Meta-analysis and public policy: Reconciling the evidence on deworming.

The WHO recommends mass drug administration (MDA) for intestinal worm infections in areas with over 20% infection prevalence. Recent Cochrane meta-analyses endorse treatment of infected individuals but recommend against MDA. We conducted a theory-agnostic random-effects meta-analysis of the effect of multiple-dose MDA and a cost-effectiveness analysis. We estimate significant effects of MDA on child weight (0.15 kg, 95% CI: 0.07, 0.24; P < 0.001), mid-upper arm circumference (0.20 cm, 95% CI: 0.03, 0.37; P = 0.02), and height (0.09 cm, 95% CI: 0.01, 0.16; P = 0.02) when prevalence is over 20% but not on Hb (0.06 g/dL, 95% CI: -0.01, 0.14; P = 0.1). These results suggest that MDA is a cost-effective intervention, particularly in the settings where it is recommended by the WHO.

Rare Phytocannabinoids Exert Anti-Inflammatory Effects on Human Keratinocytes via the Endocannabinoid System and MAPK Signaling Pathway.

Increasing evidence supports the therapeutic potential of rare cannabis-derived phytocannabinoids (pCBs) in skin disorders such as atopic dermatitis, psoriasis, pruritus, and acne. However, the molecular mechanisms of the biological action of these pCBs remain poorly investigated. In this study, an experimental model of inflamed human keratinocytes (HaCaT cells) was set up by using lipopolysaccharide (LPS) in order to investigate the anti-inflammatory effects of the rare pCBs cannabigerol (CBG), cannabichromene (CBC), Δ9-tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA). To this aim, pro-inflammatory interleukins (IL)-1ß, IL-8, IL-12, IL-31, tumor necrosis factor (TNF-ß) and anti-inflammatory IL-10 levels were measured through ELISA quantification. In addition, IL-12 and IL-31 levels were measured after treatment of HaCaT cells with THCV and CBGA in the presence of selected modulators of endocannabinoid (eCB) signaling. In the latter cells, the activation of 17 distinct proteins along the mitogen-activated protein kinase (MAPK) pathway was also investigated via Human Phosphorylation Array. Our results demonstrate that rare pCBs significantly blocked inflammation by reducing the release of all pro-inflammatory ILs tested, except for TNF-ß. Moreover, the reduction of IL-31 expression by THCV and CBGA was significantly reverted by blocking the eCB-binding TRPV1 receptor and by inhibiting the eCB-hydrolase MAGL. Remarkably, THCV and CBGA modulated the expression of the phosphorylated forms (and hence of the activity) of the MAPK-related proteins GSK3ß, MEK1, MKK6 and CREB also by engaging eCB hydrolases MAGL and FAAH. Taken together, the ability of rare pCBs to exert an anti-inflammatory effect in human keratinocytes through modifications of eCB and MAPK signaling opens new perspectives for the treatment of inflammation-related skin pathologies.

Effects of Rare Phytocannabinoids on the Endocannabinoid System of Human Keratinocytes.

The decriminalization and legalization of cannabis has paved the way for investigations into the potential of the use of phytocannabinoids (pCBs) as natural therapeutics for the treatment of human diseases. This growing interest has recently focused on rare (less abundant) pCBs that are non-psychotropic compounds, such as cannabigerol (CBG), cannabichromene (CBC), Δ9-tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA). Notably, pCBs can act via the endocannabinoid system (ECS), which is involved in the regulation of key pathophysiological processes, and also in the skin. In this study, we used human keratinocytes (HaCaT cells) as an in vitro model that expresses all major ECS elements in order to systematically investigate the effects of CBG, CBC, THCV and CBGA. To this end, we analyzed the gene and protein expression of ECS components (receptors: CB1, CB2, GPR55, TRPV1 and PPARα/γ/δ; enzymes: NAPE-PLD, FAAH, DAGLα/ß and MAGL) using qRT-PCR and Western blotting, along with assessments of their functionality using radioligand binding and activity assays. In addition, we quantified the content of endocannabinoid(-like) compounds (AEA, 2-AG, PEA, etc.) using UHPLC-MS/MS. Our results demonstrated that rare pCBs modulate the gene and protein expression of distinct ECS elements differently, as well as the content of endocannabinoid(-like) compounds. Notably, they all increased CB1/2 binding, TRPV1 channel stimulation and FAAH and MAGL catalytic activity. These unprecedented observations should be considered when exploring the therapeutic potential of cannabis extracts for the treatment of human skin diseases.

Opioid Therapy in Cancer Pain.

Cancer is a leading cause of morbidity and mortality, with up to 9.6 million cancer-related deaths worldwide in 2018 [1].

Opioid-Related Side Effects and Management.

The following areas will be discussed in relation to opioid-related side effects and approaches to their management in the cancer patient.

Clinical Implications of Opioid Therapy.

Although opioids are potent central acting broad-spectrum analgesics, their effectiveness is diminished by various factors pertaining to their metabolism, drug interactions, genetic issues, adverse/side effects, and potential for abuse. All these factors present potential barriers to effective analgesia requiring specific considerations in clinical practice, which include monitoring and case-based intervention.

Astrocytic degeneration in chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repeated head traumas. Using immunohistochemistry for glial fibrillary acidic protein as a marker, plus automated quantitative analysis, we examined the characteristics and extent of astrogliosis present in stage III and IV CTE, along with Alzheimer's disease (AD), and frontotemporal dementia (FTD) cases. Astrogliosis in CTE patients was more diffuse compared to that of AD and FTD patients, which was concentrated in the sulcal depths. Of 14 patients with CTE, 10 exhibited signs of a degenerating astrocyte pathology, characterized by beaded, broken astrocytic processes. This astrocytic degeneration was typically found to be diffuse throughout the white matter, although two cases demonstrated astrocytic degeneration in the gray matter. The degeneration was also observed in 2 of 3 AD and 2 of 3 FTD brains, with overall similar characteristics across diseases. There was minimal to no astrocytic degeneration in six age-matched controls with no neurodegenerative disease. We found that the extent of the white matter astrocytic degeneration was strongly correlated with the level of overall astrogliosis in both the white and gray matter. However, astrocytic degeneration was not correlated with the overall extent of tau pathology. Specifically, there was no correlation between levels of p-tau in the sulcal depths and astrocytic degeneration in the white matter adjacent to the sulcal depths. Thus, astrocytic degeneration and overall astrogliosis appear to represent distinct pathological features of CTE. Further investigation into these astroglial pathologies could provide new insights into underlying disease mechanisms and represent a potential target for in vivo assessment of CTE as well as other neurodegenerative disorders.

Medication Overuse in Chronic Pain.

PURPOSE OF REVIEW: Chronic pain is usually managed by various pharmacotherapies after exhausting the conservative modalities such as over-the-counter choices. The goal of this review is to investigate current state of opioids and non-opioid medication overuse that includes NSAIDs, skeletal muscle relaxants, antidepressants, membrane stabilization agents, and benzodiazepine. How to minimize medication overuse and achieve better outcome in chronic pain management? RECENT FINDINGS: Although antidepressants and membrane stabilization agents contribute to the crucial components for neuromodulation, opioids were frequently designated as a rescue remedy in chronic pain since adjunct analgesics usually do not provide instantaneous relief. The updated CDC guideline for prescribing opioids has gained widespread attention via media exposure. Both patients and prescribers are alerted to respond to the opioid epidemic and numerous complications. However, there has been overuse of non-opioid adjunct analgesics that caused significant adverse effects in addition to concurrent opioid consumption. It is a common practice to extrapolate the WHO three-step analgesic ladder for cancer pain to apply in non-cancer pain that emphasizes solely on pharmacologic therapy which may result in overuse and escalation of opioids in non-cancer pain. There has been promising progress in non-pharmacologic therapies such as biofeedback, complementary, and alternative medicine to facilitate pain control instead of dependency on pharmacologic therapies. This review article presents the current state of medication overuse in chronic pain and proposes precaution to balance the risk and benefit ratio. It may serve as a premier for future study on clinical pathway for comprehensive chronic pain management and reduce medication overuse.

Cationic Nanogel-mediated Runx2 and Osterix siRNA Delivery Decreases Mineralization in MC3T3 Cells.

BACKGROUND: Heterotopic ossification (HO) may occur after musculoskeletal trauma, traumatic brain injury, and total joint arthroplasty. As such, HO is a compelling clinical concern in both military and civilian medicine. A possible etiology of HO involves dysregulated signals in the bone morphogenetic protein osteogenic cascade. Contemporary treatment options for HO (ie, nonsteroidal antiinflammatory drugs and radiation therapy) have adverse effects associated with their use and are not biologically engineered to abrogate the molecular mechanisms that govern osteogenic differentiation. QUESTIONS/PURPOSES: We hypothesized that (1) nanogel-mediated short interfering RNA (siRNA) delivery against Runt-related transcription factor 2 (Runx2) and osterix (Osx) genes will decrease messenger RNA expression; (2) inhibit activity of the osteogenic marker alkaline phosphatase (ALP); and (3) inhibit hydroxyapatite (HA) deposition in osteoblast cell cultures. METHODS: Nanogel nanostructured polymers delivered siRNA in 48-hour treatment cycles against master osteogenic regulators, Runx2 and Osx, in murine calvarial preosteoblasts (MC3T3-E1.4) stimulated for osteogenic differentiation by recombinant human bone morphogenetic protein (rhBMP-2). The efficacy of RNA interference (RNAi) therapeutics was determined by quantitation of messenger RNA knockdown (by quantitative reverse transcription-polymerase chain reaction), downstream protein knockdown (determined ALP enzymatic activity assay), and HA deposition (determined by OsteoImage™ assay). RESULTS: Gene expression assays demonstrated that nanogel-based RNAi treatments at 1:1 and 5:1 nanogel:short interfering RNA weight ratios reduced Runx2 expression by 48.59% ± 19.53% (p < 0.001) and 43.22% ± 18.01% (both p < 0.001). The same 1:1 and 5:1 treatments against both Runx2 and Osx reduced expression of Osx by 51.65% ± 10.85% and 47.65% ± 9.80% (both p < 0.001). Moreover, repeated 48-hour RNAi treatment cycles against Runx2 and Osx rhBMP-2 administration reduced ALP activity after 4 and 7 days. ALP reductions after 4 days in culture by nanogel 5:1 and 10:1 RNAi treatments were 32.4% ± 12.0% and 33.6% ± 13.8% (both p < 0.001). After 7 days in culture, nanogel 1:1 and 5:1 RNAi treatments produced 35.9% ± 14.0% and 47.7% ± 3.2% reductions in ALP activity. Osteoblast mineralization data after 21 days suggested that nanogel 1:1, 5:1, and 10:1 RNAi treatments decreased mineralization (ie, HA deposition) from cultures treated only with rhBMP-2 (p < 0.001). However, despite RNAi attack on Runx2 and Osx, HA deposition levels remained greater than non-rhBMP-2-treated cell cultures. CONCLUSIONS: Although mRNA and protein knockdown were confirmed as a result of RNAi treatments against Runx2 and Osx, complete elimination of mineralization processes was not achieved. RNAi targeting mid- and late-stage osteoblast differentiation markers such as ALP, osteocalcin, osteopontin, and bone sialoprotein) may produce the desired RNAi-nanogel nanostructured polymer HO prophylaxis. CLINICAL RELEVANCE: Successful HO prophylaxis should target and silence osteogenic markers critical for heterotopic bone formation processes. The identification of such markers, beyond RUNX2 and OSX, may enhance the effectiveness of RNAi prophylaxes for HO.

Lower extremity vasculitis in giant cell arteritis: important differential diagnosis in patients with lower limb claudication.

Most patients with peripheral arterial disease suffer from arteriosclerosis, the prevalence of which increases with age. In some of these patients, however, the ischemic symptoms are not caused by stenotic arteriosclerosis, but by large vessel giant cell arteritis (LV-GCA), a disease also predominantly affecting patients of the older generation. Identifying large vessel vasculitis is a challenge for all physicians caring for patients with peripheral artery disease. The results of invasive treatment such as bypass surgery and angioplasty of inflammatory vascular lesions differ fundamentally from those of patients with atherosclerosis. Duplex ultrasound is a widely available diagnostic method for examining patients with lower limb claudication and pathological ankle-/toe- brachial index or pulse volume recording with or without exercise. Knowledge of characteristic sonographic findings suspicious about large vessel vasculitis is essential for a differential diagnosis of vasculitis versus atherosclerosis. In addition to clinical and laboratory findings, further imaging techniques, e.g. contrast-enhanced computed tomography, magnetic resonance imaging or a combination of positron emission tomography and computed tomography (PET-CT) can provide information on further vessel involvement and inflammatory activity. The present study focuses on diagnostic imaging of LV-GCA in patients presenting with claudication, illustrated by a series of cases.

Multicore fiber optic imaging reveals that astrocyte calcium activity in the mouse cerebral cortex is modulated by internal motivational state.

Astrocytes are a direct target of neuromodulators and can influence neuronal activity on broad spatial and temporal scales in response to a rise in cytosolic calcium. However, our knowledge about how astrocytes are recruited during different animal behaviors remains limited. To measure astrocyte activity calcium in vivo during normative behaviors, we utilize a high-resolution, long working distance multicore fiber optic imaging system that allows visualization of individual astrocyte calcium transients in the cerebral cortex of freely moving mice. We define the spatiotemporal dynamics of astrocyte calcium changes during diverse behaviors, ranging from sleep-wake cycles to the exploration of novel objects, showing that their activity is more variable and less synchronous than apparent in head-immobilized imaging conditions. In accordance with their molecular diversity, individual astrocytes often exhibit distinct thresholds and activity patterns during explorative behaviors, allowing temporal encoding across the astrocyte network. Astrocyte calcium events were induced by noradrenergic and cholinergic systems and modulated by internal state. The distinct activity patterns exhibited by astrocytes provides a means to vary their neuromodulatory influence in different behavioral contexts and internal states.

Association of differential censoring with survival and suboptimal control arms among oncology clinical trials.

Differential censoring, which refers to censoring imbalance between treatment arms, may bias the interpretation of survival outcomes in clinical trials. In 146 phase III oncology trials with statistically significant time-to-event surrogate primary endpoints, we evaluated the association between differential censoring in the surrogate primary endpoints, control arm adequacy, and the subsequent statistical significance of overall survival results. Twenty-four (16%) trials exhibited differential censoring that favored the control arm, whereas 15 (10%) exhibited differential censoring that favored the experimental arm. Positive overall survival was more common in control arm differential censoring trials (63%) than in trials without differential censoring (37%) or with experimental arm differential censoring (47%; odds ratio = 2.64, 95% confidence interval = 1.10 to 7.20; P = .04). Control arm differential censoring trials more frequently used suboptimal control arms at 46% compared with 20% without differential censoring and 13% with experimental arm differential censoring (odds ratio = 3.60, 95% confidence interval = 1.29 to 10.0; P = .007). The presence of control arm differential censoring in trials with surrogate primary endpoints, especially in those with overall survival conversion, may indicate an inadequate control arm and should be examined and explained.

Modeling gamma knife radiosurgical toxicity for multiple brain metastases.

BACKGROUND AND PURPOSE: Radiation oncology protocols for single fraction radiosurgery recommend setting dosing criteria based on assumed risk of radionecrosis, which can be predicted by the 12 Gy normal brain volume (V12). In this study, we show that tumor surface area (SA) and a simple power-law model using only preplan variables can estimate and minimize radiosurgical toxicity. MATERIALS AND METHODS: A 245-patient cohort with 1217 brain metastases treated with single or distributed Gamma Knife sessions was reviewed retrospectively. Univariate and multivariable linear regression models and power-law models determined which modeling parameters best predicted V12. The V12 power-law model, represented by a product of normalized Rx dose Rxn, and tumor longest axial dimension LAD (V12 âˆ¼ Rxn1.5*LAD2), was independently validated using a secondary 63-patient cohort with 302 brain metastases. RESULTS: Surface area was the best univariate linear predictor of V12 (adjR2 = 0.770), followed by longest axial dimension (adjR2 = 0.755) and volume (adjR2 = 0.745). The power-law model accounted for 90% variance in V12 for 1217 metastatic lesions (adjR2 = 0.906) and 245 patients (adjR2 = 0.896). The average difference ΔV12 between predicted and measured V12s was (0.28 ± 0.55) cm3 per lesion and (1.0 ± 1.2) cm3 per patient. The power-law predictive capability was validated using a secondary 63-patient dataset (adjR2 = 0.867) with 302 brain metastases (adjR2 = 0.825). CONCLUSION: Surface area was the most accurate univariate predictor of V12 for metastatic lesions. We developed a preplan model for brain metastases that can help better estimate radionecrosis risk, determine prescription doses given a target V12, and provide safe dose escalation strategies without the use of any planning software.

Norepinephrine modulates calcium dynamics in cortical oligodendrocyte precursor cells promoting proliferation during arousal in mice.

Oligodendrocytes, the myelinating cells of the central nervous system (CNS), are generated from oligodendrocyte precursor cells (OPCs) that express neurotransmitter receptors. However, the mechanisms that affect OPC activity in vivo and the physiological roles of neurotransmitter signaling in OPCs are unclear. In this study, we generated a transgenic mouse line that expresses membrane-anchored GCaMP6s in OPCs and used longitudinal two-photon microscopy to monitor OPC calcium (Ca2+) dynamics in the cerebral cortex. OPCs exhibit focal and transient Ca2+ increases within their processes that are enhanced during locomotion-induced increases in arousal. The Ca2+ transients occur independently of excitatory neuron activity, rapidly decline when OPCs differentiate and are inhibited by anesthesia, sedative agents or noradrenergic receptor antagonists. Conditional knockout of α1A adrenergic receptors in OPCs suppresses spontaneous and locomotion-induced Ca2+ increases and reduces OPC proliferation. Our results demonstrate that OPCs are directly modulated by norepinephrine in vivo to enhance Ca2+ dynamics and promote population homeostasis.

Multicore fiber optic imaging reveals that astrocyte calcium activity in the cerebral cortex is modulated by internal motivational state.

Astrocytes are a direct target of neuromodulators and can influence neuronal activity on broad spatial and temporal scales through their close proximity to synapses. However, our knowledge about how astrocytes are functionally recruited during different animal behaviors and their diverse effects on the CNS remains limited. To enable measurement of astrocyte activity patterns in vivo during normative behaviors, we developed a high-resolution, long working distance, multi-core fiber optic imaging platform that allows visualization of cortical astrocyte calcium transients through a cranial window in freely moving mice. Using this platform, we defined the spatiotemporal dynamics of astrocytes during diverse behaviors, ranging from circadian fluctuations to novelty exploration, showing that astrocyte activity patterns are more variable and less synchronous than apparent in head-immobilized imaging conditions. Although the activity of astrocytes in visual cortex was highly synchronized during quiescence to arousal transitions, individual astrocytes often exhibited distinct thresholds and activity patterns during explorative behaviors, in accordance with their molecular diversity, allowing temporal sequencing across the astrocyte network. Imaging astrocyte activity during self-initiated behaviors revealed that noradrenergic and cholinergic systems act synergistically to recruit astrocytes during state transitions associated with arousal and attention, which was profoundly modulated by internal state. The distinct activity patterns exhibited by astrocytes in the cerebral cortex may provide a means to vary their neuromodulatory influence in response to different behaviors and internal states.

Prevalence and implications of significance testing for baseline covariate imbalance in randomised cancer clinical trials: The Table 1 Fallacy.

BACKGROUND: The 'Table 1 Fallacy' refers to the unsound use of significance testing for comparing the distributions of baseline variables between randomised groups to draw erroneous conclusions about balance or imbalance. We performed a cross-sectional study of the Table 1 Fallacy in phase III oncology trials. METHODS: From ClinicalTrials.gov, 1877 randomised trials were screened. Multivariable logistic regressions evaluated predictors of the Table 1 Fallacy. RESULTS: A total of 765 randomised controlled trials involving 553,405 patients were analysed. The Table 1 Fallacy was observed in 25% of trials (188 of 765), with 3% of comparisons deemed significant (59 of 2353), approximating the typical 5% type I error assertion probability. Application of trial-level multiplicity corrections reduced the rate of significant findings to 0.3% (six of 2345 tests). Factors associated with lower odds of the Table 1 Fallacy included industry sponsorship (adjusted odds ratio [aOR] 0.29, 95% confidence interval [CI] 0.18-0.47; multiplicity-corrected P < 0.0001), larger trial size (≥795 versus <280 patients; aOR 0.32, 95% CI 0.19-0.53; multiplicity-corrected P = 0.0008), and publication in a European versus American journal (aOR 0.06, 95% CI 0.03-0.13; multiplicity-corrected P < 0.0001). CONCLUSIONS: This study highlights the persistence of the Table 1 Fallacy in contemporary oncology randomised controlled trials, with one of every four trials testing for baseline differences after randomisation. Significance testing is a suboptimal method for identifying unsound randomisation procedures and may encourage misleading inferences. Journal-level enforcement is a possible strategy to help mitigate this fallacy.

Comprehensive, Evidence-Based, Consensus Guidelines for Prescription of Opioids for Chronic Non-Cancer Pain from the American Society of Interventional Pain Physicians (ASIPP).

BACKGROUND: Opioid prescribing in the United States is decreasing, however, the opioid epidemic is continuing at an uncontrollable rate. Available data show a significant number of opioid deaths, primarily associated with illicit fentanyl use. It is interesting to also note that the data show no clear correlation between opioid prescribing (either number of prescriptions or morphine milligram equivalent [MME] per capita), opioid hospitalizations, and deaths. Furthermore, the data suggest that the 2016 guidelines from the Centers for Disease Control and Prevention (CDC) have resulted in notable problems including increased hospitalizations and mental health disorders due to the lack of appropriate opioid prescribing as well as inaptly rapid tapering or weaning processes. Consequently, when examined in light of other policies and complications caused by COVID-19, a fourth wave of the opioid epidemic has been emerging. OBJECTIVES: In light of this, we herein seek to provide guidance for the prescription of opioids for the management of chronic non-cancer pain. These clinical practice guidelines are based upon a systematic review of both clinical and epidemiological evidence and have been developed by a panel of multidisciplinary experts assessing the quality of the evidence and the strength of recommendations and offer a clear explanation of logical relationships between various care options and health outcomes. METHODS: The methods utilized included the development of objectives and key questions for the various facets of opioid prescribing practice. Also utilized were employment of trustworthy standards, and appropriate disclosures of conflicts of interest(s). The literature pertaining to opioid use, abuse, effectiveness, and adverse consequences was reviewed. The recommendations were developed after the appropriate review of text and questions by a panel of multidisciplinary subject matter experts, who tabulated comments, incorporated changes, and developed focal responses to questions posed. The multidisciplinary panel finalized 20 guideline recommendations for prescription of opioids for chronic non-cancer pain. Summary of the results showed over 90% agreement for the final 20 recommendations with strong consensus. The consensus guidelines included 4 sections specific to opioid therapy with 1) ten recommendations particular to initial steps of opioid therapy; 2) five recommendations for assessment of effectiveness of opioid therapy; 3) three recommendations regarding monitoring adherence and side effects; and 4) two general, final phase recommendations. LIMITATIONS: There is a continued paucity of literature of long-term opioid therapy addressing chronic non-cancer pain. Further, significant biases exist in the preparation of guidelines, which has led to highly variable rules and regulations across various states. CONCLUSION: These guidelines were developed based upon a comprehensive review of the literature, consensus among expert panelists, and in alignment with patient preferences, and shared decision-making so as to improve the long-term pain relief and function in patients with chronic non-cancer pain. Consequently, it was concluded - and herein recommended - that chronic opioid therapy should be provided in low doses with appropriate adherence monitoring and understanding of adverse events only to those patients with a proven medical necessity, and who exhibit stable improvement in both pain relief and activities of daily function, either independently or in conjunction with other modalities of treatments.

Preparation of cationic nanogels for nucleic acid delivery.

Cationic nanogels with site-selected functionality were designed for the delivery of nucleic acid payloads targeting numerous therapeutic applications. Functional cationic nanogels containing quaternized 2-(dimethylamino)ethyl methacrylate and a cross-linker with reducible disulfide moieties (qNG) were prepared by activators generated by electron transfer (AGET) atom transfer radical polymerization (ATRP) in an inverse miniemulsion. Polyplex formation between the qNG and nucleic acid exemplified by plasmid DNA (pDNA) and short interfering RNA (siRNA duplexes) were evaluated. The delivery of polyplexes was optimized for the delivery of pDNA and siRNA to the Drosophila Schneider 2 (S2) cell-line. The qNG/nucleic acid (i.e., siRNA and pDNA) polyplexes were found to be highly effective in their capabilities to deliver their respective payloads.

Abnormal uterine bleeding following lumbar epidural corticosteroid injections and facet medial branch blocks in both pre- and postmenopausal women: a case series.

BACKGROUND: Epidural steroid injections (ESIs) are now increasing in popularity with regard to the management of chronic lumbar radiculopathy. While ESIs have been shown to be effective in relieving low back and radicular pain, adverse reactions have also been reported, notably abnormal vaginal bleeding. OBJECTIVE: We present a case series of four women, both pre- and postmenopausal, with chronic lumbar radiculopathy and corresponding pathology who developed abnormal vaginal bleeding after receiving either ESIs or facet medial branch blocks (MBBs) for pain management. Setting. University of California, Los Angeles. PATIENTS: Four women, both pre- and postmenopausal. CONCLUSIONS: We discuss the potential effects of corticosteroids on the hypothalamic-pituitary-ovarian axis and highlight our patients' risk factors for abnormal vaginal bleeding, both exogenous and endogenous, as well as focus on the technical approaches to corticosteroid administration utilized in our patients' procedures. We acknowledge that because this is a small case series, further prospective investigation is warranted regarding the above topics. Until then, it may be beneficial to consider whether patients, both pre- and postmenopausal, have risk factors for abnormal uterine bleeding prior to undergoing interventional pain management strategies, specifically ESI and MBB, and to inform all women upon consent that abnormal vaginal bleeding is a potential risk following procedures with corticosteroids.

How many referrals to a pediatric orthopaedic hospital specialty clinic are primary care problems?

PURPOSE: Many primary care physicians believe that there are too few pediatric orthopaedic specialists available to meet their patients' needs. However, a recent survey by the Practice Management Committee of the Pediatric Orthopaedic Society of North America found that new referrals were often for cases that could have been managed by primary care practitioners. We wished to determine how many new referral cases seen by pediatric orthopaedic surgeons are in fact conditions that can be readily managed by a primary care physician should he/she chose to do so. METHODS: We prospectively studied all new referrals to our hospital-based orthopaedic clinic during August 2010. Each new referral was evaluated for whether it met the American Board of Pediatrics criteria for being a condition that could be managed by a primary care pediatrician. Each referral was also evaluated for whether it met the American Academy of Pediatrics Surgery Advisory Panel guidelines recommending referral to an orthopaedic specialist, regardless of whether it is for general orthopaedics or pediatric orthopaedics. On the basis of these criteria, we classified conditions as either a condition manageable by primary care physicians or a condition that should be referred to an orthopaedic surgeon or a pediatric orthopaedic surgeon. We used these guidelines not to identify diagnosis that primary care physicians should treat but, rather, to compare the guideline-delineated referrals with the actual referrals our specialty pediatric orthopaedic clinic received over a period of 1 month. RESULTS: A total of 529 new patient referrals were seen during August 2010. A total of 246 (47%) were considered primary care conditions and 283 (53%) orthopaedic specialty conditions. The most common primary care condition was a nondisplaced phalanx fracture (25/246, 10.1%) and the most common specialty condition was a displaced single-bone upper extremity fracture needing reduction (36/283, 13%). Only 77 (14.6%) of the total cases met the strict American Academy of Pediatrics Surgery Advisory Panel guidelines recommending referral to pediatric orthopaedics, with scoliosis being the most frequent condition. For 38 (7.2%) cases, surgical treatment was required or recommended. Patient age, referral source, or type of insurance did not influence whether the condition was a primary care or a specialty care case. A total of 134 (25%) cases were referred without having an initial diagnosis made by the referring clinician. These patients were more likely to have been referred from a primary care practitioner than from a tertiary care practitioner whether the diagnosis eventually made was considered to be a primary care condition (P=0.03; relative risk, 1.9; 95% confidence interval, 96-3.86). CONCLUSIONS: Almost half of all new referrals to a tertiary pediatric orthopaedic clinic were for conditions considered to be manageable by primary care physicians should they chose to do so. SIGNIFICANCE: This has implications for pediatric orthopaedic workforce availability, reimbursement under the Affordable Care Act, and pediatric musculoskeletal training needs for providers of primary care.