Antonia Jelicic Kadic

Extracting data from figures with software was faster, with higher interrater reliability than manual extraction

OBJECTIVES To compare speed and accuracy of graphical data extraction using manual estimation and open source software. STUDY DESIGN AND SETTING Data points from eligible graphs/figures published in randomized controlled trials (RCTs) from 2009 to 2014 were extracted by two authors independently, both by manual estimation and with the Plot Digitizer, open source software. Corresponding authors of each RCT were contacted up to four times via e-mail to obtain exact numbers that were used to create graphs. Accuracy of each method was compared against the source data from which the original graphs were produced. RESULTS Software data extraction was significantly faster, reducing time for extraction for 47%. Percent agreement between the two raters was 51% for manual and 53.5% for software data extraction. Percent agreement between the raters and original data was 66% vs. 75% for the first rater and 69% vs. 73% for the second rater, for manual and software extraction, respectively. CONCLUSIONS Data extraction from figures should be conducted using software, whereas manual estimation should be avoided. Using software for data extraction of data presented only in figures is faster and enables higher interrater reliability.

Reduced epidermal thickness, nerve degeneration and increased pain-related behavior in rats with diabetes type 1 and 2.

To examine the mechanisms contributing to pain genesis in diabetic neuropathy, we investigated epidermal thickness and number of intraepidermal nerve fibers in rat foot pad of the animal model of diabetes type 1 and type 2 in relation to pain-related behavior. Male Sprague-Dawley rats were used. Diabetes type 1 was induced with intraperitoneal injection of streptozotocin (STZ) and diabetes type 2 was induced with a combination of STZ and high-fat diet. Control group for diabetes type 1 was fed with regular laboratory chow, while control group for diabetes type 2 received high-fat diet. Body weights and blood glucose levels were monitored to confirm induction of diabetes. Pain-related behavior was analyzed using thermal (hot, cold) and mechanical stimuli (von Frey fibers, number of hyperalgesic responses). Two months after induction of diabetes, glabrous skin samples from plantar surface of the both hind paws were collected. Epidermal thickness was evaluated with hematoxylin and eosin staining. Intraepidermal nerve fibers quantification was performed after staining skin with polyclonal antiserum against protein gene product 9.5. We found that induction of diabetes type 1 and type 2 causes significant epidermal thinning and loss of intraepidermal nerve fibers in a rat model, and both changes were more pronounced in diabetes type 1 model. Significant increase of pain-related behavior two months after induction of diabetes was observed only in a model of diabetes type 1. In conclusion, animal models of diabetes type 1 and diabetes type 2 could be used in pharmacological studies, where cutaneous changes could be used as outcome measures for predegenerative markers of neuropathies.

Interventions for Neuropathic Pain: An Overview of Systematic Reviews.

Numerous interventions for neuropathic pain (NeuP) are available, but its treatment remains unsatisfactory. We systematically summarized evidence from systematic reviews (SRs) of randomized controlled trials on interventions for NeuP. Five electronic databases were searched up to March 2015. Study quality was analyzed using A Measurement Tool to Assess Systematic Reviews. The most common interventions in 97 included SRs were pharmacologic (59%) and surgical (15%). The majority of analyzed SRs were of medium quality. More than 50% of conclusions from abstracts on efficacy and approximately 80% on safety were inconclusive. Effective interventions were described for painful diabetic neuropathy (pregabalin, gabapentin, certain tricyclic antidepressants [TCAs], opioids, antidepressants, and anticonvulsants), postherpetic neuralgia (gabapentin, pregabalin, certain TCAs, antidepressants and anticonvulsants, opioids, sodium valproate, topical capsaicin, and lidocaine), lumbar radicular pain (epidural corticosteroids, repetitive transcranial magnetic stimulation [rTMS], and discectomy), cervical radicular pain (rTMS), carpal tunnel syndrome (carpal tunnel release), cubital tunnel syndrome (simple decompression and ulnar nerve transposition), trigeminal neuralgia (carbamazepine, lamotrigine, and pimozide for refractory cases, rTMS), HIV-related neuropathy (topical capsaicin), and central NeuP (certain TCAs, pregabalin, cannabinoids, and rTMS). Evidence about interventions for NeuP is frequently inconclusive or completely lacking. New randomized controlled trials about interventions for NeuP are necessary; they should address safety and use clear diagnostic criteria.

Using the WHO essential medicines list to assess the appropriateness of insurance coverage decisions: a case study of the Croatian national medicine reimbursement list.

Purpose To investigate the use of the WHO EML as a tool with which to evaluate the evidence base for the medicines on the national insurance coverage list of the Croatian Institute of Health Insurance (CIHI). Methods Medicines from 9 ATC categories with highest expenditures from 2012 CIHI Basic List (n = 509) were compared with 2011 WHO EML for adults (n = 359). For medicines with specific indication listed only in CIHI Basic List we assessed whether there was evidence in Cochrane Database of Systematic Reviews questioning their efficacy and safety. Results The two lists shared 188 medicines (52.4% of WHO EML and 32.0% of CIHI list). CIHI Basic List had 254 medicines and 33 combinations of these medicines which were not on the WHO EML, plus 14 medicines rejected and 20 deleted from WHO EML by its Evaluation Committee. For deleted medicines, we could obtain data that showed 2,965,378 prescriptions issued to 617,684 insured patients, and the cost of approximately € 41.2 million for 2012 and the first half of 2013, when the CIHI Basic List was in effect. For CIHI List-only medicines with a specific indication (n = 164 or 57.1% of the analyzed set), fewer benefits or more serious side-effects than other medicines were found for 17 (10.4%) and not enough evidence for recommendations for specific indication for 21 (12.8%) medicines in Cochrane systematic reviews. Conclusions National health care policy should use high-quality evidence in deciding on adding new medicines and reassessing those already present on national medicines lists, in order to rationalize expenditures and ensure wider and better access to medicines. The WHO EML and recommendations from its Evaluation Committee may be useful tools in this quality assurance process.

Expression of PTHrP and PTH/PTHrP receptor 1 in the superior cervical ganglia of rats.

PTHrP and its receptor PTHR1 are found in the CNS and peripheral nervous system. The presence of PTHrP mRNA has been detected in the superior cervical ganglion (SCG), but there are no data on the cellular distribution of PTHrP and PTHR1 in the SCG. Although it is known that ovarian activity and reproductive status influence sympathetic activity, and the PTHrP/PTHR1 system is influenced by estrogens in different tissues, it is not known whether these factors have a similar effect on expression of PTHrP and PTHR1 in the nervous system. Hence, we investigated the presence and distribution of PTHrP and PTHR1 in neurons and glia of the SCG of rats, as well as the influence of ovariectomy on their expression, by using immunohistochemistry. PTHrP and PTHR1 immunoreactivity was observed in cytoplasm as well as in nuclei of almost all neurons in the SCG. In male rats, intensity of PTHrP fluorescence was significantly higher in cytoplasm of NPY-, in comparison to NPY+ neurons (p < 0.05). In female rats, 2 months post-ovariectomy, significantly lower intensity of PTHrP fluorescence in cytoplasm of the SCG neurons was observed in comparison to sham operated animals (p < 0.05). In addition to neurons, PTHrP and PTHR1 immunoreactivity was observed in most of the glia and was not influenced by ovariectomy. Results show the expression of PTHrP and its receptor, PTHR1, in the majority of neurons and glial cells in the SCG of rats. Expression of PTHrP, but not PTHR1 in the cytoplasm of SCG neurons is influenced by ovarian activity.

Interventions for postoperative pain in children: An overview of systematic reviews

The aim of this study was to conduct an overview of systematic reviews that summarizes the results about efficacy and safety from randomized controlled trials involving the various strategies used for postoperative pain management in children. We searched the Cochrane Database of Systematic Reviews, CINAHL, Database of Reviews of Effect, Embase, MEDLINE, and PsycINFO from the earliest date to January 24, 2016. This overview included 45 systematic reviews that evaluated interventions for postoperative pain in children. Out of 45 systematic reviews that investigated various interventions for postoperative pain in children, 19 systematic reviews (42%) presented conclusive evidence of efficacy. Positive conclusive evidence was reported in 18 systematic reviews (40%) for the efficacy of diclofenac, ketamine, caudal analgesia, dexmedetomidine, music therapy, corticosteroid, epidural analgesia, paracetamol, and/or nonsteroidal anti‐inflammatory drugs and transversus abdominis plane block. Only one systematic review reported conclusive evidence of equal efficacy that involved a comparison of dexmedetomidine vs morphine and fentanyl. Safety of interventions was reported as conclusive in 14 systematic reviews (31%), with positive conclusive evidence for dexmedetomidine, corticosteroid, epidural analgesia, transversus abdominis plane block, and clonidine. Seven systematic reviews reported equal conclusive safety for epidural infusion, diclofenac intravenous vs ketamine added to opioid analgesia, bupivacaine, ketamine, paracetamol, and dexmedetomidine vs intravenous infusions of various opioid analgesics, oral suspension and suppository of diclofenac, only opioid, normal saline, no treatment, placebo, and midazolam. Negative conclusive statement for safety was reported in one systematic review for caudal analgesia vs noncaudal regional analgesia. More than half of systematic reviews included in this overview were rated as having medium methodological quality. Of 45 included systematic reviews, 10 were Cochrane reviews and they had higher methodological quality than non‐Cochrane reviews. As evidence concerning efficacy and safety is inconclusive for most of the analyzed interventions, our review points out the need for more rigorous trials concerning pain management in children.

Diabetes mellitus affects activity of calcium/calmodulin-dependent protein kinase II alpha in rat trigeminal ganglia

The activity of calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) may play a critical role in the modulation of nociceptor activity and plasticity of primary sensory trigeminal neurons. The aim of this study was to investigate the immunoreactivity of phosphorylated CaMKIIα (pCaMKIIα) in subpopulations of trigeminal ganglion (TG) neurons in rat models of early diabetes type 1 (dm1) and 2 (dm2). DM1 model was induced with intraperitoneally (i.p.) injected streptozotocin (STZ) (55mg/kg). DM2 rats were fed with the high fat diet (HFD) for 2 weeks and then received 35mg/kg of STZ i.p. Two weeks and 2 months after the STZ-diabetes induction, rats were sacrificed and immunohistochemical analysis for detection of pCaMKIIα immunoreactivity and double immunofluorescence labelling with isolectin (IB4) was performed. Increased intensity of pCaMKIIα immunofluorescence, restricted to IB4-negative small-diameter neurons, was seen in TG neurons two months after STZ-DM1 induction. DM1 model, as well as the obesity (control dm2 groups) resulted in neuronal impaired growth while dm2 model led to neuron hypertrophy in TG. Observed changes may play a critical role in the modulation of nociceptor activity and plasticity of primary sensory trigeminal neurons. In future, innovative strategies for modulation of CaMKIIα activity in specific subpopulations of neurons could be a novel approach in therapy of diabetic trigeminal neuropathy.

Changes in epidermal thickness and cutaneous innervation during maturation in long-term diabetes

AIM Peripheral nerve fiber depletion in patients with chronic diabetes mellitus (DM) was linked to neuropathic symptoms, development of pain, foot ulcerations and lower extremity amputation. The aim of this study was to analyze cutaneous changes, including paw epidermal thickness and intraepidermal nerve fiber (IENF) density in long-term diabetes, in rats 6 months and 12 months after induction of diabetes. MATERIALS AND METHODS Epidermal thickness and IENF density were studied in Sprague-Dawley diabetic rats 6 months and 12 months after diabetes induction with streptozotocin. Epidermal thickness was evaluated using hematoxylin and eosin staining. Peripheral nerve fibers were stained with polyclonal antiserum against protein gene product 9.5 (PGP 9.5). Successful diabetes induction was validated by measuring plasma glucose and body mass regularly throughout the experiment. RESULTS This study showed that long-term diabetes, induced in Sprague-Dawley rats with streptozotocin, is characterized with significant epidermal thinning and reduction of intraepidermal nerve fibers, 6 months and 12 months after induction of diabetes. CONCLUSION Long-term studies of streptozotocin models of diabetes could be used for making normative IENF densities that can be later used as age-dependent normative values for studying new treatment modalities.

Intrathecal inhibition of calcium/calmodulin-dependent protein kinase II in diabetic neuropathy adversely affects pain-related behavior.

Calcium/calmodulin-dependent protein kinase II (CaMKII) is considered an important enzyme contributing to the pathogenesis of persistent pain. The aim of this study was to test whether intrathecal injection of CaMKII inhibitors may reduce pain-related behavior in diabetic rats. Male Sprague-Dawley rats were used. Diabetes was induced with intraperitoneal injection of 55mg/kg streptozotocin. Two weeks after diabetes induction, CaMKII inhibitor myristoil-AIP or KN-93 was injected intrathecally. Behavioral testing with mechanical and thermal stimuli was performed before induction of diabetes, the day preceding the injection, as well as 2h and 24h after the intrathecal injection. The expression of total CaMKII and its alpha isoform in dorsal horn was quantified using immunohistochemistry. Intrathecal injection of mAIP and KN-93 resulted in significant decrease in expression of total CaMKII and CaMKII alpha isoform activity. Also, mAIP and KN93 injection significantly increased sensitivity to a mechanical stimulus 24h after i.t. injection. Intrathecal inhibition of CaMKII reduced the expression of total CaMKII and its CaMKII alpha isoform activity in diabetic dorsal horn, which was accompanied with an increase in pain-related behavior. Further studies about the intrathecal inhibition of CaMKII should elucidate its role in nociceptive processes of diabetic neuropathy.

Authors’ lack of awareness and use of core outcome set on postoperative pain in children is hindering comparative effectiveness research

AIM To analyze awareness about and acceptability of core outcome set (COS) for pediatric pain recommended by the PedIMMPACT. METHODS We invited authors of systematic reviews and randomized controlled trials about interventions for postoperative pain in children to participate in a survey. RESULTS Only a third of surveyed authors of systematic reviews and randomized controlled trials about postoperative pain in children had heard about the PedIMMPACT COS for acute pediatric pain. Problems indicated as preventing them from using the COS were lack of awareness, difficulties with implementation, and lack of resources. CONCLUSION Further discussions about the adequacy of COS for acute pediatric pain, as well as interventions to increase the uptake of COS may be warranted.