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Pain management and opioid consumption following outpatient orthopedic surgery may be influenced by several variables, including knowledge of safe opioid use. A prospective randomized study was undertaken to understand the effect of preoperative opioid education on opioid consumption following outpatient orthopedic surgeries. A total of 237 patients undergoing outpatient orthopedic surgeries were prospectively randomized to receive preoperative opioid education or not. Postoperative data collected included the number of pills taken, daily visual analog scale (VAS) pain scores, adverse events, and attitude toward the pain experience. A total of 107 patients were randomized to receive preoperative education and 130 to not receive preoperative education. On average, 27 pills were prescribed to each patient. The preoperative opioid education group consumed significantly fewer opioids (6 pills) when compared with the group not receiving education (12 pills) ( P Orthopedics . 2021;44(2):123–127.]

Lymphoepithelioma-like carcinoma of the skin is an extremely rare tumour whose aetiology is yet to be established. An 83-year-old female presented with a rapidly growing plaque on the chest wall diagnosed as lymphoepithelioma-like carcinoma histologically.

AIMS The aim of this study was to establish the pharmacokinetic profile of serum oestriol (E3 ) concentrations over 24 h following application of vaginal E3 in chronic users (>12 weeks of E3 use). The interindividual and intraindividual differences before and after E3 were examined. METHODS Ten women participated. Vaginal cream was omitted for ≥36 h prior to the study days. Blood sampling was performed for E3 , oestradiol and oestrone concentrations prior to cream application and at 1, 2, 3, 5, 8, 10, 12 and 24 h afterwards. In five women, all samples were repeated on a separate day. RESULTS E3 was absorbed rapidly in most women. Peak serum E3 concentration occurred around 2 h (range 1-5 h). The decline in E3 concentrations was also rapid: falling

Glioblastoma (GBM) is the most common primary brain tumor and has a poor prognosis; as such, there is an urgent need to develop innovative new therapies. Tumoricidal stem cells are an emerging therapy that has the potential to combat limitations of traditional local and systemic chemotherapeutic strategies for GBM by providing a source for high, sustained concentrations of tumoricidal agents locally to the tumor. One major roadblock for tumoricidal stem cell therapy is that the persistence of tumoricidal stem cells injected as a cell suspension into the GBM surgical resection cavity is limited. Polymeric biomaterial scaffolds have been utilized to enhance the delivery of tumoricidal stem cells in the surgical resection cavity and extend their persistence in the brain, ultimately increasing their therapeutic efficacy against GBM. In this review, we examine three main scaffold categories explored for tumoricidal stem cell therapy: microcapsules, hydrogels, and electrospun scaffolds. Furthermore, considering the significant impact of surgery on the brain and recurrent GBM, we survey a brief history of orthotopic models of GBM surgical resection.

Purpose To determine the risk for infection in trigger finger release surgery after preoperative corticosteroid injection. Methods We retrospectively evaluated all patients undergoing trigger finger release by 16 surgeons over a 2-year period. Data collected included demographic information, medical comorbidities, trigger finger(s) operated on, presence of a prior corticosteroid injection, date of most recent corticosteroid injection, postoperative signs of infection, and need for surgery owing to deep infection. Superficial infection was defined per Centers for Disease Control criteria. Deep infection was defined as the need for surgery related to a surgical site infection. Results In this cohort of 2,480 fingers in 1,857 patients undergoing trigger release surgery, 53 (2.1%) developed an infection (41 superficial [1.7%] and 12 deep [0.5%]). Before surgery, 1,137 fingers had no corticosteroid injection. These patients developed 1 deep (0.1%) and 17 superficial (1.5%) infections. In contrast, 1,343 fingers had been given a corticosteroid injection before surgery. These patients developed 11 deep (0.8%) and 24 superficial (1.8%) infections. Median time from corticosteroid injection to trigger release surgery was shorter for fingers that developed a deep infection (63 days) compared with those that developed no infection (183 days). The risk for developing a deep infection in patients who were operated on within 90 days of an injection (8 infections in 395 fingers) was increased compared with patients who were operated on greater than 90 days after an injection (3 infections in 948 fingers). Conclusions Preoperative corticosteroid injections are associated with a small but statistically significantly increased rate of deep infection after trigger finger release surgery. The risk for postoperative deep infection seems to be time dependent and greater when injections are performed within 90 days of surgery, especially in the 31- to 90-day postinjection period. Type of study/level of evidence Therapeutic IV.

Introduction Radial nerve palsies with humeral shaft fractures have historically been treated with expectant management. A previous systematic review by Shao et al, based on studies published from 1964 to 2004, purported no difference in the rate of recovery between patients treated with early surgical intervention versus expectant treatment. However, the authors combined expectant treatment to include patients treated nonsurgically and those with delayed surgery. To better understand the effect of surgery and its timing on radial nerve recovery, an updated analysis was performed with stricter treatment definitions. Methods An updated systematic review of the published literature was undertaken. An electronic database search was performed to identify publications that met specific inclusion criteria. A total of 23 articles published since 2000 met our eligibility requirements. Data were abstracted from these articles and analyzed in conjunction with the results of the systematic review by Shao et al. RESULTS:: The overall prevalence of radial nerve palsy was 12.3% (890/7,262). Patients with radial nerve palsy treated nonsurgically had a rate of spontaneous radial nerve recovery of 77.2%. Patients who failed nonsurgical management and underwent nerve exploration more than 8 weeks after their injury had a rate of recovery of 68.1%. Patients treated with early (within 3 weeks of the injury) surgical exploration and fracture repair had a rate of recovery of 89.8%. Discussion From the published data from 1964 to 2017, patients who underwent surgical exploration within 3 weeks of injury had a significantly higher likelihood of regaining radial nerve function than patients who underwent nonsurgical management with or without late surgical exploration.

Gout is increasing in prevalence despite effective pharmacotherapies. Barriers to effective management are largely educational deficiencies. Sufferers, usually men, need to understand more about gout, especially that maintaining serum urate below 0.36 mmol/L will eliminate recurrent attacks. Also, of great importance is appreciating that sub-optimal adherence to urate-lowering therapy (ULT) will result in a return of attacks. Prescribers also need to understand that acute attacks are likely to occur in the first few months of urate-lowering therapy (ULT), but these can be mitigated by commencing with a dose of ULT reflective of renal function and escalating the dose slowly, every 2–5 weeks until target serum urate is achieved. Prophylaxis against acute attacks over the initial 6 months period of ULT can be enhanced further with concomitant colchicine or nonsteroidal anti-inflammatory drugs (NSAIDs). Gout is largely managed in primary care. Rates of adherence to ULT are 50% or less, worse than most other chronic illnesses. Efforts at educating primary care physicians to, firstly, manage gout effectively and, secondly, to educate their gout patients sufficiently have not been successful. Allied health practitioners, such as nurses, working with prescribers in primary care settings and given the mandate to educate and manage patients with gout, have been spectacularly effective. However, this approach is resource intensive. ‘Personalised’ eHealth interventions show promise as an alternative strategy, notably in improving adherence to ULT. Numerous applications for smart phones (apps) are now available to assist people with chronic health conditions. Their design needs to accommodate the barriers and enablers perceived by patients to maintaining adherence to prescribed therapies. Personalised feedback of serum urate may represent an important enabler of adherence to ULT in the case of gout. Harnessing mobile apps to support patients managing their chronic illnesses represents an important opportunity to enhance health outcomes. Rigorous, patient-centred and driven development is critical. These tools also require careful evaluation for effectiveness.

Purpose: Thumb basal joint arthritis is a common degenerative condition of the hand that is often managed with thumb basal joint arthroplasty (BJA). This procedure generally results in a high level of patient satisfaction; however, the rate and cause of early unplanned reoperation after thumb BJA are not well-understood. Therefore, we performed a review to better understand the rate and cause of early reoperation. Methods: A retrospective review of all thumb BJA cases performed at a single private academic center between 2014 and 2016 yielded 637 patients and 686 primary thumb BJAs with a minimum 1-year follow-up (mean, 2.4 years). Data collection included patient demographics, surgical technique and type of thumb BJA performed, time to reoperation, reason for early reoperation (within 2 years), and type of reoperation. Results: Of 686 patients undergoing thumb BJAs, 10 had unplanned early reoperation (1.5%). Mean duration between the index procedure and reoperation was 5.2 months (range, 0.5–14.3 months). Of the 10 unplanned early reoperations, 4 thumbs in 4 patients required revision arthroplasties owing to persistent pain. Time to reoperation for revision arthroplasty was 9.6 months (range, 3.9–14.3 months). Three of 10 reoperations resulted from early infection, 2 from unplanned early removal of symptomatic K-wires, and one from radial sensory neuritis. Conclusions: In this series of nearly 700 consecutive cases, we identified an unexpected early reoperation rate of 1.5%, with only a 0.6% reoperation rate specifically for painful subsidence requiring a revision arthroplasty. Mean time to revision was 9.6 months. These rates are lower than those published previously and should be considered by patients and surgeons when planning thumb BJA. Type of study/level of evidence: Prognostic IV. Key words: Basal joint arthroplasty, Reoperation, Revision, Thumb, Trapeziometacarpal arthritis

Cancer vaccines have contributed significantly to immune-based treatment for this devastating disease. As the field has evolved, these therapies need enhanced delivery to better elicit protective immunity and overcome the suppressive tumor environment. In this chapter, we discuss current and new formulation approaches for cancer antigens and adjuvants that have been evaluated at the clinical and preclinical level. These vaccine platforms can be based on lipids, polymers, and inorganic materials, with a variety of constructs from particles to scaffolds to microneedles. The vaccine platforms reviewed show great promise in clinical and preclinical models and often rely on codelivery with checkpoint inhibitors to have the greatest effect. Furthermore, the inclusion of multiple antigens in combination with an adjuvant or GM-CSF has led to great advances. Overall, the reviewed platforms illustrate great progress in the field of cancer vaccines and provide hope for development of robust immune-based therapies.

AIMS: Metformin may have clinical benefits in dialysis patients; however, its safety in this population is unknown. This systematic review evaluated the safety of metformin in dialysis patients. METHODS: MEDLINE, Embase, CENTRAL, PsycINFO and the Cochrane Library were searched for randomised controlled trials and observational studies evaluating metformin use in dialysis patients. Three authors reviewed the studies and extracted data. The primary outcomes were mortality, occurrence of lactic acidosis and myocardial infarction (MI) in patients taking metformin during dialysis treatment for ≥12 months (long term). Risk of bias was assessed using Risk Of Bias In Nonrandomised Studies of Interventions (ROBINS‐1). Overall quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Fifteen observational studies were eligible; 7 were prospective observational studies and 8 were case reports/case series. No randomised controlled trials were identified. The 7 prospective observational studies (n = 194) reported on cautious metformin use in patients undergoing maintenance dialysis. Only 3 provided long‐term follow‐up data. In 2 long‐term studies of metformin therapy (≤1000 mg/d) in patients undergoing peritoneal dialysis (PD), 1 reported 6 deaths (6/83; 7%) due to major cardiovascular events (3 MI) and the other reported no deaths (0/35). One long‐term study of metformin therapy (250 mg to 500 mg thrice weekly) in patients undergoing haemodialysis reported 4 deaths (4/61; 7%) due to major cardiovascular events (2 MI). These findings provide very low‐quality evidence as they come from small observational studies. CONCLUSION: The evidence regarding the safety of metformin in people undergoing dialysis is inconclusive. Appropriately designed randomised controlled trials are needed to resolve this uncertainty.

Background: Vancomycin pharmacokinetics are best described using a 2-compartment model. However, 1-compartment population models are commonly used as the basis for dose prediction software.Therefore, the validity of using a 1-compartment model to guide vancomycin drug dosing was examined Methods: Published plasma concentration-time data from adult subjects (n = 30) with stable renal function administered a single intravenous infusion of vancomycin were extracted from previous studies. The vancomycin area under the curve (AUC0-N) was calculated for each subject using noncompartmental methods (AUCNCA) and by fitting 1- (AUC1CMT), 2- (AUC2CMT), and 3- (AUC3CMT)compartment infusion models. The optimal model fit was determined using the Akaike information criterion and visual inspection of the residual plots. The individual compartmental AUC0-N values from the 1- and 2-compartment models were compared with AUCNCA values using one-way repeated measures analysis of variance Results: The mean (6SD) AUC estimates were similar for the different methods: AUCNCA 180 6 86 mg$h/L, AUC1CMT 167 679 mg$h/L, and AUC2CMT 183 6 88 mg$h/L. Despite the overlapping AUC values, AUC2CMT and AUCNCA were significantly greater than AUC1CMT (P , 0.05). The 3-compartment model was excluded from the analysis because of the failure to converge in some instances Conclusions: Dose prediction software using a 1-compartmentmodel as the basis for Bayesian forecasting underestimates drug exposure (estimated as the AUC) by less than 10%. This is unlikely to be clinically significant with respect to dose adjustment.Therefore, a 1-compartment model may be sufficient to guide vancomycin dosing in adult patients with stable renal function. Refereed/Peer-reviewed

Phospholipase A2 (PLA2) enzymes were first recognized as an enzyme activity class in 1961. The secreted (sPLA2) enzymes were the first of the five major classes of human PLA2s to be identified and now number nine catalytically-active structurally homologous proteins. The best-studied of these, group IIA sPLA2, has a clear role in the physiological response to infection and minor injury and acts as an amplifier of pathological inflammation. The enzyme has been a target for anti-inflammatory drug development in multiple disorders where chronic inflammation is a driver of pathology since its cloning in 1989. Despite intensive effort, no clinically approved medicines targeting the enzyme activity have yet been developed. This review catalogues the major discoveries in the human group IIA sPLA2 field, focusing on features of enzyme function that may explain this lack of success and discusses future research that may assist in realizing the potential benefit of targeting this enzyme. Functionally-selective inhibitors together with isoform-selective inhibitors are necessary to limit the apparent toxicity of previous drugs. There is also a need to define the relevance of the catalytic function of hGIIA to human inflammatory pathology relative to its recently-discovered catalysis-independent function.

Patient: Female, 69 Final Diagnosis: Chronic cavitation pulmonary aspergillosis Symptoms: Shortness of breath • weight loss Medication: — Clinical Procedure: — Specialty: Pulmonology Objective: Challenging differential diagnosis Background: Aspergillus spores have the ability to affect patients with or without intact immune systems; because of this disease’s wide patient involvement it deserves a place on the differential diagnosis list, with endocarditis and tuberculosis, for those presenting with new pulmonary nodules or cavitation. Case Report: This case report involves the presentation, diagnosis, and treatment of a 69-year-old female who presented with new rapidly progressing cavitary lung lesions in the setting of copious administration of systemic steroid use. Given the patient’s past history of alcoholism and environmental exposure, her case was not straight forward in regard to a diagnosis. Ultimately, she was diagnosed with chronic cavity pulmonary aspergillosis in the setting of chronic immunosuppression secondary to systemic steroid administration. Due to her convoluted medical history and the poor differential diagnosis list, there was a delay in final diagnosis. Conclusions: This case report and clinical review aims to prevent anchoring when the patient’s presentation is not straight forward and aims to remind the clinician of the importance of a differential diagnosis.

Background Bilateral distal radius fracture (DRF) is an uncommon injury. We described the outcomes of 10 consecutive cases of bilateral DRF treated with open reduction and internal fixation (ORIF) at our institution. Materials and Methods We retrospectively searched our electronic medical records data for all patients 18 years of age or older treated surgically for bilateral DRF over a 6-year period (2011–2016). Patient demographics, fracture classification, fixation method, postoperative complications, QuickDASH (Quick Disabilities of the Arm, Shoulder and Hand) questionnaire scores, wrist range of motion (ROM), and radiographic measurements of X-rays at final follow-up were collected and analyzed. Results Ten patients (8 women; 2 men; mean age: 63 years) with 20 fractures were assessed. A volar approach for ORIF was used in 90% of cases. Six of 20 (30%) wrists experienced postoperative complications and required hardware removal. Mean QuickDASH score was 24.8 at final follow-up. On average, ROM reached 58-degree extension, 52-degree flexion, 75-degree pronation, and 75-degree supination. Mean measurements of radial shortening, radial inclination, and volar tilt taken from final postoperative radiographs were 1.3 mm, 21.2 degrees, and 7.8 degrees, respectively. Conclusion In bilateral DRF treated with concomitant ORIF, functional outcomes, recovery of wrist ROM, and restoration of radiographic parameters are comparable to those seen in patients with ipsilateral DRF.

Contemporary bioinformatic and chemoinformatic capabilities hold promise to reshape knowledge management, analysis and interpretation of data in natural products research. Currently, reliance on a disparate set of non-standardized, insular, and specialized databases presents a series of challenges for data access, both within the discipline and for integration and interoperability between related fields. The fundamental elements of exchange are referenced structure-organism pairs that establish relationships between distinct molecular structures and the living organisms from which they were identified. Consolidating and sharing such information via an open platform has strong transformative potential for natural products research and beyond. This is the ultimate goal of the newly established LOTUS initiative, which has now completed the first steps toward the harmonization, curation, validation and open dissemination of 750,000+ referenced structure-organism pairs. LOTUS data is hosted on Wikidata and regularly mirrored on https://lotus.naturalproducts.net. Data sharing within the Wikidata framework broadens data access and interoperability, opening new possibilities for community curation and evolving publication models. Furthermore, embedding LOTUS data into the vast Wikidata knowledge graph will facilitate new biological and chemical insights. The LOTUS initiative represents an important advancement in the design and deployment of a comprehensive and collaborative natural products knowledge base.

Plankton form the base of the marine food web and are sensitive indicators of environmental change. Plankton time series are therefore an essential part of monitoring progress towards global biodiversity goals, such as the Convention on Biological Diversity Aichi Targets, and for informing ecosystem-based policy, such as the EU Marine Strategy Framework Directive. Multiple plankton monitoring programmes exist in Europe, but differences in sampling and analysis methods prevent the integration of their data, constraining their utility over large spatio-temporal scales. The Plankton Lifeform Extraction Tool brings together disparate European plankton datasets into a central database from which it extracts abundance time series of plankton functional groups, called “lifeforms”, according to shared biological traits. This tool has been designed to make complex plankton datasets accessible and meaningful for policy, public interest, and scientific discovery. It allows examination of large-scale shifts in lifeform abundance or distribution (for example, holoplankton being partially replaced by meroplankton), providing clues to how the marine environment is changing. The lifeform method enables datasets with different plankton sampling and taxonomic analysis methodologies to be used together to provide insights into the response to multiple stressors and robust policy evidence for decision making. Lifeform time series generated with the Plankton Lifeform Extraction Tool currently inform plankton and food web indicators for the UK's Marine Strategy, the EU's Marine Strategy Framework Directive, and for the Convention for the Protection of the Marine Environment of the North-East Atlantic (OSPAR) biodiversity assessments. The Plankton Lifeform Extraction Tool currently integrates 155 000 samples, containing over 44 million plankton records, from nine different plankton datasets within UK and European seas, collected between 1924 and 2017. Additional datasets can be added, and time series can be updated. The Plankton Lifeform Extraction Tool is hosted by The Archive for Marine Species and Habitats Data (DASSH) at https://www.dassh.ac.uk/lifeforms/ (last access: 22 November 2021, Ostle et al., 2021). The lifeform outputs are linked to specific, DOI-ed, versions of the Plankton Lifeform Traits Master List and each underlying dataset.

Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.

Glioblastoma (GBM) is a highly aggressive and heterogeneous form of brain cancer. Genotypic and phenotypic heterogeneity drives drug resistance and tumor recurrence. Combination chemotherapy could overcome drug resistance; however, GBM's location behind the blood-brain barrier severely limits chemotherapeutic options. Interstitial therapy, delivery of chemotherapy locally to the tumor site, via a biodegradable polymer implant can overcome the blood-brain barrier and increase the range of drugs available for therapy. Ideal drug candidates for interstitial therapy are those that are potent against GBM and work in combination with both standard-of-care therapy and new precision medicine targets. Herein we evaluated paclitaxel for interstitial therapy, investigating the effect of combination with both temozolomide, a clinical standard-of-care chemotherapy for GBM, and everolimus, a mammalian target of rapamycin (mTOR) inhibitor that modulates aberrant signaling present in >80% of GBM patients. Tested against a panel of GBM cell lines in vitro, paclitaxel was found to be effective at nanomolar concentrations, complement therapy with temozolomide, and synergize strongly with everolimus. The strong synergism seen with paclitaxel and everolimus was then explored in vivo. Paclitaxel and everolimus were separately formulated into fibrous scaffolds composed of acetalated dextran, a biodegradable polymer with tunable degradation rates, for implantation in the brain. Acetalated dextran degradation rates were tailored to attain matching release kinetics (~3% per day) of both paclitaxel and everolimus to maintain a fixed combination ratio of the two drugs. Combination interstitial therapy of both paclitaxel and everolimus significantly reduced GBM growth and improved progression free survival in two clinically relevant orthotopic models of GBM resection and recurrence. This work illustrates the advantages of synchronized interstitial therapy of paclitaxel and everolimus for post-surgical tumor control of GBM.

BackgroundCurrent guidelines for intravenous vancomycin identify drug exposure (as indicated by the AUC) as the best pharmacokinetic (PK) indicator of therapeutic outcome.ObjectivesTo assess the accuracy of two Bayesian forecasting programs in estimating vancomycin AUC0–∞ in adults with limited blood concentration sampling.MethodsThe application of seven vancomycin population PK models in two Bayesian forecasting programs was examined in non-obese adults (n = 22) with stable renal function. Patients were intensively sampled following a single (1000 mg or 15 mg/kg) dose. For each patient, AUC was calculated by fitting all vancomycin concentrations to a two-compartment model (defined as AUCTRUE). AUCTRUE was then compared with the Bayesian-estimated AUC0–∞ values using a single vancomycin concentration sampled at various times post-infusion.ResultsOptimal sampling times varied across different models. AUCTRUE was generally overestimated at earlier sampling times and underestimated at sampling times after 4 h post-infusion. The models by Goti et al. (Ther Drug Monit 2018;40212–21) and Thomson et al. (J Antimicrob Chemother 2009;631050–7) had precise and unbiased sampling times (defined as mean imprecision ConclusionsWhen using a single vancomycin concentration for Bayesian estimation of vancomycin drug exposure (AUC), the predictive performance was generally most accurate with sample collection between 1.5 and 6 h after infusion, though optimal sampling times varied across different population PK models.

Peripheral nerve injuries (PNI) resulting from trauma can be severe and permanently debilitating. Despite the armamentarium of meticulous microsurgical repair techniques that includes direct repair, grafting of defects with autograft nerve, and grafting with cadaveric allografts, approximately one-third of all PNI demonstrate incomplete recovery with poor restoration of function. This may include total loss or incomplete recovery of motor and/or sensory function, chronic pain, muscle atrophy, and profound weakness, which can result in lifelong morbidity. Much of this impaired nerve healing can be attributed to perineural scarring and fibrosis at the site of injury and repair. To date, this challenging clinical problem has not been adequately addressed. In this review, we summarize the existing literature surrounding biological aspects of perineural fibrosis following PNI, detail current strategies to limit nerve scarring, present our own work developing reliable nerve injury models in animal studies, and discuss potential future studies which may ultimately lead to new therapeutic strategies.

This article reviews and develops a perspective for the meaning of authenticity in the context of quality assessment of botanical materials and the challenges associated with discerning adulterations vs. contaminations vs. impurities. Authentic botanicals are by definition non-adulterated, a mutually exclusive relationship that is confirmed through the application of a multilayered set of analytical methods designed to validate the (chemo) taxonomic identity of a botanical and certify that it is devoid of any adulteration. In practice, the ever-increasing sophistication in the process of intentional adulteration, as well as the growing number of botanicals entering the market, altogether necessitate a constant adaptation and reinforcement of authentication methods with new approaches, especially new technologies. This article summarizes the set of analytical methods - classical and contemporary – that can be employed in the authentication of botanicals. Particular emphasis is placed on the application of untargeted metabolomics and chemometrics. An NMR-based untargeted metabolomic model is proposed as a rapid, systematic, and complementary screening for the discrimination of authentic vs. potentially adulterated botanicals. Such analytical model can help advance the evaluation of botanical integrity in natural product research.

OBJECTIVE Elevated resting blood pressure (BP) is associated with risk for hypertension and emotional dampening, including reduced responses to emotionally meaningful stimuli. Perception of threat is a critical motivator in avoidance of risky health-damaging behavior. We hypothesize that BP-associated dampening of threat appraisal may increase risk-taking behavior. METHODS We measured resting BP, perception of affect, and risk behavior in 92 healthy women (n = 49) and men (n = 43) recruited from university students and staff as well as members of the surrounding community. Mean (SE) age for the sample was 21.5 (4.3) year. BP was measured using an automated BP monitor, and risk behavior was assessed with a modified National College Health Risk Behavior Survey. We also measured recognition of affect using the Perception of Affect Task (PAT). RESULTS Risk-taking behavior was positively correlated with both systolic (r(89) = .278, p = .008) and diastolic BP (r(89) = .309, p < .003). Regression analyses indicated that the association between risk-taking behavior and BP was not mediated by PAT scores. CONCLUSIONS Results show that persons with higher resting BP levels report increased risk-taking behavior. PAT scores, while correlated with systolic BP, did not mediate the relationship between BP and risk. The relationship between BP and risk behavior reflects the potential involvement of central nervous system regulation of both BP and emotional responsivity, and its relationship to health-damaging behavior and risk for hypertension.

The primary cause of mortality for glioblastoma (GBM) is local tumor recurrence following standard-of-care therapies, including surgical resection. With most tumors recurring near the site of surgical resection, local delivery of chemotherapy at the time of surgery is a promising strategy. Herein drug-loaded polymer scaffolds with two distinct degradation profiles were fabricated to investigate the effect of local drug delivery rate on GBM recurrence following surgical resection. The novel biopolymer, acetalated dextran (Ace-DEX), was compared with commercially available polyester, poly(l-lactide) (PLA). Steady-state doxorubicin (DXR) release from Ace-DEX scaffolds was found to be faster when compared with scaffolds composed of PLA, in vitro. This increased drug release rate translated to improved therapeutic outcomes in a novel surgical model of orthotopic glioblastoma resection and recurrence. Mice treated with DXR-loaded Ace-DEX scaffolds (Ace-DEX/10DXR) resulted in 57% long-term survival out to study completion at 120 days compared with 20% survival following treatment with DXR-loaded PLA scaffolds (PLA/10DXR). Additionally, all mice treated with PLA/10DXR scaffolds exhibited disease progression by day 38, as defined by a 5-fold growth in tumor bioluminescent signal. In contrast, 57% of mice treated with Ace-DEX/10DXR scaffolds displayed a reduction in tumor burden, with 43% exhibiting complete remission. These results underscore the importance of polymer choice and drug release rate when evaluating local drug delivery strategies to improve prognosis for GBM patients undergoing tumor resection.

The aims of this study were to investigate the relationship between metformin exposure, renal clearance (CLR), and apparent non-renal clearance of metformin (CLNR/F) in patients with varying degrees of kidney function and to develop dosing recommendations.Plasma and urine samples were collected from three studies consisting of patients with varying degrees of kidney function (creatinine clearance, CLCR; range, 14-112 mL/min). A population pharmacokinetic model was built (NONMEM) in which the oral availability (F) was fixed to 0.55 with an estimated inter-individual variability (IIV). Simulations were performed to estimate AUC(0-tau), CLR, and CLNR/F.The data (66 patients, 327 observations) were best described by a two-compartment model, and CLCR was a covariate for CLR. Mean CLR was 17 L/h (CV 22%) and mean CLNR/F was 1.6 L/h (69%).The median recovery of metformin in urine was 49% (range 19-75%) over a dosage interval. When CLR increased due to improved renal function, AUC(0-tau) decreased proportionally, while CLNR/F did not change with kidney function. Target doses (mg/day) of metformin can be reached using CLCR/3 x 100 to obtain median AUC(0-12) of 18-26 mg/L/h for metformin IR and AUC(0-24) of 38-51 mg/L/h for metformin XR, with C-max The proposed dosing algorithm can be used to dose metformin in patients with various degrees of kidney function to maintain consistent drug exposure. However, there is still marked IIV and therapeutic drug monitoring of metformin plasma concentrations is recommended.

AIMS The aims of the study were to: 1) determine if a plasma oxypurinol concentration-response relationship or an allopurinol dose-response relationship best predicts the dose requirements of allopurinol in the treatment of gout; and 2) to construct a nomogram for calculating the optimum maintenance dose of allopurinol to achieve target serum urate (SU) concentrations. METHODS A nonlinear regression analysis was used to examine the plasma oxypurinol concentration- and allopurinol dose-response relationships with serum urate. In 81 patients (205 samples), creatinine clearance (CLCR ), concomitant diuretic use and SU concentrations before (UP ) and during (UT ) treatment were monitored across a range of allopurinol doses (D, 50-700 mg daily). Plasma concentrations of oxypurinol (C) were measured in 47 patients (98 samples). Models (n = 47 patients) and predictions from each relationship were compared using F-tests, r2 values and paired t-tests. The best model was used to construct a nomogram. RESULTS The final plasma oxypurinol concentration-response relationship (UT = UP - C*(UP - UR )/(ID50 + C), r2 = 0.64) and allopurinol dose-response relationship (UT = UP - D* (UP - UR )/(ID50 + D), r2 = 0.60) did not include CLCR or diuretic use as covariates. There was no difference (P = 0.87) between the predicted SU concentrations derived from the oxypurinol concentration- and allopurinol dose-response relationships. The nomogram constructed using the allopurinol dose-response relationship for all recruited patients (n = 81 patients) required pretreatment SU as the predictor of allopurinol maintenance dose. CONCLUSIONS Plasma oxypurinol concentrations, CLCR and diuretic status are not required to predict the maintenance dose of allopurinol. Using the nomogram, the maintenance dose of allopurinol estimated to reach target concentrations can be predicted from UP .

BACKGROUND The FDA approved 'label' for metformin lists hepatic insufficiency as a risk for lactic acidosis. Little evidence supports this warning. AIMS To investigate the safety and pharmacokinetics of metformin in patients with chronic liver disease (CLD). METHODS Chronic liver disease patients with and without type 2 diabetes mellitus (T2DM) were studied by a cross-sectional survey of patients already prescribed metformin (n = 34), and by a prospective study where metformin (500 mg, immediate release, twice daily) for up to 6 weeks was prescribed (n = 24). Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were obtained and compared to previously published values from healthy and T2DM populations without CLD. RESULTS All plasma metformin and lactate concentrations remained below the putative safety thresholds (metformin, 5 mg/L; lactate, 5 mmol/L). Lactate concentrations were unrelated to average steady-state metformin concentrations. In patients with CLD, T2DM was associated with higher plasma lactate concentrations (48% higher than those without T2DM, P

Background The volume of the carpometacarpal joint of the thumb (TCMC) and its capacity to accommodate fluid injection is unknown. Questions/Purpose The purpose of the present study is to assess the volume of the TCMC. Methods Forty-two thumbs undergoing surgical treatment for symptomatic TCMCJ osteoarthritis (OA) were evaluated. Prior to the start of the surgical procedure saline was injected into the TCMC until resistance was felt and no further saline could be injected. The maximum volume (MaxVol) of injectate was measured and recorded. Results Mean MaxVol among all patients was 0.9 cc (range: 0.2–3.0 cc). There were 15 patients with 1 cc or more injected, the rest were less than 1 cc. The mean MaxVol for Eaton 2 thumbs was 1.5 cc, for Eaton 3 thumbs 0.9 cc, and for Eaton 4 thumbs 0.7 cc, with negative correlation between Eaton stage and MaxVol. Conclusion TCMC has limited capacity for injected fluid. Level of Evidence This is a Level II, diagnostic study.

Intentional drug overdoses with antidepressant and antipsychotic medications are an increasingly common problem. Currently, there is little guidance with regard to reintroduction of these medications after intentional overdoses. We have used published toxicological and pharmacokinetic data to obtain factors which control the recovery from overdoses. From such data, we have proposed guidance regarding their reintroduction, provided there are no adverse effects or contraindications. Tentatively, we suggest that when adverse effects from the overdose are lost, treatment could recommence after a further mean half-life of elimination. Most antidepressant and antipsychotic drugs are metabolized by cytochrome P450 enzymes and, where cytochrome P450 inhibitors are co-ingested, serial plasma concentrations should optimally be obtained in order to assess a suitable time for reintroduction of the psychoactive drugs. We hope the proposals presented will stimulate research and discussion that lead to better guidance for clinicians concerning reintroduction of psychoactive medication after intentional overdose.

Interference of ANTIBACTERIAL AGENTS with immune and inflammatory systems, and the possible clinical implications, has long been a focus of attention worldwide. In particular, toxic effects with immunological implications (neutropenia, ALLERGY, INFLAMMATION, etc.) influence the development and clinical use of these drugs. However, favourable effects are also very important. Possible effects of ANTIBACTERIAL AGENTS on immune and inflammatory systems are shown in Table 29.1 and in sections on individual ANTIBACTERIAL AGENTS.

We have experimentally investigated the influence of repeated laser pulses on laser-induced breakdown (LIB) in water following a focused 1064 nm laser pulse, for repetition rates between 0.5 and 20 Hz and up to 100 pulses. LIB plasma image data are collected as a function of repetition rate and laser pulse number, using an intensified CCD camera with sub-nanosecond camera-laser timing. Each pulse induces multiple breakdowns, shockwaves, and macroscopic cavitation bubbles. These effects disappear by the time the next pulse arrives. Even so, we find that the water target retains effects from previous pulses that persist up to roughly a second and that modify subsequent LIB properties including plasma location, spatial extension, and total emission intensity. We quantify the effects by tracking the first moment of the plasma emission intensity, which we call the “center of intensity” (CoI). Three distinct reproducible repetition-rate-dependent phases are identified with repeated pulses. In particular, (1) with initial pulses, emission intensity decreases and the CoI broadens and propagates downstream from the laser focus reaching a maximum axial distance away from the focal point, (2) with additional pulses, the CoI narrows and travels back upstream toward the laser, and (3) with continued pulses, the plasma gains back a portion of the lost intensity and the CoI reaches a steady state position, not at the focal point. Two possible causal effects are highlighted; particle inclusion concentration changes and microbubbles in the laser path.

To investigate the contributions towards hyperuricaemia of known risk factors, focusing on fractional (renal) clearance of urate (FCU) and variation in the ATP-binding cassette transporter, sub-family G 2 (ABCG2) gene.The contributions of age, sex, ancestry, Q141K genotype for ABCG2, FCU, sugar-sweetened beverage and alcohol consumption, metabolic syndrome disorders and measures of renal function to the risk of hyperuricaemia were evaluated by comparing hyperuricaemic (serum urate≥0.42 mmol/L, n=448) with normouricaemic (serum urate0.42 mmol/L, n=344) participants using stepwise logistic regression. Model performance was evaluated using the area under the receiver operator characteristic curve (AUROC).ABCG2 genotype, FCU, male sex, body mass index, serum triglyceride concentrations, estimated glomerular filtration rate and consumption of alcohol were the best predictors of hyperuricaemia (AUROC 0.90, 81% accuracy). Homozygosity in the 141K variant for ABCG2 conferred an adjusted OR of 10.5 for hyperuricaemia (95% CI 2.4 to 46.2). For each 1% decrease of FCU, the adjusted OR increased by 51% (OR 1.51, 95% CI 1.37 to 1.66). There was no association between ABCG2 genotype and FCU (r=0.02, p=0.83).The ABCG2 141K variant and the FCU contribute strongly but independently to hyperuricaemia. These findings provide further evidence for a significant contribution of ABCG2 to extra-renal (gut) clearance of urate.

Background We prospectively evaluated the surgical anatomy during first dorsal compartment release for De Quervain's tenosynovitis, with special attention to the superficial branch of the radial nerve (SBRN). Additionally, the incidence of tendon instability during surgery was assessed. Methods This prospective cohort study consisted of 130 De Quervain's patients undergoing first dorsal compartment release. The treating surgeons recorded the type of incision used, the number of abductor pollicis longus (APL) and extensor pollicis brevis (EPB) tendon slips, the number of SBRN branches encountered, additional subcompartments created by any septations, and active/passive tendon stability. Results A singular first dorsal compartment was found in 37% of cases, whereas 55% of patients had two subcompartments and 8% had three. Multiple APL tendon slips (range: 1–4) were identified in 78% of patients. In contrast, a single EPB tendon was found in 92% of patients (range: 0–2). At least one SBRN was encountered in 61% of cases. Following surgery, instability was evident in 9% of patients, who had tendons perch with passive wrist flexion. In one of these patients ( Conclusions The anatomical findings in our relatively large, prospective study of De Quervain's patients undergoing first dorsal compartment release are consistent with previous smaller and/or retrospective studies. Overall, we expect to encounter the SBRN during first dorsal compartment release in more than 50% of patients but are unconcerned if it is not visualized during a careful approach. Tendon instability has an incidence of 9%; however, dislocation is rare (

Tendon injuries of the hand that require surgical repair often heal with excess scarring and adhesions to adjacent tissues. This can compromise the natural gliding mechanics of the flexor tendons in particular, which operate within a fibro-osseous tunnel system similar to a set of pulleys. Even combining the finest suture repair techniques with optimal hand therapy protocols cannot ensure predictable restoration of hand function in these cases. To date, the majority of research regarding tendon injuries has revolved around the mechanical aspects of the surgical repair (i.e. suture techniques) and postoperative rehabilitation. The central principles of treatment gleaned from this literature include using a combination of core and epitendinous sutures during repair and initiating motion early on in hand therapy to improve tensile strength and limit adhesion formation. However, it is likely that the best clinical solution will utilize optimal biological modulation of the healing response in addition to these core strategies and, recently, the research in this area has expanded considerably. While there are no proven additive biological agents that can be used in clinical practice currently, in this review, we analyze the recent literature surrounding cytokine modulation, gene and cell-based therapies, and tissue engineering, which may ultimately lead to improved clinical outcomes following tendon injury in the future.

Malayalam is a highly agglutinated resource-poor language. A lot of words in Malayalam are formed by the repeated addition of suffixes into root forms of the words called stems. Such words are called compound words. Identifying root words from the compound words is a key challenge in the preprocessing of Malayalam text. The grammar rules in Malayalam known as sandhi rules play a vital role in the splitting and formation of compound words. In this paper, we have proposed a hybrid methodology for suffix separation in Malayalam compound words. The sandhi rule associated with each compound word is recognized through machine learning approach. And suffix separation is performed using a rule-based approach. Since a lot of rules are required for suffix separation in Malayalam, we have only considered ‘Agamasandhi’ words for rule-based splitting. The proposed system provides better results and can be extended to prepare a complete suffix separation system for Malayalam.

To review the extent of treatment success or failure with the xanthine oxidoreductase inhibitors allopurinol and febuxostat and indicate how the dosage of urate-lowering therapy (ULT) may be modified to increase the response in the majority of patients with gout. Gout flares are associated with serum concentrations of urate above 0.42 mmol/L (7 mg/dL). Achieving and maintaining serum urate below 0.36 mmol/L is considered an effective response to ULT. On an intention to treat basis, clinical trials indicate that allopurinol at daily doses of 100 to 300 mg decreases serum urate adequately in only about 40% of gout patients while febuxostat 80 mg daily reduces serum urate adequately in approximately 70% of gout patients. Higher doses of ULT may be required in patients receiving concomitant diuretics. The addition of a uricosuric agent to allopurinol and febuxostat therapy significantly increases the proportion of patients achieving adequate lowering of serum urate. Finally, carriers of a genetic variant of the transporter, ABCG2 (BCRP), have a decreased response to allopurinol. Careful examination of medication adherence, titration of doses, and the addition of uricosuric agents increase the percentage of patients responding to allopurinol and febuxostat.

Purpose The reported incidence of postoperative complications after distal biceps tendon repairs (DBTRs) has been determined largely by retrospective studies. We hypothesized that a large prospective cohort study of DBTRs would demonstrate increased complication rates relative to existing literature values. Secondarily, we hypothesized that most complications would be transient and self-limiting, regardless of the surgical technique employed for the repair. Methods Consecutive patients undergoing acute, primary DBTR from July 2016 to December 2017 were enrolled. The repair technique, postoperative protocol, and follow-up intervals were determined by the individual surgeons’ protocols. Demographic information, surgical data, and complications were tabulated prospectively. Exclusion criteria included chronic DBTRs, secondary DBTRs requiring allograft, DBTRs of partial tears, and postoperative follow-up of less than 12 weeks. We included 212 repairs performed by 37 orthopedic surgeons in 3 different subspecialties. Results Sixty-five patients (30.7%) had 73 complications. Fifty patients (44.6%) in the 1-incision group experienced complications compared with 15 (15.0%) in the 2-incision group. Sixty patients (28.3%) developed a minor complication. Fifty-seven patients (26.9%) had sensory neurapraxias, 47 after a 1-incision procedure and 10 after a 2-incision procedure, a statistically significant difference. Of the patients with neurapraxias, 94.7% were resolved or improving at the time of the latest follow-up. Five patients (2.4%) developed a major complication, defined as a return to the operating room in the postoperative period due to deep infection or rerupture. Conclusions The complication rate after DBTR appears to be higher than 2 other retrospective studies and is predominantly in the form of transient neurapraxias. This study confirms that there is a higher complication rate in 1-incision techniques as compared with 2-incision techniques. Type of study/level of evidence Therapeutic II.

Aims To compare the pharmacokinetics of metformin between diabetic Indigenous (Aboriginal and Torres Strait Islander) and non-Indigenous patients. Methods An observational, cross-sectional study was conducted on type 2 diabetic Indigenous and non-Indigenous patients treated with metformin. Blood samples were collected to determine metformin, lactate, creatinine and vitamin B12 concentrations and glycosylated haemoglobin levels. A population model was used to determine the pharmacokinetic parameters. Results The Indigenous patients (median age 55 years) were younger than the non-Indigenous patients (65 years), with a difference of 10 years (95% confidence interval 6–14 years, P < 0.001). The median glycosylated haemoglobin was higher in the Indigenous patients (8.5%) than in the non-Indigenous patients (7.2%), with a difference of 1.4% (0.8–2.2%, P < 0.001). Indigenous patients had a higher creatinine clearance (4.3 l h−1) than the non-Indigenous patients (4.0 l h−1), with a median difference of 0.3 l h−1 (0.07–1.17 l h−1; P < 0.05). The ratio of the apparent clearance of metformin to the creatinine clearance in Indigenous patients (13.1, 10.2–15.2; median, interquartile range) was comparable to that in non-Indigenous patients (12.6, 9.9–14.9). Median lactate concentrations were also similar [1.55 (1.20–1.88) vs. 1.60 (1.35–2.10) mmol l−1] for Indigenous and non-Indigenous patients, respectively. The median vitamin B12 was 306 pmol l−1 (range 105–920 pmol l−1) for the Indigenous patients. Conclusions There were no significant differences in the pharmacokinetics of metformin or plasma concentrations of lactate between Indigenous and non-Indigenous patients with type 2 diabetes mellitus. Further studies are required in Indigenous patients with creatinine clearance

Background Spontaneous pneumomediastinum with concurrent pneumorrhachis (air in the spinal canal) and subcutaneous emphysema can be an alarming presentation, both clinically and radiographically. These clinical entities often require only conservative measures after ruling out any worrisome underlying causes. Management often involves appropriate imaging, hospital admission, and sub-specialty consultation as needed to help determine any potential causes for the presentation that may require anything more than a period of medical observation. Case Report A 20-year-old man presented to the Emergency Department (ED) with acute onset of chest pain. Physical examination was significant for subcutaneous emphysema across the anterior chest wall. Radiographs of the neck revealed extensive soft tissue emphysema extending into the upper mediastinum. Computed tomography (CT) of the neck with contrast revealed a small amount of air within the central canal of the spinal cord, in addition to extensive pneumomediastinum and subcutaneous emphysema. The patient remained stable and was discharged home on hospital day 2, after significant threats for morbidity or mortality were ruled out. Why Should an Emergency Physician Be Aware of This? Spontaneous pneumomediastinum, pneumorrhachis, and subcutaneous emphysema are rare clinical entities, but each requires thorough investigation in the ED to rule out any underlying life-threatening cause. A conservative treatment approach is appropriate for most patients without evidence of cardiorespiratory compromise or neurologic deficits accruing due to these problems.

Trapeziectomy with suture-button suspensionplasty is a surgical treatment option for thumb carpometacarpal osteoarthritis refractory to nonsurgical management. We describe the cases of 3 patients who presented with index metacarpal fracture, in the absence of traumatic injury, over 4 months after trapeziectomy with suture-button suspensionplasty. All 3 fractures demonstrated the same pattern: short oblique/spiral, oriented proximal radial to distal ulnar with the distal end in the vicinity of the index metacarpal button, presumably after the orientation of the metacarpal drill hole. Two of the fractures were treated with surgical fixation. Fracture healing was obtained in all cases. Two of the 3 patients remained symptomatic with thumb pain, but decided against revision treatment for the carpometacarpal osteoarthritis. The third underwent restabilization of the suture button at the time of fracture fixation. Although uncommon, index metacarpal fracture after trapeziectomy with suture-button suspensionplasty can present without trauma several months after surgery.