Editorial for the Themed Issue: Addressing the Dual Challenges of Opioid Use Disorder and Chronic Pain in the Context of the Opioid CrisisMehmet Sofuoglu, M.D., Ph.D. 1,2R. Ross MacLean, Ph.D. 1,2Joao P. De Aquino, M.D.1,2,3Yale University School of Medicine, Department of Psychiatry, 300 George Street, New Haven, CT 06511, USAVA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516, USAClinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park Street, 3rd Floor, New Haven, CT, 06519CORRESPONDING AUTHOR: Mehmet Sofuoglu, VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516, USA

Background: Left bundle branch area pacing (LBBAP) and endocardial resynchronization (Endo-CRT) are alternatives to biventricular pacing for cardiac resynchronization therapy (CRT). Objective: To compare the outcomes of LBBAP vs. Endo-CRT using conventional pacing leads. Methods: Patients with heart failure (HF) undergoing CRT with LBBAP or Endo-CRT were included. The primary efficacy outcome was a composite of HF-related hospitalization and all-cause mortality. The primary safety outcome was any procedure-related complication. Secondary outcomes included procedural characteristics, electrocardiographic, and echocardiographic parameters. Results: A total of 223 patients (LBBAP n=197, Endo-CRT n=26; mean age 69±10.3 years, 32.3% female) were included. Patients in the LBBAP group had lower NYHA class, shorter preprocedural QRS durations (161 [142-183] vs. 180 [170-203] msec, p<0.001), and a lower preprocedural spironolactone use (57.4% vs. 84.6%, p=0.009) than patients in the Endo-CRT group. Fluoroscopy time was significantly shorter in patients undergoing LBBAP (11.4 [7.2-20] vs. 23 [14.2-34.5] min; p<0.001). There was no significant difference in the primary efficacy outcome between both groups (Cox proportional HR 1.21, 95% CI 0.635-2.31; p=0.56). During follow-up, patients undergoing LBBAP had a lower incidence of stroke than patients in the Endo-CRT group (0% vs. 11.5%, p=0.001). Postprocedural LVEF (35% [25-45] vs. 40% [20-55]; p=0.307) and change in LVEF (7% [0-20] vs. 11% [2-18]; p=0.384) between the LBBAP and the Endo-CRT groups, respectively. Conclusion: LBBAP and Endo-CRT using conventional leads are associated with similar clinical outcomes, as well as improvements in LVEF. Endo-CRT is associated with longer fluoroscopy times and a higher risk of stroke.

On the flanks of >6000 m Andean volcanoes that tower over the Atacama Desert, leaf-eared mice (Phyllotis vaccarum) live at extreme elevations that surpass known vegetation limits. What the mice eat in these barren, hyperarid environments has been the subject of much speculation. According to the arthropod fallout hypothesis, sustenance is provided by windblown insects that accumulate in snowdrifts (‘aolian deposits’). It is also possible that mice feed on saxicolous lichen or forms of cryptic vegetation that have yet to be discovered at such high elevations. We tested hypotheses about the diet of mice living at extreme elevations on Atacama volcanoes by combining metagenomic and DNA metabarcoding analyses of gut contents with stable-isotope analyses of mouse tissues. Genomic analyses of contents of the gastrointestinal tract of a live-captured mouse from the 6739 m summit of Volcán Llullaillaco revealed evidence for an opportunistic but purely herbivorous diet, including lichens. Although we found no evidence of animal DNA in gut contents of the summit mouse, stable isotope data for a larger sample of mice indicate that mice native to elevations at or near vegetation limits (~5100 m) include a larger fraction of animal prey in their diet than mice from lower elevations. Some plants detected in the gut contents of the summit mouse are known to exist at lower elevations at the base of the volcano and in the surrounding Altiplano, suggesting that such species may occur at higher elevations beneath the snowpack or in other cryptic microhabitats.

Drug development for children presents unique challenges and is highly regulated. Novel approaches, such as the use of extrapolation to address for example the need to avoid unethical studies, whilst supporting robust evidence generation have been developed in support of benefit/risk considerations by regulatory authorities. This is only one step in the decision-making process towards access, which in Europe also includes health technology assessment (HTA) bodies. Discussions related to evidentiary requirements in small populations through the use of evidence transfer has been identified as a priority action by EMA/ EUnetHTA 21. We describe the outcome of this work; reflect on the discussions taken place how to leverage prior knowledge through identifying and addressing uncertainties during life cycle management to support regulatory and HTA decision making. Through examples, we discussed the spectrum of use to support evidence generation, and developed regulatory and HTA reflections on general design considerations important for robust evidence generation; reflective of the joint ambition. Early interactions with all respective stakeholders, particularly between regulators and HTA bodies are key to optimise data generation and utility in children. In Europe, the HTA regulation will offer opportunities for collaborations, which are important for all development efforts. We collaboratively explored the unique specific challenges relating to paediatric drug development, ethically and in its ability to leverage prior knowledge, as exemplified using extrapolation. Learnings from these offers opportunities to further develop methodology how to leverage uncertainties across a product’s life cycle for small populations generally.

1. In oviparous vertebrates, maternal androgens can alter offspring immune function, particularly early in development, but the potential for negative health effects of maternal androgens in mammals remains unclear. 2. We investigated the relation between maternal androgens, particularly in late gestation, and offspring health in the meerkat (Suricata suricatta) by comparing offspring from (a) normative dominant and subordinate matrilines, whose dams naturally express high versus lower circulating androgen concentrations, respectively, and (b) normative dominant and antiandrogen-treated dominant matrilines, whose dams’ androgen function was intact versus blocked owing to experimental antagonism of the latter’s androgen receptors (using Flutamide©). Foetal offspring thus experienced three different endocrine environments (‘high,’ ‘lower,’ ‘blocked’ androgens) late in prenatal development. We assessed parasitism, immune function, steroid concentrations and survivorship in these three offspring groups, both during juvenility and early adulthood. 3. The juvenile offspring of subordinate control and dominant treated dams generally had lower intensities of parasite infections and greater immune function than did their peers from dominant control dams – patterns not found in adult offspring, nor in relation to the offspring’s concurrent hormone concentrations. Survivorship to adulthood was greatest in the progeny of treated dams. 4. Descendants of dominant female meerkats – those in the ‘high’ prenatal androgen category – suffered increased parasitism and decreased immunocompetence as juveniles, as well as reduced survivorship relative to antiandrogen-exposed peers, providing evidence in mammals that maternal androgens can negatively impact offspring health and survival. These intergenerational, androgen-mediated, health effects represent early costs imposed by female intrasexual competition and its associated selection pressures.

Simplifying implant planning and placement in the fully edentulous arch with in-office guide fabricationSean W. Meitner, DDS1, Charles M. Oster, DDS2 and Gregori M. Kurtzman, DDS3Clinical Professor  – University of Rochester, Eastman Dental Center, Department of Dentistry, Rochester, NY and private practice Periodontics, Pittsford, NY.Clinical Associate Professor  – University of Rochester, Eastman Dental Center, Department of Dentistry, Rochester, NY.Private practice, Silver Spring, MD.

The Domain Name System (DNS) plays a critical role in the functioning of the Internet. It provides a hierarchical name space for locating resources. Data is typically stored in plain text files, possibly spanning gigabytes. Frequent parsing of these files to refresh the data is computationally expensive: processing a zone file can take minutes. We propose a novel approach called simdzone to enhance DNS parsing throughput. We use data parallelism, specifically the Single Instruction Multiple Data (SIMD) instructions available on commodity processors. We show that we can multiply the parsing speed compared to state-of-the-art parsers found in Knot DNS and the NLnet Labs Name Server Daemon (NSD). The resulting software library replaced the parser in NSD.

Imbalance in the levels of ascorbic acid (AA) can pose a risk to human health. Therefore, it’s essential to establish an accurate method for the detection of AA. In this work, a novel N-doped carbon composite (MnOx@NC) with dual enzyme-like activities to detect AA was prepared by calcination of Mn-MOF containing H3TTPCA ligand. Interestingly, the •O2− that leads to its oxidase-like activity was not formed by dissolved oxygen, but came from the synergistic effect of lattice oxygen generated by calcination and the transformation of MnⅡ/MnⅢ/MnⅣ, and the presence of H2O2 provided much •OH, which cause its peroxidase-like activity. Meanwhile, the residual N element came from H3TTPCA ligand assisted the catalytic process. Accordingly, a dual-signal sensing platform and smartphone-assisted recognition for detection of AA was developed and a colorimetric sensor array was established to distinguish three antioxidants. This work also demonstrates considerable promise for the detection of AA in authentic pharmaceuticals.

Rationale: These experiments were conducted to measure the diversity of organo-U(IV) and U(III) ions created using multidimensional tandem MS and collision-induced dissociation of halogen-substituted U VIO 2-phenide complexes [UO 2(C 6H 3FX)] +, X = Cl, Br, or I. Methods: Samples of UO 2(O 2C-C 6H 3FX) 2 were prepared by digesting UO 3 with appropriate halogen-substituted carboxylic acids in deionized water. Solutions for ESI were created by diluting the digested sample in 50:50 H 2O/CH 3OH. Precursor ions for multiple-stage tandem MS were generated by electrospray ionization (ESI). Multiple-stage collision-induced dissociation (He collision gas) in a linear quadrupole ion trap mass spectrometer was used to prepare species such as [U IVFX(C≡CH)] + and U IIIF(C≡CH)] + for subsequent study of ion-molecule reactions with adventitious neutrals in the ion trap. Results: Multiple-stage CID of the [UO 2(C 6H 3FX)] +, X= Cl, Br, or I, complexes caused removal of both “yl” oxo ligands from of the UO 2 2+ moiety to create ions such as [U IVFX(C≡CH)] + and [U IIIFX] +. For [U IVFXC≡CH] + and [U IIIFC≡CH] + products, hydrolysis to generate [U IVFX(OH)] + and [U IIIF(OH)] +, with concomitant loss of HC≡CH, was observed. When X = Cl and Br, elimination of HX was competitive with loss of HC≡CH. CID of [UO 2(C 6H 3FBr)] + and [UO 2(C 6H 3FI)] + caused reductive elimination of the respective halogen radicals to generate interesting organo-U(III) species such as [U IIIF(C≡CH)] + and [U IIIC 2] +. Conclusions: The use of “preparative” tandem mass spectrometry and a suite of halogen substituted benzoic acid ligands can be used to remove both oxo ligands of UO 2 2+ and generate a group of homologous organo-U(IV) and organo-U(III) ions for studies of intrinsic reactivity.

Enzymatically modified cheeses (EMC) aim to achieve, in a shorter time frame, a composition and sensory characteristics akin to those of aged cheese. This study analyzed the lipid profile, composition, free fatty acid (FFA) content, and sensory attributes of EMC pastes with the objective of emulating the flavor profile of a red smear-ripened cheese (SR). Two different smear ripened cheeses were utilized as references: SR1, aged for 2–3 months, and SR2 aged for 10 months. Twelve formulations of EMC were prepared using a fatty medium moisture cheese corresponding to Mercosur’s Danbo type cheese (MD) as sole base, with the addition of the two types of SR cheeses and enzymes including exopeptidase, endopeptidase, and lipase, with varying concentrations of the latter. The EMC formulations exhibited a different physicochemical composition compared to the SR cheeses, with higher moisture, ash content, lower fat, and protein content. The highest total FFA contents were found in formulations with SR2, followed by formulations with SR1. As the concentration of lipase increased in the formulations, a greater degree of lipolysis was observed. Sensory profile was not influenced by the concentration of lipase, but rather depended on the type of cheese used as the base. All samples prepared with SR1 besides those prepared with SR2 as the base cheese and the highest concentration of lipase, exhibited sensory profiles more closely resembling that of lightly aged SR1. The enzymatic modification of cheeses proved to be a useful tool for generating sensory profiles similar to slightly aged SR cheese.

This article briefly reviews the causes of unilateral nasal discharge associated with sinonasal disease in the horse. Whilst, computed tomographic and radiographic imaging are often of great diagnostic value, clinical and nasal endoscopic examinations are the initial steps in investigating these disorders. This article reviews the use of oral examination and nasal endoscopy in the investigation of nasal discharge caused by sinonasal disease.

Garra is a kind of small- to medium-sized fish that is widely distributed from southern Eurasia to central Africa. As one of the most diverse genera of Cyprinidae, investigating the phylogeny and biogeography of Garra remains challenging. In this study, we combined sequences of Garra samples collected from Myanmar with sequences downloaded from GenBank to investigate the phylogeny, diversification, and biogeography of Garra on a global scale, with an emphasis on Southeast Asia. Species delimitation results indicated that there are at least 22 potential species, including eight undescribed species in Myanmar, suggesting that the diversity of Garra in this region have been largely underestimated. Diversification analysis suggested a relatively high diversification rate in the early branches of Garra. Ancestral distribution reconstruction results revealed that Garra originated from the Southeast Asia in the late Eocene, approximately 34 million years ago, with subsequent dispersals across different drainages influenced by the uplift of the Qinghai-Tibet Plateau. Our study provided a new insight into the evolutionary history of Garra and the basis for further research on this genus.

Our understanding of sexual selection is advancing with new technologies that tag individuals or their sperm, revealing how females use post-copulatory processes to discriminate between competing mates. Many tagging methods have been devised primarily for model insect organisms like Drosophila or Gryllidae. Developing such novel methods, however, is expensive and requires intensive investment. In this experiment, we trial the use of Rhodamine B and Rhodamine 110 in a small arachnid, the bulb mite Rhizoglyphus echinopus, for pre and post copulatory observations as it is a relatively inexpensive and simple way to tag individuals and their ejaculate proteins. First, we tested whether Rhodamine B and Rhodamine 110 applied to food can be used as a tagging method to track and distinguish between individuals. Second, we explored whether Rhodamine applied in this way can be used to track sperm transfer. We found that both tagging probes worked well in tagging individuals and that we were able to distinguish between individuals using both LED and fluorescent microscopy. We also found that Rhodamine degraded rapidly in the animals, likely due to their fast metabolism. Due to the rapid degradation, we observed variable results in the sperm transfer trials. We suggest multiple uses for Rhodamine and highlight other invertebrates where this method may come into use for the study of sexual selection.

A document by Tyson Wepprich. Click on the document to view its contents.

Algorithm for the management of Primary Diffuse Chronic RhinosinusitisW.J. Fokkens1, , E. de Corso2 , P.W.Hellings3,4, R. J. Harvey5,6, C. Hopkins7, S. Reitsma11 Amsterdam UMC, University of Amsterdam, Department of Otorhinolarynogology, Amsterdam2. Unit of Otorhinolaryngology and Head-Neck Surgery, ”A. Gemelli” University Hospital Foundation IRCCS, 00168 Rome, Italy.3. University of Leuven, Department of Otorhinolaryngology, Leuven,4.The European Forum for Research and Education in Allergy and Airway Diseases Scientific Expert Team Members, Brussels, Belgium.5. Rhinology and Skull Base Research Group, St Vincent’s Centre for Applied Medical Research, University of New South Wales, Sydney, Australia.6. Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.7. King’s College London, London, UK.

Introduction BK polyomavirus-associated nephropathy (BKPyVAN) is a well-known complication of kidney transplantation (KTx).The mainstay of prevention is reduction of immunosuppression upon detection of BK polyomavirus (BKPyV) viremia, which precedes BKPyVAN. However, this reduction may inadvertently increase the risk of alloimmunity particularly in patients with a high BKPyV load, where significant immunosuppression reduction is often necessary. This single-center, retrospective cohort study assesses the risk of de novo donor-specific antibodies (dnDSA) development and biopsy-proven acute rejection (BPAR) following high and low BKPyV viremia. Methods All patients who underwent KTx at Leiden University Medical Center between 2011 and 2020 were included. Patients were grouped according to high (maximum BKPyV serum load >10E4 copies/ml), low (maximum serum BKPyV load <10E4 copies/ml) and absent BKPyV viremia, and analyzed for the development of dnDSA and BPAR, using Cox regression. Results Of 1076 KTx recipients included, 108(10%) developed a BKPyV viremia with a maximum serum load below 10E4 copies/ml, whereas 121(11.2%) developed a BKPyV viremia exceeding 10E4 copies/ml. The risk of dnDSA development was higher in patients with a high BKPyV viremia, compared to patients without viremia (adjusted Hazard Ratio of 1.9(95% CI1.1-3.2, p=0.017). No significant difference in dnDSA risk was observed between patients with low and absent BKPyV viremia. Risk of BPAR did not differ between groups. Conclusion Our study shows that higher BKPyV loads in KTx patients are associated with a higher risk for dnDSA development, highlighting the importance of exploring additional strategies for the prevention and treatment of BKPyV infections in KTx recipients.

By increasing smart objects as high-potential computing devices and 5G technology, the Internet of Things (IoT) has emerging technology to provide a data-centric infrastructure for detecting safe device-to-device communications by supporting security and privacy issues. As 5G-enabled communication technology, Vehicle-to-Vehicle (V2V) communication provides a wirelessly exchange information connection between smart vehicles, intelligent devices and cloud-edge computing environment. This connection should be established with a safe and secured run-time protection system to avoid many critical anomalies and misbehavior problems. Detecting run-time malicious transformations with data-centric misbehaving reactions is a main challenge for autonomous vehicle communications with 5G-enabled communication technology. This paper provides a hybrid Genetic Algorithm-based Ensemble Bagged Trees (GA-EBT) algorithm for a data-centric misbehavior detection approach to support the V2V communications against malicious and misbehavior transactions. For evaluation of the proposed algorithm, four real test-cases are applied for messaging injection attacks in the V2V environments with compare to the state-of-the-art machine learning algorithms. The experimental results show that the proposed hybrid approach can achieve to optimal high rate accuracy factor with 99.999, precision and recall factors with 100% and F1-Score factor with 100% to detect unexpected cyber-attacks for the V2V communications in the IoT environment.

Title: Streptococcus pneumoniae Parotitis in a Patient with Poor Oral HygieneAuthor/corresponding author and Affiliation: Dr Mohammad Salhab, Centre for Bone Disease and Surgery (CBDS), Beirut, Lebanon. Email: [email protected]: We report a case of a 23-year-old female university student with poor oral hygiene who presented with recurrent right parotid gland swelling and pain. Despite multiple courses of antibiotics, the patient experienced persistent symptoms. Methodology: Magnetic resonance sialography revealed two intraductal stones in the right parotid gland. Purulent discharge from the parotid duct grew Streptococcus pneumoniae . Results: The patient was successfully treated with levofloxacin, parotid massage, and hydration. She was also advised to receive pneumococcal vaccination and reported no side effects after the first dose. Conclusion: This case highlights the importance of considering S. pneumoniae as a potential cause of parotitis in patients with poor oral hygiene, the role of imaging, microbiology, and targeted therapy in managing recurrent parotitis, and the potential benefits of pneumococcal vaccination in preventing future infections.KeywordsStreptococcus pneumoniae; parotitis; pain; vaccination; magnatic saliogram.Key Clinical Message: Streptococcus pneumoniae should be considered as a potential cause of recurrent parotitis, especially in patients with poor oral hygiene. Comprehensive management includes targeted antibiotic therapy based on culture results, addressing underlying factors like sialolithiasis, and considering pneumococcal vaccination to prevent future infections. This case highlights the importance of thorough diagnostic workup and multidisciplinary approach in managing challenging parotitis cases.Introduction: Acute bacterial parotitis is an uncommon condition, usually caused by Staphylococcus aureus or oral anaerobes (McQuone 1999). Streptococcus pneumoniae is a rare cause of parotitis, primarily seen in immunocompromised individuals (Yii, Tan, and Fong 2016). Risk factors for parotitis include poor oral hygiene, dehydration, and ductal obstruction (Brook 1992). The management of acute parotitis that can develop to acute on chronic suppurative condition can be challenging and also impactful on patient’s quality of life (Patel, Scott, and Cunningham 2017). We present a case of recurrent S. pneumoniae parotitis in a young female with poor oral hygiene and subacute sialolithiasis and discuss the role of pneumococcal vaccination in preventing future infections.Case History and Examination: A 23-year-old female university student presented to the ENT clinic with a 10-day history of right parotid gland swelling that became painful over the last 48 hours. She had no previous episodes but reported a few episodes of colds and sore throat during the past year. The patient was a smoker with poor oral hygiene, including several dental caries, and did not regularly brush her teeth. She was also anaemic and vitamin D insufficient. She had no significant medical or surgical history and no family history of parotitis or cancer. She had a compete up to date record of vaccinations including mumps, measles, and rubella.Method: On examination, she had right parotid gland swelling and enlargement of submental, submandibular, and neck lymph nodes. Oral examination revealed poor oral hygiene and dry mucosa without halitosis. Bimanual palpation of the parotid gland showed a mobile soft, painful swelling.Results: Investigations including FBC, CRP, ESR, electrolytes, vitamin D, LFTs, TFTs, calcium, lipid profile, and urinalysis were unremarkable except for vitamin D insufficiency. The patient was treated with amoxicillin for one week and vitamin D3 supplementation and discharged.Two weeks later, the patient returned with recurrent right parotid swelling. Symptoms had initially improved with antibiotics but recurred two days after completing the course. A ”wait and watch” approach was adopted, but the patient reported fluctuating swelling and pain. She was given another course of amoxicillin-clavulanate and discharged.One month later, the patient presented again with painful parotid swelling. An MRI sialogram demonstrated a relatively enlarged and hyperintense right parotid gland measuring 59x42x29mm, without nodules or ductal dilation-see fig 1a. Contrast injection revealed two intraductal stones- see fig 1b. Interestingly, blood works, inflammatory markers and cultures were negative. The patient was advised to maintain hydration and discharged.