Complement C5a receptor 1 blockade reverses cognitive deficits following cranial radiation therapy for brain cancer.

Cranial radiation therapy (RT) for brain cancers leads to an irreversible decline in cognitive function without an available remedy. Radiation-induced cognitive deficits (RICD) are particularly a pressing problem for the survivors of pediatric and low grade glioma (LGG) patients who often live long post-RT. Radiation-induced elevated neuroinflammation and gliosis, triggered by the detrimental CNS complement cascade, lead to excessive synaptic and cognitive loss. Using intact and brain cancer-bearing mouse models, we now show that targeting anaphylatoxin complement C5a receptor (C5aR1) is neuroprotective against RICD. We used a genetic knockout, C5aR1 KO mouse, and a pharmacologic approach, employing the orally active, brain penetrant C5aR1 antagonist PMX205, to reverse RICD. Irradiated C5aR1 KO and WT mice receiving PMX205 showed significant neurocognitive improvements in object recognition memory and memory consolidation tasks. C5aR1 inhibition reduced microglial activation, astrogliosis, and synaptic loss in the irradiated brain. Importantly, C5aR1 inhibition in the syngeneic, orthotopic astrocytoma, and glioblastoma-bearing mice protected against RICD without interfering with the therapeutic efficacy of RT to reduce tumor volume in vivo . PMX205 is currently in clinical trials for amyotrophic lateral sclerosis (ALS). Thus, C5aR1 inhibition is a translationally feasible approach to address RICD, an unmet medical need.

Early pregnancy imaging predicts ischemic placental disease.

INTRODUCTION: To characterize early-gestation changes in placental structure, perfusion, and oxygenation in the context of ischemic placental disease (IPD) as a composite outcome and in individual sub-groups. METHODS: In a single-center prospective cohort study, 199 women were recruited from antenatal clinics between February 2017 and February 2019. Maternal magnetic resonance imaging (MRI) studies of the placenta were temporally conducted at two timepoints: 14-16 weeks gestational age (GA) and 19-24 weeks GA. The pregnancy was monitored via four additional study visits, including at delivery. Placental volume, perfusion, and oxygenation were assessed at both MRI timepoints. The primary outcome was defined as pregnancy complicated by IPD, with group assignment confirmed after delivery. RESULTS: In early gestation, mothers with IPD who subsequently developed fetal growth restriction (FGR) and/or delivered small-for gestational age (SGA) infants showed significantly decreased MRI indices of placental volume, perfusion, and oxygenation compared to controls. The prediction of FGR or SGA by multiple logistic regression using placental volume, perfusion, and oxygenation revealed receiver operator characteristic curves with areas under the curve of 0.81 (Positive predictive value (PPV) = 0.84, negative predictive value (NPV) = 0.75) at 14-16 weeks GA and 0.66 (PPV = 0.78, NPV = 0.60) at 19-24 weeks GA. DISCUSSION: MRI indices showing decreased placental volume, perfusion and oxygenation in early pregnancy were associated with subsequent onset of IPD, with the greatest deviation evident in subjects with FGR and/or SGA. These early-gestation MRI changes may be predictive of the subsequent development of FGR and/or SGA.

Erratum: Author Correction: Telemedicine-Rehabilitation and Virtual Reality in Orthopaedics and Sports Medicine.

[This corrects the article DOI: 10.1007/s43465-022-00766-6.].

Plasma sphingolipids, lung function and COPD: the Cardiovascular Health Study.

Rationale: COPD is the third leading cause of death in the United States. Sphingolipids, structural membrane constituents that play a role in cellular stress and apoptosis signalling, may be involved in lung function. Methods: In the Cardiovascular Health Study, a prospective cohort of older adults, we cross-sectionally examined the association of plasma levels of 17 sphingolipid species with lung function and COPD. Multivariable linear regression and logistic regression were used to evaluate associations of sphingolipid concentrations with forced expiratory volume in 1 s (FEV1) and odds of COPD, respectively. Results: Of the 17 sphingolipids evaluated, ceramide-18 (Cer-18) and sphingomyelin-18 (SM-18) were associated with lower FEV1 values (-0.061 L per two-fold higher Cer-18, p=0.001; -0.092 L per two-fold higher SM-18, p=0.002) after correction for multiple testing. Several other associations were significant at a 0.05 level, but did not reach statistical significance after correction for multiple testing. Specifically, Cer-18 and SM-18 were associated with higher odds of COPD (odds ratio per two-fold higher Cer-18 1.29, p=0.03 and SM-18 1.73, p=0.008). Additionally, Cer-16 and SM-16 were associated with lower FEV1 values, and Cer-14, SM-14 and SM-16 with a higher odds of COPD. Conclusion: In this large cross-sectional study, specific ceramides and sphingomyelins were associated with reduced lung function in a population-based study. Future studies are needed to examine whether these biomarkers are associated with longitudinal change in FEV1 within individuals or with incident COPD.

Justifying the implementation of intraoperative computed tomography for midface fracture treatment in improving outcomes.

Intraoperative CT scanning is the international standard for treating midface fractures as it allows intraoperative assessment of reduction and fixation. To our knowledge, no NHS hospital in the UK has this facility yet due to the financial and logistical burden of its implementation. The aim of this study was to determine if complications including the requirement for a return to theatre (RTT) could have been predicted from the post-fixation CT scan. All treated midface fractures that had presented to a regionalised major trauma centre within two years (01 January 2020 - 31 December 2021) were identified. Those developing complications including RTT were determined. All postoperative CT scans (including those without complication or RTT) were re-analysed with the clinicians blinded to the outcomes to determine the positive predictive value (PPV) and negative predictive value (NPV) of requiring RTT to alter plate position intraoperatively based on CT scan alone. In all, there were eight episodes of unplanned return to theatre, resulting in an overall RTT rate of 8/119 (6.7%). When only analysing patients treated for orbital fractures this RTT rises to 8/40 (20%). Of those eight patients who had a postoperative CT and required RTT, this could have been predicted in 7/8 (87.5%). A total of 16/44 (36.4%) patients that did not have RTT would have additionally been recommended to have the plate position altered based on CT alone. Based upon those that had a CT, the PPV of CT alone being able to predict those requiring RTT was 40.6% and the NPV 96.2%. Our results would suggest intraoperative CT would likely have prevented eight patients requiring RTT in two years and could have improved outcomes in 16 cases. In preventing RTT as well as potentially improving the outcomes of a further 16 cases in maxillofacial surgery, the purchase of an intraoperative CT scanner could yield net savings of £75534-£114990 over two years.

Haptools: a toolkit for admixture and haplotype analysis.

SUMMARY: Leveraging local ancestry and haplotype information in genome-wide association studies and downstream analyses can improve the utility of genomics for individuals from diverse and recently admixed ancestries. However, most existing simulation, visualization and variant analysis frameworks are based on variant-level analysis and do not automatically handle these features. We present haptools, an open-source toolkit for performing local ancestry aware and haplotype-based analysis of complex traits. Haptools supports fast simulation of admixed genomes, visualization of admixture tracks, simulation of haplotype- and local ancestry-specific phenotype effects and a variety of file operations and statistics computed in a haplotype-aware manner. AVAILABILITY AND IMPLEMENTATION: Haptools is freely available at https://github.com/cast-genomics/haptools. DOCUMENTATION: Detailed documentation is available at https://haptools.readthedocs.io. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Telemedicine-Rehabilitation and Virtual Reality in Orthopaedics and Sports Medicine.

Introduction: Tele-rehabilitation is a method of delivering rehabilitation services using information, technology and communication to everyone, irrespective of their geographic location. National zeal for competitive sports and COVID pandemic has led to an increase in its demand and popularity worldwide. The athletes need immediate treatment and correct rehabilitation to keep them in their game. This review aims to bring into perspective the importance of telemedicine and telerehabilitation in orthopaedics and sports medicine with a focus on virtual reality. Methods: Articles were searched based on suitable keywords 'telemedicine', 'telerehabilitation' 'orthopedics', 'orthopaedics', 'sports' and 'India*' which were combined using suitable boolean operators in PubMed, Scopus and Web of Science. Government guidelines and laws were also reviewed in view of telehealth and telemedicine. Conclusion: Tele-rehabilitation and virtual physical therapy are innovative and cost-effective ways to provide the best rehabilitative services to the patients at their doorstep. Virtual reality should be incorporated into the Indian telehealth delivering system with a special focus on the remote athlete population.

Non-surgical management of non-condylar mandibular fractures.

Unlike fractures of the remaining facial skeleton, fractures of the non-condylar part of the mandible are invariably treated surgically, with the potential risk of further iatrogenic injury. There is, however, a substantial evidence gap pertaining to the potential non-surgical management of such injuries. The aim of this study was to determine the outcomes of mandibular fractures treated with non-surgical management. All patients with mandibular fractures who were referred to a large regional major trauma service over a one-year period (1 January-31 December 2021) were identified. Those treated with surgery or who sustained fractures of the condylar portion of the mandible were excluded. Of all the patients referred to our unit with mandibular fractures, 34/155 (22%) underwent non-surgical management. In all cases plain radiographs demonstrated minimal displacement. Thirty-two (94%) fractures were unilateral, of which 24 (70%) involved the angle. Two of 34 patients subsequently required open reduction and internal fixation due to pain that did not improve over time, one of whom declined. A minimally extruded tooth in the fracture line, which altered the occlusion in one additional patient, required minimal reduction of the enamel. The remaining patients healed without complication six weeks after injury. Non- surgical management requires careful case selection and regular follow up, so is of value to only a small proportion of patients. Twenty-two per cent of all mandibular fractures were managed non-surgically at our unit in one year, with a 97% success rate, demonstrating the potential utility of this strategy in carefully selected cases.

Renal Salt-Wasting Syndrome Induced by Neoadjuvant Chemotherapy Containing Cisplatin - A Case Report.

Hyponatremia is one of the most common electrolyte abnormality seen in oncology practice. The underlying pathogenetic mechanism for chemotherapy-induced hyponatremia is renal salt-wasting syndrome (RSWS) and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Fluid restriction is the treatment of choice in SIADH, whereas salt supplements is the mode of treatment in RSWS. Hence, differentiation between RSWS and SIADH is very important though difficult. Case reports of cisplatin (cis-dichloro-diammine-platinum-2)-induced RSWS and SIADH are rare in the literature. We report about a patient who developed hyponatremia, hypokalemia with excessive urinary excretion of sodium and potassium, renal glycosuria, and aminoaciduria on the third day of the first cycle of cisplatin-containing chemotherapy.

A comparative study on the morphology, radiography and computed tomography of the skull bones of barking deer (Muntiacus muntjak) and sambar deer (Rusa unicolor).

BACKGROUND: There is scanty information on the skull morphology of barking and sambar deer; thus the present study was designed to provide information on morphology, radiography and computed tomography (CT) of the skull bones of both deer species. MATERIALS AND METHODS: The study was conducted on 12 skulls of adult barking deer (n = 6) and sambar deer (n = 6) of either sex (n = 3 males and n = 3 females) collected from Aizawl Zoological Park, Aizawl, Mizoram. The skulls of both species were macerated as per the standard maceration techniques. RESULTS: The skull bones of both deer species were divided into a neurocranium and a viscerocranium. The neurocranium was comprised of occipital, sphenoid, temporal, frontal, parietal, interparietal and ethmoid bones. The viscerocranium consisted of nasal, lacrimal, zygomatic, maxilla, incisive, palatine, pterygoid, vomer, mandible, turbinates and hyoid bones. The cranial cavity was oval and elongated caudally. The orbit was round, complete in barking deer; however, it was oval, complete in sambar deer. The facial tuberosity was present caudal to infraorbital foramen and dorsally at superior third premolar tooth in barking deer whereas dorsally at the superior first molar tooth in sambar deer. The infraorbital foramina were small, elliptical and placed at the level of the superior first premolar tooth. The alveolus for a canine tooth was present rostrally in the maxilla of both species. Turbinates bones were visible and mandibular symphysis remained unossified on radiographs and CT in both species. The radiographs of both species showed that the nasal canal was divided by the nasal septum. The CT scan demonstrated the paranasal, frontal and maxillary sinuses. CONCLUSIONS: The present study is important in the comparative anatomy of ruminant species and may help the wildlife forensic officials to identify and differentiate the bones of these two species from those of other domestic and wild small ruminants.

Is Revision Bankart Repair with Remplissage a Viable Option for Failed Bankart Repair in Non-contact Sports Person Aiming to Return to Sports?

PURPOSE: Failure of a well-executed Bankart repair in non-contact athletes is difficult to predict and its management is a lesser investigated area with uncertain outcome in terms of return to sports (RTS). This study analyses effectiveness of revision Bankart repair with remplissage for failed Bankart repair in non-contact athletes, focusing on time and level of RTS. MATERIALS AND METHODS: Fifty-five consecutive non-contact athletes with evidence of instability after primary arthroscopic Bankart repair having glenoid loss < 25% and off-track Hill-Sachs lesion were included in the study according to algorithm mentioned. All cases underwent revision arthroscopic Bankart repair with remplissage and followed-up for 24 months. Rowe, UCLA, WOSI and Quick-DASH scores were recorded preoperative and at 24 months. RTS was allowed after unilateral seated shot-put test. RESULTS: Out of 55 cases, 6 were excluded because of poor tissue quality, 7 were lost to follow-up. Forty-two cases with a mean age of 28.2 ± 5.2 years were included. Mean duration between primary surgery and failure was 7.3 ± 1.4 months with a mean 1.9 redislocations. The mean Rowe, WOSI, UCLA, Quick-DASH scores improved from 37 to 89, 39.3 to 83.7%, 18.4 to 30.5, 45.3 to 18.7 at 24 months. Thirty-five cases could RTS in a mean time 15.4 ± 1.4 months. Out of seven cases who could not RTS, four had instability, one had pain and two voluntarily quit sports. CONCLUSION: Revision Bankart repair with remplissage is a feasible option for failed primary Bankart repair in non-contact athletes who have glenoid bone loss < 25% with off-track Hill-Sachs. LEVEL OF EVIDENCE: Level IV.

Discovering single nucleotide variants and indels from bulk and single-cell ATAC-seq.

Genetic variants and de novo mutations in regulatory regions of the genome are typically discovered by whole-genome sequencing (WGS), however WGS is expensive and most WGS reads come from non-regulatory regions. The Assay for Transposase-Accessible Chromatin (ATAC-seq) generates reads from regulatory sequences and could potentially be used as a low-cost 'capture' method for regulatory variant discovery, but its use for this purpose has not been systematically evaluated. Here we apply seven variant callers to bulk and single-cell ATAC-seq data and evaluate their ability to identify single nucleotide variants (SNVs) and insertions/deletions (indels). In addition, we develop an ensemble classifier, VarCA, which combines features from individual variant callers to predict variants. The Genome Analysis Toolkit (GATK) is the best-performing individual caller with precision/recall on a bulk ATAC test dataset of 0.92/0.97 for SNVs and 0.87/0.82 for indels within ATAC-seq peak regions with at least 10 reads. On bulk ATAC-seq reads, VarCA achieves superior performance with precision/recall of 0.99/0.95 for SNVs and 0.93/0.80 for indels. On single-cell ATAC-seq reads, VarCA attains precision/recall of 0.98/0.94 for SNVs and 0.82/0.82 for indels. In summary, ATAC-seq reads can be used to accurately discover non-coding regulatory variants in the absence of whole-genome sequencing data and our ensemble method, VarCA, has the best overall performance.

A morphometrical study on the skull of goat (Capra hircus) in Mizoram / Estudio morfométrico del cráneo de cabra (Capra hircus) en Mizoram

SUMMARY: The present study was designed to elaborate on the morphometry of the skull of non-descript goats in Mizoram state of India. The study was conducted on the skull of twelve (n=12) adult goats of either sex (n=6 males and n=6 females) collected from the local slaughterhouses. Altogether, forty-one different measurements were taken morphologically. In the present study, the cranial and facial bones were the major components of the skull with a total of thirty-two bones. There were three single and four paired cranial bones with a total of eleven bones. There were one single and the rest were paired facial bones with a total of twenty-one bones. The cranial bones were occipital, parietal, interparietal, sphenoid, ethmoid, frontal and temporal. The facial bones were maxilla, premaxilla (incisive), palatine, pterygoid, nasal, lacrimal, zygomatic (malar), vomer, turbinate, mandible and hyoid. The skull measurements showed that the skull of the goat was elongated and dolichocephalic as per the cephalic index (47.82±0.05). The length and width of the skull was 19.28±0.03 cm and 9.22±0.04 cm, respectively. There were two supraorbital foramina on both sides of the frontal bone. The prominent facial tuberosity lies dorsally to the third superior premolar tooth. Single infraorbital foramen was located dorsally to the junction of the first and second superior premolar teeth on maxilla bone. The orbits were round and complete and situated on a frontolateral oblique plane. It can be concluded that the findings of this study would assist the comparative studies with other domesticated animals in the future and would be applicable in clinical veterinary practice and even in zooarchaeology.

RESUMEN: El estudio fue diseñado para elaborar la morfometría del cráneo de cabras no definidas en Mizoram. El estudio se realizó en el cráneo de 12 cabras adultas 6 machos y 6 hembras recolectadas de los mataderos locales. Se tomaron en total 41 medidas diferentes morfológicamente. Los huesos craneales y faciales fueron los componentes principales del cráneo con un total de 32 huesos. Se encontraron tres huesos craneales individuales y cuatro pares con un total de 11 huesos. Encontramos solo un hueso facial individual, los otros 22 eran pares de huesos faciales. Los huesos craneales comprendidos en el estudio fueron: occipital, parietal, interparietal, esfenoides, etmoides, frontal y temporal. Los huesos faciales estudiados fueron: maxilar, premaxilar (incisivo), palatino, pterigoideo, nasal, lagrimal, cigomático, vómer, conchas, mandíbula e hioides. Las medicio- nes mostraron que el cráneo de la cabra era alargado y dolicocefálico (47,82 ± 0,05). La longitud y el ancho del cráneo fueron 19,28 ± 0,03 cm y 9,22 ± 0,04 cm, respectivamente. Había dos forámenes supraorbitales a ambos lados del hueso frontal. La tuberosidad facial prominente se encontraba dorsalmente en el tercer diente premolar superior. El foramen infraorbitario único se localizó dorsalmente a la unión del primer y segundo dientes premolares superiores en el hueso maxilar. Las órbitas eran redondas y completas y situadas en un plano oblicuo frontolateral. En conclusión, los resultados de este estudio motivarán y ayudarán a otros estudios comparativos con otros animales domesticados o en la práctica clínica veterinaria e incluso en zooarqueología.

Craniospinal Irradiation in Medulloblastoma using High Energy Medical Linear Accelerator: an Innovative Approach to Planning Technique.

BACKGROUND: Craniospinal irradiation (CSI) of medulloblastoma poses technological challenges due to the involvement of large treatment volume. Commonly, the whole treatment length is covered with two different isocentric plans in which the junction is shifted after every five fractions to overcome the possibility of hot and cold spot. OBJECTIVE: This study aims to evaluate dosimetrically and clinically the innovative planning technique for the CSI which doesn't need re-planning and re-setup of patients after every five fractions. MATERIAL AND METHODS: Computed tomography was done for fifteen (ten children and five adults) patients diagnosed with medulloblastoma. Treatment planning for 36 Gray (Gy) in 20 fractions (#) at the rate of 1.8Gy/# was done on the treatment planning system. A single plan for children was created with two bilateral fields of 6 Mega Voltage (MV) energy for cranium and one posterior field of 6 MV for spinal cord (C1-S2). Two plans for adult patients were created, first plan was with two bilateral fields of 6 MV for cranium and two posterior oblique fields of 6 MV for cervical and the part of thoracic spinal cord (up to T8-T9). The second plan was with a single posterior field of 15 MV covering remaining thoracic (T8-T9 to T12), lumbar and sacrum (up to lower border of S2) spine. After careful evaluation of all the plans, treatment was delivered; acute toxicities were recorded. RESULTS: 95% of prescribed dose was received by more than 95% of planning target volume in all the plans with the acceptable hot spot and good homogeneity index. All the patients reported common radiation induced acute toxicities (headache, vomiting, weakness) during radiotherapy. CONCLUSION: The new planning technique for CSI has acceptable dosimetric and acute clinical possibilities; therefore it can be used for CSI for improved homogeneous dose delivery.

Antiretroviral activity of Pterois volitans (red lionfish) venom in the early development of human immunodeficiency virus/acquired immunodeficiency syndrome antiretroviral alternative source.

AIM: This study aimed to investigate the antiviral activity of Pterois volitans phospholipase A2 (PV-PLA2) from Indonesia to human immunodeficiency virus (HIV). MATERIALS AND METHODS: Fresh venomous fin parts of wild PV specimens were collected from Java Sea waters. Then, it washed using phosphate buffer pH 7.0 and immersed in phosphate buffer pH 7.0 0.01 m containing CaCl2 0.001 m for 24 h. The immersed fin then allowed for extraction process by sonicating for 2×8 min with 80% pulse and 20 kHz output with temperature controlling to avoid denaturation. The crude venom (CV) extracted from the fin is allowed for purification by 80% ethanol (ET) precipitation and ammonium sulfate fractionation method. The purified PV-PLA2 then analyzed using Lowry's method, Marinette's method, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and 3-(4, 5-dimethyl thiazol-2yl)-2, 5-diphenyl tetrazolium bromide assay. After determining the purest and safest sample of six samples analyzed, the chosen sample then tested into simian retrovirus-2 (SRV2)-A549 culture (48×104 cells/mL at 1-4 ppm), and compared to the CV sample (1-4 ppm) and lamivudine (100 ppm). The culture then is analyzed using a quantitative real time-polymerase chain reaction to find out the copy number of SRV-2 virus in each culture. RESULTS: The protein's activity, concentration, and purity analysis revealed that the PV-PLA2 purified using ammonium sulfate fractionation has the highest activity (1.81 times higher than the CV at 80% fractionation) and has higher purity than the sample from ET fractionation. The testing of the sample purified using ammonium sulfate fractionation at 80% saturation level shown that it has a 97.78% inhibition level toward SRV2-A549 culture at 4 ppm. However, in comparison to lamivudine which has 99.55% inhibition level at 100 ppm, it needs much lower concentration to achieve the same result. CONCLUSION: The significant inhibition of SRV2-A549 culture shown that the PV-PLA2 extracted from PV venom has the potential to become anti-HIV substances. It would be worthwhile to further evaluate the antiretroviral activity of PV-PLA2 in the in vivo studies.