bluuebunny/crossref_metadata_2025 huggingface dataset:
Medial Elbow Exposure: Modified Taylor-Scham Versus Flexor Carpi Ulnaris–Split
Authors: Bates Taylor , Lynch Thomas B. , Achay Jennifer , Powers Robert , Sabbag Casey M. , Plucknette Benjamin F. , Wilson David
Published: August 2022

Objective:

To compare the exposure of the coronoid process, anteromedial facet, and anterior band of the medial collateral ligament using the flexor carpi ulnaris (FCU)–splitting approach with the Taylor-Scham approach modified with an ulnar nerve transposition.

Methods:

Thirty approaches were performed on 15 fresh cadavers using a randomized cross-over design and standardized incision. Access to key anatomic landmarks was assessed, and a calibrated digital image was taken from the surgeon's best perspective of each approach. Images were analyzed using ImageJ (National Institutes of Health) software to calculate the area of osseous exposure.

Results:

All key anatomic landmarks were visualized using both approaches. The average area of exposure for the Taylor-Scham was 19.5 cm2 compared with 13.6 cm2 for the FCU-splitting (P < 0.0001). The distal extent of the FCU-splitting approach is limited by the ulnar nerve and its branches to the humeral head of the FCU.

Conclusion:

The Taylor-Scham approach provides a more extensile exposure of the anteromedial coronoid and proximal ulna than the FCU-splitting approach while avoiding cross-tensioning of the ulnar nerve.
Reconstruction of the male external genitalia in diverse disease processes: Our reconstructive algorithm, techniques, and experience
Authors: Croghan Stefanie M. , Kelly Caroline , Daniels Anne E. , Fitzgibbon Linda , Daly Pádraig J. , Cullen Ivor M.
Published: August 2022

Background

Male genital form and function may be rendered abnormal by a number of disease processes, with profound associated psychological and functional consequences. The aim of the study is to review our reconstructive experience with cases of genital loss or distortion due to nonmalignant diseases processes and atypical neoplasia.

Materials and methods

A retrospective review of a prospectively maintained database was performed to identify reconstructive cases performed from 2018 to 2020 under the care of a single surgeon. Male patients 18 years or older with a disease diagnosis other than squamous cell carcinoma affecting genital form were included. Disease processes, patient factors, surgical techniques, and both functional and cosmetic outcomes were reviewed.

Results

Fourteen cases were identified. The patients had a mean age of 52.2 years (range, 21–72 years). Acquired buried penis was present in 8 patients. Etiology of genital abnormality included balanitis xerotica obliterans (n = 6), excess skin loss at circumcision (n = 2), self-injection of petroleum jelly to penile shaft (n = 1), Fournier gangrene (n = 1), hidradenitis suppurativa (n = 1), extramammary Paget disease (n = 1), idiopathic lymphoedema (n = 1), and penoscrotal webbing (n = 1). Reconstructive techniques performed included penile debridement/shaft skin release, scrotectomy, suprapubic apronectomy, and division of penoscrotal webbing, in combination with split-thickness skin grafting where required. A penile implant was inserted in one patient. Reconstructive planning, techniques, and outcomes are described.

Conclusions

A variety of reconstructive techniques in andrology can be used to improve the aesthetic and functional outcomes of multiple disease processes affecting the male external genitalia.
The era of personalized treatments: Updates on immunotherapy within urothelial of bladder cancer
Authors: Wu Zhang-Song , Wu Song
Published: August 2022

Bladder cancer is a complex disease of the urinary system with high morbidity and mortality. Recently, the introduction of immunotherapies such as immune checkpoint inhibitors (eg, programmed cell death protein 1/programmed death-ligand 1) has proven to be a reliable means of improving survival outcomes, including patients with limited response to conventional treatment. Nevertheless, difficult questions remain in clinical practice, such as how to select appropriate patients for personalized treatment, how to predict and assess therapeutic efficacy in advance, and how to enhance the therapeutic benefits of immunotherapy treatment. These issues require urgent attention. Herein, we describe recent clinical applications of immune checkpoint inhibitors in bladder cancer therapy, examine underlying mechanisms for treatment failure in a subset of patients, and discuss potential approaches to improve their therapeutic effects.
The use of blue-light cystoscopy in the detection and surveillance of nonmuscle invasive bladder cancer
Authors: Cahill Ellen M. , Chua Kevin , Doppalapudi Sai Krishnaraya , Ghodoussipour Saum
Published: August 2022

Nonmuscle invasive bladder cancer is associated with a high risk of recurrence as well as progression to muscle-invasive disease. Therefore, adequate visualization and identification of malignant lesions as well as complete resection are critical. Traditional white-light cystoscopy is limited in its ability to detect bladder cancer, specifically carcinoma in situ. Blue-light cystoscopy makes use of the intravesical instillation of a heme precursor to differentiate areas of malignancy from normal tissue. A narrative review of the literature on the use of blue-light cystoscopy in bladder cancer was conducted. Blue-light cystoscopy has been shown in several randomized clinical trials to increase detection of Ta, T1, and carcinoma in situ, as well as reduce risk of recurrence at 12 months as compared with traditional white-light cystoscopy. Research into the effects of blue-light cystoscopy on risk of disease progression has produced mixed results, in part due to changing definitions of progression. However, more recent research suggests a correlation with decreased risk of progression. Whereas the use of blue-light was initially limited to rigid cystoscopy in the operating room, results from a recent randomized clinical trial showing enhanced detection of recurrent disease using blue-light in-office surveillance flexible cystoscopy have led to expanded Food and Drug Administration approval. Overall, blue-light cystoscopy offers promise as an enhancement to white-light cystoscopy for the detection of nonmuscle invasive bladder cancer and may yield additional benefits in reducing disease recurrence and progression. Further prospective research is needed to evaluate the true benefit of blue-light cystoscopy in terms of disease progression as well as the cost-effectiveness of this technique.
Hypnotherapy in management of pain in children with cancer: a case report
Authors: Choobi Anzali Babak , Muhammadi Sheida , Malkari Behnam , Goli Rasoul , Norouzrajabi Samira , Talebiazar Nasim
Published: August 2022

Introduction and importance:

Pain is the most common symptom in cancer patients that can affect their performance and quality of life. The present study aimed to determine the effect of hypnotherapy on the intensity of pain in children with cancer.

Case presentation:

This is a case study with a single-subject research design, in which a total of 3 female children with cancer were recruited using voluntary response sampling. Classical hypnotherapy was conducted for patients in 8 treatment sessions with a 1-month postintervention follow-up. Participants completed the Oucher Pain Scale (OPS) at 5 stages including before the intervention, third, fifth, and eighth hypnotherapy sessions, and 1 month after the intervention. Data analysis was conducted using a statistical report on the recovery rate and effect size.

Clinical discussion:

The results showed that hypnotherapy had a significant effect on the intensity of pain, in the treatment and follow-up stages.

Conclusions:

It can be stated that the use of hypnotherapy has been highly effective in reducing the intensity of pain in children with cancer.
Does a Latissimus Dorsi Flap Improve Surgical Outcomes of Implant-based Breast Reconstruction following Infected Device Explantation?
Authors: Slovacek Cedar , Asaad Malke , Mitchell David , Selber Jesse C. , Clemens Mark W. , Chu Carrie K. , Mericli Alexander F. , Robb Geoffrey L. , Hanson Summer E. , Butler Charles E.
Published: August 2022

Background:

The goal of this study was to assess whether adding a latissimus dorsi (LD) flap to a secondary implant-based reconstruction (IBR) improves outcomes following explantation of the primary device due to infection.

Methods:

We conducted a retrospective study of patients who underwent a second IBR with or without the addition of an LD flap during 2006–2019, following explantation due to infection. Surgical outcomes were collected and compared between reconstruction types.

Results:

A total of 6093 IBRs were identified during the study period. Of these, 109 underwent a second attempt at breast reconstruction with IBR alone (n = 86, 79%) or IBR/LD (n = 23, 21%) following explantation of an infected device. Rates of secondary device explantation due to a complication were similar between the two groups (26% in the IBR/LD group and 21% in the IBR group; P = 0.60). Among the patients who underwent prior radiotherapy, the IBR/LD group had lower rates of any complication (38% versus 56%; P = 0.43), infection (25% versus 44%; P = 0.39), and reconstruction failure (25% versus 44%; P = 0.39); however, differences were not statistically significant.

Conclusion:

Following a failed primary breast reconstruction due to infection, it may be appropriate to offer a secondary reconstruction. For patients with a history of radiotherapy, combining an LD flap with IBR may provide benefits over IBR alone. Although not statistically different, this outcome may have clinical significance, considering the magnitude of the effect, and may result in decreased complication rates and a higher chance of reconstructive success.
Surgical Microtia Reconstruction in Hemifacial Microsomia Patients: Current State and Future Directions
Authors: Bouhadana Gabriel , Gornitsky Jordan , Saleh Eli , Borsuk Daniel E. , Cugno Sabrina
Published: August 2022

Background:

Hemifacial microsomia (HFM) is one of the most common congenital craniofacial disorders. Among many other features, microtia is present in the large majority of these patients. However, mainly due to the unilateral hypoplastic anatomy, microtia reconstruction among this patient population remains a reconstructive challenge for plastic surgeons. Given that no clear standards exist, an evidence-based synthesis of the literature was devised.

Methods:

A systematic search of Pubmed, Medline, and Embase was carried out, in accordance with the PRISMA guidelines. Studies discussing surgical microtia reconstruction for HFM patients were retained. Qualitative data regarding study design, challenges addressed, specific recommendations, and their respective strengths/limitations were extracted from each. Retrieved recommendations were consolidated and assigned a level of evidence grade.

Results:

Although only 11 studies were included in this review, these provided 22 main recommendations regarding the eight HFM-specific challenges identified, which were of either grade C (n = 5) or D (n = 17). Included studies addressed construct location (n = 7), the low hairline (n = 6), soft tissue construct coverage (n = 6), earlobe reconstruction (n = 6), construct projection (n = 5), anomalies of the relevant neurovascular systems (n = 2), retroauricular construct coverage (n = 2), and sizing of the construct (n = 2).

Conclusions:

Given the many persisting reconstructive challenges regarding surgical microtia reconstruction for HFM patients, the authors present a comprehensive and evidence-based consolidation of recommendations specific to these challenges. The authors hope this systematic review can appropriately guide plastic surgeons and will ultimately improve care for this patient population.
Utilization of a Chimeric Medial Femoral Condyle Free Flap for Mandibular Osteoradionecrosis
Authors: Chaiyasate Kongkrit , Gupta Rohun , John Jithin , Chaiyasate Sean , Powers Jeremy , Nguyen Alan , Issa Christopher , Hart Justin , Goldman Joshua J. , Sachanandani Neil S.
Published: August 2022

Background:

Primary options for oromandibular reconstruction with osteocutaneous free flaps are the vascularized fibula and iliac crest. Complications of mandible reconstruction are not uncommon and include osteomyelitis, malunion, and osteoradionecrosis (ORN) after radiation therapy. The medial femoral condyle (MFC) free flap is an established salvage option for carpal reconstruction in hand surgery, frequently used for scaphoid nonunion and avascular necrosis. We hypothesize that the MFC flap can be utilized to restore blood supply and reverse the negative effects of radiotherapy in patients who require mandibular reconstruction due to ORN.

Methods:

A retrospective chart review was conducted at Beaumont Health System, Royal Oak, for patients who underwent MFC free flap reconstruction for mandibular ORN between the years 2012 and 2018. Demographic data, operative details, complications, medical comorbidities, and patient outcomes were retrospectively gathered.

Results:

A total of four patients were isolated. Four patients developed ORN after resection of squamous cell carcinoma and adjuvant radiotherapy. No patients experienced donor site deficits. Revisions after MFC reconstruction were dependent on individual aesthetics and involvement of neighboring tissue. All four patients continue to be followed with no current issues to the osseous component of the MFC flap.

Conclusion:

Utilization of the MFC periosteal flap is a viable option in selected patients to salvage nonunion/resorption of mandible reconstruction and ORN of the mandible. Our experience found that the MFC is able to provide pain resolution and healing of intraoral soft tissue defects, and may halt the progression of ORN of the mandible.
Primary Subretinal Hydatid Cyst Presenting as Leukocoria in a Child
Authors: Ozdemir Huseyin Baran , Ozdek Sengul , Ozkan Kaan , Akyurek Nalan
Published: August 2022

Purpose:

To describe a case of subretinal hydatid cyst presenting as leukocoria and treated with limbal vitrectomy.

Methods:

A single case report demonstrated by multimodal imaging.

Results:

An otherwise healthy 28-month-old boy was admitted to our hospital with a complaint of leukocoria and underwent combined lensectomy and vitrectomy under albendazole therapy due to vitreous space-occupying subretinal cyst. Systemic workup showed no involvement in other organs. Cyst content was adequately aspirated with a 39-gauge needle, the cyst wall was freed from surrounding attachments to the retina and the nasal choroid and was extracted through a limbal incision using a cryoprobe. Nasal retinotomy and retinectomy area was lasered and tamponaded with silicone oil. Histopathologic examination confirmed the diagnosis of hydatid cyst disease. Silicone oil was removed at postoperative 3rd month. Retina stayed attached and the patient had a fix and follow vision under contact lens and amblyopia treatment during the 21 months follow-up period.

Conclusion:

This is the youngest subretinal hydatid cyst case in the literature. Large subretinal hydatid cyst may rarely cause leukocoria in children without any involvement in other organs. Vitrectomy with limbal approach and 39G needle-assisted cyst fluid aspiration and cryo-extraction appears to be a safe and successful surgical option in such cases.
Gains in Quality of Life in Chronic Otitis Media Patients After Surgery, Adjusted for Placebo Bias
Authors: Bukurov Bojana , Haggard Mark , Spencer Helen , Arsovic Nenad , Jesic Snezana , Dudvarski Zoran
Published: August 2022

Objective

Using a short-form specific questionnaire, we sought to quantify specific and generic benefits of surgery for chronic otitis media (COM) while adjusting for expectancy (placebo) bias.

Study Design

A prospective observational pretreatment/posttreatment study.

Setting

A national tertiary referral center.

Patients

Consecutive adult COM patients were enrolled for 1 year. Of 246 patients, 205 were recommended for surgery, and 167 were operated on the (more) affected ear.

Intervention(s)

All patients filled out two questionnaires, one specific (Chronic Otitis Media Questionaire-12) and one generic (Short Form-36) at baseline, and then again 6 and 12 months after surgery.

Main Outcome Measures

Factor-based scores of questionnaires, standardized response means (SRMs) for treatment effects, with multiple linear regression for implementing bias adjustment.

Results

All but one (generic Short Form-36 “mental” scale) of the seven considered measures gave very highly significant (p < 0.001) improvements. Unadjusted SRMs were large (1.0–2.0 standard deviation units) for audiometry, symptoms of ear discharge, reported hearing, and aggregate specific quality of life, but only moderate for the less specific activity/healthcare. The proposed bias adjustment reduced SRM magnitudes for most measures by about a third, for activity/healthcare and ear discharge by only a tenth to a fifth, and for audiometry not at all.

Conclusion

Most scores of the specific questionnaire displayed definite placebo-like biases; this demands caution in interpreting improvement after COM surgery. With bias adjustments, credible and worthwhile magnitudes of improvements remained for Chronic Otitis Media Questionnaire-12 total and subscores (0.5–1.09 standard deviation SRM), but not for generic quality of life.
COVID-19 Vaccine Uptake in Southeastern Ontario, Canada: Monitoring and Addressing Health Inequities
Authors: Carter Megan A. , Biro Suzanne , Maier Allison , Shingler Clint , Guan T. Hugh
Published: August 2022

Context:

Implementation of a population-based COVID-19 vaccine strategy, with a tailored approach to reduce inequities in 2-dose coverage, by a mid-sized local public health agency in southeastern Ontario, Canada.

Program:

Coverage maps and crude and age-standardized coverage rates by material and social deprivation, urban/rural status, and sex were calculated biweekly and reviewed by local public health planners. In collaboration with community partners, the results guided targeted strategies to enhance uptake for marginalized populations.

Evaluation:

The largest gaps in vaccine coverage were for those living in more materially deprived areas and rural residents—coverage was lower by 10.9% (95% confidence interval: −11.8 to −10.0) and 9.3% (95% confidence interval: −10.4 to −8.1) for these groups compared with living in less deprived areas and urban residents, respectively. The gaps for all health equity indicators decreased statistically significantly over time. Targeted strategies included expanding clinic operating hours and availability of walk-in appointments, mobile clinics targeted to marginalized populations, leveraging primary care partners to provide pop-up clinics in rural and materially and socially deprived areas, and collaborating with multiple partners to coordinate communication efforts, especially in rural areas.

Discussion:

The scale and scope of monitoring and improving local vaccine uptake are unprecedented. Regular review of health equity indicators provided critical situational awareness for decision makers, allowing partners to align and tailor strategies locally and in collaboration with one another. Health care providers and pharmacies/pharmacists are key partners who require innovative support to increase uptake in marginalized groups. Continued engagement of other community partners such as schools, municipalities, and local service groups is also crucial. A “hyper local” approach is needed along with commitment from partners in all sectors and at all levels to reduce barriers to vaccination that lie further upstream for marginalized groups.
Peri-OPerative Pain Management, Education & De-escalation (POPPMED), a novel anaesthesiologist-led program, significantly reduces acute and long-term postoperative opioid requirements: a retrospective cohort study
Authors: Heldreich Charlotte , Meyer Ilonka , Dube Esther , Hu Raymond , Howard William , Holmes Natasha , Maroon Nada , Weinberg Laurence , Tan Chong O.
Published: August 2022

Introduction:

The opioid tolerant patient requiring surgery is highly likely to be discharged on high Oral Morphine Equivalent Daily Dosages (OMEDDs), with concomitant risk of increased morbidity and mortality.

Objectives:

We proposed that a single anaesthesiologist-led POPPMED (Peri-Operative Pain Management, Education & De-escalation) service could reduce both short and long-term postoperative patient OMEDDs.

Methods:

From April 2017, our anaesthesiologist-led POPPMED service, engaged 102 perioperative patients treated with >50mg preoperative OMEDDs. We utilized behavioural interventions; acute opioid reduction and/ or rotation; and regional, multimodal and ketamine analgesia to achieve lowest possible hospital discharge and long term OMEDDs.

Results:

Patients' preoperative OMEDDs were [median (IQR): 115mg (114mg)], and were representative of an older [age 62 (15) years], high-risk [89% ASA status 3 or 4] patient population. 46% of patients received an acute opioid rotation; 70% received ketamine infusions; and 44% regional analgesia. OMEDDs on discharge [-25mg (82mg), p=0.003] and at 6-12 months [-55mg (105mg ), p<0.0001] were significantly reduced; 84% and 87% of patients achieved OMEDD reduction on discharge and at 6-12 months. Patients with >90mg preoperative OMEDDs achieved greater reductions [discharge: 71% of patients, -52 mg (118 mg) p<0.0001; 6-12 months: 90% of patients, -90mg (115mg), p<0.0001]. On comparison with a pre-POPPMED surgical cohort, Postoperative Day 1-3 11-point Numerical Rating Scale (NRS-11) area under the curve (AUC) measurements at rest and on movement were not significantly different (largest NRS-11:hours AUC difference [median(IQR)] 22 [13], p= 0.24). Hospital length of stay was variably increased.

Conclusions:

POPPMED achieved sustained OMEDD reductions safely in an older, high-risk opioid tolerant population, with analgesia comparable to a non-POPPMED cohort, and surgery specific effects on length of stay.
Surgical Factors Influencing Local Relapse and Outcome in the Treatment of Unilateral Nephroblastoma
Authors: Meier Clemens M. , Fuchs Jörg , von Schweinitz Dietrich , Stein Raimund , Wagenpfeil Stefan , Kager Leo , Schenk Jens-Peter , Vokuhl Christian , Melchior Patrick , Welter Nils , Furtwängler Rhoikos , Graf Norbert
Published: August 2022

Objective:

This study aims to identify factors associated with the occurrence of local relapse (LR) after treatment for unilateral nephroblastoma.

Background:

Despite the fact that LR is rare (~5%) its adverse impact on the need for relapse treatment and outcome (40%–80% overall survival) cannot be neglected. Identifying the causative factors may improve initial treatment to achieve better local control.

Methods:

Altogether 2386 patients with unilateral nephroblastoma prospectively enrolled over a period of 32 years (1989–2020) by the German Society for Pediatric Oncology and Hematology (SIOP-9/GPOH, SIOP-93-01/GPOH and SIOP-2001/GPOH) were retrospectively analyzed. Hazard ratios (HR) of LR were calculated for sex, age, size, local staging, histology, type of removal, rupture, lymph node (LN) removal using univariate and multivariate Cox models.

Results:

Age >48 months, tumor volume >500 mL, histology and LN extent of removal were identified as significant risk factors for LR [HR: 1.68, P=0.018, confidence interval (CI): 1.09–2.58; HR: 1.84, P=0.015, CI: 1.13–3.00; HR: 3.19, P<0.001, CI: 2.03–5.00; HR: 2.26, P=0.002, CI: 1.36–3.576]. LR occur significantly more often in Stage I and II, even if no LN are removed. The risk of metastases is significantly increased after local recurrence (HR: 11.5, P<0.001, CI: 7.11–18.60). LR is associated with a subsequent 18.79-fold increased risk of death (HR: 18.79, P<0.001, CI: 2.07–5.28).

Conclusions:

Several factors are responsible for the occurrence of LR. Surgical ones, like LN sampling allow further reduction of LR and consequently a better outcome of patients with unilateral nephroblastoma.
Cell wall thickness has phylogenetically consistent effects on photosynthetic nitrogen-use efficiency of terrestrial plants: a meta-analysis
Authors: Liu Dan-dan , Tosens Tiina , Xiong Dong-liang , Carriquí Marc , Xiong You-cai , Xue Wei
Published: August 2022

Leaf photosynthetic nitrogen-use efficiency (PNUE) diversified significantly among C3species. However, morpho-physiological mechanisms and interrelationships forming PNUE remain unclear on the evolutionary time scale. In this study, we compiled a novel extensive matrix of morpho-anatomical and physiological traits of leaf in 679 C3species ranging from bryophytes to angiosperms to understand the intricacy of interrelationships underlying the variations in PNUE. We found that LMA, mesophyll cell wall thickness (Tcwm), Rubisco N allocation fraction (PR), and mesophyll conductance (gm) together interpreted 83% of variations in PNUE, with PRand gmaccounting for 65% of those variations. However, the PReffects were species-dependent on gm; that is, the contribution of PRon PNUE was extensively significant in high-gmspecies in comparison to low-gmspecies. Standard major analysis (SMA) and path analysis suggested a weak correlation between PNUE and LMA, whereas the SMA correlation for PNUE–Tcwmwas strong. The PRwas inversely proportional to Tcwm, which was similar to the relationship between gmand Tcwm(p-value < 0.01), so that the internal CO2drawdown from intercellular airspace to carboxylaton sites was relatively conservative over a wide range of Tcwm. Collectively, the coordination of changes in PRand gmconnecting Tcwmsuggested the complex physiological mechanisms mediated by Tcwmmodulating PNUE across contrasting plant groups.
Protein Model Refinement for Cryo-EM Maps Using DAQ score
Authors: Terashi Genki , Wang Xiao , Kihara Daisuke
Published: August 2022

As more protein structure models have been determined from cryo-electron microscopy (cryo-EM) density maps, establishing how to evaluate the model accuracy and how to correct models in case they contain errors is becoming crucial to ensuring the quality of structure models deposited to the public database, PDB. Here, we present a new protocol for evaluating a protein model built from a cryo-EM map and for applying local structure refinement in case the model has potential errors. Model evaluation is performed with a deep learning-based model-local map assessment score, DAQ, which we developed recently. Then, the subsequent local refinement is performed by a modified procedure of AlphaFold2, where we provide a trimmed template and trimmed multiple sequence alignment as input to control which structure regions to refine while leaving other more confident regions in the model intact. A benchmark study showed that our protocol, DAQ-refine, consistently improves low-quality regions of initial models. Among about 20 refined models generated for an initial structure, DAQ score was able to identify most accurate models. The observed improvements by DAQ-refine were on average larger than other existing methods.
Alternative stable states, nonlinear behavior, and predictability of microbiome dynamics
Authors: Fujita Hiroaki , Ushio Masayuki , Suzuki Kenta , Abe Masato S. , Yamamichi Masato , Iwayama Koji , Canarini Alberto , Hayashi Ibuki , Fukushima Keitaro , Fukuda Shinji , Kiers E. Toby , Toju Hirokazu
Published: August 2022

Microbiome dynamics are both crucial indicators and drivers of human health, agricultural output, and industrial bio-applications. However, predicting microbiome dynamics is notoriously difficult because communities often show abrupt structural changes, such as “dysbiosis” in human microbiomes. We here integrate theoretical and empirical bases for anticipating drastic shifts of microbial communities. We monitored 48 experimental microbiomes for 110 days and observed that various community-level events, including collapse and gradual compositional changes, occurred according to a defined set of environmental conditions. We then confirmed that the abrupt community changes observed through the time-series could be described as shifts between “alternative stable states” or dynamics around complex attractors. Furthermore, collapses of microbiome structure were successfully anticipated by means of the diagnostic threshold defined with the energy landscape analysis of statistical physics or that of a stability index of nonlinear mechanics. These results indicate that abrupt microbiome events in complex microbial communities can be forecasted by extending classic ecological concepts to the scale of species-rich microbial systems.
Using extreme value statistics to reconceptualize psychopathology as extreme deviations from a normative reference model
Authors: Fraza Charlotte , Zabihi Mariam , Beckmann Christian F. , Marquand Andre F.
Published: August 2022

For many problems in neuroimaging, the most informative features occur in the tail of the distribution. For example, when considering psychiatric disorders as deviations from a ‘norm’, the tails of the distribution are considerably more informative than the bulk of the distribution for understanding risk, for stratifying and predicting such disorders and for anomaly detection. Yet, most statistical methods used in neuroimaging focus on modelling the bulk and fail to adequately capture extreme values occurring in the tails. To address this, we propose a framework that combines normative models with multivariate extreme value statistics to accurately model extreme deviations of a reference cohort for individual participants. Normative models are now widely used in clinical neuroscience and similar to the employment of normative growth charts in pediatric medicine to track a child’s weight in relation to their age, normative models can be used with neuroimaging measurements to quantify individual neurophenotypic deviations from a reference cohort. However, formal statistical treatment of how to model the extreme deviations from these models has been lacking until now. In this article we provide such an approach, inspired by applications of extreme value statistics in meteorology. Since the presentation of extreme value statistics is usually quite technical, we begin with a non-technical introduction to the fundamental principles of extreme value statistics, to accurately map the tails of the normative distribution for biological markers, including mapping multivariate tail dependence across multiple markers. Next, we give a demonstration of this approach to the UK Biobank dataset and demonstrate how extreme values can be used to accurately estimate risk and detect atypicality. This framework provides a valuable tool for the statistical modelling of extreme deviations in neurobiological data, which could provide us with more accurate and effective diagnostic tools for neurological and psychiatric disorders.
Tackling Mitosis Domain Generalization in Histopathology Images with Color Normalization
Authors: Kondo Satoshi , Kasai Satoshi , Hirasawa Kousuke
Published: August 2022

In this report, we propose a method for mitosis detection in histopathology images of MIDOG2022 challenge dataset. Our method is based on unsupervised domain adaptation at inputlevel, and a combination of color normalization and object detection. We evaluate our method by using the preliminary test set including 20 cases and obtain 0.716 F1 score.
Partitioning genetic effects on birth weight at classical human leukocyte antigen loci into indirect maternal and direct fetal components using structural equation modelling
Authors: Wang Geng , Warrington Nicole M , Evans David M
Published: August 2022

Birth weight (BW), as a proxy for intrauterine growth, is influenced by both fetal and maternal genetic factors. Single nucleotide polymorphisms in the human leukocyte antigen (HLA) region in both maternal and fetal genomes have been robustly associated with BW in previous genetic association studies suggesting the involvement of classical HLA alleles in BW etiology. However, no study to date has partitioned the association between BW and classical HLA alleles into maternal and fetal components. We used structural equation modelling (SEM) to estimate the indirect maternal (i.e. via the intrauterine environment) and direct fetal effects of classical HLA alleles on BW. Our SEM leverages the data structure of the UK Biobank (UKB), which includes participants’ own BW and/or the BW of their firstborn child (in the case of UKB females). We show via simulation that our model yields asymptotically unbiased estimates of the maternal and fetal allelic effects on BW and appropriate type I error rates, in contrast to simple regression models that estimate unconditioned maternal and fetal effects. Asymptotic power calculations show that we have sufficient power to detect moderate-sized maternal or fetal allelic effects (standardized effect size ≥ 0.01) of common HLA alleles on BW in the UKB. Applying our SEM to imputed classical HLA alleles and own and offspring BW of ∼270,000 participants from the UKB replicated the previously reported association at the HLA-C locus (C*04:01, P = 2.13×10−7, C*05:01, P= 6.91×10−5, C*03:03, P= 4.53×10−3, respectively) and revealed strong evidence for maternal (HLA-A*03:01, P = 7.90×10−8; B*35:01, P = 7.78×10−5; B*39:06, P = 8.49 ×10−5) and fetal allelic effects (HLA-B*39:06, P = 4.03×10−4) of non-HLA-C alleles on BW. These novel allelic associations between BW and classical HLA alleles provide insight into the immunogenetics of fetal growth in utero.
Show me your neighbour and I tell what you are: fisheye transformation for deep learning-based single-cell phenotyping
Authors: Toth Timea , Sukosd Farkas , Kaptas Flora , Bauer David , Horvath Peter
Published: August 2022

Recently we have concluded that image-based features derived from the microenvironment have an enormous impact on successfully determining the class of an object1. Here we demonstrate that deep learning-based phenotypic analysis of cells with a properly chosen microenvironment-size provides results comparable to our earlier neighbourhood-based methods that utilise hand-crafted image features. We hypothesised that treating cells with equal weight, regardless of their position within the cellular microenvironment, is suboptimal, and direct neighbours have a larger impact on the phenotype of the cell-of-interest than cells in its larger proximity. Hence we present a novel approach that (1) considers the fully featured view of the cell-of-interest, (2) includes the neighbourhood and (3) gives lesser weight to cells that are far from the cell. To achieve this, we present a transformation similar to those characteristic for fisheye cameras. Such a transformation satisfies all the above defined criteria, with a fast rate of transform for any images. Using the proposed transformation with proper settings we could significantly increase the accuracy of single-cell phenotyping, both in case of cell culture and tissue-based microscopy images. The range of potential applications of the proposed method goes beyond microscopy, as we present improved results on the iWildCam 2020 dataset containing images of wild animals.
Association between food environments and fetal growth in pregnant Brazilian women
Authors: Victor Audêncio , Gotine Ana Raquel Manuel , Falcão Ila R. , Ferreira Andrea , Flores-Ortiz Renzo , Xavier Sancho Pedro , Vasco Melsequisete Daniel , de Jesus Silva Natanael , Mahoche Manuel , Silva Rodrigues Osiyallê Akanni , da Cassia Ribeiro Rita , Rondó Patrícia H. , Barreto Maurício L.
Published: August 2022

Introduction

Birth weight is described as one of the main determinants of newborns’ chances of survival. Among the associated causes, or risk factors, the mother’s nutritional status strongly influences fetal growth and birth weight outcomes of the concept. This study evaluates the association between food deserts, small for gestational age (SGA), large for gestational age (LGA) and low birth weight (LBW) newborns.

Design

This is a cross-sectional population study, resulting from individual data from the Live Birth Information System (SINASC), and municipal data from mapping food deserts (CAISAN) in Brazil. The newborn’s size was defined as follows: appropriate for gestational age (between 10th and 90th percentile), SGA (<10th percentile), LGA (>90th percentile), and low birth weight <2,500g. To characterize food environments, we used tertiles of the density of establishments which sell in natura and ultra-processed foods. Logistic regression modeling was conducted to investigate the associations of interest.

Results

We analyzed 2,632,314 live births in Brazil in 2016. Following due adjustment, it was observed that women from municipalities in which there was a limited supply of in natura foods presented a higher chance of a SGA [OR2nd tertile:1.06 (1.05-1.07)] and LBW [OR2nd tertile: 1.11(1.09-1.12)] newborn. On the other hand, municipalities in which there was a greater supply of ultra-processed foods presented higher chances for a SGA [OR3rd tertile:1.04 (1.02-1.06)] and LBW [OR2nd tertile:1.13 (1.11-1.16)] newborn. Stratification showed that Black and Mixed/Brown women were associated with SGA [OR3rd tertile: 1.09 (1.01-1.18)] and [OR3rdtertile:1.06 (1.04-1.09)], respectively, and mixed-race women were also associated with LBW [OR3rd tertile:1.17 (1.14-1.20)], while indigenous women were associated with LGA [OR3rd tertile: 1.20(1.01-1.45)].

Conclusions

Living in areas with limited access to healthy foods was associated with an increased chance of SGA and low weight newborns, especially between Black and Mixed/Brown women. Initiatives focused on minimizing the effects of these food environments, and which aim to reduce social inequalities, are urgently required in the Brazilian context.
Monkeypox treatment with tecovirimat in the Central African Republic under an Expanded Access Programme
Authors: Mbrenga Festus , Nakouné Emmanuel , Malaka Christian , Bourner Josephine , Dunning Jake , Vernet Guy , Horby Peter , Olliaro Piero
Published: August 2022

Background

There is currently no specific treatment recommended for monkeypox. This expanded access programme (EAP) aims to provide tecovirimat to patients with monkeypox and collect data on patient treatment, disease evolution and outcomes under a protocol to contribute to the evidence-base for the use of the drug for monkeypox.

Methods

Patients with confirmed monkeypox received tecovirimat according to the recommended dosing. Data on clinical signs and symptoms were recorded daily during treatment and at follow-up visits. Blood or lesion samples were taken during treatment and at day 28 to assess viral presence of monkeypox by PCR. As tecovirimat is administered via an EAP, outcome measures were not predefined. Adverse events and clinical outcomes were monitored by evaluating the total number and location of lesions, temperature, degree of incapacity, presence of adverse events, patient survival, and viral presence throughout treatment and follow-up.

Results

We report outcomes in 14 patients who were enrolled between December 2021 and February 2022. Muscle pain, headache, lymphadenopathy, lesions, fever, back pain, and upper respiratory symptoms were commonly reported at admission and during follow-up. The rate of appearance of active lesions gradually decreased throughout treatment, with the median time to no new lesions being 5 days following the start of treatment. No death attributable to monkeypox occurred in this cohort.

Conclusions

Data collected through this EAP can help improve our knowledge about the use of tecovirimat for monkeypox. We have been able to document systematically the presentation and clinical and virological evolution of monkeypox under treatment.

Registration number

ISRCTN43307947
Analysis of a genetic region affecting mouse body weight
Authors: Leung Connie L.K. , Karunakaran Subashini , Atser Michael G. , Innala Leyla , Hu Xiaoke , Viau Victor , Johnson James D. , Clee Susanne M.
Published: August 2022

Genetic factors affect an individual’s risk of developing obesity, but in most cases each genetic variant has a small effect. Discovery of genes that regulate obesity may provide clues about its underlying biological processes and point to new ways the disease can be treated. Pre-clinical animal models facilitate genetic discovery in obesity because environmental factors can be better controlled compared to the human population. We studied inbred mouse strains to identify novel genes affecting obesity and glucose metabolism. BTBR T+ Itpr3tf/J (BTBR) mice are fatter and more glucose intolerant than C57BL/6J (B6) mice. Prior genetic studies of these strains identified an obesity locus on chromosome 2. Using congenic mice, we found that obesity was affected by a ~316 kb region, with only two known genes, pyruvate dehydrogenase kinase 1 (Pdk1) and integrin alpha 6 (Itga6). Both genes had mutations affecting their amino acid sequence and reducing mRNA levels. Both genes have known functions that could modulate obesity, lipid metabolism, insulin secretion and/or glucose homeostasis. We hypothesized that genetic variation in or near Pdk1 or Itga6 causing reduced Pdk1 and Itga6 expression would promote obesity and impaired glucose tolerance. We used knockout mice lacking Pdk1 or Itga6 fed an obesigenic diet to test this hypothesis. Under the conditions we studied, we were unable to detect an individual contribution of either Pdk1 or Itga6 to body weight. However, we identified a previously unknown role for Pdk1 in cardiac lipid metabolism providing the basis for future investigations in that area.
The seed germination spectrum of 528 plant species: a global meta-regression in relation to temperature and water potential
Authors: Maleki Keyvan , Soltani Elias , Seal Charlotte E. , Pritchard Hugh W. , Lamichhane Jay Ram
Published: August 2022

The germination niche of plant species depends primarily on the seeds’ responsiveness to temperature and water potential. However, to appreciate future climate risks to natural regeneration through germination, a global level synthesis across species is needed. We performed a meta-regression of primary data from 377 studies on 528 species, including trees, grasses, crops and wild species, to determine patterns and co-correlants in the cardinal values that define species’ germination niche. A negative correlation was found between thermal time and base temperature, and positive correlations between other cardinal temperatures and base temperature. Mean values of thermal time indicate that annual crops germinate more rapidly compared to wild species, potentially as a consequence of domestication, and tropical tree seeds the slowest. Dryland species (Cactaceae and Agavaceae) have the widest upper thermal and lower moisture niche, indicative of an ability to grow under harsh conditions, while forages have the narrowest thermal and moisture niche, suggesting higher sensitivity to frost or drought. We propose a new conceptual framework for understanding germination niche as shaped by thermal and moisture traits. Our database represents a unique source of information to further determine the vegetation boundaries of wild or cultivated species, including within simulation studies on plant species adaptations under changing land-use and climate.
Targeting keratin 17-mediated reprogramming of de novo pyrimidine biosynthesis to overcome chemoresistance in pancreatic cancer
Authors: Pan Chun-Hao , Chaika Nina V. , Tseng Robert , Siraj Md Afjalus , Chen Bo , Donnelly Katie L. , Horowitz Michael , Leiton Cindy V. , Chowdhury Sumedha , Roa-Peña Lucia , Oblein Lyanne , Marchenko Natalia , Singh Pankaj K. , Shroyer Kenneth R. , Escobar-Hoyos Luisa F.
Published: August 2022

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death. We previously reported keratin 17 (K17) as a novel negative prognostic and predictive biomarker, whose overexpression confers the resistance to chemotherapies. Here, we investigated the mechanisms of chemoresistance and tumor-specific vulnerabilities that can be exploited for targeted therapies for K17-expressing PDAC. Unbiased metabolomic studies in isogenic PDAC models identified several key metabolic pathways that are upregulated in the presence of K17. We demonstrate that K17 increases pyrimidine biosynthesis, a pathway that has been linked to chemoresistance. Patient dataset analysis revealed that K17 expression and enzymes involved in pyrimidine, but not purine, de novo biosynthesis is associated with shorter patient survival. Rescue experiments showed that deoxycytidine (dC) and deoxythymidine (dT) were sufficient to promote resistance to Gemcitabine (a dC analog) and 5-fluorouracil (a dT analog), respectively. Furthermore, K17-expressing cells were more sensitive to Brequinar, a specific inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in de novo pyrimidine biosynthetic pathway. Targeting DHODH by small interfering RNA or by Brequinar with Gemcitabine synergistically inhibited the viability of K17-positive PDAC cells. Importantly, the combination of Gemcitabine and Brequinar significantly inhibited the growth of K17-expressing tumors and extended survival of mice bearing K17-expressing PDACs. Overall, we identified a novel pathway of chemoresistance and a metabolic target of which could lead to the development of a biomarker-based therapy for K17-expressing PDAC.
Diel activity patterns of vector mosquito species in the urban environment: Implications for vector control strategies
Authors: Wilke André B. B. , Mhlanga Adequate , Kummer Allisandra G. , Vasquez Chalmers , Moreno Maday , Petrie William D. , Rodriguez Art , Vitek Christopher , Hamer Gabriel L. , Mutebi John-Paul , Ajelli Marco
Published: August 2022

Florida and Texas continue to be afflicted by mosquito-borne disease outbreaks such as dengue and West Nile virus disease and were the most affected states by the Zika outbreak of 2016-2017. Mathematical models have been widely used to study the population dynamics of mosquitoes as well as to test and validate the effectiveness of arbovirus outbreak responses and mosquito control strategies. The objective of this study is to assess the diel activity of mosquitoes in Miami-Dade, Florida and Brownsville, Texas, and to evaluate the effectiveness of simulated adulticide treatments on local mosquito populations. To assess variations in the diel activity patterns, mosquitoes were collected hourly for 96 hours once a month from May through November 2019 in Miami-Dade and Brownsville, Texas. We then performed a PERMANOVA followed by the SIMPER method to assess which species contributed the most to the observed differences. Finally, we used a mathematical model to simulate the population dynamics of 5 mosquito vector species to evaluate the effectiveness of the simulated adulticide applications. A total of 14,502 mosquitoes comprising 17 species were collected in Brownsville and 10,948 mosquitoes comprising 19 species were collected in Miami-Dade. Aedes aegypti was the most common mosquito species collected every hour in both cities and peaking in abundance in the morning and the evening. Our modeling results indicate that the effectiveness of adulticide applications varied greatly depending on the hour of the treatment. Overall, 9 PM was the best time for adulticide applications targeting all mosquito vector species in Miami-Dade and Brownsville. Our results indicate that the timing of adulticide spraying interventions should be carefully considered by local authorities based on the ecology of mosquito species in the focus area.