bluuebunny/crossref_metadata_2025 huggingface dataset:
Diversity detected in commensals at host and farm level reveals implications for national antimicrobial resistance surveillance programmes
Authors: Laird Tanya J. , Jordan David , Lee Zheng Zhou , O’Dea Mark , Stegger Marc , Truswell Alec , Sahibzada Shafi , Abraham Rebecca , Abraham Sam
Published: October 2021

Background

A key component to control of antimicrobial resistance (AMR) is the surveillance of food animals. Currently, national programmes test only limited isolates per animal species per year, an approach tacitly assuming that heterogeneity of AMR across animal populations is negligible. If the latter assumption is incorrect then the risk to humans from AMR in the food chain is underestimated.

Objectives

To demonstrate the extent of phenotypic and genetic heterogeneity of Escherichia coli in swine to assess the need for improved protocols for AMR surveillance in food animals.

Methods

Eight E. coli isolates were obtained from each of 10 pigs on each of 10 farms. For these 800 isolates, AMR profiles (MIC estimates for six drugs) and PCR-based fingerprinting analysis were performed and used to select a subset (n = 151) for WGS.

Results

Heterogeneity in the phenotypic AMR traits of E. coli was observed in 89% of pigs, with 58% of pigs harbouring three or more distinct phenotypes. Similarly, 94% of pigs harboured two or more distinct PCR-fingerprinting profiles. Farm-level heterogeneity was detected, with ciprofloxacin resistance detected in only 60% of pigs from a single farm. Furthermore, 58 STs were identified, with the dominant STs being ST10, ST101, ST542 and ST641.

Conclusions

Phenotypic and genotypic heterogeneity of AMR traits in bacteria from animal populations are real phenomena posing a barrier to correct interpretation of data from AMR surveillance. Evolution towards a more in-depth sampling model is needed to account for heterogeneity and increase the reliability of inferences.
Clinical and pathological analysis of companion diagnostic testing of microsatellite instability-high for pembrolizumab in gynaecologic malignancy
Authors: Takeda Takashi , Tsuji Kosuke , Kobayashi Yusuke , Banno Kouji , Aoki Daisuke
Published: October 2021

Background

Microsatellite instability-high is a known biomarker for anti-PD-1/PD-L1 immune checkpoint therapy. It is also a known tumour feature of Lynch syndrome, detected most frequently in endometrial cancer. However, it remains unclear how microsatellite instability testing is carried out in the clinical field.

Methods

Ninety-nine patients with gynaecological malignant tumours who underwent microsatellite instability testing as a companion diagnosis for pembrolizumab and 16 patients who previously underwent microsatellite instability testing as a screening for Lynch syndrome were recruited. Clinical information, microsatellite instability status, outcomes, genetic assessments and information about cancer tissue were retrospectively analysed.

Results

Ninety-nine patients had 101 gynaecologic malignant tumours including 26 endometrial, 38 ovarian and 28 cervical cancers, 9 with other tumours including 2 synchronous endometrial and ovarian cancers. All tissue samples were successfully tested, even though some were ≥10-year-old samples. Three cases (3.0%, 3/99) showed microsatellite instability-high; all cases were endometrial cancers with one case of synchronous endometrial and ovarian cancer [11.5% (3/26) in endometrial cancer, 2.6% (1/38) in ovarian cancer], and there was no microsatellite instability-high in cervical and other cancers. One of the endometrial cancer patients received pembrolizumab treatment, but finally died of cancer. Two other cases underwent genetic testing; both were diagnosed as Lynch syndrome. Six cases (37.5%) showed microsatellite instability-high in screening for Lynch syndrome.

Conclusions

Microsatellite instability-high was less commonly detected as a companion diagnosis for pembrolizumab in unselected gynaecologic patients. Genetic counselling should be always provided along with treatment selection.
Śaṅkaran Monism and the Limits of Thought
Authors: Gasparri Luca
Published: October 2021

A growing movement in contemporary philosophy of mind is looking back on Indian thought to gain new insights into the problem of consciousness. This paper weighs the prospects of thinking about mentality through the lenses of Śaṅkaran Advaita Vedānta. To start, I outline micropsychist and cosmopsychist accounts of consciousness, introduce Śaṅkaran monism, and describe a potential reason of attraction of the framework over micropsychist and cosmopsychist alternatives. I then show that the eliminativist commitments of the view threaten to yield a self-defeating account of ordinary experience, and that Advaitins took the accommodation of the issue to be beyond the reach of rational inquiry. Finally, I discuss how the analytical debate over Śaṅkaran monism might proceed based on these premises.
dbAMP 2.0: updated resource for antimicrobial peptides with an enhanced scanning method for genomic and proteomic data
Authors: Jhong Jhih-Hua , Yao Lantian , Pang Yuxuan , Li Zhongyan , Chung Chia-Ru , Wang Rulan , Li Shangfu , Li Wenshuo , Luo Mengqi , Ma Renfei , Huang Yuqi , Zhu Xiaoning , Zhang Jiahong , Feng Hexiang , Cheng Qifan , Wang Chunxuan , Xi Kun , Wu Li-Ching , Chang Tzu-Hao , Horng Jorng-Tzong , Zhu Lizhe , Chiang Ying-Chih , Wang Zhuo , Lee Tzong-Yi
Published: October 2021

The last 18 months, or more, have seen a profound shift in our global experience, with many of us navigating a once-in-100-year pandemic. To date, COVID-19 remains a life-threatening pandemic with little to no targeted therapeutic recourse. The discovery of novel antiviral agents, such as vaccines and drugs, can provide therapeutic solutions to save human beings from severe infections; however, there is no specifically effective antiviral treatment confirmed for now. Thus, great attention has been paid to the use of natural or artificial antimicrobial peptides (AMPs) as these compounds are widely regarded as promising solutions for the treatment of harmful microorganisms. Given the biological significance of AMPs, it was obvious that there was a significant need for a single platform for identifying and engaging with AMP data. This led to the creation of the dbAMP platform that provides comprehensive information about AMPs and facilitates their investigation and analysis. To date, the dbAMP has accumulated 26 447 AMPs and 2262 antimicrobial proteins from 3044 organisms using both database integration and manual curation of >4579 articles. In addition, dbAMP facilitates the evaluation of AMP structures using I-TASSER for automated protein structure prediction and structure-based functional annotation, providing predictive structure information for clinical drug development. Next-generation sequencing (NGS) and third-generation sequencing have been applied to generate large-scale sequencing reads from various environments, enabling greatly improved analysis of genome structure. In this update, we launch an efficient online tool that can effectively identify AMPs from genome/metagenome and proteome data of all species in a short period. In conclusion, these improvements promote the dbAMP as one of the most abundant and comprehensively annotated resources for AMPs. The updated dbAMP is now freely accessible at http://awi.cuhk.edu.cn/dbAMP.
Knowledge and Adoption of Complex Agricultural Technologies: Evidence from an Extension Experiment
Authors: Hörner Denise , Bouguen Adrien , Frölich Markus , Wollni Meike
Published: October 2021

In most of Sub-Saharan Africa, agricultural extension models have become more decentralized and participatory and thus rely on effective farmer-to-farmer learning, while increasingly including nontraditional forms of education. At the same time, agricultural technologies become more complex and are now often promoted as integrated packages, which are likely to increase the complexity of the diffusion process. Based on a randomized controlled trial, this study assesses the effects of “farmer-to-farmer” extension and a video intervention on adoption of a complex technology package among 2,382 smallholders in Ethiopia. Both extension-only and extension combined with video increase adoption and knowledge of the package, especially of its more complex components; on average, however, the video intervention has no additional effect on adoption. Knowledge and the number of adopted practices also increase among farmers not actively participating in extension activities, which suggests information diffusion. For this group, the additional video intervention has a reinforcing effect, and particularly fosters adoption of the integrated package.
Defining and Describing Terminal Ulcers in Adults at End of Life: An Integrative Review
Authors: Latimer Sharon , Walker Rachel M. , Ray-Barruel Gillian , Shaw Joanie , Mackrell Kristyn , Hunt Tracey , Gillespie Brigid M.
Published: October 2021

OBJECTIVE

The authors identify and synthesize the published primary literature on unavoidable skin breakdown and end-of-life wounds known as terminal ulcers.

DATA SOURCES

Sources were identified through a systematic search of the Cochrane Library, Medline, ProQuest, EMBASE, CINAHL complete, and PubMed databases.

STUDY SELECTION

The date limiters were set between 1984 and 2020 to locate primary qualitative, quantitative, and/or mixed-methods studies on terminal ulcers.

DATA EXTRACTION

Investigators examined 180 sources and ultimately included four quantitative studies in this review. All were conducted in the US and published between 1989 and 2019. Retrospective chart audits of deceased patients’ medical files were undertaken in three of the studies, and prospective observations were used in the fourth.

DATA SYNTHESIS

Descriptive and inductive content analyses were conducted. Three categories emerged: (1) distinguishing the ulcer development patterns, (2) identifying the ulcer characteristics, and (3) delivering specialized and individualized end-of-life care.

CONCLUSIONS

Limited primary evidence has been published on terminal ulcers. Pressure injuries and terminal ulcers have similar appearances, but their development differs significantly. The lack of a specific terminal ulcer assessment tool and staging system increases the risk of these unavoidable end-of-life wounds being incorrectly assessed and managed as pressure injuries. Further research on terminal ulcers is needed to inform clinical practice and ensure specialized care is delivered to patients who develop these wounds.
Bone in osteoarthritis: imaging and interventions
Authors: Khokhar Kiran , Conaghan Philip G.
Published: October 2021

Purpose of review

To review the recent literature on bone in osteoarthritis (OA), with a focus on imaging and intervention studies

Recent findings

Most studies focused on knee OA; hip and hand studies were uncommon. Bone shape studies demonstrated that shape changes precede radiographic OA, predict joint replacement, and have demonstrated high responsiveness. Novel quantitative 3D imaging markers (B-score) have better characterized OA severity, including preradiographic OA status. The addition of computerized tomography-derived 3D metrics has improved the prediction of hip joint replacement when compared to radiographs alone.

Recent studies of bisphosphonates for knee OA have reported no benefits on pain or bone marrow lesion (BML) size. A meta-analysis on Vitamin D supplementation in knee OA suggested minimal symptom improvement and no benefits on the structure. Cathepsin K inhibition demonstrated reduction in OA bone change progression, but with no symptom benefit. Studies of injections of bone substitutes into BMLs (subchondroplasty) have generally been small and potential benefits remain unclear.

Subchondral bone features are associated with pain, incidence and progression of OA. Recent studies have validated quantitative bone shape as a biomarker for OA trials. Trials of bone-targeted OA therapies have been disappointing although cathepsin K inhibition may slow structural progression.
Percutaneous hemiepiphysiodesis using transphyseal screws for adolescent tibia vara
Authors: Braga Susana R. , Akkari Miguel , Waisberg Gilberto , Sutton Carlos H. , Gama Natalia F. , Santili Claudio
Published: October 2021

Hemiepiphysiodesis around the knee is becoming the mainstay procedure in adolescents for a wide range of aetiological deformities, when considering adolescent tibia vara (ATV), the published series have variable results. The purpose of this study was to review our experience with the percutaneous transphyseal screw (PETS) in these patients followed until bone maturity. We analysed the charts from 13 patients (20 knees) that underwent lateral tibial hemiepiphysiodesis using PETS. The radiographs were accessed before surgery, at implant removal, when occurred, and at the final follow-up. The clinical evaluation noted if there were complaints regarding pain or range of motion, and the radiographic assessment included: the femorotibial angle, the mechanical axis zone, the anatomic lateral distal femoral angle, and medial mechanical proximal tibial angle. There was one overcorrection, and after the screw removal (14 knees), rebound was observed in two knees modifying the result from excellent to good in all three knees. No bone bars and no implant breakage were observed. At the last appointment, all patients had normal knee range of motion, and two patients had unilateral alignment complaints, one of whom referred to occasional pain. Overall, the surgery was excellent in 12 knees (60%), good in six knees (30%), and poor in two knees (10%). This technique is indicated to be well tolerated and effective for treating ATV. When a complete correction cannot be obtained, in our opinion, it is advantageous to at least stabilise the deformity and postpone osteotomies until after skeletal maturity. Level of Evidence: Level IV – Case Series, Therapeutic Study.
Impact of Sodium-Glucose Cotransporter-2 Inhibitors on Cardiac Bioenergetic Properties and Cardiorespiratory Fitness: A Special Effect of SGLT2i In Heart Failure?
Authors: Farooq Muhammad , Jorde Ulrich P.
Published: October 2021

Recent clinical trials have highlighted the profound benefits of sodium-glucose linked transporter 2 inhibitors (SGLT2i) on cardiovascular mortality and hospitalization for heart failure patients. Modest improvements in glycemic, lipid, or blood pressure control are unlikely to contribute to these significant beneficial outcomes, generating much interest in the relevant mechanisms leading to outcome improvements. In this review, we discuss the current evidence supporting a shift in myocardial substrate utilization from carbohydrates and fat oxidation toward energy efficient ketone bodies in the failing heart and the role of SGLT2i in this key metabolic adaptation to optimize myocardial fuel energetics. Further insights into the effect of SGLT2i on the indices of cardiorespiratory fitness are outlined and provide important clues into their mechanism of benefit. This mechanistic discussion in the context of recent trials of SGLT2i denotes a promising treatment paradigm of heart failure in individuals with and without diabetes.
Expression of proto-oncogene c-Myc in patients with urinary bladder transitional cell carcinoma
Authors: Fragkoulis Charalampos , Ntoumas Georgios , Glykas Ioannis , Papadopoulos Georgios , Stathouros Georgios , Kostopoulou Akrivi , Choreftaki Theodosia , Ntoumas Konstantinos
Published: October 2021

Background:

c-Myc is a proto-oncogene located on human chromosome 8. It encodes a transcriptional factor which regulates the expression of approximately 10% to 15% of human genes, playing a crucial role in cell growth, differentiation, cellular metabolism, apoptosis, and cell transformation. The aim of this study is to correlate the expression of c-Myc in patients suffering from urinary bladder transitional cell carcinoma with tumor grade, stage, and lymph node metastases.

Materials and methods:

Formalin-fixed, paraffin-embedded tissue samples were obtained from 54 consecutive patients who underwent transurethral resection of bladder tumor or radical cystectomy (RC) as treatment for urinary bladder transitional cell carcinoma. Immunohistochemistry was performed using c-Myc monoclonal antibody and c-Myc expression was then analyzed for correlation with tumor stage, grade, and lymph node metastases.

Results:

From a total of 54 patients, 42 (77.8%) had c-Myc positive staining and 12 (22.2%) were c-Myc negative. In the c-Myc positive group, 28 patients (66.7%) had low grade tumors and 33 (78.6%) presented with non-muscle-invasive disease (p < 0.05). In the c-Myc negative group, 10 patients (83.3%) had high-grade disease and 8 (66.7%) presented with muscle-invasive disease (p < 0.05). Lymph node metastases were evaluated in 17 patients who underwent RC. Of these, 5 had lymph node metastases, 4 of whom had c-Myc negative staining (p < 0.05).

Conclusions:

In our study, c-Myc negative staining was associated with higher grade and higher stage disease. On the contrary, most c-Myc positive tumors were low grade and non-muscle-invasive disease. In patients who underwent RC, c-Myc negative staining was associated with lymph node metastases.
Associations between different measures of intra-operative tachycardia during noncardiac surgery and adverse postoperative outcomes
Authors: Shcherbakov Anna , Bisharat Naiel
Published: October 2021

BACKGROUND

Intra-operative tachycardia during noncardiac surgery has been associated with adverse postoperative outcomes. However, harm thresholds for tachycardia have not been uniformly defined. The definition of intra-operative tachycardia that best correlates with adverse postoperative outcomes remains unclear.

OBJECTIVE

We aimed to identify the definition of intra-operative tachycardia during noncardiac surgery that is associated with the best predictive ability for adverse postoperative outcomes.

DESIGN

A single-centre retrospective cohort analysis.

SETTING

Secondary care hospital, Afula, Israel.

PATIENTS AND METHODS

Adults who underwent elective or nonelective noncardiac surgery during 2015 to 2019. Five intra-operative heart rate (HR) cut-off values and durations were applied with penalised logistic regression modelling for the outcome measures.

MAIN OUTCOME MEASURES

The primary outcome was all-cause 30-day mortality; the secondary outcome was myocardial ischaemia or infarction (MI) within 30 days after noncardiac surgery.

RESULTS

The derivation and validation datasets included 6490 and 4553 patients, respectively. Altogether, all-cause 30-day mortality and MI rates averaged 2.1% and 3.2%, respectively. Only two definitions of intra-operative tachycardia were significantly associated with the outcome measures: HR ≥ 100 bpm for ≥ 30 min and HR ≥ 120 bpm for ≥ 5 min. The C-statistics of the base models without tachycardia exposure for all-cause 30-day mortality and MI were 0.75 (95% confidence interval, CI, 0.74 to 0.78) and 0.73 (95% CI, 0.72 to 0.76), respectively. The addition of intra-operative tachycardia exposure to the base models significantly improved their predictive performance. The highest area under the curve (AUC) was achieved when tachycardia was defined as an intra-operative HR ≥ 100 bpm for at least 30 min: AUC 0.81 (95% CI, 0.80 to 0.84) and AUC 0.80 (95% CI, 0.79 to 0.82) for all-cause 30-day mortality and MI, respectively.

CONCLUSION

Intra-operative tachycardia, defined as an intra-operative HR ≥ 100 bpm for at least 30 min, was associated with the highest predictive power for adverse postoperative outcomes.
Efficacy of Hibiscus sabdariffa on Reducing Blood Pressure in Patients With Mild-to-Moderate Hypertension: A Systematic Review and Meta-Analysis of Published Randomized Controlled Trials
Authors: Abdelmonem Mohamed , Ebada Mahmoud Ahmed , Diab Sherein , Ahmed Mariam Mohamed , Zaazouee Mohamed Sayed , Essa Tarek Mohamed , ElBaz Zainab Salah , Ghaith Hazem S. , Abdella Walid Shaban , Ebada Mohamed , Negida Ahmed
Published: October 2021

We aimed to assess the efficacy of Hibiscus sabdariffa in patients with mild-to-moderate hypertension or metabolic syndrome (MetS) by comparing it against placebo, antihypertensive drugs, or other herbal products. Four databases were searched for randomized clinical trials (RCTs) examining the efficacy of H. sabdariffa in patients with mild-to-moderate hypertension or hypertension associated with MetS. Data on the change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were extracted and analyzed using Review Manager Version 5.3. A total of 13 RCTs (1205 participants) were analyzed. Hibiscus sabdariffa significantly reduced both SBP and DBP compared with placebo (mean difference −6.67, P = 0.004 and −4.35 mm Hg, P = 0.02). Subgroup analysis showed that change in SBP and DBP was statistically significant in patients with only hypertension, whereas not significant in patients with hypertension associated with MetS. When H. sabdariffa was compared with active controls (antihypertensive drugs or other herbals), the change in SBP and DBP was not statistically significant (all P > 0.05). Hibiscus sabdariffa is effective in reducing the SBP and DBP in patients with mild-to-moderate hypertension, but was neither effective in those with MetS nor superior to antihypertensive drugs. Further RCTs are required to determine the long-term efficacy of H. sabdariffa and to describe patients who would benefit most from this treatment.
In-vitro characterization of coding variants with predicted functional implications in the efflux transporter multidrug resistance protein 4 (MRP4, ABCC4)
Authors: Mailloux Jaymie , Medwid Samantha , Facey Amanda , Sung Inmo , Russell Laura E. , Tirona Rommel G. , Kim Richard B. , Schwarz Ute I.
Published: October 2021

MRP4 (gene ABCC4) is a polymorphic efflux transporter that has been implicated in drug-induced toxicity. We selected ten commonly observed MRP4 coding variants among Europeans for experimental characterization including nine variants predicted to be deleterious or functional (combined annotation-dependent depletion score >15). We assessed protein localization and activity by quantifying intracellular accumulation of two prototypic substrates, taurocholic acid (TCA) and estradiol 17-β-glucuronide (E217βG), in HEK293T over-expressing MRP4 wildtype or variant where cellular substrate loading was optimized through co-transfection with an uptake transporter. V458M, a novel variant not previously studied, and T1142M, showed reduced activity compared to MRP4 wildtype for E217βG and TCA (P < 0.01), while L18I, G187W, K293E, and R531Q moderately increased activity in a substrate-dependent manner. Protein expression analysis indicated reduced cell surface expression for V458M (P < 0.01) but not T1142M compared to wildtype. Reduced activity may result from altered surface expression (V458M) or intrinsic activity as both variants map within the nucleotide-binding domains of MRP4. G187W showed a trend for reduced surface expression (P = 0.054) despite transport comparable or increased to wildtype suggesting enhanced intrinsic activity. Our findings suggest moderately altered MRP4 activity in six out of nine predicted functional variants with likely different mechanisms and substrate-specific effects. Cell-based studies using multiple known substrates are warranted to more accurately predict functional variants in this clinically important transporter.
Automated 3D Analysis of Zygomaticomaxillary Fracture Rotation and Displacement
Authors: Prabhu Shamit S. , Chung Scotty A. , Rudolph Megan A. , Hemal Kshipra , Brown Philip J. , Runyan Christopher M.
Published: October 2021

Background:

The zygomaticomaxillary complex (ZMC) can experience a multitude of deforming forces. There is limited understanding on which deformities alter patient outcomes. This study utilized an automated, three-dimensional analysis to elucidate which fracture patterns and rotational deformities are most prevalent and associated with postoperative complications.

Methods:

This study was a 7-year retrospective review of patients with unilateral ZMC fractures who underwent surgical intervention. Patient demographics, injury mechanisms, presenting symptoms, and postoperative outcomes were collected. Segmentation was completed using Mimics software. The lateral-medial, superior-inferior, and anterior-posterior axes were manually identified on the zygoma and then displacement, rotational direction, and rotational degrees were automatically calculated using Geomagic software. Total displacement score was generated by summation of individual displacement scores at each of the five sutures.

Results:

Eighty-one patients satisfied inclusion criteria. The most prevalent rotational pattern of the zygoma was medially-superiorly-posteriorly (P < 0.001). When comparing rotation along the three axes, the zygoma had the greatest rotation along the lateral-medial axis compared with the superior-inferior (P = 0.003) and anterior-posterior (P < 0.001) axes. Within each axis, the zygoma was more likely to rotate medially than laterally (P = 0.003) and posteriorly than anteriorly (P = 0.01). Multivariate analysis identified total displacement scores and degrees rotated along the lateral-medial axis as significant predictors of facial complications and reoperation.

Conclusions:

This study suggests that patients with unilateral ZMC fractures who undergo surgical intervention are at an increased risk for adverse outcomes with greater rotation along the lateral-medial axis and higher total displacement scores. Additionally, the automated analysis method described can provide objective data to better characterize ZMC fractures.
Associations Between Central Obesity and Lifelong Antiviral Therapy in Adults Living With HIV Acquired From Early Childhood
Authors: Sahagun Seynt Jiro , Yeramosu Teja , Purdy Julia B. , Reynolds James C. , Hadigan Colleen M.
Published: October 2021

Background:

Little is known regarding the long-term effects of antiretroviral (ARV) exposure on body composition for people living with HIV (PLWH) since early childhood. This study explores changes in body fat distribution in relation to ARV exposure.

Methods:

We conducted a prospective study of adults with perinatal HIV (n = 70) using dual-energy X-ray absorptiometry and standard anthropometrics. Trunk to limb fat ratio and waist to hip ratio were compared cross-sectionally to 47 matched controls. Furthermore, changes in body composition and ARV exposure were evaluated longitudinally in a subset of 40 PLWH with a median follow-up of 7 years.

Results:

Cross-sectional comparisons of PLWH with controls revealed significantly higher waist to hip ratio, trunk to limb fat ratio, HOMA-IR, and triglycerides, whereas BMI did not differ. Among PLWH with longitudinal follow-up, the prevalence of overweight increased from 27.5% to 52.5% and obesity from 12.5% to 25%; waist to hip and trunk to limb fat ratios also increased (P < 0.0001). Changes in waist to hip ratio were positively correlated with longer exposure during follow-up to darunavir (r = 0.36; P = 0.02), whereas increases in trunk to limb fat ratio were positively correlated with longer exposure to stavudine (r = 0.39; P = 0.01) and didanosine (r = 0.39; P = 0.01) but inversely associated with emtricitabine (r = −0.33; P = 0.04). Increases in waist to hip ratio were correlated with increases in triglyceride levels (r = 0.35; P = 0.03).

Conclusion:

This study presents strong evidence for persistent and worsening central adiposity in young adults with lifelong HIV and extensive ARV exposure. As this cohort ages, continued evaluation of the body composition and metabolic impact of lifelong ARV therapy is warranted to optimize long-term health.
The Learning Curve of a Craniofacial Surgeon: A Retrospective Study of 100 Consecutive Cases
Authors: Sakamoto Yoshiaki , Miwa Tomoru
Published: October 2021

Mastering the techniques of craniofacial surgery is difficult owing to the small number of cases and the special skills required. To improve the outcomes of craniofacial surgery in Japan, the authors charted the progress of a craniofacial surgeon by reviewing the results for the 100 consecutive craniosynostosis cases, in which the authors performed fronto-orbital advancement (FOA). in this study, all FOA surgeries were performed by the first author beginning in 2012. The number of FOA surgeries previously performed by the surgeon at the time of the current surgery served as an indicator of his level of experience; the cases were grouped in 5 consecutive sets of 20. The preparation time before the operation, the operative time, and the amount of bleeding were retrospectively investigated. The operative and preparation times decreased as the surgeon's experience increased until a plateau was reached after 41 to 60 surgeries. Increases in operative time also corresponded to decreases in the amount of bleeding. Everyone has a learning curve, including surgeons performing craniofacial surgeries. Surgery is not performed by the surgeon alone. Reductions in preparation time, operative time, and the time needed to leave the operation room after the completion of the surgery were attributed to better collaborations with nurses and anesthesiologists. Hence, the growth of the team is very important to the success of the craniofacial surgeon and ensures safe and effective treatment of the patient.
Household contact tracing with intensified tuberculosis and HIV screening in South Africa: a cluster randomised trial
Authors: Martinson Neil A , Lebina Limakatso , Webb Emily L , Ratsela Andrew , Varavia Ebrahim , Kinghorn Anthony , Lala Sanjay G , Golub Jonathan E. , Bosch Zama , Motsomi Kegaugetswe P , MacPherson Peter
Published: October 2021

Background

Household contact tracing for tuberculosis (TB) may facilitate TB diagnosis and identify individuals who may benefit from TB preventive therapy (TPT). In this cluster-randomised trial, we investigated whether household contact tracing and intensive TB/HIV screening would improve TB-free survival.

Methods

Household contacts of index TB patients in two Provinces of South Africa were randomised to home tracing and intensive HIV/TB screening (sputum Xpert and culture; HIV testing with treatment linkage; and TPT, if eligible), or standard of care (SOC, clinic referral letters). The primary outcome was incident TB or death at 15-months. Secondary outcomes included tuberculin skin test (TST) positivity in children ≤14 years and undiagnosed HIV. (ISRCTN16006202).

Results

From December 2016-March 2019, 1,032 index patients (4,459 contacts) and 1,030 (4,129 contacts) were randomised to the intervention and SOC arms. 3.2% (69/2166) of intervention arm contacts had prevalent microbiologically-confirmed TB. At 15-months, the cumulative incidence of TB or death did not differ between the intensive screening (93/3230, 2.9%) and SOC (80/2600, 3.1%) arms (hazard ratio: 0.90, 95% confidence interval (CI): 0.66-1.24). TST positivity was higher in the intensive screening arm (38/845, 4.5%) compared to the SOC arm (15/800, 1.9%, odds ratio: 2.25, 95% CI: 1.07-4.72). Undiagnosed HIV was similar between arms (41/3185, 1.3% vs. 32/2543, 1.3%; odds ratio: 1.02, 95% CI: 0.64-1.64).

Conclusions

Household contact tracing with intensive screening and referral did not reduce incident TB or death. Providing referral letters to household contacts of index patients is an alternative strategy to home visits in high TB/HIV-prevalence settings.

Author Summary

In South Africa, household contacts of TB cases received referral letters or home-tracing with intensified TB/HIV screening. At 15-months, the cumulative incidence of TB or death did not differ between the intensive screening (93/3230, 2.9%) and SOC (80/2600, 3.1%) arms.
Building tools for machine learning and artificial intelligence in cancer research: best practices and a case study with the PathML toolkit for computational pathology
Authors: Rosenthal Jacob , Carelli Ryan , Omar Mohamed , Brundage David , Halbert Ella , Nyman Jackson , Hari Surya Narayanan , Allen Eliezer Mendel Van , Marchionni Luigi , Umeton Renato , Loda Massimo
Published: October 2021

Imaging datasets in cancer research are growing exponentially in both quantity and information density. These massive datasets may enable derivation of insights for cancer research and clinical care, but only if researchers are equipped with the tools to leverage advanced computational analysis approaches such as machine learning and artificial intelligence. In this work, we highlight three themes to guide development of such computational tools: scalability, standardization, and ease of use. We then apply these principles to develop PathML, a general-purpose research toolkit for computational pathology. We describe the design of the PathML framework and demonstrate applications in diverse use-cases. PathML is publicly available at www.pathml.com.
The Impact of SARS-CoV-2 Lineages (Variants) on the COVID-19 Epidemic in South Africa
Authors: Mabuka Thabo , Naidoo Natalie , Ncube Nesisa , Yiga Thabo , Ross Michael , Kurehwa Kuzivakwashe , Nare Mothabisi , Silaji Andrea , Ndemera Tinashe , Lemeke Tlaleng , Ademola Taiwo Ridwan , Macharia Willie , Sithole Mthokozisi
Published: October 2021

Emerging SARS-CoV-2 variants have been attributed to the occurrence of secondary and tertiary COVID-19 epidemic waves and also threatening vaccine efforts due to their immune invasiveness. Since the importation of SARS-CoV-2 in South Africa, with the first reported COVID-19 case on the 5th of March 2020, South Africa has observed 3 consecutive COVID-19 epidemic waves. The evolution of SARS-CoV-2 has played a significant role in the resurgence of COVID-19 epidemic waves in South Africa and across the globe. South Africa has a unique observation of the evolution of SARS-CoV-2, with distinct SARS-CoV-2 lineages dominating certain epidemic periods. This unique observation allows for an investigation of the detected SARS-CoV-2 lineages’ impact on COVID-19 transmissibility and severity through analysis of epidemiological data. In this study, inferential statistical analysis was conducted on South African COVID-19 epidemiological data to investigate the impact of SARS-CoV-2 lineages in the South African COVID-19 epidemiology. The general methodology in this study involved the collation of South African COVID-19 epidemiological data, the regression and normalisation of the epidemiological data, and inferential statistical analysis. This study shows that the evolution of SARS-CoV-2 resulted in an increase in COVID-19 transmissibility and severity in South Africa. The Delta SARS-CoV-2 VOC resulted in increased COVID-19 transmissibility in the South African population by 53.9 to 54.8 % more than the Beta SARS-CoV-2 VOC and the predominantly B.1.1.54, B.1.1.56 C.1 SA SARS-CoV-2 lineage cluster. The Beta SARS-CoV-2 VOC resulted in more severe COVID-19 in South Africa than the Delta SARS-CoV-2 VOC. While, both the Beta and Delta SARS-CoV-2 VOC resulted in more severe COVID-19 than the initial SARS-CoV-2 lineages detected in South Africa’s first epidemic wave period. The Delta, Beta SARS-CoV-2 VOCs and the predominantly B.1.1.54, B.1.1.56 C.1 SA SARS-CoV-2 lineage cluster were observed to cause similar COVID-19 hospital case fatality and discharge rates in South African hospitals.
An updated framework to account for inter-individual variability when quantifying phenotypic variation
Authors: Puglielli Giacomo , Carmona Carlos P. , Varone Laura , Laanisto Lauri , Ricotta Carlo
Published: October 2021

In trait-based ecology, phenotypic variation (PVar) is often quantified with measures that express average differences between populations standardized in the range 0-1. A major problem with these measures is that they disregard the within-population trait variability. In addition, most of these measures cannot be decomposed across scales. This can alter their interpretation, thus limiting their applicability.

To overcome these problems, we propose a new measure, the Phenotypic Dissimilarity Index (PhD) that is insensitive to the within-population interindividual trait variability. Likewise, PhD can be used to quantify PVar between individuals in a population while accounting for the PVar within individuals.

Using simulated and real data, we showed that PhD index correctly quantifies PVar when the within-population trait variability is not negligible, as in many ecological studies. By accounting for within-population trait variability, the PhD index generally provides a more parsimonious quantification of PVar across an environmental gradient compared to other estimators.

Traits sampled within a species have an inherent variability. Accounting for such variability is essential to understand species phenotypic responses to environmental cues. As such, the PhD index will provide ecologists with an asset to reliably quantify and compare PVar within and between species across environmental gradients at different scales. We also provide an R function to calculate the PhD index.
Fitness tracking reveals task-specific associations between memory, mental health, and physical activity
Authors: Manning Jeremy R. , Notaro Gina M. , Chen Esme , Fitzpatrick Paxton C.
Published: October 2021

Physical activity can benefit both physical and mental well-being. Different forms of exercise (e.g., aerobic versus anaerobic; running versus walking, swimming, or yoga; high-intensity interval training versus endurance workouts; etc.) impact physical fitness in different ways. For example, running may substantially impact leg and heart strength but only moderately impact arm strength. We hypothesized that the mental benefits of physical activity might be similarly differentiated. We focused specifically on how different intensities of physical activity might relate to different aspects of memory and mental health. To test our hypothesis, we collected (in aggregate) roughly a century’s worth of fitness data. We then asked participants to fill out surveys asking them to self-report on different aspects of their mental health. We also asked participants to engage in a battery of memory tasks that tested their short and long term episodic, semantic, and spatial memory performance. We found that participants with similar physical activity habits and fitness profiles tended to also exhibit similar mental health and task performance profiles. These effects were task-specific in that different physical activity patterns or fitness characteristics varied with different aspects of memory, on different tasks. Taken together, these findings provide foundational work for designing physical activity interventions that target specific components of cognitive performance and mental health by leveraging low-cost fitness tracking devices.
A model that predicts resistant starch in a dog kibble using a small-scale twin-screw extruder
Authors: Alvarenga Isabella Corsato , Waldy Christopher , Keller Lewis C. , Aldrich Charles G.
Published: October 2021

The objective of this work was to modify extrusion parameters to yield greater resistant starch (RS) in a kibble and create a model to predict its concentration. A dog food was extruded through a small-scale twin-screw extruder as a central composite design with 6 central points (replicates) and 14 single replicates. There were three factors tested at three levels: corn particle size, extruder shaft speed, and in-barrel moisture (IBM). The remaining processing inputs were kept constant. Chemical and physical starch analyses were performed. A model to predict RS was created using the REG procedure from SAS. Pearson correlations between extrusion parameters and starch analyses were conducted. A model to predict RS was created (R2adj= 0.834; P < .0001). Both SME and extrudate temperature had a high negative correlation with RS and RVA raw starch. Results suggest that low mechanical energy and high IBM increase kibble RS.
A humanized nanobody phage display library yields potent binders of SARS CoV-2 spike
Authors: Fu Ying , Rezende e Mello Juliana da Fonseca , Fleming Bryan D. , Renn Alex , Chen Catherine Z. , Hu Xin , Xu Miao , Gorshkov Kirill , Hanson Quinlin , Zheng Wei , Lee Emily M. , Perera Lalith , Petrovich Robert , Pradhan Manisha , Eastman Richard T. , Itkin Zina , Stanley Thomas , Hsu Allen , Dandey Venkata , Gillette William , Taylor Troy , Ramakrishnan Nitya , Perkins Shelley , Esposito Dominic , Oh Eunkeu , Susumu Kimihiro , Wolak Mason , Ferrer Marc , Hall Matthew D. , Borgnia Mario J. , Simeonov Anton
Published: October 2021

Neutralizing antibodies targeting the SARS-CoV-2 spike protein have shown a great preventative/therapeutic potential. Here, we report a rapid and efficient strategy for the development and design of SARS-CoV-2 neutralizing humanized nanobody constructs with sub-nanomolar affinities and nanomolar potencies. CryoEM-based structural analysis of the nanobodies in complex with spike revealed two distinct binding modes. The most potent nanobody, RBD-1-2G(NCATS-BL8125), tolerates the N501Y RBD mutation and remains capable of neutralizing the B.1.1.7 (Alpha) variant. Molecular dynamics simulations provide a structural basis for understanding the neutralization process of nanobodies exclusively focused on the spike-ACE2 interface with and without the N501Y mutation on RBD. A primary human airway air-lung interface (ALI) ex vivo model showed that RBD-1-2G-Fc antibody treatment was effective at reducing viral burden following WA1 and B.1.1.7 SARS-CoV-2 infections. Therefore, this presented strategy will serve as a tool to mitigate the threat of emerging SARS-CoV-2 variants.
A suspension technique for efficient large-scale cancer organoid culturing and perturbation screens
Authors: Price Stacey , Bhosle Shriram , Gonçalves Emanuel , Li Xiaodun , McClurg Dylan P , Barthorpe Syd , Beck Alex , Hall Caitlin , Lightfoot Howard , Farrow Luke , Ansari Rizwan , Jackson David A , Allen Laura , Roberts Kirsty , Beaver Charlotte , Francies Hayley E , Garnett Mathew J
Published: October 2021

Organoid cell culture methodologies are enabling the generation of cell models from healthy and diseased tissue. Patient-derived cancer organoids that recapitulate the genetic and histopathological diversity of patient tumours are being systematically generated, providing an opportunity to investigate novel cancer biology and therapeutic approaches. The use of organoid cultures for many applications, including genetic and chemical perturbation screens, is limited due to the technical demands and cost associated with their handling and propagation. Here we report and benchmark a suspension culture technique for cancer organoids which allows for the expansion of models to tens of millions of cells with increased efficiency in comparison to standard organoid culturing protocols. Using whole-genome DNA and RNA sequencing analyses, as well as medium-throughput drug sensitivity testing and genome-wide CRISPR-Cas9 screening, we demonstrate that cancer organoids grown as a suspension culture are genetically and phenotypically similar to their counterparts grown in standard conditions. This culture technique simplifies organoid cell culture and extends the range of organoid applications, including for routine use in large-scale perturbation screens.
Protection from SARS-CoV-2 Delta one year after mRNA-1273 vaccination in nonhuman primates is coincident with an anamnestic antibody response in the lower airway
Authors: Gagne Matthew , Corbett Kizzmekia S. , Flynn Barbara J. , Foulds Kathryn E. , Wagner Danielle A. , Andrew Shayne F. , Todd John-Paul M. , Honeycutt Christopher Cole , McCormick Lauren , Nurmukhambetova Saule T. , Davis-Gardner Meredith E. , Pessaint Laurent , Bock Kevin W. , Nagata Bianca M. , Minai Mahnaz , Werner Anne P. , Moliva Juan I. , Tucker Courtney , Lorang Cynthia G. , Zhao Bingchun , McCarthy Elizabeth , Cook Anthony , Dodson Alan , Mudvari Prakriti , Roberts-Torres Jesmine , Laboune Farida , Wang Lingshu , Goode Adrienne , Kar Swagata , Boyoglu-Barnum Seyhan , Yang Eun Sung , Shi Wei , Ploquin Aurélie , Doria-Rose Nicole , Carfi Andrea , Mascola John R. , Boritz Eli A. , Edwards Darin K. , Andersen Hanne , Lewis Mark G. , Suthar Mehul S. , Graham Barney S. , Roederer Mario , Moore Ian N. , Nason Martha C. , Sullivan Nancy J. , Douek Daniel C. , Seder Robert A.
Published: October 2021

mRNA-1273 vaccine efficacy against SARS-CoV-2 Delta wanes over time; however, there are limited data on the impact of durability of immune responses on protection. We immunized rhesus macaques at weeks 0 and 4 and assessed immune responses over one year in blood, upper and lower airways. Serum neutralizing titers to Delta were 280 and 34 reciprocal ID50 at weeks 6 (peak) and 48 (challenge), respectively. Antibody binding titers also decreased in bronchoalveolar lavage (BAL). Four days after challenge, virus was unculturable in BAL and subgenomic RNA declined ∼3-log10 compared to control animals. In nasal swabs, sgRNA declined 1-log10 and virus remained culturable. Anamnestic antibody responses (590-fold increase) but not T cell responses were detected in BAL by day 4 post-challenge. mRNA-1273-mediated protection in the lungs is durable but delayed and potentially dependent on anamnestic antibody responses. Rapid and sustained protection in upper and lower airways may eventually require a boost.
The proteasome regulator PSME4 drives immune evasion and abrogates anti-tumor immunity in NSCLC
Authors: Javitt Aaron , Shmueli Merav D. , Kramer Matthias P , Kolodziejczyk Aleksandra A. , Cohen Ivan J. , Kamer Iris , Litchfield Kevin , Bab-Dinitz Elizabeta , Zadok Oranit , Neiens Vanessa , Ulman Adi , Radomir Lihi , Wolf-Levy Hila , Eisenberg-Lerner Avital , Kacen Assaf , Alon Michal , Rêgo Ana Toste , Stacher-Priehse Elvira , Lindner Michael , Koch Ina , Bar Jair , Swanton Charles , Samuels Yardena , Levin Yishai , da Fonseca Paula C. A. , Elinav Eran , Friedman Nir , Meiners Silke , Merbl Yifat
Published: October 2021

Protein degradation by proteasomes is important for the immune response against tumors. Antigens generated by the proteasome promote immune cell infiltration into tumors and improve tumors’ responses to immunotherapy. For example, immunoproteasomes – a subset of proteasomes induced by inflammatory signals – may improve the response of melanomas to immune checkpoint inhibitors (ICI) by eliciting tumor inflammation. Yet, it is unclear whether and how protein degradation by proteasomes impacts cancer progression and contributes to immune evasion and resistance. Here, we profile the proteasome-cleaved peptides in lung cancers and find that PSME4 serves as a novel inhibitory regulator of the immunoproteasome, playing an anti-inflammatory role in cancer. Biochemical assays combined with scRNA-seq, immunopeptidomics and in vivo analyses demonstrate that PSME4 promotes an immunosuppressive environment around the tumor and abrogates anti-tumor immunity by inhibiting antigen presentation and attenuating tumor inflammation. Furthermore, we find that PSME4 expression is correlated with responsiveness to ICI across several cancer types. Our findings suggest that PSME4-mediated regulation of proteasome activity is a novel mechanism of immune evasion in non-small-cell lung carcinoma and may be targeted therapeutically for restoring anti-tumor immunity.

Graphical Abstract

Highlights

Mapping the degradation landscape in Non-Small Cell Lung Cancer (NSCLC) uncovers altered proteasome activity and composition

Proteasome regulator PSME4 plays an anti-inflammatory role in NSCLC by attenuating immunoproteasome activity

PSME4 restricts tumor antigen presentation and cytokine secretion, defining a ‘cold’ tumor environment

PSME4 drives tumor immune evasion and is associated with resistance to immunotherapy