bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and Safety of Cilostazol for Atherosclerosis: A Meta-analysis of Randomized Controlled Trials
Authors: Wan Hongbing , Huang Tieqiu , Yang Pingping , Wu Tao , Zhang Hongzhou , Wu Qinghua
Published: December 2021

To investigate the efficacy and safety of cilostazol for atherosclerosis. PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to May 29, 2021, were searched for randomized clinical trials (RCTs). Ten trials with 1577 patients were included. Treatment with cilostazol significantly reduced carotid intima–media thickness [mean difference (MD), −0.12 mm; 95% confidence interval (CI), −0.17 to −0.06]. According to the difference in intervening measures, the cilostazol group was superior to the control group in inhibiting the progression of carotid intima–media thickness: cilostazol versus placebo (MD, −0.04 mm; 95% CI, −0.06 to −0.02; P < 0.00001), cilostazol versus no antiplatelet drug (MD, −0.14 mm; 95% CI, −0.26 to −0.03; P = 0.02), cilostazol versus aspirin (MD, −0.17 mm; 95% CI, −0.32 to −0.02; P = 0.02), cilostazol + aspirin versus aspirin (MD, −0.08 mm; 95% CI, −0.14 to −0.02; P = 0.007), cilostazol + aspirin versus clopidogrel + aspirin (MD, −0.07 mm; 95% CI, −0.14 to −0.00; P = 0.04), and cilostazol + clopidogrel + aspirin versus clopidogrel + aspirin (MD, −0.16 mm; 95% CI, −0.30 to −0.02; P = 0.03). Cilostazol treatment considerably decreased triglyceride (MD, −20.18 mg/dL; 95% CI, −39.03 to −1.34) and improved high-density lipoprotein cholesterol (MD, 4.35 mg/dL; 95% CI, 2.61–6.10). Cilostazol therapy significantly increased the risk of adverse events of headache (odds ratio, 12.91; 95% CI 5.33–31.29). Our research has revealed that cilostazol has potent antiatherosclerotic effects and can reverse atherosclerosis progress even in high-risk patients, such as those with type 2 diabetes mellitus, and does not increase the risk of bleeding.
Understanding the Pharmacokinetics of Antibiotics in Pregnancy: Is There a Role for Therapeutic Drug Monitoring? A Narrative Review
Authors: Stojanova Jana , Arancibia Marcelo , Ghimire Samiksha , Sandaradura Indy
Published: December 2021

Purpose:

Antibiotics are commonly used during pregnancy. However, physiological changes during pregnancy can affect the pharmacokinetics of drugs, including antibiotics, used during this period. Pharmacokinetic evaluations have shed light on how antibiotics are affected during pregnancy and have influenced dosing recommendations in this context.

Methods:

A narrative review was conducted and included reports providing data reflecting drug distribution and exposure in the context of pregnancy.

Results:

Pharmacokinetic parameters of antibiotics in pregnancy and transplacental passage of antibiotics are comprehensively presented.

Conclusions:

Knowledge about the impact on pharmacokinetics and fetal exposure is especially helpful for complicated or severe infections, including intra-amniotic infection and sepsis in pregnancy, where both mother and fetus are at risk. Further studies are warranted to consolidate the role of therapeutic drug monitoring in complicated or severe infections in pregnant patients.
Factors Influencing Turnover Intention Among Operating Room Nurses in South Korea
Authors: GU Minkyung , KIM Yeong Seung , SOK Sohyune
Published: December 2021

Background

Operating room nurses experience verbal abuse, high levels of job stress, and burnout that may increase turnover intention.

Purpose

This study was designed to investigate and identify factors influencing turnover intention among operating room nurses in South Korea.

Methods

This study used a cross-sectional descriptive design. The sample included 193 nurses, all of whom had over 3 months of work experience at operating rooms in hospitals in Seoul, South Korea. Measures used included the Verbal Abuse Experience Scale, Job Stress Scale, Burnout Scale, and Turnover Intention Scale.

Results

Burnout was found to have the greatest influence on turnover intention (β = .34, p < .001), followed by verbal abuse (β = −.23, p = .004), job stress (β = .22, p = .001), age (β = −20, p = .032), and job satisfaction (β = −.14, p = .020).

Conclusions/Implications for Practice

The findings support burnout and verbal abuse, respectively, as the most significant and second most significant predictors of turnover intention among operating room nurses in South Korea. These factors should be proactively and effectively addressed to reduce turnover intention in this important group of healthcare professionals.
Building the Science to Guide Nursing Administration and Leadership Decision Making
Authors: Joseph M. Lindell , Nelson-Brantley Heather V. , Caramanica Laura , Lyman Bret , Frank Betsy , Hand Mikel W. , Parchment Joy , Ward Danielle M. , Weatherford Barbara , Chipps Esther
Published: December 2021

OBJECTIVE

The aim of this study was to identify the challenges, barriers, and solutions for conducting nursing administration and leadership science (NALS) research.

BACKGROUND

Evidence from leadership science should be at the forefront of nurse leaders' decision making. Yet, challenges remain in building the evidence and moving it into nursing administration and leadership practice.

METHODS

This study used a Delphi technique with open-ended questions and direct content analysis to evaluate survey responses of members of the Association for Leadership Science in Nursing and American Organization for Nursing Leadership.

RESULTS

Open-ended responses were coded to yield super categories and supportive codes for areas with limited evidence to guide leadership practice and the challenges for conducting NALS research.

CONCLUSIONS

These findings provide future directions for continuously driving NALS research and for building and leveraging leadership science to support nursing administration decision making.
A Survey of Interim Nurse Managers to Understand the Role and the Impact on Nurse and Patient Outcomes
Authors: Galura Sandra , Warshawsky Nora , Hu Wenfang , Utt Leah
Published: December 2021

OBJECTIVE

The aim of this study was to describe the current state of the interim manager (IM) role and the impact of the role on job performance.

BACKGROUND

Interim managers provide leadership during organizational change, yet little is known about the role and its impact on outcomes.

METHODS

An electronic survey was completed by 179 IMs working in acute care hospitals. Instruments included the Nurse Manager Practice Environment Scale, Decision Involvement Scale, Subjective Stress Scale, Maslach Burnout Inventory, and Brief Resilience Scale.

RESULTS

The average tenure for IMs was 10 months. Despite moderately high levels of stress and exhaustion, IMs were resilient, positively viewed their work environment, and perceived their job performance as positively impacting nurse and patient outcomes. Interim managers were generally satisfied in their roles and likely to pursue nursing leadership as a career.

CONCLUSION

Interim managers desire permanent leadership opportunities providing a pool for replacing exiting nurse managers. Support is needed to be successful.
Normative Data for Parameters of Accommodation in African Schoolchildren
Authors: Darko-Takyi Charles , Moodley Vanessa R. , Boadi-Kusi Samuel B.
Published: December 2021

SIGNIFICANCE

The reported interracial differences in normative data for parameters of accommodation call for investigating population-specific normative values. The study investigated and presents expected data for accommodative parameters among Ghanaian children.

PURPOSE

This study aimed to determine expected values for parameters of accommodation among schoolchildren in the Central Region of Ghana.

METHODS

This prospective cross-sectional study used a multistage cluster sampling approach. Normal participants were asymptomatic (Convergence Insufficiency Symptom Survey score ˂16), with unaided visual acuity or best-corrected visual acuity of 0.0 or better logMAR for each eye and having no ocular disease or no manifest strabismus. Normal participants underwent push-up and minus-lens-to-blur amplitude of accommodation tests, accuracy of accommodative response (using the monocular estimation method), and monocular and binocular accommodative facility testing.

RESULTS

A total of 1261 normal participants within ages 11 to 17 years (mean, 14.75 ± 1.53 years) met the inclusion criteria. The mean normative data for the population include push-up amplitude of accommodation (14.04 ± 2.95 D), minus-lens-to-blur amplitude of accommodation (12.33 ± 2.55 D), and accuracy of accommodative response using the monocular estimation method (0.62 ± 0.22 D), monocular accommodative facility (9.80 ± 3.20 cycles per minute), and binocular accommodative facility (9.40 ± 3.30 cycles per minute). Age-predicted linear regression equations for the amplitude of accommodation are push-up amplitude of accommodation (16.74 − 0.18 × age in years) and minus-lens-to-blur amplitude of accommodation (15.7 − 0.23 × age in years).

CONCLUSIONS

The study provides normative data for accommodative parameters that clinicians may use with Ghanaian populations of similar ages.
Automatic Screening for Ocular Anomalies Using Fundus Photographs
Authors: Matta Sarah , Lamard Mathieu , Conze Pierre-Henri , Le Guilcher Alexandre , Ricquebourg Vincent , Benyoussef Anas-Alexis , Massin Pascale , Rottier Jean-Bernard , Cochener Béatrice , Quellec Gwenolé
Published: December 2021

SIGNIFICANCE

Screening for ocular anomalies using fundus photography is key to prevent vision impairment and blindness. With the growing and aging population, automated algorithms that can triage fundus photographs and provide instant referral decisions are relevant to scale-up screening and face the shortage of ophthalmic expertise.

PURPOSE

This study aimed to develop a deep learning algorithm that detects any ocular anomaly in fundus photographs and to evaluate this algorithm for “normal versus anomalous” eye examination classification in the diabetic and general populations.

METHODS

The deep learning algorithm was developed and evaluated in two populations: the diabetic and general populations. Our patient cohorts consist of 37,129 diabetic patients from the OPHDIAT diabetic retinopathy screening network in Paris, France, and 7356 general patients from the OphtaMaine private screening network, in Le Mans, France. Each data set was divided into a development subset and a test subset of more than 4000 examinations each. For ophthalmologist/algorithm comparison, a subset of 2014 examinations from the OphtaMaine test subset was labeled by a second ophthalmologist. First, the algorithm was trained on the OPHDIAT development subset. Then, it was fine-tuned on the OphtaMaine development subset.

RESULTS

On the OPHDIAT test subset, the area under the receiver operating characteristic curve for normal versus anomalous classification was 0.9592. On the OphtaMaine test subset, the area under the receiver operating characteristic curve was 0.8347 before fine-tuning and 0.9108 after fine-tuning. On the ophthalmologist/algorithm comparison subset, the second ophthalmologist achieved a specificity of 0.8648 and a sensitivity of 0.6682. For the same specificity, the fine-tuned algorithm achieved a sensitivity of 0.8248.

CONCLUSIONS

The proposed algorithm compares favorably with human performance for normal versus anomalous eye examination classification using fundus photography. Artificial intelligence, which previously targeted a few retinal pathologies, can be used to screen for ocular anomalies comprehensively.
Analysis of Optical Coherence Tomography in Acute versus Chronic Central Serous Chorioretinopathy
Authors: Li Yanzhen , Jin Pengfei , Lu Jianmin , Ma Li , Qin Xiuhong
Published: December 2021

SIGNIFICANCE

Central serous chorioretinopathy (CSC) is a common retinal disease that causes vision loss worldwide. Studying the imaging characteristics of CSC is helpful for the differential diagnosis of diseases. This study analyzed the differences between acute and chronic CSC and provide related information.

PURPOSE

The aim of this study was to describe the optical coherence tomography features in patients with acute and chronic CSC.

METHODS

Sixty-two eyes of 56 patients with CSC were included in the study. Optical coherence tomography was performed to observe the image features. The photoreceptor outer-segment (PROS) thickness above the pigment epithelium detachment (PED) coinciding with the leakage point in fundus fluorescein angiography was measured and compared with the mean PROS thickness outside the PED in acute cases. The SPSS 23.0 software (IBM Co., Chicago, IL) was used for statistical analysis.

RESULTS

Of our 56 patients (62 eyes), 41 (73.21%) were male and 15 (26.79%) were female. There were 53 eyes (85.48%) with acute CSC and 9 eyes (14.52%) with chronic CSC. Besides other common features, the new feature of a high-reflection band in the outer nuclear layer was found to be limited to the macular detachment area. In acute cases, the mean PROS thickness above the retinal pigment epithelium layer protuberance coinciding with the leakage point was 22.7 ± 8.8 μm, which was less than the mean PROS thickness outside the PED at 64.3 ± 21.3 μm (P ≤ .001).

CONCLUSIONS

The high-reflection band in the outer nuclear layer within the serous neurosensory detachment limited to the macular area was a new finding in CSC patients. This finding can be used as an imaging feature to aid in the diagnosis of CSC.
Estimations of the Passing Height of Approaching Objects
Authors: Sander Jacob , Fogt Nick
Published: December 2021

SIGNIFICANCE

Limited optical cues associated with ball flight were inadequate to estimate the vertical passing distance of approaching balls. These results suggest that these optical cues either must be integrated with contextual and kinematic cues or must be of larger amplitude to contribute to estimates of vertical passing distance.

PURPOSE

To intercept or avoid approaching objects, individuals must estimate both when and where the object will arrive. The purpose of this experiment was to determine whether individuals could estimate the vertical passing height of a ball approaching at different linear speeds when vertical angular retinal image velocity and cues for time to contact were minimized.

METHODS

Twenty participants stood 40 feet from a pitching machine that projected tennis balls toward observers at six random speeds from 56 to 80 mph. The flight of the balls was stopped after 9 feet. The actual passing height ranged from about 35 (lowest speed) to 136 cm (highest speed). Observers indicated the height at which they expected the balls to arrive. Overall, the height estimates increased as ball speed increased (means, 121 ± 13 cm [lowest speed] and 131 ± 10 cm [highest speed]). However, only at the higher speeds were the absolute height estimates close to the actual height of the ball. At the higher ball speeds, estimates for participants with some experience in baseball or softball were more accurate (86.4% correct at the highest speed) than estimates for participants with no experience.

CONCLUSIONS

Overall, estimates of vertical passing distance were inaccurate particularly at the lower speeds. Underestimates of vertical drop at lower speeds may have resulted from overestimates of ball speeds. At short exposure durations, optical cues associated with ball flight were inadequate for predictions of vertical passing distance at all speeds for the no-experience group and at lower speeds for the experienced group.
Case Report: Multimodal Imaging Features of an ABCA4 Cone Dystrophy
Authors: Monferrer-Adsuara Clara , Montero-Hernández Javier , Castro-Navarro Verónica , Remolí-Sargues Lidia , Cervera-Taulet Enrique
Published: December 2021

SIGNIFICANCE

Cone dystrophies and cone-rod dystrophies are a group of rare inherited pathologies characterized by degeneration of cone photoreceptors and subsequent rod involvement. The identification of causative genes is essential for diagnosis, and advanced imaging is acquiring great value in the characterization of the different phenotypic expressions.

PURPOSE

We describe genotype-phenotype associations of an autosomal recessive ABCA4-associated cone dystrophy using multimodal imaging.

CASE REPORT

A 34-year-old woman presented with progressive visual acuity decay. Visual acuity was 20/32 for her right eye and 20/25 for her left eye. A central scotoma was detected on a 10-2 Humphrey visual field in both eyes. Funduscopy revealed perifoveal retinal pigment epithelial changes, and fundus autofluorescence using blue excitation light showed decreased autofluorescence in the central fovea of both eyes with surrounding annular ring of increased autofluorescence in the perifoveal zone; green excitation light fundus autofluorescence was more accurate in the characterization of the size, perimeter, and circularity of central hypofluorescent lesions. Optical coherence tomography revealed an incomplete focal cavitation in both foveas, and optical coherence tomography angiography images showed a reduction in the superficial and deep capillary plexus density, an increased foveal avascular area, and subtle voids in choriocapillaris blood flow. Electroretinography was consistent with cone dystrophy, and molecular testing revealed the alteration of the ABCA4 gene.

CONCLUSIONS

The identification of an incomplete focal cavitation could alert the clinician to consider early ABCA4 central cone dystrophy. The patient in this case also exhibited reduced vessel density in the foveal area. Both of these characteristics could be important features related to the underlying genetic mutation.
Individual Differences and Transfer of Visual Anticipation in Expert Female Field Hockey Goalkeepers
Authors: Morris-Binelli Khaya , Müller Sean , van Rens Fleur E. C. A. , Harbaugh Allen G. , Rosalie Simon M.
Published: December 2021

SIGNIFICANCE

Visual anticipation is vital for performance in several domains such as driving, military, and high-speed interceptive sports, as it enables performers to handle severe time constraints. There has been little investigation into individual differences of anticipation skill transfer within a domain, which can guide training of anticipation to improve performance.

PURPOSE

The purpose of this study was to investigate individual differences in the transfer of anticipation within a domain, specifically anticipation of the field hockey penalty corner drag-flick across different opponents.

METHODS

Eight female Australian international and national field hockey goalkeepers participated. Goalkeepers completed female and male opponent penalty corner drag-flick temporal occlusion tests that presented contextual defensive runner positioning relative to the penalty spot, drag-flicker kinematics, and ball flight.

RESULTS

Drag-flick movement time and ball velocity were significantly different across female and male opponents confirming that a transfer continuum existed. Five goalkeepers could transfer integration of runner contextual and drag-flicker kinematic information to anticipate loose runs above chance from female to male opponent tests. None of the goalkeepers could transfer integration of contextual and kinematic information for the tight runs across female to male opponents.

CONCLUSIONS

An individual differences approach with truly expert performers provided unique insights into the mechanism of anticipation transfer within a domain. The findings of this study contribute to theoretical and applied knowledge, which can guide the training of anticipation skill to prepare individuals for superior performance.
Topical Review: Studies of Ocular Function and Disease Using Hyperspectral Imaging
Authors: Beach James M. , Rizvi Madeeha , Lichtenfels Caitlin B. , Vince Robert , More Swati S.
Published: December 2021

SIGNIFICANCE

Advances in imaging technology over the last two decades have produced significant innovations in medical imaging. Hyperspectral imaging (HSI) is one of these innovations, enabling powerful new imaging tools for clinical use and greater understanding of tissue optical properties and mechanisms underlying eye disease.

Hyperspectral imaging is an important and rapidly growing area in medical imaging, making possible the concurrent collection of spectroscopic and spatial information that is usually obtained from separate optical recordings. In this review, we describe several mainstream techniques used in HSI, along with noteworthy advances in optical technology that enabled modern HSI techniques. Presented also are recent applications of HSI for basic and applied eye research, which include a novel method for assessing dry eye syndrome, clinical slit-lamp examination of corneal injury, measurement of blood oxygen saturation in retinal disease, molecular changes in macular degeneration, and detection of early stages of Alzheimer disease. The review also highlights work resulting from integration of HSI with other imaging tools such as optical coherence tomography and autofluorescence microscopy and discusses the adaptation of HSI for clinical work where eye motion is present. Here, we present the background and main findings from each of these reports along with specific references for additional details.
The Impact of Axial Eye Growth on Foveal Avascular Zone Measurements in Children
Authors: Linderman Rachel E. , Heffernan Elizabeth , Ferrante Samantha , Bachman Groth Jane , Carroll Joseph
Published: December 2021

SIGNIFICANCE

Foveal avascular zone (FAZ) area is a frequently used biomarker in diseases impacting the retinal vasculature in pediatric populations. Variation in axial length between individuals results in differences in lateral image scale, which affect the accuracy of FAZ area measurements. Accordingly, changes in axial length over time within individual children would affect estimates of FAZ area change.

PURPOSE

This study aimed to quantify how changes in axial length over time affect estimates of FAZ area change using optical coherence tomography angiography (OCT-A) images.

METHODS

Twenty pediatric participants (<18 years old) and 40 adult participants were imaged on Optovue's Avanti system (Fremont, CA) and had axial length measurements acquired at two time points. The FAZ was segmented twice using the OCT-A image at each time point. Foveal avascular zone area was estimated at both time points using the assumed/fixed axial length of the OCT-A device (unscaled) and using the participant's axial length (scaled). Changes in FAZ area over time were compared between the pediatric and adult groups using both unscaled and scaled data.

RESULTS

The average ± standard deviation follow-up time was 3.35 ± 1.66 years for the pediatric group and 2.90 ± 1.65 years for the adult group. Using unscaled data, FAZ area seemed to decrease between visits in the pediatric group (P = .004), whereas the FAZ area increased between visits in the adult group (P = .003). When correctly scaled data were used, the FAZ area still increased between visits for the adult group (P < .001), although the FAZ area no longer showed a significant change between visits for the pediatric group (P = .37). When comparing the normalized FAZ area change across visits between unscaled and scaled data, a significant difference was found between the adult and pediatric groups (P < .001).

CONCLUSIONS

Scaled data should be used when measuring FAZ area in pediatric populations, especially in longitudinal studies.
Design of a segmented custom ankle foot orthosis with custom-made metal strut and 3D-printed footplate and calf shell
Authors: Funes-Lora Miguel A. , Posh Ryan , Wensman Jeffrey , Shih Albert J.
Published: December 2021

Background:

3D-printing is a potential manufacturing process for optimizing the design and manufacture of ankle foot orthosis (AFOs). The feasibility of an AFO with interchangeable strut that is suitable for 3D-printing is created and evaluated.

Objective:

A segmented AFO with 3D-printed custom footplate and calf shell connected by a custom-made strut is studied.

Study design:

The duration of a healthy subject wearing the 3D-printed segmented AFO in daily activities is used to evaluate the feasibility and durability to integrate 3D-printed AFOs into orthotics practice.

Technique:

The 3D-scanning of a patient's leg is first conducted. The scanned 3D surface is modified by creating the clearance around bony prominences and trimlines for the footplate and calf shell. The footplate has a custom-shaped inside to match with the foot and a standard shape outside at the top to match and connect with the strut. For the calf shell, the inside shape is custom fit with the shank and the outside shape is standard to connect with the strut. Material extrusion is the 3D-printing process selected. Tree-like support structures are used to avoid the use of soluble support material and to eliminate the risk of residual chemical solvent in the orthosis.

Results:

The segmented AFO with material extrusion footplate and calf shell was tested in a healthy subject with an active lifestyle, offering comfort, and stability for over 4 months without breakage.

Conclusions:

This segmented AFO is durable, requires short 3D-printing time, and enables the quick adjustment of bending stiffness via an interchangeable strut design.
Increased reengagement of out-of-care HIV patients using Lost & Found, a clinic-based intervention
Authors: Linthwaite Blake , Kronfli Nadine , Marbaniang Ivan , Ruppenthal Luciana , Lessard David , Engler Kim , Lebouché Bertrand , Cox Joseph
Published: December 2021

Background:

Negative health outcomes associated with being out of HIV care (OOC) warrant reengagement strategies. We aimed to assess effectiveness of Lost & Found, a clinic-based intervention to identify and reengage OOC patients.

Methods:

Developed and delivered using implementation science, Lost & Found consists of two core elements: identification, operationalized through nurse validation of a real-time list of possible OOC patients; and contact, via nurse-led phone calls. It was implemented over a 12-month period (2018–2019) at the Chronic Viral Illness Service, McGill University Health Centre (CVIS-MUHC) during a type-II implementation-effectiveness hybrid pilot study. Descriptive outcomes of interest were identification as possibly OOC, OOC confirmation, contact, and successful reengagement. We present results from a pre-post analysis comparing overall reengagement to the year prior, using robust Poisson regression controlled for sex, age, and Canadian birth. Time to reengagement is reported using a Cox proportional hazards model.

Results:

Over half (56%; 1312 of 2354) of CVIS-MUHC patients were identified as possibly OOC. Among these, 44% (n = 578) were followed elsewhere, 19% (n = 249) engaged in care, 3% (n = 33) deceased, 2% (n = 29) otherwise not followed, and 32% (n = 423) OOC. Of OOC patients contacted (85%; 359/423), 250 (70%) reengaged and 40 (11%) had upcoming appointments; the remainder were unreachable, declined care, or missed given appointments. Pre-post results indicate people who received Lost & Found were 1.18 [95% confidence interval (CI) 1.02–1.36] times more likely to reengage, and reengaged a median 55 days (95% CI 14–98) sooner.

Conclusion:

Lost & Found may be a viable clinic-based reengagement intervention for OOC patients. More robust evaluations are needed.
Brief Report: Bictegravir/Emtricitabine/Tenofovir Alafenamide Efficacy in Participants With Preexisting Primary Integrase Inhibitor Resistance Through 48 Weeks of Phase 3 Clinical Trials
Authors: D'Antoni Michelle L. , Andreatta Kristen , Acosta Rima , Martin Hal , Chang Silvia , Martin Ross , White Kirsten L.
Published: December 2021

Background:

Preexisting drug resistance limits the utility of HIV antiretroviral therapy. Studies have demonstrated safety and efficacy of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), including in patients with M184V/I substitutions.

Setting:

We investigated virologic outcomes through 48 weeks of B/F/TAF treatment in individuals with preexisting primary integrase strand transfer inhibitor resistance (INSTI-R).

Methods:

Preexisting INSTI-R was retrospectively evaluated from 7 B/F/TAF studies. INSTI-R was assessed by historical genotypes and/or baseline RNA or DNA sequencing. Viral loads were measured at all visits.

Results:

Preexisting primary INSTI-R substitutions were detected in 20 of the 1907 participants (1.0%). The 20 participants were predominantly male (75%), were Black (65%), had HIV-1 subtype B (85%), and had baseline median CD4 counts of 594 cells/mm3 and median age of 52 years. Most of the participants (n = 19) were virologically suppressed at baseline and had one primary INSTI-R substitution, E92G, Y143C/H, S147G, Q148H/K/R, N155S, or R263K, +/−secondary substitutions. All suppressed participants maintained virologic suppression throughout 48 weeks without any viral blips. One treatment-naive participant had virus with Q148H+G140S that was fully sensitive to bictegravir but only partially to dolutegravir (phenotype <2.5-fold change and >4-fold change, respectively). With a baseline viral load of 30,000 copies/mL, this participant was virologically suppressed by week 4 and maintained <50 copies/mL through week 48.

Conclusions:

This small cohort with primary INSTI-R achieved and/or maintained virologic suppression through 48 weeks of B/F/TAF treatment. Consistent with the potent in vitro activity of bictegravir against most INSTI-R patterns, B/F/TAF may be a potential treatment option for patients with select preexisting INSTI-R, if confirmed by further studies.
Viral Suppression Levels in Men Who Have Sex With Men and Transgender Women With Newly Diagnosed HIV and Alcohol Use Disorder in Peru: Results From a Randomized, Double-Blind, Placebo-Controlled Trial Using Oral Naltrexone
Authors: Gonzales Pedro , Bachireddy Chethan , Grieco Arielle , Ding Rona , Galvez de Leon Samy J. , Ulrich Angela , Lama Javier , Duerr Ann C , Altice Frederick L.
Published: December 2021

Background:

Alcohol use disorders (AUDs) are common in men who have sex with men (MSM) and transgender women (TGW) in Peru and undermine antiretroviral therapy (ART) adherence. Oral naltrexone (NTX) is an evidence-based treatment for AUD that has not been assessed in cotreating AUD in MSM/TGW with HIV.

Setting and Design:

A multi-site, randomized, double-blind, placebo-controlled trial among MSM/TGW with AUD and newly diagnosed with HIV in Lima, Peru.

Methods:

Newly diagnosed MSM/TGW with HIV and AUD were prescribed a single-treatment regimen of EFV/TDF/FTC from 2014 to 2015 and randomized 2:1 to oral NTX (N = 103) or placebo (N = 53) for 24 weeks. The primary and secondary outcomes were proportion achieving viral suppression (VS: HIV-1 RNA < 400 copies/mL) or maximal viral suppression (MVS: HIV-1 RNA < 40 copies/mL) at 24 weeks.

Results:

There were no significant differences between the arms in VS (81.6% NTX arm vs 75.5% placebo arm; P = 0.37) or MVS (61.2% NTX arm vs 66.0% placebo arm; P = 0.48). Adherence to study medication was low (mean = 34.6%) overall with only 21.4% of participants meeting recommended adherence levels (≥80% daily doses/month). Participants allocated to NTX had significantly lower adherence compared with placebo for both the first and second 12-week study periods, respectively (44.0% vs 35.2%, P = 0.04; 31.4% vs 35.2%, P = 0.03).

Conclusions:

Findings are inconclusive regarding the use of NTX for treatment of AUD in MSM/TGW newly diagnosed with HIV. VS and MVS levels were high irrespective of allocation. Adherence to study medication was low, requiring further exploration of strategies to optimize adherence to NTX as AUD treatment.
Algorithmic Approach to Antibiotic Prophylaxis for Traumatic Craniomaxillofacial Injuries
Authors: Caruso Daniel Phillip , Aquino Vincent Mario , Tannyhill R. John
Published: December 2021

Prophylactic antibiotics are commonly used in the management of traumatic injuries to the maxillofacial complex, yet there are no set guidelines for when and when not to prescribe. The purpose of this review is to present the evidence for antibiotic prophylaxis in different clinical scenarios and to propose algorithms to facilitate the decision making process with the ultimate goal of improving antibiotic prescribing practices. A number of databases were searched using a wide range of keywords to ensure the topic was fully encapsulated. The review is divided into 3 sections: soft tissue trauma, maxillofacial fractures, and ballistic injuries. The algorithms were constructed using the current evidence as well as pathophysiologic principles, especially when there were insufficient studies. This review found the literature on antibiotic prophylaxis to be highly varied and not standardized. Creating an algorithm for providers to follow will help to set a standard of care and decrease the misuse of antibiotics.
Benign Nasal Mass as a Delayed Complication of Barbed Thread Rhinoplasty
Authors: Kim Kyung Soo , Min Hyun Jin
Published: December 2021

Barbed thread rhinoplasty for nasal tip projection, dorsal length elongation, and nostril correction is usually performed at private clinics. The procedure is minimally invasive and does not cause permanent external scarring, which is a common challenge in rhinoplasty. Limited studies have described the complications of this procedure, with no reports on its late complications. A patient presented to the authors’ clinic with a nasal septal mass, which had developed 3 months before the visit. She had undergone rhinoplasty 10 years prior. During excisional biopsy, the authors found barbed threads impacted in the mass, which may have been inserted during the rhinoplasty. The mass was pathologically demonstrated as a chronic inflammatory lesion that may have originated due to the foreign body. The use of barbed threads in rhinoplasty can induce complications as late as 10 years after surgery; clinicians should consider this and explain the possible late complications to patients before surgery.
TSG101 Associates with PARP1 and is Essential for PARylation and DNA Damage-induced NF-κB Activation
Authors: Tufan Ahmet Bugra , Lazarow Katina , Kolesnichenko Marina , Sporbert Anje , von Kries Jens Peter , Scheidereit Claus
Published: December 2021

In a genome-wide screening for components of the dsDNA-break-induced IKK-NF-κB pathway we identified scores of regulators, including tumor susceptibility protein TSG101. TSG101 is essential for DNA damage-induced formation of cellular poly(ADP-ribose) (PAR). TSG101 directly binds to PARP1 and is required for PARP1 activation. This function of TSG101 is independent of its role in the ESCRT-I endosomal sorting complex. In the absence of TSG101, the PAR-dependent formation of a nuclear PARP1-IKKγ signalosome, which triggers IKK activation, is impaired. According to its requirement for PARP1 and NF-κB activation, TSG101 deficient cells are defective in DNA repair and apoptosis protection. Loss of TSG101 results in PARP1 trapping at damage sites and mimics the effect of pharmacological PARP-inhibition. We also show that loss of TSG101 in connection with inactivated tumor suppressors BRCA1/2 in breast cancer cells is lethal. Our results imply TSG101 as a therapeutic target to achieve synthetic lethality in cancer treatment.
The T cell receptor repertoire reflects the dynamics of the immune response to vaccination
Authors: Mohammed Kevin , Meadows Austin , Hekmaty Saboor , Hatem Sandra , Simon Viviana , Jayaprakash Anitha D. , Sachidanandam Ravi
Published: December 2021

Early, high-resolution metrics are needed to ascertain the immune response to vaccinations. The T cell receptor (TCR), a heterodimer of one α and one β chain, is a promising target, with the complete TCR repertoire reflecting the T cells present in an individual. To this end, we developed Tseek, an unbiased and accurate method for profiling the TCR repertoire by sequencing the TCR α and β chains and developing a suite of tools for repertoire analysis. An added advantage is the ability to non-invasively analyze T cells in peripheral blood mononuclear cells (PBMCs). Tseek and the analytical suite were used to explore the T cell response to both the COVID-19 mRNA vaccine (n=9) and the seasonal inactivated Influenza vaccine (n=5) at several time points. Neutralizing antibody titers were also measured in the covid vaccine samples. The COVID-19 vaccine elicited a broad T cell response involving multiple expanded clones, whereas the Influenza vaccine elicited a narrower response involving fewer clones. Many distinct T cell clones responded at each time point, over a month, providing temporal details lacking in the antibody measurements, especially before the antibodies are detectable. In individuals recovered from a SARS-CoV-2 infection, the first vaccine dose elicited a robust T cell response, while the second dose elicited a comparatively weaker response, indicating a saturation of the response. The physical symptoms experienced by the recipients immediately following the vaccinations were not indicative of the TCR/antibody responses. The TCR responses broadly presaged the antibody responses. We also found that the TCR repertoire acts as an individual fingerprint: donors of blood samples taken years apart could be identified solely based upon their TCR repertoire, hinting at other surprising uses the TCR repertoire may have. These results demonstrate the promise of TCR repertoire sequencing as an early and sensitive measure of the adaptive immune response to vaccination, which can help improve immunogen selection and optimize vaccine dosage and spacing between doses.
Validation of neutralizing antibody titers for estimating vaccine effectiveness for the Omicron SARS-CoV-2 variant, BA.1
Authors: Gardner Billy J. , Kilpatrick A. Marm
Published: December 2021

Background

The emergence of new virus variants, including the Omicron variant (B.1.1.529) of SARS-CoV-2, can lead to immune escape and reduced vaccine effectiveness. Neutralizing antibody titers could be used to quickly estimate vaccine effectiveness (VE), because they can be easily measured following the emergence of a new virus variant and have been shown to be a correlate of protection for SARS-CoV-2 and other pathogens. However, few studies have examined VE-neutralizing antibody titer relationships with multiple virus variants, and none have validated relationships for immune evasive variants.

Methods

We leveraged variation among vaccines and virus variants to estimate VE-neutralizing antibody titer relationships across a 54-fold range of neutralizing antibody titers for two endpoints for COVID-19: symptomatic disease, and hospitalization. We predicted VEs for Omicron three days after the first neutralizing antibody titer became available. We tested these predictions using subsequently collected observational VE data.

Findings

For two mRNA vaccines (mRNA-1273, BNT162b2), fitted models predicted that infection with the BA.1 Omicron variant would increase the risk of hospitalization 2.8-4.4-fold and increase the risk of symptomatic disease 1.7-4.2-fold compared to the Delta variant. However, a third vaccine dose was predicted to restore protection. Out-of-sample validation data indicated that model predictions were quite accurate, with all predictions being within 10% of observed VE estimates, and all empirical estimates fell within the model prediction intervals.

Interpretation

These analyses demonstrate that models using neutralizing antibody titers can provide rapid VE estimates which can inform vaccine design and selection.

Funding

California Department of Health, National Science Foundation
Entorhinal cortex directs learning-related changes in CA1 representations
Authors: Grienberger Christine , Magee Jeffrey C.
Published: December 2021

Learning-related changes in brain activity are thought to underlie adaptive behaviors1,2. For instance, the learning of a reward site by rodents requires the development of an over-representation of that location in the hippocampus3-6. However, how this learning-related change occurs remains unknown. Here we recorded hippocampal CA1 population activity as mice learned a reward location on a linear treadmill. Physiological and pharmacological evidence suggests that the adaptive over-representation required behavioral timescale synaptic plasticity (BTSP)7. BTSP is known to be driven by dendritic voltage signals that we hypothesized were initiated by input from entorhinal cortex layer 3 (EC3). Accordingly, the CA1 over-representation was largely removed by optogenetic inhibition of EC3 activity. Recordings from EC3 neurons revealed an activity pattern that could provide an instructive signal directing BTSP to generate the over-representation. Consistent with this function, exposure to a second environment possessing a prominent reward-predictive cue resulted in both EC3 activity and CA1 place field density that were more elevated at the cue than the reward. These data indicate that learning-related changes in the hippocampus are produced by synaptic plasticity directed by an instructive signal from the EC3 that appears to be specifically adapted to the behaviorally relevant features of the environment.
The human thalamus orchestrates neocortical oscillations during NREM sleep
Authors: Schreiner Thomas , Kaufmann Elisabeth , Noachtar Soheyl , Mehrkens Jan-Hinnerk , Staudigl Tobias
Published: December 2021

A hallmark of non-rapid eye movement sleep is the coordinated interplay of slow oscillations (SOs) and sleep spindles. Traditionally, a cortico-thalamo-cortical loop is suggested to coordinate these rhythms: neocortically-generated SOs trigger spindles in the thalamus that are projected back to neocortex. Here, we used intrathalamic recordings from human epilepsy patients to test this canonical interplay. We show that SOs in the anterior thalamus precede neocortical SOs (peak -50 ms), whereas concurrently-recorded SOs in the mediodorsal thalamus are led by neocortical SOs (peak +50 ms). Sleep spindles, detected in both thalamic nuclei, preceded their neocortical counterparts (peak -100 ms) and were initiated during early phases of thalamic SOs. Our findings indicate an active role of the anterior thalamus in organizing sleep rhythms in the neocortex and highlight the functional diversity of thalamic nuclei in humans. The thalamic coordination of sleep oscillations could have broad implications for the mechanisms underlying memory consolidation.
Insights into bear evolution from a Pleistocene polar bear genome
Authors: Lan Tianying , Leppälä Kalle , Tomlin Crystal , Talbot Sandra L. , Sage George K. , Farley Sean D. , Shideler Richard T. , Bachmann Lutz , Wiig Øystein , Albert Victor A. , Salojärvi Jarkko , Mailund Thomas , Drautz-Moses Daniela I. , Schuster Stephan C. , Herrera-Estrella Luis , Lindqvist Charlotte
Published: December 2021

The polar bear (Ursus maritimus) has become a symbol of the threat to biodiversity from climate change. Understanding polar bear evolutionary history may provide insights into apex carnivore responses and prospects during periods of extreme environmental perturbations. In recent years, genomic studies have examined bear speciation and population history, including evidence for ancient admixture between polar bears and brown bears (Ursus arctos). Here, we extend our earlier studies of a 130,000–115,000-year-old polar bear from the Svalbard Archipelago using a 10X coverage genome sequence and ten new genomes of polar and brown bears from contemporary zones of overlap in northern Alaska. We demonstrate a dramatic decline in effective population size for this ancient polar bear’s lineage, followed by a modest increase just before its demise. A slightly higher genetic diversity in the ancient polar bear suggests a severe genetic erosion over a prolonged bottleneck in modern polar bears. Statistical fitting of data to alternative admixture graph scenarios favors at least one ancient introgression event from brown bears into the ancestor of polar bears, possibly dating back over 150,000 years. Gene flow was likely bidirectional, but allelic transfer from brown into polar bear is the strongest detected signal, which contrasts with other published works. These findings may have implications for our understanding of climate change impacts: polar bears, a specialist Arctic lineage, may not only have undergone severe genetic bottlenecks, but also been the recipient of generalist, boreal genetic variants from brown bear during critical phases of Northern Hemisphere glacial oscillations.

Significance

Interspecific hybridization is a widespread phenomenon, but measuring its extent, directionality, and adaptive importance remains challenging. Ancient genomes, however, can help illuminate the history of modern organisms. Here, we present a genome retrieved from a 130,000–115,000-year-old polar bear and perform genome analyses of modern polar and brown bears throughout their geographic range. We find that the principal direction of ancient allele sharing was from brown bear into polar bear, although gene flow between them has likely been bidirectional. This inverts the current paradigm of unidirectional gene flow from polar into brown bear, and it suggests that polar bears were recipients of external genetic variation prior to their extensive population decline.
Multiple genes in cis mediate the effects of a single chromatin accessibility variant on aberrant synaptic development and function in human neurons
Authors: Zhang Siwei , Zhang Hanwen , Forrest Marc P. , Zhou Yifan , Bagchi Vikram A. , Kozlova Alena , Santos Marc Dos , Piguel Nicolas H. , Dionisio Leonardo E. , Sanders Alan R. , Pang Zhiping P. , He Xin , Penzes Peter , Duan Jubao
Published: December 2021

Despite hundreds of risk loci from genome-wide association studies of neuropsychiatric disorders, causal variants/genes remain largely unknown. Here, in NEUROG2-induced human neurons, we identified 31 risk SNPs in 26 schizophrenia (SZ) risk loci that displayed allele-specific open chromatin (ASoC) and were likely to be functional. Editing the strongest ASoC SNP rs2027349 near vacuolar protein sorting 45 homolog (VPS45) altered the expression of VPS45, lncRNA AC244033.2, and a distal gene, C1orf54, in human neurons. Notably, the global gene expression changes in neurons were enriched for SZ risk and correlated with post-mortem brain gene expression signatures of neuropsychiatric disorders. Neurons carrying the risk allele exhibited increased dendritic complexity, synaptic puncta density, and hyperactivity, which were reversed by knocking-down distinct cis-regulated genes (VPS45, AC244033.2, or C1orf54), suggesting a phenotypic contribution from all three genes. Interestingly, transcriptomic analysis of knockdown cells suggested a non-additive effects of these genes. Our study reveals a compound effect of multiple genes at a single SZ locus on synaptic development and function, providing a mechanistic link between a non-coding SZ risk variant and disease-related cellular phenotypes.