bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decoding ‘Unnecessary Complexity’: A Law of Complexity and a Concept of Hidden Variation Behind “Missing Heritability” in Precision Medicine
Authors: Singh Rama S. 
Published: August 2021

AbstractThe high hopes for the Human Genome Project and personalized medicine were not met because the relationship between genotypes and phenotypes turned out to be more complex than expected. In a previous study we laid the foundation of a theory of complexity and showed that because of the blind nature of evolution, and molecular and historical contingency, cells have accumulated unnecessary complexity, complexity beyond what is necessary and sufficient to describe an organism. Here we provide empirical evidence and show that unnecessary complexity has become integrated into the genome in the form of redundancy and is relevant to molecular evolution of phenotypic complexity. Unnecessary complexity creates uncertainty between molecular and phenotypic complexity, such that phenotypic complexity (CP) is higher than molecular complexity (CM), which is higher than DNA complexity (CD). The qualitative inequality in complexity is based on the following hierarchy: CP > CM > CD. This law-like relationship holds true for all complex traits, including complex diseases. We present a hypothesis of two types of variation, namely open and closed (hidden) systems, show that hidden variation provides a hitherto undiscovered “third source” of phenotypic variation, beside genotype and environment, and argue that “missing heritability” for some complex diseases is likely to be a case of “diluted heritability”. There is a need for radically new ways of thinking about the principles of genotype–phenotype relationship. Understanding how cells use hidden, pathway variation to respond to stress can shed light on why two individuals who share the same risk factors may not develop the same disease, or how cancer cells escape death.
Effectiveness of Repair of Aortic Coarctation in Neonates: A Long-Term experience
Authors: Minotti Chiara , Scioni Manuela , Castaldi Biagio , Guariento Alvise , Biffanti Roberta , Di Salvo Giovanni , Vida Vladimiro , Padalino Massimo A. 
Published: August 2021

AbstractTo evaluate early and long-term results of surgical treatment of aortic coarctation (CoAo) in neonates. This is a retrospective clinical review of neonates with CoAo, who underwent surgery between 1995 and 2019. Data were retrieved from our institutional database, to identify preoperative and postoperative characteristics. Statistical analysis was performed by means of relative risk ratio and Cox and logistic multivariate analysis. 218 consecutive neonates (M/F: 129/89, median age 11 days, IQR 7–17 days) were included; 202 (92.7%) had a left thoracotomy; 178 underwent extended end-to-end anastomosis (EEEA, 81.6%). Hypoplastic aortic arch (HAA) was present in 102 patients (46.8%); complex cardiac anomalies in 85 (39%). Significant postoperative complications occurred in 20 (9.2%). Thirty-day mortality was 2.3% (most in complex types). At a median follow-up of 10.4 years (IQR 5.6–15.0 years; FU completeness 95.9%), there were 8 late deaths (3.7%), all associated to complex CoAo. Among 196 survivors, 177 (93.2%) were in NYHA class I; re-interventions on aortic arch occurred in 9.2% (2.0% were surgical). Freedom from mortality and re-intervention on aorta at 10 years were 94.3% and 96.7%, respectively. Surgical repair of CoAo in newborns without CPB in our series was safe and low-risk, with excellent early and late outcomes.
We Asked the Experts: The Role of Rural Hospitals in Achieving Equitable Surgical Access in Low‐Resourced Settings
Authors: Chu Kathryn , Maine Rebecca , Duvenage Riaan 
Published: August 2021

AbstractStrengthening and defining the role of rural hospitals within a surgical ecosystem is essential to improving quality and timely surgical access for rural people in low and middle‐income countries (LMICs). Regional hospitals are the cornerstone of LMIC rural surgical care but have insufficient human resources and infrastructure that limit the surgical care they can provide. District hospitals are most accessible for many rural patients but also have limited surgical capacity. In order to surgical access for rural people, both regional and district hospital surgical services must be strengthened. A strong relationship between regional and district hospitals through a hub and spoke model is needed. Regional hospital surgeons can support training and supervision for and referrals from district hospitals. Telemedicine can play a key role to leapfrog physical barriers and surgical specialist shortages. The changing demographics of surgical disease will continue to worsen the strain on tertiary hospitals where most subspecialists in LMICs work. The fewer rural patients who need to travel to urban referral and tertiary facilities for problems that can be managed at lower‐level facilities, the better access to timely surgical care for all.
The female mouse is resistant to mild vitamin B3 deficiency
Authors: van der Stelt Inge , Shi Wenbiao , Bekkenkamp-Grovenstein Melissa , Zapata-Pérez Rubén , Houtkooper Riekelt H. , de Boer Vincent C. J. , Hegeman Maria A. , Keijer Jaap 
Published: August 2021

Abstract
Purpose
Vitamin B3 provides nicotinamide adenine dinucleotide (NAD+), an essential coenzyme in oxidoreductase reactions. Severe vitamin B3 deficiency leads to the disease Pellagra, while mild vitamin B3 deficiency has been linked to age-related and metabolic diseases. Mild vitamin B3 deficiency is understudied, especially in females. Therefore, we examined how female mice responded to a diet that induced mild vitamin B3 deficiency in male mice.

Methods
Female C57BL/6RccHsd mice were subjected for 18 weeks to a diet without vitamin B3 and low but sufficient tryptophan (0.115%) (0NR) and were compared to control female mice on the same diet with the reference dose of vitamin B3 (30NR, 30 mg nicotinamide riboside/ kg diet).

Results
In the female mice, no differences between the two dietary groups were found in liver nicotinamide mononucleotide (NMN) levels, body composition, whole body energy and substrate metabolism measured by indirect calorimetry, or liver triacylglycerol metabolism. Expression of seven genes that previously were shown to respond to mild vitamin B3 deficiency in male white adipose tissue were not differentially expressed between the female dietary groups, neither was insulin sensitivity.

Conclusion
We concluded that the female 0NR mice were not vitamin B3 deficient; the role of age, sex and health status is discussed. Demonstrated by clear differences between females and males, the latter showing mild deficiency under the same conditions, this study highlights the importance of studying both sexes.
Lessons learned with the Cobra prosthesis in elderly patients with complex distal radius fractures—a retrospective follow-up study
Authors: Benedikt Stefan , Kaiser Peter , Schmidle Gernot , Kastenberger Tobias , Stock Kerstin , Arora Rohit 
Published: August 2021

AbstractIntroductionRecently, the Cobra prostheses were introduced in the treatment of distal radius fractures (DRF) of elderly patients. Fracture prostheses provide an alternative treatment option for complex fractures where conservative therapy seems not acceptable and osteosynthesis seems not possible. Data reporting the feasibility of the Cobra prosthesis are sparse. Therefore, this retrospective follow-up study investigated the clinical and radiological mid-term outcome of the Cobra implant in complex DRFs of elderly patients.Materials and methodsThirteen patients (mean age 73.5 years, range 65–87 years) were retrospectively evaluated with at least a 1-year follow-up after surgery. Objective and subjective clinical parameters as well as the radiological outcome and complications were analyzed.ResultsThe mean follow-up period was 31.2 months. Seven cases required a cemented prosthesis. The mean relative range-of-motion compared to the healthy side was 72.3% and 51.8% for extension and flexion, respectively, and 87.9% and 85.7% for pronation and supination, respectively. The mean grip strength was 78.3% compared to the non-operated side. Eight patients were very satisfied, five patients were partly satisfied with the result. The DASH, PRWE, MHQ and Lyon-Scores averaged 39.1, 36.2, 64.9 and 63.3 points, respectively. The mean VAS-Score for pain was 1.1 at rest and 3.2 during activities. Perioperative complications included one dissection of the extensor pollicis longus tendon, one heterotopic ossification, one radiocarpal dislocation and two cases of an ulnar impaction syndrome due to implant subsidence.ConclusionThe prosthetic treatment of complex DRFs in elderly patients with the Cobra implant led to clinically and radiologically satisfactory mid-term results. The Cobra prosthesis still does not represent a gold standard but can be regarded as a feasible salvage option for complex DRFs when osteosyntheses may not be possible and non-operative treatment will lead to further functional restrictions and wrist pain during performing activities of daily life in high functional demand patients.
Lateral femoral notch sign and posterolateral tibial plateau fractures and their associated injuries in the setting of an anterior cruciate ligament rupture
Authors: Korthaus Alexander , Warncke Malte , Pagenstert Geert , Krause Matthias , Frosch Karl-Heinz , Kolb Jan Philipp 
Published: August 2021

Abstract
Introduction
ACL injury is one of the most common injuries of the knee joint in sports. As accompanying osseous injuries of the ACL rupture a femoral impression the so-called lateral femoral notch sign and a posterolateral fracture of the tibial plateau are described. However, frequency, concomitant ligament injuries and when and how to treat these combined injuries are not clear. There is still a lack of understanding with which ligamentous concomitant injuries besides the anterior cruciate ligament injury these bony injuries are associated.

Materials and methods
One hundred fifteen MRI scans with proven anterior cruciate ligament rupture performed at our center were retrospectively evaluated for the presence of a meniscus, collateral ligament injury, a femoral impression, or a posterolateral impression fracture. Femoral impressions were described according to their local appearance and posterolateral tibial plateau fractures were described using the classification of Menzdorf et al.

Results
In 29 cases a significant impression in the lateral femoral condyle was detected. There was a significantly increased number of lateral meniscal (41.4% vs. 18.6% p = 0.023) and medial ligament (41.4% vs. 22.1%; p = 0.040) injuries in the group with a lateral femoral notch sign. 104 patients showed a posterolateral bone bruise or fracture of the tibial plateau. Seven of these required an intervention according to Menzdorf et al. In the group of anterior cruciate ligament injuries with posterolateral tibial plateau fracture significantly more lateral meniscus injuries were seen (p = 0.039).

Conclusion
In the preoperative planning of ACL rupture accompanied with a positive femoral notch sign, attention should be paid to possible medial collateral ligament and lateral meniscus injuries. As these are more likely to occur together. A posterolateral impression fracture of the tibial plateau is associated with an increased likelihood of the presence of a lateral meniscal injury. This must be considered in surgical therapy and planning and may be the indication for necessary early surgical treatment.
Outcome measures assisting treatment optimization in multiple sclerosis
Authors: Pardo Gabriel , Coates Samantha , Okuda Darin T. 
Published: August 2021

Abstract
Objective
To review instruments used to assess disease stability or progression in persons with multiple sclerosis (pwMS) that can guide clinicians in optimizing therapy.

Methods
A non-systematic review of scientific literature was undertaken to explore modalities of monitoring symptoms and the disease evolution of MS.

Results
Multiple outcome measures, or tools, have been developed for use in MS research as well as for the clinical management of pwMS. Beginning with the Expanded Disability Status Scale, introduced in 1983, clinicians and researchers have developed monitoring modalities to assess all aspects of MS and the neurological impairment it causes.

Conclusions
Much progress has been made in recent decades for the management of MS and for the evaluation of disease progression. New technology, such as wearable sensors, will provide new opportunities to better understand changes in function, dexterity, and cognition. Essential work over the decades since EDSS was introduced continues to improve our ability to treat this debilitating disease.
One-year outcomes of microhook trabeculotomy versus suture trabeculotomy ab interno
Authors: Yokoyama Hiroshi , Takata Masashi , Gomi Fumi 
Published: August 2021

Abstract
Purpose
To compare clinical success rates and reductions in intraocular pressure (IOP) and IOP-lowering medication use following suture trabeculotomy ab interno (S group) or microhook trabeculotomy (μ group).

Methods
This retrospective review collected data from S (n = 104, 122 eyes) and μ (n = 42, 47 eyes) groups who underwent treatment between June 1, 2016, and October 31, 2019, and had 12-month follow-up data including IOP, glaucoma medications, complications, and additional IOP-lowering procedures. The Kaplan–Meier survival analysis was used to evaluate treatment success rates defined as normal IOP (> 5 to ≤ 18 mm Hg), ≥ 20% reduction of IOP from baseline at two consecutive visits, and no further glaucoma surgery.

Results
Schlemm’s canal opening was longer in the S group than in the μ group (P < 0.0001). The Kaplan–Meier survival analysis of all eyes showed cumulative clinical success rates in S and µ groups were 71.1% and 61.7% (P = 0.230). The Kaplan–Meier survival analysis of eyes with preoperative IOP ≥ 21 mmHg showed cumulative clinical success rates in S and μ groups were 80.4% and 60.0% (P = 0.0192). There were no significant differences in postoperative IOP at 1, 3, and 6 months (S group, 14.9 ± 5.6, 14.6 ± 4.5, 14.6 ± 3.9 mmHg; μ group, 15.8 ± 5.9, 15.2 ± 4.4, 14.7 ± 3.7 mmHg; P = 0.364, 0.443, 0.823), but postoperative IOP was significantly lower in the S group at 12 months (S group, 14.1 ± 3.1 mmHg; μ group, 15.6 ± 4.1 mmHg; P = 0.0361). There were no significant differences in postoperative numbers of glaucoma medications at 1, 3, 6, and 12 months (S group, 1.8 ± 1.6, 1.8 ± 1.5, 2.0 ± 1.6, 1.8 ± 1.5; μ group, 2.0 ± 1.6, 2.0 ± 1.6, 2.1 ± 1.6, 2.2 ± 1.7; P = 0.699, 0.420, 0.737, 0.198).

Conclusion
S and µ group eyes achieved IOP reduction, but μ group eyes had lower clinical success rates among patients with high preoperative IOP at 12 months.
Immune checkpoint inhibitor treatment induces colitis with heavy infiltration of CD8 + T cells and an infiltration pattern that resembles ulcerative colitis
Authors: Hone Lopez Sara , Kats-Ugurlu Gursah , Renken Remco J. , Buikema Henk J. , de Groot Marco R. , Visschedijk Marijn C. , Dijkstra Gerard , Jalving Mathilde , de Haan Jacco J. 
Published: August 2021

AbstractColitis is a common, but poorly understood, adverse event of immune checkpoint inhibitors that are standard-of-care for an expanding range of cancer types. This explorative study aimed to describe the immune infiltrates in the colon from individuals developing checkpoint inhibitor colitis and compare them to well-known immunophenotypes of acute graft-versus-host disease, ulcerative colitis, and Crohn’s disease. Colon biopsies (n = 20 per group) of patients with checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis and Crohn’s disease, all colitis treatment-naïve, and of individuals with a normal colon were analyzed using immunohistochemistry: CD8 for cytotoxic T cells, CD4 for T helper cells, and CD68 to identify cells of macrophage lineage. CD8 + T cell, CD4 + T cell, and CD68 + cell counts were performed. Cell infiltration was scored as scattered/patchy or band-like in the superficial and deep gut mucosa. Checkpoint inhibitor colitis was found to be heavily infiltrated by CD8 + T cells. Comparative analysis between groups showed that both CD8 + T cell counts (P < 0.01) and immune cell infiltration patterns in checkpoint inhibitor colitis were most similar to those observed in ulcerative colitis, with a deep band-like CD4 + T cell infiltration pattern and a superficial band-like CD68 + cell infiltration pattern in both. In conclusion, this is the first immunohistopathological study comparing infiltrate characteristics of checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis, and Crohn’s disease. Checkpoint inhibitor colitis samples are heterogeneous, heavily infiltrated by CD8 + T cells, and show an immune cell infiltration pattern that is more similar to ulcerative colitis than to colonic acute graft-versus-host disease or colonic Crohn’s disease.
Effectiveness of experimental and commercial pertussis vaccines in the elimination of Bordetella pertussis isolates with different genetic profiles in murine model
Authors: Prygiel Marta , Mosiej Ewa , Wdowiak Karol , Górska Paulina , Polak Maciej , Lis Klaudia , Krysztopa-Grzybowska Katarzyna , Zasada Aleksandra Anna 
Published: August 2021

AbstractThe aim of this study was to compare the elimination of Bordetella pertussis clinical isolates, representing different genotypes in relation to alleles encoding virulence factors (MLST—multi-locus antigen sequence typing), MLVA type (multi-locus variable-number tandem repeat analysis) and PFGE group (pulsed-field gel electrophoresis) from the lungs of naive mice or mice were immunised with the commercial whole-cell pertussis vaccine, the acellular pertussis vaccine and the experimental whole-cell pertussis vaccine. Molecular data indicate that the resurgence of pertussis in populations with high vaccine coverage is associated with genomic adaptation of B. pertussis, to vaccine selection pressure. Pertactin-negative B. pertussis isolates were suspected to contribute to the reduced vaccine effectiveness. It was shown that one of the isolates used is PRN deficient. The mice were intranasally challenged with bacterial suspension containing approximately 5 × 10 7 CFU/ml B. pertussis. The immunogenicity of the tested vaccines against PT (pertussis toxin), PRN (pertactin), FHA (filamentous haemagglutinin) and FIM (fimbriae types 2 and 3) was examined. The commercial whole-cell and acellular pertussis vaccines induced an immunity effective at eliminating the genetically different B. pertussis isolates from the lungs. However, the elimination of the PRN-deficient isolate from the lungs of mice vaccinated with commercial vaccines was delayed as compared to the PRN ( +) isolate, suggesting phenotypic differences with the circulating isolates and vaccine strains. The most effective vaccine was the experimental vaccine with the composition identical to that of the strains used for infection.
Non-mucinous adenocarcinomas and squamous cell carcinomas of the anal region masquerading as abscess or fistula: a retrospective analysis and systematic review of literature
Authors: Tekbaş Aysun , Mothes Henning , Settmacher Utz , Schuele Silke 
Published: August 2021

Abstract
Purpose
Abscess or fistula of the anal region is an uncommon presentation of malignancy. Under the assumption of a benign condition, diagnostics is often delayed, resulting in advanced tumour stages at first diagnosis. Due to the case rarity, treatment guidelines for cancers of anorectal region masquerading as abscess or fistula are missing.

Methods
We analysed all patients presenting with an abscess or fistula of the anal region in our department between January 2004 and August 2020. The malignancies were included to our study to acquire data on clinical presentation, treatment and outcome. Furthermore, a systematic review to present adenocarcinomas and squamous cell carcinomas associated to an abscess or fistula was performed.

Results
0.5% of the patients treated for an abscess or fistula of the anal region met the selection criteria. Mean time from the onset of symptoms to diagnosis of malignancy was 100 days. Histology revealed adenocarcinoma and squamous cell carcinoma each in two patients. All patients had locally advanced tumours without distant metastases, in two cases with regional lymph-node metastases. Neoadjuvant chemoradiation was applied in two patients. All patients underwent abdomino-perineal resection of the rectum. The overall outcome reveals a recurrence-free survival of 4.5 and 3 years for two patients. Further two patients died within 5 months after the primary resection.

Conclusion
Advanced carcinomas of the anorectal region may masquerade as abscess or fistula, cause diagnostic problems and delay oncologic treatment. However, even in these very advanced situations, surgical therapy with curative intent should be attempted.
Development and validation of the scoliosis misconception scale (SMS) for assessing level of misconception of patients with adolescent idiopathic scoliosis
Authors: Cheung Amy Ka Po , Lau Charlie Chiu Yi , Chan Meanne Ching Man , Kwan Kenny Yat Hong 
Published: August 2021

Abstract
Background
Little is known about patients’ understanding of adolescent idiopathic scoliosis (AIS). This paper aims to develop and validate the Scoliosis Misconception Scale (SMS) and to explore patients’ level of misconception about AIS.

Methods
A total of 195 patients who were newly referred with newly diagnosed AIS were recruited to assess their levels of misconception and psychological distress before and after their first consultation with a specialist. The 17-item SMS was administered to assess patients’ level of misconception about AIS and the Kessler Psychological Distress Scale (K10) was used to measure their level of distress.

Results
According to the Item Response Theory, all items were within the acceptable range from -3.69 to 2.39 for difficulty parameters, which determined the difficulty of the scale, while most of the items were within the acceptable range from 0.11 to 1.54 for the discrimination parameters, which determined the rate at which the probability of endorsing a correct item changes given ability levels. Internal consistency by marginal reliability was 0.66. One-sample t test revealed that participants on average scored 6.79 (SD = 2.12) before the first clinic session and 6.45 (SD = 2.51) after the first clinic session, both significantly higher than 0 [t(75) = 27.86, p < .001; t(75) = 22.43, p < .001].

Conclusions
Despite a longstanding clinical model that functions well to treat AIS, most patients still have significant misconceptions about the condition. This highlights the necessity to assess patients’ knowledge level of a medical condition and potential generalisability of misconception–distress link to the forefront across other illnesses.