Single-dose intravenous ketorolac for acute postoperative pain in adults.

BACKGROUND: Postoperative pain is common and may be severe. Postoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs) reduces patient opioid requirements and, in turn, may reduce the incidence and severity of opioid-induced adverse events (AEs). OBJECTIVES: To assess the analgesic efficacy and adverse effects of single-dose intravenous ketorolac, compared with placebo or an active comparator, for moderate to severe postoperative pain in adults. SEARCH METHODS: We searched the following databases without language restrictions: CENTRAL, MEDLINE, Embase and LILACS on 20 April 2020. We checked clinical trials registers and reference lists of retrieved articles for additional studies. SELECTION CRITERIA: Randomized double-blind trials that compared a single postoperative dose of intravenous ketorolac with placebo or another active treatment, for treating acute postoperative pain in adults following any surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane.  Our primary outcome was the number of participants in each arm achieving at least 50% pain relief over a four- and six-hour period. Our secondary outcomes were time to and number of participants using rescue medication; withdrawals due to lack of efficacy, adverse events (AEs), and for any other cause; and number of participants experiencing any AE, serious AEs (SAEs), and NSAID-related or opioid-related AEs. For subgroup analysis, we planned to analyze different doses of parenteral ketorolac separately and to analyze results based on the type of surgery performed. We assessed the certainty of evidence using GRADE. MAIN RESULTS: We included 12 studies, involving 1905 participants undergoing various surgeries (pelvic/abdominal, dental, and orthopedic), with 17 to 83 participants receiving intravenous ketorolac in each study. Mean study population ages ranged from 22.5 years to 67.4 years. Most studies administered a dose of ketorolac of 30 mg; one study assessed 15 mg, and another administered 60 mg. Most studies had an unclear risk of bias for some domains, particularly allocation concealment and blinding, and a high risk of bias due to small sample size. The overall certainty of evidence for each outcome ranged from very low to moderate. Reasons for downgrading certainty included serious study limitations, inconsistency and imprecision. Ketorolac versus placebo Very low-certainty evidence from eight studies (658 participants) suggests that ketorolac results in a large increase in the number of participants achieving at least 50% pain relief over four hours compared to placebo, but the evidence is very uncertain (risk ratio (RR) 2.81, 95% confidence interval (CI) 1.80 to 4.37). The number needed to treat for one additional participant to benefit (NNTB) was 2.4 (95% CI 1.8 to 3.7). Low-certainty evidence from 10 studies (914 participants) demonstrates that ketorolac may result in a large increase in the number of participants achieving at least 50% pain relief over six hours compared to placebo (RR 3.26, 95% CI 1.93 to 5.51). The NNTB was 2.5 (95% CI 1.9 to 3.7). Among secondary outcomes, for time to rescue medication, moderate-certainty evidence comparing intravenous ketorolac versus placebo demonstrated a mean median of 271 minutes for ketorolac versus 104 minutes for placebo (6 studies, 633 participants). For the number of participants using rescue medication, very low-certainty evidence from five studies (417 participants) compared ketorolac with placebo. The RR was 0.60 (95% CI 0.36 to 1.00), that is, it did not demonstrate a difference between groups. Ketorolac probably results in a slight increase in total adverse event rates compared with placebo (74% versus 65%; 8 studies, 810 participants; RR 1.09, 95% CI 1.00 to 1.19; number needed to treat for an additional harmful event (NNTH) 16.7, 95% CI 8.3 to infinite, moderate-certainty evidence). Serious AEs were rare. Low-certainty evidence from eight studies (703 participants) did not demonstrate a difference in rates between ketorolac and placebo (RR 0.62, 95% CI 0.13 to 3.03). Ketorolac versus NSAIDs  Ketorolac was compared to parecoxib in four studies and diclofenac in two studies. For our primary outcome, over both four and six hours there was no evidence of a difference between intravenous ketorolac and another NSAID (low-certainty and moderate-certainty evidence, respectively). Over four hours, four studies (337 participants) produced an RR of 1.04 (95% CI 0.89 to 1.21) and over six hours, six studies (603 participants) produced an RR of 1.06 (95% CI 0.95 to 1.19). For time to rescue medication, low-certainty evidence from four studies (427 participants) suggested that participants receiving ketorolac waited an extra 35 minutes (mean median 331 minutes versus 296 minutes). For the number of participants using rescue medication, very low-certainty evidence from three studies (260 participants) compared ketorolac with another NSAID. The RR was 0.90 (95% CI 0.58 to 1.40), that is, there may be little or no difference between groups.   Ketorolac probably results in a slight increase in total adverse event rates compared with another NSAID (76% versus 68%, 5 studies, 516 participants; RR 1.11, 95% CI 1.00 to 1.23; NNTH 12.5, 95% CI 6.7 to infinite, moderate-certainty evidence). Serious AEs were rare. Low-certainty evidence from five studies (530 participants) did not demonstrate a difference in rates between ketorolac and another NSAID (RR 3.18, 95% CI 0.13 to 76.99). Only one of the five studies reported a single serious AE. AUTHORS' CONCLUSIONS: The amount and certainty of evidence for the use of intravenous ketorolac as a treatment for postoperative pain varies across efficacy and safety outcomes and amongst comparators, from very low to moderate. The available evidence indicates that postoperative intravenous ketorolac administration may offer substantial pain relief for most patients, but further research may impact this estimate. Adverse events appear to occur at a slightly higher rate in comparison to placebo and to other NSAIDs. Insufficient information is available to assess whether intravenous ketorolac has a different rate of gastrointestinal or surgical-site bleeding, renal dysfunction, or cardiovascular events versus other NSAIDs. There was a lack of studies in cardiovascular surgeries and in elderly populations who may be at increased risk for adverse events.

Single-dose intravenous ibuprofen for acute postoperative pain in adults.

BACKGROUND: Postoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs) reduces patient opioid requirements and, in turn, may reduce the incidence and severity of opioid-induced adverse events (AEs). OBJECTIVES: To assess the analgesic efficacy and adverse effects of single-dose intravenous (IV) ibuprofen, compared with placebo or an active comparator, for moderate-to-severe postoperative pain in adults. SEARCH METHODS: We searched the following databases without language restrictions: CENTRAL, MEDLINE, Embase and LILACS on 10 June 2021. We checked clinical trials registers and reference lists of retrieved articles for additional studies. SELECTION CRITERIA: We included randomized trials that compared a single postoperative dose of intravenous (IV) ibuprofen with placebo or another active treatment, for treating acute postoperative pain in adults following any surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for review inclusion, assessed risk of bias, and extracted data. Our primary outcome was the number of participants in each arm achieving at least 50% pain relief over a 4- and 6-hour period. Our secondary outcomes were time to, and number of participants using rescue medication; withdrawals due to lack of efficacy, adverse events (AEs), and for any other cause; and number of participants reporting or experiencing any AE, serious AEs (SAEs), and specific NSAID-related or opioid-related AEs. We were not able to carry out any planned meta-analysis. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: Only one study met our inclusion criteria, involving 201 total participants, mostly female (mean age 42 years), undergoing primary, unilateral, distal, first metatarsal bunionectomy (with osteotomy and internal fixation). Ibuprofen 300 mg, placebo or acetaminophen 1000 mg was administered intravenously to participants reporting moderate pain intensity the day after surgery. Since we identified only one study for inclusion, we did not perform any quantitative analyses. The study was at low risk of bias for most domains. We downgraded the certainty of the evidence due to serious study limitations, indirectness and imprecision. Ibuprofen versus placebo Findings of the single study found that at both the 4-hour and 6-hour assessment period, the proportion of participants with at least 50% pain relief was 32% (24/76) for those assigned to ibuprofen and 22% (11/50) for those assigned to placebo. These findings produced a risk ratio (RR) of 1.44 (95% confidence interval (CI) 0.77 to 2.66 versus placebo for at least 50% of maximum pain relief over the 4-hour and 6-hour period (very low-certainty evidence). Median time to rescue medication was 101 minutes for ibuprofen and 71 minutes for placebo (1 study, 126 participants; very low-certainty evidence). The number of participants using rescue medication was not reported within the included study. During the study (1 study, 126 participants), 58/76 (76%) of participants assigned to ibuprofen and 39/50 (78%) assigned to placebo reported or experienced any adverse event (AE), (RR 0.98, 95% CI 0.81 to 1.19; low-certainty evidence). No serious AEs (SAEs) were experienced (1 study, 126 participants; very low-certainty evidence). Ibuprofen versus active comparators Ibuprofen (300 mg) was similar to the active comparator, IV acetaminophen (1000 mg) at 4 hours and 6 hours (1 study, 126 participants). For those assigned to active control (acetaminophen), the proportion of participants with at least 50% pain relief was 35% (26/75) at 4 hours and 31% (23/75) at 6 hours. At 4 hours, these findings produced a RR of 0.91 (95% CI 0.58 to 1.43; very low-certainty evidence) versus active comparator (acetaminophen). At 6 hours, these findings produced a RR of 1.03 (95% CI 0.64 to 1.66; very low-certainty evidence) versus active comparator (acetaminophen). Median time to rescue medication was 101 minutes for ibuprofen and 125 minutes for the active comparator, acetaminophen (1 study, 151 participants; very low-certainty evidence). The number of participants using rescue medication was not reported within the included study. During the study, 8/76 (76%) of participants assigned to ibuprofen and 45/75 (60%) assigned to active control (acetaminophen) reported or experienced any AE, (RR 1.27, 95% CI 1.02 to 1.59; very low-certainty evidence). No SAEs were experienced (1 study, 151 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: There is insufficient evidence to support or refute the suggestion that IV ibuprofen is effective and safe for acute postoperative pain in adults.

Computerised analysis of intrapartum fetal heart rate patterns and adverse outcomes in the INFANT trial.

OBJECTIVE: To assess if a computerised decision support system reliably identified abnormal fetal heart rate (FHR) patterns in fetuses with adverse neonatal outcomes in the INFANT trial, and whether its use reduced substandard care. DESIGN: Prospective cohort study within a randomised controlled trial. SETTING: Twenty-four maternity units in the UK and Ireland. POPULATION OR SAMPLE: A total of 46 614 labours between January 6 2010 and August 31 2013 in the INFANT trial. METHODS: Panel review of intrapartum and neonatal care in infants with adverse outcome, and an assessment of the effectiveness of computerised interpretation of fetal heart rate in reducing substandard care. Descriptive analysis of other factors associated with adverse outcome. MAIN OUTCOME MEASURES: Incidence and detection rate of abnormal fetal heart rate patterns, other characteristics associated with perinatal adverse outcome, and frequency of substandard care. RESULTS: Computer interpretation of FHR patterns was deemed to be completely valid in only 24 of 71 (33.8%) cases of adverse outcome. On a scale of 0-10 (completely invalid to completely valid), 28 cases (39.4%) had a score of 6 or less, mainly due to lack of recognition of decelerations (15 cases), or reduced variability (seven cases), or failure to recognise tachysystole (five cases). There were multiple associated factors that modified the clinical assessment of FHR patterns. There was substandard care in 45/71 cases (63%). CONCLUSION: A significant proportion of abnormal fetal heart rate patterns were not detected accurately by computer analysis, and its use did not reduce the incidence of substandard care. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme (project number 06.38.01). TWEETABLE ABSTRACT: Improved recognition of abnormal fetal heart rate patterns is insufficient to reduce the incidence of substandard care.

Age at death and the effect of lead-time bias in patients with colorectal cancer: a 10-year follow-up.

AIM: Studies addressing the benefit of early intervention are prone to lead-time bias, which results in an artificial improvement in cancer-specific mortality. We have previously compared the age at death for patients with colorectal cancer presenting on an emergency or elective basis. In this study, we aimed to repeat the analysis with a minimum follow-up of 10 years. METHOD: A nonscreen-detected cohort of patients presenting with colorectal cancer to three Lanarkshire Hospitals between 2000 and 2006 were entered into a prospective database, with analysis performed on 28 November 2016. The following data were collected: age at death, presentation type (emergency/elective), operative intent (palliative/curative) and Dukes stage. Results are presented as [mean (95% confidence intervals)]. Statistical analysis was undertaken using Student's t-test and multivariate analysis performed using Cox proportional hazard models. RESULTS: One thousand six hundred and thirty-six patients were identified. Elective patients presented younger than emergency patients [67.9 (67.3-68.5) vs 70.9 (69.6-72.2) years; P < 0.0001]. Overall mortality was 71.1% at time of analysis; no difference was seen in the mean age at death between emergency and elective presentation [73.5 (72.4-74.8) vs 73.6 (72.3-74.9) years; P = 0.841]. CONCLUSION: Current early detection strategies to diagnose colorectal cancer may improve cancer-specific survival by increasing lead-time bias. However, in our cohort of symptomatic patients, treatment on an elective or emergency basis does not influence overall survival. These data suggest that in selected patients, particularly where there is comorbidity, it may be reasonable to adopt a more expectant approach to investigate and treat colorectal symptoms.

Alteration in propagating colonic contractions by dairy proteins in isolated rat large intestine.

Gastrointestinal conditions in which the transit of contents is altered may benefit from nutritional approaches to influencing health outcomes. Milk proteins modulate the transit of contents along different regions, suggesting that they have varying effects on neuromuscular function to alter gastrointestinal motility. We tested the hypothesis that bovine whey and casein milk protein hydrolysates could have direct modulatory effects on colonic motility patterns in isolated rat large intestine. Casein protein hydrolysate (CPH), whey protein concentrate (WPC), whey protein hydrolysate (WPH), and a milk protein hydrolysate (MPH; a hydrolyzed blend of 60% whey to 40% casein) were compared for their effects on spontaneous contractile waves. These contractions propagate along the length of the isolated intact large intestine (22 cm) between the proximal colon and rectum and were detected by measuring activity at 4 locations. Milk proteins were perfused through the tissue bath, and differences in contraction amplitude and frequency were quantified relative to pretreatment controls. Propagation frequency was decreased by CPH, increased by MPH, and unaffected by intact whey proteins. The reduced motility with CPH and increased motility with MPH indicate a direct action of these milk proteins on colon tissue and provide evidence for differential modulation by hydrolysate type. These findings mirror actions on lower gastrointestinal transit reported in vivo, with the exception of WPH, suggesting that other factors are required.

Single-dose intravenous diclofenac for acute postoperative pain in adults.

BACKGROUND: Postoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs) reduces patient opioid requirements and, in turn, reduces the incidence and severity of opioid-induced adverse events (AEs). OBJECTIVES: To assess the analgesic efficacy and adverse effects of single-dose intravenous diclofenac, compared with placebo or an active comparator, for moderate to severe postoperative pain in adults. SEARCH METHODS: We searched the following databases without language restrictions: the Cochrane Central Register of Controlled Trials (Cochrane Register of Studies Online), MEDLINE, and Embase on 22 May 2018. We checked clinical trials registers and reference lists of retrieved articles for additional studies. SELECTION CRITERIA: We included randomized trials that compared a single postoperative dose of intravenous diclofenac with placebo or another active treatment, for treating acute postoperative pain in adults following any surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for review inclusion, assessed risk of bias, and extracted data.Our primary outcome was the number of participants in each arm achieving at least 50% pain relief over a four- and six-hour period.Our secondary outcomes were time to, and number of participants using rescue medication; withdrawals due to lack of efficacy, AEs, and for any cause; and number of participants experiencing any AE, serious AEs (SAEs), and NSAID-related AEs. We performed a post hoc analysis of opioid-related AEs, to enable indirect comparisons with other analyses of postoperative analgesics.For subgroup analysis, we planned to analyze different doses and formulations of parenteral diclofenac separately.We assessed the overall quality of the evidence for each outcome using GRADE and created two 'Summary of findings' tables. MAIN RESULTS: We included eight studies, involving 1756 participants undergoing various surgeries (dental, mixed minor, abdominal, and orthopedic), with 20 to 175 participants receiving intravenous diclofenac in each study. Mean study population ages ranged from 24.5 years to 54.5 years. Intravenous diclofenac doses varied among and within studies, ranging from 3.75 mg to 75 mg. Five studies assessed newer formulations of parenteral diclofenac that could be administered as an undiluted intravenous bolus. Most studies had an unclear risk of bias for several domains and a high risk of bias due to small sample size. The overall quality of evidence for each outcome was generally low for reasons including unclear risk of bias in studies, imprecision, and low event numbers.Primary outcomeThree studies (277 participants) produced a number needed to treat for an additional beneficial outcome (NNTB) for at least 50% of maximum pain relief versus placebo of 2.4 (95% confidence interval (CI) 1.9 to 3.1) over four hours (low-quality evidence). Four studies (436 participants) produced an NNTB of 3.8 versus placebo (95% CI 2.9 to 5.9) over six hours (low-quality evidence). No studies provided data for the comparison of intravenous diclofenac with another NSAID over four hours. At six hours there was no difference between intravenous diclofenac and another NSAID (low-quality evidence).Secondary outcomesFor secondary efficacy outcomes, intravenous diclofenac was generally superior to placebo and similar to other NSAIDs.For time to rescue medication, comparison of intravenous diclofenac versus placebo demonstrated a median of 226 minutes for diclofenac versus 80 minutes for placebo (5 studies, 542 participants, low-quality evidence). There were insufficient data for pooled analysis for comparisons of diclofenac with another NSAID (very low-quality evidence).For the number of participants using rescue medication, two studies (235 participants) compared diclofenac with placebo. The number needed to treat to prevent one additional harmful event (NNTp) (here, the need for rescue medication) compared with placebo was 3.0 (2.2 to 4.5, low-quality evidence). The comparison of diclofenac with another NSAID included only one study (98 participants). The NNTp was 4.5 (2.5 to 33) for ketorolac versus diclofenac (very low-quality evidence).The numbers of participants withdrawing were generally low and inconsistently reported (very low-quality evidence). Participant withdrawals were: 6% (8/140) diclofenac versus 5% (7/128) placebo, and 9% (8/87) diclofenac versus 7% (6/82) another NSAID for lack of efficacy; 2% (4/211) diclofenac versus 0% (0/198) placebo, and 3% (4/138) diclofenac versus 2% (2/129) another NSAID due to AEs; and 11% (21/191) diclofenac versus 17% (30/179) placebo, and 18% (21/118) diclofenac versus 15% (17/111) another NSAID for any cause.Overall adverse event rates were similar between intravenous diclofenac and placebo (71% in both groups, 2 studies, 296 participants) and between intravenous diclofenac and another NSAID (55% and 58%, respectively, 2 studies, 265 participants) (low-quality evidence for both comparisons). Serious and specific AEs were rare, preventing meta-analysis.There were sufficient data for a dose-effect analysis for our primary outcome for only one alternative dose, 18.75 mg. Analysis of the highest dose employed in each study demonstrated a relative benefit compared with placebo of 1.9 (1.4 to 2.4), whereas for the group receiving 18.75 mg, the relative benefit versus placebo was 1.6 (1.2 to 2.1, 2 studies). Compared to another NSAID, the high-dose analysis demonstrated a relative benefit of 0.9 (0.8 to 1.1), for the group receiving 18.75 mg, the relative benefit was 0.78 (0.65 to 0.93). For direct comparison of high dose versus 18.75 mg, the proportion of participants with at least 50% pain relief was 66% (90/137) for the high-dose arm versus 57% (77/135) in the low-dose arm. There were insufficient data for subgroup meta-analysis of different diclofenac formulations. AUTHORS' CONCLUSIONS: The amount and quality of evidence for the use of intravenous diclofenac as a treatment for postoperative pain is low. The available evidence indicates that postoperative intravenous diclofenac administration offers good pain relief for the majority of patients, but further research may impact this estimate. Adverse events appear to occur at a similar rate to other NSAIDs. Insufficient information is available to assess whether intravenous diclofenac has a different rate of bleeding, renal dysfunction, or cardiovascular events versus other NSAIDs. There was insufficient information to evaluate the efficacy and safety of newer versus traditional formulations of intravenous diclofenac. There was a lack of studies in major and cardiovascular surgeries and in elderly populations, which may be at increased risk for adverse events.

Macronutrient intake of dogs, self-selecting diets varying in composition offered ad libitum.

The diet of the domestic dog has changed significantly from that of its wolf ancestor, with to date only two studies having examined macronutrient self-selection in dogs. Whilst the first focused solely on protein intake, determining an intake of 30% metabolisable energy (ME), the second investigated dietary protein, fat and carbohydrate (PFC), indicating an intake ratio of 30:63:7% by energy. This study's aim was to further elucidate macronutrient intake by providing greater macronutrient range, energy content, and to investigate over a longer duration than previous studies. Fifteen adult dogs were given access to three wet diets providing 500% of daily ME, twice daily over 10 days. The diets were nutritionally complete and formulated using the same four ingredients in different proportions to supply high levels of protein (58% ME), fat (86% ME) or carbohydrate (54% ME). Overall fat and carbohydrate consumption significantly declined from 6,382 to 917 kcals per day (p < 0.001) and 553 to 214 kcals day-1 (p < .01) respectively. Protein intake, however, remained constant over the study and ranged from 4,786 to 4,156 kcals day-1 . Such results impacted on percentage total energy intake, with fat decreasing from 68% to 52% (p < .001) and protein increasing from 29% to 44% (p < .01). Our findings suggest that dogs still possess a "feast or famine" mentality, wherein energy dense fat is prioritised over protein initially. With continued feeding over 10 days, a transition to a more balanced energy contribution from both macronutrients is evident. The study also shows that given the option, dogs do not select carbohydrate to be a significant portion of the diet. The health implications of such dietary selection are of interest.

Development of mobile technologies for the prevention of cervical cancer in Santiago, Chile study protocol: a randomized controlled trial.

BACKGROUND: In Chile, more than 500 women die every year from cervical cancer, and a majority of Chilean women are not up-to-date with their Papanicolau (Pap) test. Mobile health has great potential in many health areas, particularly in health promotion and prevention. There are no randomized controlled trials in Latin America assessing its use in cervical cancer screening. The 'Development of Mobile Technologies for the Prevention of Cervical Cancer in Santiago, Chile' study aims to determine the efficacy of a text-message intervention on Pap test adherence among Chilean women in the metropolitan region of Santiago. METHODS/DESIGN: This study is a parallel randomized-controlled trial of 400 Chilean women aged 25-64 who are non-adherent with current recommendations for Pap test screening. Participants will be randomly assigned to (1) a control arm (usual care) or (2) an intervention arm, where text and voice messages containing information and encouragement to undergo screening will be sent to the women. The primary endpoint is completion of a Pap test within 6 months of baseline assessment, as determined by medical record review at community-based clinics. Medical record reviewers will be blinded to randomization arms. The secondary endpoint is an evaluation of the implementation and usability of the text message intervention as a strategy to improve screening adherence. DISCUSSION: This intervention using mobile technology intends to raise cervical cancer screening adherence and compliance among a Chilean population of low and middle-low socioeconomic status. If successful, this strategy may reduce the incidence of cervical cancer. TRIAL REGISTRATION: Clinicaltrials.gov NCT02376023 Registered 2/17/2015. First participant enrolled Feb 22nd 2016.

From impulses to maladaptive actions: the insula is a neurobiological gate for the development of compulsive behavior.

Impulsivity is an endophenotype of vulnerability for compulsive behaviors. However, the neural mechanisms whereby impulsivity facilitates the development of compulsive disorders, such as addiction or obsessive compulsive disorder, remain unknown. We first investigated, in rats, anatomical and functional correlates of impulsivity in the anterior insular (AI) cortex by measuring both the thickness of, and cellular plasticity markers in, the AI with magnetic resonance imaging and in situ hybridization of the immediate early gene zif268, respectively. We then investigated the influence of bilateral AI cortex lesions on the high impulsivity trait, as measured in the five-choice serial reaction time task (5-CSRTT), and the associated propensity to develop compulsivity as measured by high drinking levels in a schedule-induced polydipsia procedure (SIP). We demonstrate that the AI cortex causally contributes to individual vulnerability to impulsive-compulsive behavior in rats. Motor impulsivity, as measured by premature responses in the 5-CSRTT, was shown to correlate with the thinness of the anterior region of the insular cortex, in which highly impulsive (HI) rats expressed lower zif268 mRNA levels. Lesions of AI reduced impulsive behavior in HI rats, which were also highly susceptible to develop compulsive behavior as measured in a SIP procedure. AI lesions also attenuated both the development and the expression of SIP. This study thus identifies the AI as a novel neural substrate of maladaptive impulse control mechanisms that may facilitate the development of compulsive disorders.

Methadone for neuropathic pain in adults.

BACKGROUND: This review replaces an earlier review, "Methadone for chronic non-cancer pain in adults". This review serves to update the original and includes only studies of neuropathic pain. Methadone belongs to a class of analgesics known as opioids, that are considered the cornerstone of therapy for moderate-to-severe postsurgical pain and pain due to life-threatening illnesses; however, their use in neuropathic pain is controversial. Methadone has many characteristics that differentiate it from other opioids, which suggests that it may have a different efficacy and safety profile. OBJECTIVES: To assess the analgesic efficacy and adverse events of methadone for chronic neuropathic pain in adults. SEARCH METHODS: We searched the following databases: CENTRAL (CRSO), MEDLINE (Ovid), and Embase (Ovid), and two clinical trial registries. We also searched the reference lists of retrieved articles. The date of the most recent search was 30 November 2016. SELECTION CRITERIA: We included randomised, double-blind studies of two weeks' duration or longer, comparing methadone (in any dose, administered by any route, and in any formulation) with placebo or another active treatment in chronic neuropathic pain. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for inclusion in the review, assessed risk of bias, and extracted data. There were insufficient data to perform pooled analyses. We assessed the overall quality of the evidence for each outcome using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We included three studies, involving 105 participants. All were cross-over studies, one involving 19 participants with diverse neuropathic pain syndromes, the other two involving 86 participants with postherpetic neuralgia. Study phases ranged from 20 days to approximately eight weeks. All administered methadone orally, in doses ranging from 10 mg to 80 mg daily. Comparators were primarily placebo, but one study also included morphine and tricyclic antidepressants.The included studies had several limitations related to risk of bias, particularly incomplete reporting, selective outcome reporting, and small sample sizes.There were very limited data for our primary outcomes of participants with at least 30% or at least 50% pain relief. Two studies reported that 11/29 participants receiving methadone achieved 30% pain relief versus 7/29 participants receiving placebo. Only one study presented data in a manner that allowed us to calculate the number of participants with at least 50% pain relief. None of the 19 participants achieved a 50% reduction in pain intensity, either when receiving methadone or when receiving placebo. No study provided data for our other primary outcomes of Patient Global Impression of Change scale (PGIC) much or very much improved (equivalent to at least 30% pain relief) and PGIC very much improved (equivalent to at least 50% pain relief).For secondary efficacy outcomes, one study reported maximum and mean pain intensity and pain relief, and reported statistically significant improvements versus placebo for all outcomes with 20 mg daily doses of methadone, but not with 10 mg daily doses. The second study reported differences in pain reduction between methadone (n = 26) and morphine (n = 38) and found morphine to be statistically superior. The third study reported the number of responders (variously defined) for several pain and functional outcomes and found methadone to be statistically superior to placebo for the outcomes of categorical pain intensity and evoked pain. In the two studies that reported data, 0/29 participants withdrew due to lack of efficacy, whereas 4/29 participants withdrew due to adverse events while taking methadone versus 3/29 while taking placebo.One study reported incidences for several individual adverse events, but found a statistically significant increased incidence for methadone over placebo for only one event, dizziness. The other studies did not report data in a manner that enabled us to analyze adverse events. There were no serious adverse events or deaths reported.We assessed the quality of the evidence as very low for all efficacy and safety outcomes using GRADE, primarily because of the heterogeneity of study designs and populations, short durations, cross-over methodology, and few participants and events. AUTHORS' CONCLUSIONS: The three studies provide very limited, very low quality evidence of the efficacy and safety of methadone for chronic neuropathic pain, and there were too few data for pooled analysis of efficacy or harm, or to have confidence in the results of the individual studies. No conclusions can be made regarding differences in efficacy or safety between methadone and placebo, other opioids, or other treatments.

Single dose intravenous paracetamol or intravenous propacetamol for postoperative pain.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 10, 2011. Paracetamol (acetaminophen) is the most commonly prescribed analgesic for the treatment of acute pain. It may be administered orally, rectally, or intravenously. The efficacy and safety of intravenous (IV) formulations of paracetamol, IV paracetamol, and IV propacetamol (a prodrug that is metabolized to paracetamol), compared with placebo and other analgesics, is unclear. OBJECTIVES: To assess the efficacy and safety of IV formulations of paracetamol for the treatment of postoperative pain in both adults and children. SEARCH METHODS: We ran the search for the previous review in May 2010. For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1), MEDLINE (May 2010 to 16 February 2016), EMBASE (May 2010 to 16 February 2016), LILACS (2010 to 2016), a clinical trials registry, and reference lists of reviews for randomized controlled trials (RCTs) in any language and we retrieved articles. SELECTION CRITERIA: Randomized, double-blind, placebo- or active-controlled single dose clinical trials of IV paracetamol or IV propacetamol for acute postoperative pain in adults or children. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, which included demographic variables, type of surgery, interventions, efficacy, and adverse events. We contacted study authors for additional information. We graded each included study for methodological quality by assessing risk of bias and employed the GRADE approach to assess the overall quality of the evidence. MAIN RESULTS: We included 75 studies (36 from the original review and 39 from our updated review) enrolling a total of 7200 participants.Among primary outcomes, 36% of participants receiving IV paracetamol/propacetamol experienced at least 50% pain relief over four hours compared with 16% of those receiving placebo (number needed to treat to benefit (NNT) = 5; 95% confidence interval (CI) 3.7 to 5.6, high quality evidence). The proportion of participants in IV paracetamol/propacetamol groups experiencing at least 50% pain relief diminished over six hours, as reflected in a higher NNT of 6 (4.6 to 7.1, moderate quality evidence). Mean pain intensity at four hours was similar when comparing IV paracetamol and placebo, but was seven points lower on a 0 to 100 visual analog scale (0 = no pain, 100 = worst pain imaginable, 95% CI -9 to -6, low quality evidence) in those receiving paracetamol at six hours.For secondary outcomes, participants receiving IV paracetamol/propacetamol required 26% less opioid over four hours and 16% less over six hours (moderate quality evidence) than those receiving placebo. However, this did not translate to a clinically meaningful reduction in opioid-induced adverse events.Meta-analysis of efficacy comparisons between IV paracetamol/propacetamol and active comparators (e.g., opioids or nonsteroidal anti-inflammatory drugs) were either not statistically significant, not clinically significant, or both.Adverse events occurred at similar rates with IV paracetamol or IV propacetamol and placebo. However, pain on infusion occurred more frequently in those receiving IV propacetamol versus placebo (23% versus 1%). Meta-analysis did not demonstrate clinically meaningful differences between IV paracetamol/propacetamol and active comparators for any adverse event. AUTHORS' CONCLUSIONS: Since the last version of this review, we have found 39 new studies providing additional information. Most included studies evaluated adults only. We reanalyzed the data but the results did not substantially alter any of our previously published conclusions. This review provides high quality evidence that a single dose of either IV paracetamol or IV propacetamol provides around four hours of effective analgesia for about 36% of patients with acute postoperative pain. Low to very low quality evidence demonstrates that both formulations are associated with few adverse events, although patients receiving IV propacetamol have a higher incidence of pain on infusion than both placebo and IV paracetamol.

The Influence of Optimal Handheld Load on the Technical Ability to Apply Ground Reaction Forces during Horizontal Jumping in Female Netball Players.

Handheld load has been reported to enhance horizontal jump performance, however little is known about its influence on ground reaction forces (GRF), especially in female athletes. This study investigated the effects of individualized optimal handheld loading on the technical and physical ability to apply GRF during horizontal jumping in female netball players. Maximal effort, single standing, horizontal jumps were performed by 13 female netballers. Participants performed the jumps under 2 conditions: 1) unloaded, and 2) loaded. Eccentric mean horizontal GRF significantly increased with loading (p<0.05; Effect Size [ES]= 0.74). The ratio of horizontal-to-total GRF significantly increased (p<0.05; ES=0.57), however resultant GRF did not, suggesting that the technical ability to apply force in the direction of intended movement may be of greater importance than the magnitude of force applied. Jump distance also increased from 188.2±16.1 cm to 196.4±13.6 cm (p<0.01; ES=0.55) with handheld load. In conclusion, individualized optimal handheld loading improved single horizontal jump performance in this population of athletes; most likely through various mechanisms that allowed for increased eccentric horizontal GRFs and the technical ability of force application. Findings could have practical implications for the strength and conditioning coach, trainer and athlete.

Jump Training in Youth Soccer Players: Effects of Haltere Type Handheld Loading.

The aim of this study was to compare the effects of a jump training program, with or without haltere type handheld loading, on maximal intensity exercise performance. Youth soccer players (12.1±2.2 y) were assigned to either a jump training group (JG, n=21), a jump training group plus haltere type handheld loading (LJG, n=21), or a control group following only soccer training (CG, n=21). Athletes were evaluated for maximal-intensity performance measures before and after 6 weeks of training, during an in-season training period. The CG achieved a significant change in maximal kicking velocity only (ES=0.11-0.20). Both jump training groups improved in right leg (ES=0.28-0.45) and left leg horizontal countermovement jump with arms (ES=0.32-0.47), horizontal countermovement jump with arms (ES=0.28-0.37), vertical countermovement jump with arms (ES=0.26), 20-cm drop jump reactive strength index (ES=0.20-0.37), and maximal kicking velocity (ES=0.27-0.34). Nevertheless, compared to the CG, only the LJG exhibited greater improvements in all performance tests. Therefore, haltere type handheld loading further enhances performance adaptations during jump training in youth soccer players.

Patient controlled opioid analgesia versus non-patient controlled opioid analgesia for postoperative pain.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 4, 2006. Patients may control postoperative pain by self administration of intravenous opioids using devices designed for this purpose (patient controlled analgesia or PCA). A 1992 meta-analysis by Ballantyne et al found a strong patient preference for PCA over non-patient controlled analgesia, but disclosed no differences in analgesic consumption or length of postoperative hospital stay. Although Ballantyne's meta-analysis found that PCA did have a small but statistically significant benefit upon pain intensity, a 2001 review by Walder et al did not find statistically significant differences in pain intensity or pain relief between PCA and groups treated with non-patient controlled analgesia. OBJECTIVES: To evaluate the efficacy and safety of patient controlled intravenous opioid analgesia (termed PCA in this review) versus non-patient controlled opioid analgesia of as-needed opioid analgesia for postoperative pain relief. SEARCH METHODS: We ran the search for the previous review in November 2004. For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 12), MEDLINE (1966 to 28 January 2015), and EMBASE (1980 to 28 January 2015) for randomized controlled trials (RCTs) in any language, and reference lists of reviews and retrieved articles. SELECTION CRITERIA: We selected RCTs that assessed pain intensity as a primary or secondary outcome. These studies compared PCA without a continuous background infusion with non-patient controlled opioid analgesic regimens. We excluded studies that explicitly stated they involved patients with chronic pain. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, which included demographic variables, type of surgery, interventions, efficacy, and adverse events. We graded each included study for methodological quality by assessing risk of bias and employed the GRADE approach to assess the overall quality of the evidence. We performed meta-analysis of outcomes that included pain intensity assessed by a 0 to 100 visual analog scale (VAS), opioid consumption, patient satisfaction, length of stay, and adverse events. MAIN RESULTS: Forty-nine studies with 1725 participants receiving PCA and 1687 participants assigned to a control group met the inclusion criteria. The original review included 55 studies with 2023 patients receiving PCA and 1838 patients assigned to a control group. There were fewer included studies in our updated review due to the revised exclusion criteria. For the primary outcome, participants receiving PCA had lower VAS pain intensity scores versus non-patient controlled analgesia over most time intervals, e.g., scores over 0 to 24 hours were nine points lower (95% confidence interval (CI) -13 to -5, moderate quality evidence) and over 0 to 48 hours were 10 points lower (95% CI -12 to -7, low quality evidence). Among the secondary outcomes, participants were more satisfied with PCA (81% versus 61%, P value = 0.002) and consumed higher amounts of opioids than controls (0 to 24 hours, 7 mg more of intravenous morphine equivalents, 95% CI 1 mg to 13 mg). Those receiving PCA had a higher incidence of pruritus (15% versus 8%, P value = 0.01) but had a similar incidence of other adverse events. There was no difference in the length of hospital stay. AUTHORS' CONCLUSIONS: Since the last version of this review, we have found new studies providing additional information. We reanalyzed the data but the results did not substantially alter any of our previously published conclusions. This review provides moderate to low quality evidence that PCA is an efficacious alternative to non-patient controlled systemic analgesia for postoperative pain control.

Clinical spectrum of disease and outcomes in children with Omicron SARS-COV-2 infection in Cape Town, South Africa.

INTRODUCTION: Children with underlying comorbidities and infants are most severely affected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, including in low- and middle-income countries with a high prevalence of HIV and TB. We describe the clinical presentation of SARS-CoV-2 infection in children during the Omicron wave, in Cape Town, South Africa. METHODS: We analysed routine care data from a prospective cohort of children aged 0-13 years, with a positive SARS-CoV-2 real-time reverse-transcription polymerase chain reaction (rRT-PCR) or SARS-CoV-2 antigen test, admitted to Tygerberg Hospital between 1 November 2021 until 1 March 2022. Risk factors for severity of disease were assessed. RESULTS: Ninety-five children tested positive for SARS-CoV-2, of whom 87 (91.6%) were symptomatic. Clinical data were available for 86 children. The median age was 11 months (IQR 3.0-60.0), 37 (43.0%) were females, 21 (24.7%) were HIV-exposed and 7 (8.1%) were living with HIV (CLHIV). In total, 44 (51.2%) children had at least one underlying comorbidity. TB co-infection was seen in 11 children, 6 children were newly diagnosed and 5 children were already on TB treatment at the time of admission. CONCLUSION: There was no evidence of more severe disease in children living with HIV or TB.

INTRODUCTION: Les enfants et les nourrissons présentant des comorbidités sous-jacentes sont les plus gravement touchés par l'infection par le coronavirus-2 du syndrome respiratoire aigu sévère (SARS-CoV-2), y compris dans les pays à revenu faible ou intermédiaire où la prévalence du VIH et de la TB est élevée. Nous décrivons la présentation clinique de l'infection par le SARS-CoV-2 chez les enfants pendant la vague Omicron, au Cap, en Afrique du Sud. MÉTHODES: Nous avons analysé les données de soins de routine d'une cohorte prospective d'enfants âgés de 0 à 13 ans, avec un test positif de réaction en chaîne de la polymérase de transcription inverse en temps réel (rRT-PCR) ou d'antigène du SARS-CoV-2, admis à l'hôpital Tygerberg entre le 1er novembre 2021 et le 1er mars 2022. Les facteurs de risque de gravité de la maladie ont été évalués. RÉSULTATS: Quatre-vingt-quinze enfants ont été testés positifs au SARS-CoV-2, dont 87 (91,6%) étaient symptomatiques. Des données cliniques étaient disponibles pour 86 enfants. L'âge médian était de 11 mois (IQR 3,0­60,0), 37 (43,0%) étaient des filles, 21 (24,7%) étaient exposés au VIH et 7 (8,1%) vivaient avec le VIH (CLHIV). Au total, 44 (51,2%) enfants présentaient au moins une comorbidité sous-jacente. La co-infection par la TB a été observée chez 11 enfants, 6 enfants ont été nouvellement diagnostiqués et 5 enfants étaient déjà sous traitement antituberculeux au moment de l'admission. CONCLUSION: Il n'y a pas de preuve d'une maladie plus grave chez les enfants vivant avec le VIH ou la TB.

The basis of antagonistic pleiotropy in hfq mutations that have opposite effects on fitness at slow and fast growth rates.

Mutations beneficial in one environment may cause costs in different environments, resulting in antagonistic pleiotropy. Here, we describe a novel form of antagonistic pleiotropy that operates even within the same environment, where benefits and deleterious effects exhibit themselves at different growth rates. The fitness of hfq mutations in Escherichia coli affecting the RNA chaperone involved in small-RNA regulation is remarkably sensitive to growth rate. E. coli populations evolving in chemostats under nutrient limitation acquired beneficial mutations in hfq during slow growth (0.1 h(-1)) but not in populations growing sixfold faster. Four identified hfq alleles from parallel populations were beneficial at 0.1 h(-1) and deleterious at 0.6 h(-1). The hfq mutations were beneficial, deleterious or neutral at an intermediate growth rate (0.5 h(-1)) and one changed from beneficial to deleterious within a 36 min difference in doubling time. The benefit of hfq mutations was due to the greater transport of limiting nutrient, which diminished at higher growth rates. The deleterious effects of hfq mutations at 0.6 h(-1) were less clear, with decreased viability a contributing factor. The results demonstrate distinct pleiotropy characteristics in the alleles of the same gene, probably because the altered residues in Hfq affected the regulation of expression of different genes in distinct ways. In addition, these results point to a source of variation in experimental measurement of the selective advantage of a mutation; estimates of fitness need to consider variation in growth rate impacting on the magnitude of the benefit of mutations and on their fitness distributions.

Beyond the randomized clinical trial: citrate for continuous renal replacement therapy in clinical practice.

BACKGROUND: Premature circuit clotting is a major problem during continuous renal replacement therapy (CRRT). Six randomized controlled trials confirmed that regional anticoagulation with citrate is superior to heparin. Our objective was to compare circuit patency with citrate, heparin and epoprostenol in routine clinical practice. METHODS: We retrospectively analysed data on circuit patency of all circuits used in a single centre between September 2008 and August 2009. We differentiated between premature filter clotting, elective discontinuation and waste. RESULTS: 309 patients were treated with CRRT (n = 2,059 circuits). The mean age was 65.7; 63.8% were male. The methods to maintain circuit patency were unfractionated heparin (42.3%), epoprostenol (23.0%), citrate (14.7%), combinations of different anticoagulants (14.6%) and no anticoagulation (4.7%). Premature clotting was the most common reason for circuit discontinuation among circuits anticoagulated with heparin, epoprostenol or combinations of different anticoagulants (59-62%). Among circuits anticoagulated with citrate the main reason for discontinuation was elective (61%). Hazard regression analysis confirmed significantly better circuit survival with citrate. Changing from heparin to citrate decreased the risk of premature circuit clotting by 75.8%. CONCLUSION: In routine clinical practice, regional anticoagulation with citrate is associated with significantly better circuit patency than heparin or epoprostenol.

Prevalence of overweight and obesity among children six to ten years of age in the north-east health region of Jamaica.

OBJECTIVE: To estimate the prevalence and correlates of overweight and obesity among children six to ten years old in the North-East Health Region (NEHR) ofJamaica. METHODS: Weights and heights were measured in a representative sample of 5710 children between the ages of six and ten years in 34 schools between October 2008 and March 2009. Overweight and obesity were defined as body mass index (BMI) Z-score > 1SD and >2SD, respectively based on the World Health Organization (WHO)-endorsed age and gender-specific growth standards for children. Point prevalence estimates of overweight and obesity were calculated. Odds ratios (OR) and 95% confidence intervals (CI) were used to estimate associations between overweight and obesity and age, gender and school location. RESULTS: Overweight and obesity prevalence among children six to ten years old in NEHR, Jamaica, was 10.6% and 7.1%, respectively. Overweight (OR = 1.11, 95% CI: 1.04, 1.18) and obesity (OR = 1.17, 95% CI: 1.08, 1.26) prevalence increased significantly with age. Overweight (OR = 1.51, 95% CI: 1.27, 1.80) and obesity (OR = 1.36, 95% CI: 1.11, 1.67) prevalence was significantly higher among girls than boys. Children attending rural-public schools had less risk of being overweight (OR = 0.57, 95% CI: 0.46, 0.70) and obese (OR = 0.35, 95% CI: 0.28, 0.44) when compared with urban-public schools and private schools. Both overweight (OR = 2.11, 95% CI: 1.60, 2.78) and obesity (OR = 1.68, 95% CI: 1.24, 2.28) were significantly more common among children attending private schools. After adjusting for age and gender the results still remained statistically significant. CONCLUSIONS: Overweight/obesity prevalence among children six to ten years old in NEHR of Jamaica is 17.7% with older children and girls having higher rates. Children attending urban-public and private schools have higher prevalence than those attending rural schools. Appropriately targeted interventions are needed to combat this problem.