Medial patellofemoral ligament MRI abnormalities in the setting of MCL injuries: are they clinically relevant?

OBJECTIVE: To assess MRI abnormalities of the medial patellofemoral ligament (MPFL) in patients with clinically and MRI-proven superficial medial collateral ligament (sMCL) injuries and determine the clinical significance. MATERIALS AND METHODS: High-field strength knee MRI examinations were selected which demonstrated sMCL injuries. These cases were retrospectively reviewed for the presence, location, and severity of MPFL abnormality. The MPFL was divided into a more superior transverse component arising from a femoral attachment (tMPFL), and a broader more inferior oblique decussation component (odMPFL) arising from the anterior margin of the upper sMCL. Chart review was performed to determine the clinical relevance of any MPFL findings. RESULTS: One hundred patients with MCL injury were identified. These included 37 grade I sprains, 33 partial tears, 20 high-grade partial tears, and 10 full thickness tears. Abnormal edema was present at the femoral attachment of the tMPFL in 83%. The odMPFL was abnormal in 90%, most commonly involving the femoral third. No patients had imaging evidence of concurrent lateral patellar dislocation on the initial MRI study. No patients had documented patellofemoral instability at the time of original injury or upon follow-up. No patients required MPFL reconstruction. CONCLUSION: The MRI appearance of the MPFL is abnormal in the majority of patients with clinically and MRI-documented sMCL sprains and tears. These cases had no evidence of concurrent lateral patellar dislocation on the initial MRI and did not develop patellar instability symptoms.

Medication Use Among Patients Reporting Xerostomia of an Academic Dental Clinic.

Background: Global prevalence of xerostomia has been reported at 22% (range 0.01%-45%), negatively impacting oral health, nutrition intake, and quality of life. The causal relationship between xerostomia and medications remains uncertain but greater understanding could guide interventions. Objective: To describe the demographic characteristics and medication regimens in patients with xerostomia of an academic dental clinic. Method: This is a retrospective academic dental clinic record review from July 1, 2018 to October 27, 2020. Patient records were obtained from the University at Buffalo, School of Dental Medicine. Xerostomia status was determined via query of electronic health records and validated by manual review. Pharmacologic class and xerostomic potential of medications were identified by the Veterans Affairs Drug Classification System and drug compendia, respectively. Predictors of medication use were assessed using a multiple logistic regression model. Results: Of 37 403 examined records, 366 (0.98%) were identified as xerostomic. After excluding confounding factors (Sjogren's and radiation), 275 of 317 patients received at least one xerostomic medication, majority were female (240, 66%) versus male (126, 34%). Mean ± (SD) age was 64.9 ± 15.11 years. A total of 208 (57%) patients were aged ≥65. The median number of total and xerostomic medications were 8 (interquartile range [IQR], 4-12) and 4 (IQR, 2-7), respectively. The 3 most prevalent xerostomic pharmacologic classes were antidepressants (131, 35%), gastric medications (101, 28%), and vitamin D (87, 24%). Conclusion: Despite observed prevalence of xerostomia lower than global prevalence, xerostomic medication burden for patients experiencing xerostomia was high. Pharmacist-led interprofessional collaborations should be investigated to reduce xerostomic burden.

Pharmacologic Characterization of JNJ-42226314, [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone, a Reversible, Selective, and Potent Monoacylglycerol Lipase Inhibitor.

The serine hydrolase monoacylglycerol lipase (MAGL) is the rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. Inhibition of 2-AG degradation leads to elevation of 2-AG, the most abundant endogenous agonist of the cannabinoid receptors (CBs) CB1 and CB2. Activation of these receptors has demonstrated beneficial effects on mood, appetite, pain, and inflammation. Therefore, MAGL inhibitors have the potential to produce therapeutic effects in a vast array of complex human diseases. The present report describes the pharmacologic characterization of [1-(4-fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone (JNJ-42226314), a reversible and highly selective MAGL inhibitor. JNJ-42226314 inhibits MAGL in a competitive mode with respect to the 2-AG substrate. In rodent brain, the compound time- and dose-dependently bound to MAGL, indirectly led to CB1 occupancy by raising 2-AG levels, and raised norepinephrine levels in cortex. In vivo, the compound exhibited antinociceptive efficacy in both the rat complete Freund's adjuvant-induced radiant heat hypersensitivity and chronic constriction injury-induced cold hypersensitivity models of inflammatory and neuropathic pain, respectively. Though 30 mg/kg induced hippocampal synaptic depression, altered sleep onset, and decreased electroencephalogram gamma power, 3 mg/kg still provided approximately 80% enzyme occupancy, significantly increased 2-AG and norepinephrine levels, and produced neuropathic antinociception without synaptic depression or decreased gamma power. Thus, it is anticipated that the profile exhibited by this compound will allow for precise modulation of 2-AG levels in vivo, supporting potential therapeutic application in several central nervous system disorders. SIGNIFICANCE STATEMENT: Potentiation of endocannabinoid signaling activity via inhibition of the serine hydrolase monoacylglycerol lipase (MAGL) is an appealing strategy in the development of treatments for several disorders, including ones related to mood, pain, and inflammation. [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl)piperazin-1-yl]azetidin-1-yl]methanone is presented in this report to be a novel, potent, selective, and reversible noncovalent MAGL inhibitor that demonstrates dose-dependent enhancement of the major endocannabinoid 2-arachidonoylglycerol as well as efficacy in models of neuropathic and inflammatory pain.

A novel rabbit derived anti-HER2 antibody with pronounced therapeutic effectiveness on HER2-positive breast cancer cells in vitro and in humanized tumor mice (HTM).

BACKGROUND: Antibody based cancer therapies have achieved convincing success rates combining enhanced tumor specificity and reduced side effects in patients. Trastuzumab that targets the human epidermal growth factor related receptor 2 (HER2) is one of the greatest success stories in this field. For decades, trastuzumab based treatment regimens are significantly improving the prognosis of HER2-positive breast cancer patients both in the metastatic and the (neo-) adjuvant setting. Nevertheless, ≥ 50% of trastuzumab treated patients experience de-novo or acquired resistance. Therefore, an enhanced anti-HER2 targeting with improved treatment efficiency is still aspired. METHODS: Here, we determined cellular and molecular mechanisms involved in the treatment of HER2-positive BC cells with a new rabbit derived HER2 specific chimeric monoclonal antibody called "B100″. We evaluated the B100 treatment efficiency of HER2-positive BC cells with different sensitivity to trastuzumab both in vitro and in the presence of a human immune system in humanized tumor mice. RESULTS: B100 not only efficiently blocks cell proliferation but more importantly induces apoptotic tumor cell death. Detailed in vitro analyses of B100 in comparison to trastuzumab (and pertuzumab) revealed equivalent HER2 internalization and recycling capacity, similar Fc receptor signaling, but different HER2 epitope recognition with high binding and treatment efficiency. In trastuzumab resistant SK-BR-3 based humanized tumor mice the B100 treatment eliminated the primary tumor but even more importantly eradicated metastasized tumor cells in lung, liver, brain, and bone marrow. CONCLUSION: Overall, B100 demonstrated an enhanced anti-tumor activity both in vitro and in an enhanced preclinical HTM in vivo model compared to trastuzumab or pertuzumab. Thus, the use of B100 is a promising option to complement and to enhance established treatment regimens for HER2-positive (breast) cancer and to overcome trastuzumab resistance. Extended preclinical analyses using appropriate models and clinical investigations are warranted.

The discovery of azetidine-piperazine di-amides as potent, selective and reversible monoacylglycerol lipase (MAGL) inhibitors.

Monoacylglycerol lipase (MAGL) is the enzyme that is primarily responsible for hydrolyzing the endocannabinoid 2-arachidononylglycerol (2-AG) to arachidonic acid (AA). It has emerged in recent years as a potential drug target for a number of diseases. Herein, we report the discovery of compound 6g from a series of azetidine-piperazine di-amide compounds as a potent, selective, and reversible inhibitor of MAGL. Oral administration of compound 6g increased 2-AG levels in rat brain and produced full efficacy in the rat complete Freund's adjuvant (CFA) model of inflammatory pain.

Discovery and optimization of a novel series of pyrazolyltetrahydropyran N-type calcium channel (Cav 2.2) blockers for the treatment of pain.

A novel series of pyrazolyltetrahydropyran N-type calcium channel blockers are described. Structural modifications of the series led to potent compounds in both a cell-based fluorescent calcium influx assay and a patch clamp electrophysiology assay. Representative compounds from the series were bioavailable and showed efficacy in the rat CFA and CCI models of inflammatory and neuropathic pain.

Primary care specialty career choice among Canadian medical students: Understanding the factors that influence their decisions.

OBJECTIVE: To identify which factors influence medical students' decision to choose a career in family medicine and pediatrics, and which factors influence their decision to choose careers in non-front-line specialties. DESIGN: Survey that was created based on a comprehensive literature review to determine which factors are considered important when choosing practice specialty. SETTING: Ontario medical school. PARTICIPANTS: An open cohort of medical students in the graduating classes of 2008 to 2011 (inclusive). MAIN OUTCOME MEASURES: The main factors that influenced participants' decision to choose a career in primary care or pediatrics, and the main factors that influenced participants' decision to choose a career in a non-front-line specialty. RESULTS: A total of 323 participants were included in this study. Factors that significantly influenced participants' career choice in family medicine or pediatrics involved work-life balance (acceptable hours of practice [P = .005], acceptable on-call demands [P = .012], and lifestyle flexibility [P = .006]); a robust physician-patient relationship (ability to promote individual health promotion [P = .014] and the opportunity to form long-term relationships [P < .001], provide comprehensive care [P = .001], and treat patients and their families [P = .006]); and duration of residency program (P = .001). The career-related factors that significantly influenced participants' decision to choose a non-front-line specialty were as follows: becoming an expert (P < .001), maintaining a focused scope of practice (P < .001), having a procedure-focused practice (P = .001), seeing immediate results from one's actions (P < .001), potentially earning a high income (P < .001), and having a perceived status among colleagues (P < .001). CONCLUSION: In this study, 8 factors were found to positively influence medical students' career choice in family medicine and pediatrics, and 6 factors influenced the decision to choose a career in a non-front-line specialty. Medical students can be encouraged to explore a career in family medicine or pediatrics by addressing misinformation, by encouraging realistic expectations of career outcomes in the various specialties, and by demonstrating the capacity of primary care fields to incorporate specific motivating factors.

Prevention of hepatitis C virus infection and spread in human liver chimeric mice by an anti-CD81 monoclonal antibody.

UNLABELLED: CD81 is a required receptor for hepatitis C virus (HCV) infection of human hepatocytes in vitro. We generated several high-affinity anti-human CD81 monoclonal antibodies (mAbs) that demonstrated potent, specific, and cross-genotype inhibition of HCV entry. One of these mAbs, K04, was administered to human liver chimeric mice before or after HCV infection to determine its ability to prevent HCV infection or spread of HCV infection, respectively. All vehicle control mice established HCV infection, reaching steady-state levels of serum HCV RNA by day 21. Pretreatment of mice with K04 prevented HCV infection in all mice (n = 5). Treatment of mice with mAb K04 every 3 days for 21 days, starting at 6 hours postinfection, resulted in effective inhibition of virus spread. In 3 mice that were sacrificed on day 24, serum HCV levels remained detectable, below the limit of quantification (LOQ), indicating that infection was established, but virus spread was blocked, by the anti-CD81 mAb. In 5 additional mice that were followed for a longer time, virus remained detectable, below LOQ, until days 24 and 30 in 4 of 5 mice. In the fifth mouse, viral load was quantifiable, but reduced to 64-fold below the mean viral load in vehicle control at day 24. In addition, 2 of 5 mice cleared the infection by day 30 and 1 mouse had undetectable virus load from day 6 onward. CONCLUSION: These results demonstrate that CD81 is required for HCV infection and virus spread in vivo, and that anti-CD81 antibodies such as K04 may have potential as broad-spectrum antiviral agents for prevention and treatment of HCV infection.

Discovery and SAR of novel tetrahydropyrrolo[3,4-c]pyrazoles as inhibitors of the N-type calcium channel.

A novel series of substituted tetrahydropyrrolo[3,4-c]pyrazoles were investigated as blockers of the N-type calcium channel (Cav2.2 channels), a chronic pain target.

Discovery and SAR of a novel series of 2,4,5,6-tetrahydrocyclopenta[c]pyrazoles as N-type calcium channel inhibitors.

A novel series of substituted 2,4,5,6-tetrahydrocyclopenta[c]pyrazoles were investigated as N-type calcium channel blockers (Cav2.2 channels), a chronic pain target. One compound was active in vivo in the rat CFA pain model.

Impact of nasal surgery on speech resonance.

OBJECTIVES: The nose and paranasal sinuses contribute to speech resonance and changes to these structures may alter speech nasality. This change may influence one's vocational and social functioning and quality of life. Our investigation explored objective and subjective changes in nasality following nasal surgery in a prospective and longitudinal fashion. METHODS: Recordings of sustained vowel and sentence stimuli and voice-related quality of life measurements were obtained preoperatively and at 2, 4, 8, and 24 weeks postoperatively from individuals undergoing nasal and/or sinus surgery. Objective measures of fundamental frequency, jitter, shimmer, and harmonic to noise ratio (HNR) were determined. Pre- and postoperative speech samples were assessed by 15 naïve listeners. RESULTS: In all, 15 subjects completed the study. Neither speakers nor listeners perceived a subjective change in nasality following surgery. No statistically significant change in microacoustic measures were identified. Although nasal sentences did not reveal differences for 3 microacoustic measures, a difference in HNR was identified. CONCLUSIONS: Patients undergoing nasal surgery did not exhibit subjective changes in resonance postoperatively. Aside from a difference in HNR for the nasal sentence, objective microacoustics remained unchanged. These results demonstrate the stability of oranasal resonance despite nasal surgery and provide valuable data for patient informed decision-making.

Conformational fluidity of intrinsically disordered proteins in crowded environment: a molecular dynamics simulation study.

The class of intrinsically disordered proteins lacks stable three-dimensional structures. Their flexibility allows them to engage in a wide variety of interactions with other biomolecules thus making them biologically relevant and efficient. The intrinsic disorders of these proteins, which undergo binding-induced folding, allow alterations in their topologies while conserving their binding sites. Due to the lack of well-defined three-dimensional structures in the absence of their physiological partners, the folding and the conformational dynamics of these proteins remained poorly understood. Particularly, it is unclear how these proteins exist in the crowded intracellular milieu. In the present study, molecular dynamic simulations of two intrinsically unstructured proteins and two controls (folded proteins) were conducted in the presence and absence of molecular crowders to obtain an in-depth insight into their conformational flexibility. The present study revealed that polymer crowders stabilize the disordered proteins through enthalpic as well as entropic effects that are significantly more than their monomeric counterpart. Taken together, the study delves deep into crowding effects on intrinsically disordered proteins and provides insights into how molecular crowders induce a significantly diverse ensemble of dynamic scaffolds needed to carry out diverse functions.Communicated by Ramaswamy H. Sarma.

Arylglycine derivatives as potent transient receptor potential melastatin 8 (TRPM8) antagonists.

A series of arylglycine-based analogs was synthesized and tested for TRPM8 antagonism in a cell-based functional assay. Following structure-activity relationship studies in vitro, a number of compounds were identified as potent TRPM8 antagonists and were subsequently evaluated in an in vivo pharmacodynamic assay of icilin-induced 'wet-dog' shaking in which compound 12 was fully effective. TRPM8 antagonists of the type described here may be useful in treating pain conditions wherein cold hypersensitivity is a dominant feature.

Polyethylene Glycol 20k. Does It Fluoresce?

Polyethylene glycol (PEG) is a polyether compound commonly used in biological research and medicine because it is biologically inert. This simple polymer exists in variable chain lengths (and molecular weights). As they are devoid of any contiguous π-system, PEGs are expected to lack fluorescence properties. However, recent studies suggested the occurrence of fluorescence properties in non-traditional fluorophores like PEGs. Herein, a thorough investigation has been conducted to explore if PEG 20k fluoresces. Results of this combined experimental and computational study suggested that although PEG 20k could exhibit "through-space" delocalization of lone pairs of electrons in aggregates/clusters, formed via intermolecular and intramolecular interactions, the actual contributor of fluorescence between 300 and 400 nm is the stabilizer molecule, i.e., 3-tert-butyl-4-hydroxyanisole present in the commercially available PEG 20k. Therefore, the reported fluorescence properties of PEG should be taken with a grain of salt, warranting further investigation.

A novel series of pyrazolylpiperidine N-type calcium channel blockers.

Selective blockers of the N-type calcium channel have proven to be effective in animal models of chronic pain. However, even though intrathecally delivered synthetic ω-conotoxin MVIIA from Conus magnus (ziconotide [Prialt®]) has been approved for the treatment of chronic pain in humans, its mode of delivery and narrow therapeutic window have limited its usefulness. Therefore, the identification of orally active, small-molecule N-type calcium channel blockers would represent a significant advancement in the treatment of chronic pain. A novel series of pyrazole-based N-type calcium channel blockers was identified by structural modification of a high-throughput screening hit and further optimized to improve potency and metabolic stability. In vivo efficacy in rat models of inflammatory and neuropathic pain was demonstrated by a representative compound from this series.

The design and synthesis of novel, phosphonate-containing transient receptor potential melastatin 8 (TRPM8) antagonists.

A series of benzothiophene-based phosphonates was synthesized and many analogs within the series were shown to be potent antagonists of the TRPM8 channel. The compounds were obtained as a racemic mixture in 5 synthetic steps, and were tested for TRPM8 antagonist activity in a recombinant, canine TRPM8-expressing cell line using a fluorometric imaging plate reader (FLIPR) assay. Structure-activity relationships were developed initially by modification of the core structure and subsequently by variation of the aromatic substituents and the phosphonate ester. Compound 9l was administered intraperitoneally to rats and demonstrated engagement of the TRPM8 target in both prevention and reversal-modes in an icilin-induced 'wet-dog' shake model.

Methicillin-resistant Staphylococcus aureus-associated infections following septorhinoplasty.

Septorhinoplasty is associated with postoperative infection in less than 2% of cases, even without the use of prophylactic antibiotics. However, there is a concern that increasingly prevalent, highly virulent pathogens such as MRSA may predispose to postoperative infections. Over the past several decades, MRSA has emerged as the most important cause of antibiotic-resistant nosocomial infection. MRSA-associated infections related to nasal surgery are underreported in the literature. We present a case of MRSA-associated infection following a routine septorhinoplasty in a health care worker. We discuss the incidence of this complication and contributing risk factors. The classification of MRSA-associated infections into genotypically distinct hospital-acquired and community-acquired subtypes is reviewed, and the associated differences in epidemiology, clinical presentation, and antibiotic susceptibility are discussed. A comprehensive strategy incorporating diagnostic workup, preventative management based upon preoperative risk stratification, and treatment of MRSA-associated soft tissue infections is presented.

Comparison of citation rates between Covid-19 and non-Covid-19 articles across 24 major scientific journals.

Covid-19 has been front and center in the global landscape since the beginning of 2020. In response, the scientific field has dedicated enormous amounts of resources to researching the virus and its effects. The number of times Covid-19 publications are being cited throughout the literature appears remarkably high but has not been directly compared to non-Covid-19 papers in the same journals over an extended period. In our study, we use Clarivate's Web of Science-Science Citation Index Expanded™ database to identify Covid-19 papers published in 24 major scientific journals over a period of 24 months from January 1, 2020 to December 31, 2021. We conduct our search using keywords "Covid-19", "coronavirus", and "sars-cov-2" to locate publications with these words in the title. We then quantify the number of citations these papers have received and compare rates to non-Covid-19 papers in the same journals over the same timeframe. We find that, across 24 open-access and subscription-based scientific journals, Covid-19 papers published in the past 2 years currently have a median citation rate of 120.79 compared to 21.63 for non-Covid-19 papers. When negative binomial regression is used to minimize the influence of other variables such as article number variation and field of research, Covid-19 papers have still experienced more than 80% increase in citations relative to non-Covid-19 papers. These novel findings demonstrate that Covid-19 papers are being cited at remarkably higher rates than non-Covid-19 articles contained within the same journals. This suggests that journal impact factor, which is a product of the number of citations that recently published articles receive, will likely be drastically influenced by the number of Covid-19 papers that a journal has included within its pages in the previous years.

BigMouth: development and maintenance of a successful dental data repository.

Few clinical datasets exist in dentistry to conduct secondary research. Hence, a novel dental data repository called BigMouth was developed, which has grown to include 11 academic institutions contributing Electronic Health Record data on over 4.5 million patients. The primary purpose for BigMouth is to serve as a high-quality resource for rapidly conducting oral health-related research. BigMouth allows for assessing the oral health status of a diverse US patient population; provides rationale and evidence for new oral health care delivery modes; and embraces the specific oral health research education mission. A data governance framework that encouraged data sharing while controlling contributed data was initially developed. This transformed over time into a mature framework, including a fee schedule for data requests and allowing access to researchers from noncontributing institutions. Adoption of BigMouth helps to foster new collaborations between clinical, epidemiological, statistical, and informatics experts and provides an additional venue for professional development.

Attenuated cold sensitivity in TRPM8 null mice.

Thermosensation is an essential sensory function that is subserved by a variety of transducer molecules, including those from the Transient Receptor Potential (TRP) ion channel superfamily. One of its members, TRPM8 (CMR1), a ligand-gated, nonselective cation channel, is activated by both cold and chemical stimuli in vitro. However, its roles in cold thermosensation and pain in vivo have not been fully elucidated. Here, we show that sensory neurons derived from TRPM8 null mice lack detectable levels of TRPM8 mRNA and protein and that the number of these neurons responding to cold (18 degrees C) and menthol (100 microM) is greatly decreased. Furthermore, compared with WT mice, TRPM8 null mice display deficiencies in certain behaviors, including icilin-induced jumping and cold sensation, as well as a significant reduction in injury-induced responsiveness to acetone cooling. These results suggest that TRPM8 may play an important role in certain types of cold-induced pain in humans.