators rely on assumptions that constrain survey design or become less reasonable as larger areas are sampled. Efficient methods that avoid assumptions about similarity of detectability or density among replicates are therefore appealing. Using simulations and data from >3500 black bears sampled on 73 independent study areas in Ontario, Canada, we (1) quantified bias induced by unmodelled spatial heterogeneity in detectability and density, (2) evaluated novel, design-based estimators of average density across replicate study areas, and (3) evaluated two estimators of the variance of average density across study areas: an analytic estimator that assumed an underlying homogeneous spatial Poisson point process for the distribution of animals’ activity centers, and an empirical estimator of variance across study areas. In simulations where detectability varied in space, assuming spatially constant detectability yielded density estimates that were negatively biased by 20 to 30%; estimating local detectability and density from local data and treating study areas as independent, equal replicates when estimating average density across study areas using the design-based estimator yielded unbiased estimates at local and landscape scales. Similarly, detectability of black bears varied among study areas and estimates of bear density at landscape scales were higher when no information was shared across study areas when estimating detectability. This approach also maximized precision (relative standard errors of estimates of average black bear density ranged from 7 to 18%) and computational efficiency. In simulations, the analytic variance estimator was robust to threefold variation in local densities but the empirical estimator performed poorly. Conducting multiple, similar SECR surveys and treating them as independent replicates during analyses allowed us to efficiently estimate density at multiple scales and extents while avoiding biases caused by pooling spatially heterogeneous data. This approach enables researchers to address a wide range of ecological or management-related questions and is applicable with most types of SECR data.

PMID:35441452 | DOI:10.1002/eap.2638

Int J Exp Pathol. 2022 Apr 20. doi: 10.1111/iep.12441. Online ahead of print.

ABSTRACT

Wound healing is a dynamic process initiated in response to injury. There are many factors that have detrimental effects on the wound healing process. Numerous studies have been conducted for improving wound healing processes. Dexpanthenol is widely used to accelerate wound healing. Sucralfate is used for the treatment of peptic ulcers. We aimed to compare the efficacy of topical Dexpanthenol and Sucralfate in an experimental wound model in rats via histopathological examinations and immune histochemical determinations, as well, to evaluate their effects on EGF levels. Three different groups were formed: the Control Group, the Dexpanthenol Group and the Sucralfate Group. Full-thickness skin wounds were created on the back of each rat and isotonic saline was applied to the wounds of the rats in the control group, Bepanthol^® cream was applied in Dexpanthenol Group and 10% Sucralfate cream was applied in Sucralfate Group, once a day. On the 7th, 14th and 21st days the wounds were measured and seven rats from each group were sacrificed and the wounds were excised for histopathological examination. Sucralfate increased wound healing rates by increasing neovascularization, fibroblast activation, reepithelialization and collagen density, as well as dexpanthenol. Our study revealed that the dexpanthenol and sucralfate groups were better than the control group in terms of their effects on wound healing, however there was no statistically significant difference among these two groups. Sucralfate improves EGF expression in skin wounds and has positive results on skin wound healing comparable to dexpanthenol.

PMID:35441448 | DOI:10.1111/iep.12441

J Eval Clin Pract. 2022 Apr 19. doi: 10.1111/jep.13687. Online ahead of print.

ABSTRACT

RATIONALE, AIMS AND OBJECTIVES: Clinical practice guidelines (CPGs) have been evaluated for reporting transparency and methodological quality in a number of studies in various disciplines, but few studies have focused on critical care and none on pharmacotherapy-related guidelines specifically. The objective of this study was to evaluate the quality of critical care CPGs with a focus on pharmacotherapy using the Appraisal of Guidelines, Research and Evaluation (AGREE) II instrument.

METHOD: A cross-sectional study of CPGs published from 2013 through August 2021 was conducted. Following establishment of interrater reliability, guidelines were independently evaluated by three reviewers to rate guidelines on criteria set forth by the AGREE II instrument. Domain scores and item scores were calculated using the AGREE II user manual, and results described with descriptive statistics.

RESULTS: Out of 192 guidelines identified, 73 met inclusion criteria and were screened using the AGREE II instrument. Most guidelines were authored by a professional organization or government agency. Domain quality scores were calculated for each domain as recommended by the AGREE II instrument. Domain 4 (clarity of presentation) had the highest AGREE II domain score with a median score of 87.0% (interquartile range: 79.6%-92.6%). Domain 5 (applicability) received the lowest domain score with a mean score of 41.8 ± 21.1%. The majority of guidelines were recommended for use as published or with modifications, while only six guidelines (8.2%) were not recommended for use.

CONCLUSIONS: The majority of critical care guidelines that include pharmacotherapy recommendations were recommended for use by study authors when the AGREE II instrument was applied. While guidelines generally scored highly in clarity of presentation, additional time and effort should focus on providing solutions to guideline implementation and inclusion of patient preferences.

PMID:35441442 | DOI:10.1111/jep.13687

Glob Chang Biol. 2022 Apr 20. doi: 10.1111/gcb.16187. Online ahead of print.

ABSTRACT

Identifying climate refugia is key to effective biodiversity conservation under a changing climate, especially for mountain-specialist species adapted to cold conditions and highly threatened by climate warming. We combined species distribution models (SDMs) with climate forecasts to identify climate refugia for high-elevation bird species (Lagopus muta, Anthus spinoletta, Prunella collaris, Montifringilla nivalis) in the European Alps, where the ecological effects of climate changes are particularly evident and predicted to intensify. We considered future (2041-2070) conditions (SSP585 scenario, four climate models) and identified three types of refugia: (1) in-situ refugia potentially suitable under both current and future climate conditions, ex-situ refugia suitable (2) only in the future according to all future conditions, or (3) under at least three out of four future conditions. SDMs were based on a very large, high-resolution occurrence dataset (2901-12,601 independent records for each species) collected by citizen scientists. SDMs were fitted using different algorithms, balancing statistical accuracy, ecological realism and predictive/extrapolation ability. We selected the most reliable ones based on consistency between training and testing data and extrapolation over distant areas. Future predictions revealed that all species (with the partial exception of A. spinoletta) will undergo a range contraction towards higher elevations, losing 17%-59% of their current range (larger losses in L. muta). We identified ~15,000 km² of the Alpine region as in-situ refugia for at least three species, of which 44% are currently designated as protected areas (PAs; 18%-66% among countries). Our findings highlight the usefulness of spatially accurate data collected by citizen scientists, and the importance of model testing by extrapolating over independent areas. Climate refugia, which are only partly included within the current PAs system, should be priority sites for the conservation of Alpine high-elevation species and habitats, where habitat degradation/alteration by human activities should be prevented to ensure future suitability for alpine species.

PMID:35441422 | DOI:10.1111/gcb.16187

Trop Med Int Health. 2022 Apr 19. doi: 10.1111/tmi.13754. Online ahead of print.

ABSTRACT

OBJECTIVE: To describe the urological outcomes in children with congenital Zika syndrome (CZS) and investigate the relationship between clinical and urological findings in this population.

METHODS: This cross-sectional study involved children with CZS followed up by a referral center for children with microcephaly in the state of Paraiba in northeast Brazil. Urological evaluation included clinical history, urine culture results, ultrasonography of the urinary tract, and urodynamic evaluation, following the protocol proposed by Costa Monteiro et al. (2017). Descriptive statistical analysis was performed in addition to association and correlation tests, considering clinical and urodynamic variables.

RESULTS: Among the 88 children with CZS (35.5±5.5 months), 97.7% had microcephaly and 51% presented urinary tract infection (UTI) confirmed with clinical history and lab tests. The number of confirmed UTI episodes varied from one to 14 per child. Urodynamic evaluation confirmed the presence of an overactive bladder in 78 children and incomplete voiding in 50. Urodynamic findings were associated with the number of confirmed UTI episodes, child’s sex, and actual weight, in addition to the use of anticonvulsant and myorelaxant drugs.

CONCLUSIONS: UTIs were confirmed in most children. Other urological outcomes observed were overactive bladder and low bladder capacity, which were associated with the number of confirmed UTI episodes, use of anticonvulsants and myorelaxants, and the child’s sex and weight. These are treatable conditions, and it is paramount that pediatricians, neonatologists, and infection disease specialists are aware of them to make clinical decisions and help reduce the risk of renal damage and other morbidities.

PMID:35441418 | DOI:10.1111/tmi.13754

Suicide Life Threat Behav. 2022 Apr 20. doi: 10.1111/sltb.12870. Online ahead of print.

ABSTRACT

INTRODUCTION: Suicidal ideation (SI) has numerous limitations in predicting suicidal behavior. The Suicide Crisis Syndrome (SCS) is proposed as an alternative method of detecting risk. This study compares the relative utility of SI and SCS in statistically predicting SI and behaviors at one-month follow-up.

METHODS: 382 psychiatric patients (98 inpatients, 284 outpatients) completed baseline measures and provided information about suicide-related outcomes one month later. Participants were grouped based on responses to measures assessing SCS and SI.

RESULTS: Rates of follow-up suicidal behavior were significantly higher among those reporting both SCS and SI (22.2%) than those reporting SI alone (6.0%) or neither SCS nor SI (0.9%). SCS alone (8.3%) had descriptively, but not statistically, higher rates of suicidal behavior than those with neither SCS nor SI, and did not differ from SI alone and the combination of SCS and SI. Those reporting SI-with and without SCS-had higher levels of follow-up suicidal thoughts than those without SI.

CONCLUSION: The SCS was equivalent to SI, and incrementally informative alongside SI, in detecting individuals at risk of future suicidal behavior, whereas SI was more strongly related to future SI than SCS. The combination of SCS and SI may be clinically useful in detecting individuals who are at risk for suicide.

PMID:35441411 | DOI:10.1111/sltb.12870

Ultrasound Obstet Gynecol. 2022 Apr 20. doi: 10.1002/uog.24916. Online ahead of print.

ABSTRACT

OBJECTIVES: Currently, there is little evidence related to the effects of the Omicron variant on pregnancy outcomes, particularly in unvaccinated women. This study aims to compare pregnancy outcomes of SARS-CoV-2 infected, unvaccinated women during the pre-Delta, Delta, and Omicron waves.

METHODS: This was a retrospective cohort study at two tertiary care facilities: Sancaktepe Training and Research Hospital, Istanbul, Turkey, and St. George’s University Hospitals NHS Foundation Trust, London, UK. Included were people testing RT-PCR positive for SARS-CoV-2 during pregnancy, between April 01, 2020 and February 14, 2022, and divided into three epochs: (i) pre-Delta, 1 Apr 2020 to 8 Jun 2021 in Turkey, and 1 Apr 2020 to 31 Jul 2021 in the UK; (ii) Delta, 9 Jun 2021 to 27 Dec 2021 in Turkey, and 1 Aug 2021 to 27 Dec 2021 in the UK; and (iii) Omicron, after 27 Dec 2021 in each of Turkey and the UK, according to the date of their positive RT-PCR test. Baseline data collected included maternal age, parity, body mass index (BMI), smoking status, gestational age at diagnosis, and comorbidities. The primary outcome was the need for oxygen supplementation, classified as oxygen support via nasal cannula or breather mask, non-invasive mechanical ventilation with continuous positive airway pressure (CPAP) or high-flow oxygen, mechanical ventilation with intubation, or extracorporeal membrane oxygenation (ECMO). Inferences were made after balancing of confounders, using an evolutionary search algorithm.

RESULTS: 1285 RT-PCR-proven SARS-CoV-2 infections of unvaccinated pregnant women were identified during the pre-Delta (N=870), Delta (N=339), and Omicron (N=77) epochs. In the confounder-balanced cohort, infection during the Delta wave was associated with increased need for nasal oxygen support (RR 2.53, 95% confidence interval [CI] 1.75-3.65, P<.001), CPAP or high-flow oxygen (RR 2.50, 95% CI 1.37-4.56, P=.002), mechanical ventilation (RR 4.20, 95% CI 1.60-11.0, P=.003), and ECMO (RR 11.0, 95% CI 1.43-84.7, P=.021). The maternal mortality rate was also 3-4 fold higher during the Delta wave compared to pre-Delta (5.3% vs 1.5%, P=0.010). An infection during the Omicron wave was not associated with an increased need for nasal oxygen support (RR 0.62, 95% CI 0.25-1.55, P=0.251), CPAP or high-flow oxygen (RR 1.07, 95% CI 0.36-3.12, P=0.906), or mechanical ventilation (RR 0.44, 95% CI 0.06-3.45, P=0.438). The maternal mortality rate was similar during the Omicron wave and the pre-Delta period (1.3% vs 1.3%, P=0.999). Nasal oxygen support during the Omicron wave was significantly lower compared to Delta-wave infection (RR 0.26, 95% CI 0.11-0.64, P=0.003). Perinatal outcomes were available for a subset of the confounder-balanced cohort. Preterm birth below 34 weeks’ gestation was significantly increased (P<0.001) during the Delta wave compared with pre-Delta.

CONCLUSIONS: Among unvaccinated pregnant women, SARS-CoV-2 infection during (vs. before) the Delta wave was associated with increased requirement for oxygen support (including ECMO) and higher maternal mortality. Disease severity and pregnancy complications were similar during the Omicron wave (vs. pre-Delta). SARS-CoV-2 infection in unvaccinated pregnant women carries considerable risks of morbidity and mortality, and COVID-19 vaccination remains key. Miscommunication of risks of Omicron infection may adversely impact the vaccination rate among pregnant women, who are already at increased risk of complications related to COVID-19. This article is protected by copyright. All rights reserved.

PMID:35441407 | DOI:10.1002/uog.24916