Opioids for procedural pain in neonates.

BACKGROUND: Neonates might be exposed to numerous painful procedures due to diagnostic reasons, therapeutic interventions, or surgical procedures. Options for pain management include opioids, non-pharmacological interventions, and other drugs. Morphine, fentanyl, and remifentanil are the opioids most often used in neonates. However, negative impact of opioids on the structure and function of the developing brain has been reported. OBJECTIVES: To evaluate the benefits and harms of opioids in term or preterm neonates exposed to procedural pain, compared to placebo or no drug, non-pharmacological intervention, other analgesics or sedatives, other opioids, or the same opioid administered by a different route. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was December 2021. SELECTION CRITERIA: We included randomized controlled trials conducted in preterm and term infants of a postmenstrual age (PMA) up to 46 weeks and 0 days exposed to procedural pain where opioids were compared to 1) placebo or no drug; 2) non-pharmacological intervention; 3) other analgesics or sedatives; 4) other opioids; or 5) the same opioid administered by a different route. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were pain assessed with validated methods and any harms. We used a fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, and their confidence intervals (CI). We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 13 independent studies (enrolling 823 newborn infants): seven studies compared opioids to no treatment or placebo (the main comparison in this review), two studies to oral sweet solution or non-pharmacological intervention, and five studies (of which two were part of the same study) to other analgesics and sedatives. All studies were performed in a hospital setting. Opioids compared to placebo or no drug Compared to placebo, opioids probably reduce pain score assessed with the Premature Infant Pain Profile (PIPP)/PIPP-Revised (PIPP-R) scale during the procedure (MD -2.58, 95% CI -3.12 to -2.03; 199 participants, 3 studies; moderate-certainty evidence); may reduce Neonatal Infant Pain Scale (NIPS) during the procedure (MD -1.97, 95% CI -2.46 to -1.48; 102 participants, 2 studies; low-certainty evidence); and may result in little to no difference in pain score assessed with the Douleur Aiguë du Nouveau-né (DAN) scale one to two hours after the procedure (MD -0.20, 95% CI -2.21 to 1.81; 42 participants, 1 study; low-certainty evidence). The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R scale up to 30 minutes after the procedure (MD 0.14, 95% CI -0.17 to 0.45; 123 participants, 2 studies; very low-certainty evidence) or one to two hours after the procedure (MD -0.83, 95% CI -2.42 to 0.75; 54 participants, 2 studies; very low-certainty evidence). The evidence is very uncertain about the effect of opioids on episodes of bradycardia (RR 3.19, 95% CI 0.14 to 72.69; 172 participants, 3 studies; very low-certainty evidence). Opioids may result in an increase in episodes of apnea compared to placebo (RR 3.15, 95% CI 1.08 to 9.16; 199 participants, 3 studies; low-certainty evidence): with one study reporting a concerning increase in severe apnea (RR 7.44, 95% CI 0.42 to 132.95; 31 participants, 1 study; very low-certainty). The evidence is very uncertain about the effect of opioids on episodes of hypotension (RR not estimable, risk difference 0.00, 95% CI -0.06 to 0.06; 88 participants, 2 studies; very low-certainty evidence). No studies reported parent satisfaction with care provided in the neonatal intensive care unit (NICU). Opioids compared to non-pharmacological intervention The evidence is very uncertain about the effect of opioids on pain score assessed with the Crying Requires oxygen Increased vital signs Expression Sleep (CRIES) scale during the procedure when compared to facilitated tucking (MD -4.62, 95% CI -6.38 to -2.86; 100 participants, 1 study; very low-certainty evidence) or sensorial stimulation (MD 0.32, 95% CI -1.13 to 1.77; 100 participants, 1 study; very low-certainty evidence). The other main outcomes were not reported. Opioids compared to other analgesics or sedatives The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R during the procedure (MD -0.29, 95% CI -1.58 to 1.01; 124 participants, 2 studies; very low-certainty evidence); up to 30 minutes after the procedure (MD -1.10, 95% CI -2.82 to 0.62; 12 participants, 1 study; very low-certainty evidence); and one to two hours after the procedure (MD -0.17, 95% CI -2.22 to 1.88; 12 participants, 1 study; very low-certainty evidence). No studies reported any harms. The evidence is very uncertain about the effect of opioids on episodes of apnea during (RR 3.27, 95% CI 0.85 to 12.58; 124 participants, 2 studies; very low-certainty evidence) and after the procedure (RR 2.71, 95% CI 0.11 to 64.96; 124 participants, 2 studies; very low-certainty evidence) and on hypotension (RR 1.34, 95% CI 0.32 to 5.59; 204 participants, 3 studies; very low-certainty evidence). The other main outcomes were not reported. We identified no studies comparing different opioids (e.g. morphine versus fentanyl) or different routes for administration of the same opioid (e.g. morphine enterally versus morphine intravenously). AUTHORS' CONCLUSIONS: Compared to placebo, opioids probably reduce pain score assessed with PIPP/PIPP-R scale during the procedure; may reduce NIPS during the procedure; and may result in little to no difference in DAN one to two hours after the procedure. The evidence is very uncertain about the effect of opioids on pain assessed with other pain scores or at different time points. The evidence is very uncertain about the effect of opioids on episodes of bradycardia, hypotension or severe apnea. Opioids may result in an increase in episodes of apnea. No studies reported parent satisfaction with care provided in the NICU. The evidence is very uncertain about the effect of opioids on any outcome when compared to non-pharmacological interventions or to other analgesics. We identified no studies comparing opioids to other opioids or comparing different routes of administration of the same opioid.

Systemic opioid regimens for postoperative pain in neonates.

BACKGROUND: Postoperative pain clinical management in neonates has always been a challenging medical issue. Worldwide, several systemic opioid regimens are available for pediatricians, neonatologists, and general practitioners to control pain in neonates undergoing surgical procedures. However, the most effective and safe regimen is still unknown in the current body of literature. OBJECTIVES: To determine the effects of different regimens of systemic opioid analgesics in neonates submitted to surgery on all-cause mortality, pain, and significant neurodevelopmental disability. Potentially assessed regimens might include: different doses of the same opioid, different routes of administration of the same opioid, continuous infusion versus bolus administration, or 'as needed' administration versus 'as scheduled' administration. SEARCH METHODS: Searches were conducted in June 2022 using the following databases: Cochrane Central Register of Controlled Trials [CENTRAL], PubMed, and CINAHL. Trial registration records were identified via CENTRAL and an independent search of the ISRCTN registry. SELECTION CRITERIA: We included randomized controlled trials (RCTs), quasi-randomized, cluster-randomized, and cross-over controlled trials evaluating systemic opioid regimens' effects on postoperative pain in neonates (pre-term or full-term). We considered suitable for inclusion: I) studies evaluating different doses of the same opioid; 2) studies evaluating different routes of administration of the same opioid; 3) studies evaluating the effectiveness of continuous infusion versus bolus infusion; and 4) studies establishing an assessment of an 'as needed' administration versus 'as scheduled' administration. DATA COLLECTION AND ANALYSIS: According to Cochrane methods, two investigators independently screened retrieved records, extracted data, and appraised the risk of bias. We stratified meta-analysis by the type of intervention: studies evaluating the use of opioids for postoperative pain in neonates through continuous infusion versus bolus infusion and studies assessing the 'as needed' administration versus 'as scheduled' administration. We used the fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD), standardized mean difference (SMD), median, and interquartile range (IQR) for continuous data. Finally, we used the GRADEpro approach for primary outcomes to evaluate the quality of the evidence across included studies. MAIN RESULTS: In this review, we included seven randomized controlled clinical trials (504 infants) from 1996 to 2020. We identified no studies comparing different doses of the same opioid, or different routes. The administration of continuous opioid infusion versus bolus administration of opioids was evaluated in six studies, while one study compared 'as needed' versus 'as scheduled' administration of morphine given by parents or nurses. Overall, the effectiveness of continuous infusion of opioids over bolus infusion as measured by the visual analog scale (MD 0.00, 95% confidence interval (CI) -0.23 to 0.23; 133 participants, 2 studies; I² = 0); or using the COMFORT scale (MD -0.07, 95% CI -0.89 to 0.75; 133 participants, 2 studies; I² = 0), remains unclear due to study designs' limitations, such as the unclear risk of attrition, reporting bias, and imprecision among reported results (very low certainty of the evidence).  None of the included studies reported data on other clinically important outcomes such as all-cause mortality rate during hospitalization, major neurodevelopmental disability, the incidence of severe retinopathy of prematurity or intraventricular hemorrhage, and cognitive- and educational-related outcomes.  AUTHORS' CONCLUSIONS: Limited evidence is available on continuous infusion compared to intermittent boluses of systemic opioids. We are uncertain whether continuous opioid infusion reduces pain compared with intermittent opioid boluses; none of the studies reported the other primary outcomes of this review, i.e. all-cause mortality during initial hospitalization, significant neurodevelopmental disability, or cognitive and educational outcomes among children older than five years old. Only one small study reported on morphine infusion with parent- or nurse-controlled analgesia.

Opioids for procedural pain in neonates.

BACKGROUND: Neonates might be exposed to numerous painful procedures due to diagnostic reasons, therapeutic interventions, or surgical procedures. Options for pain management include opioids, non-pharmacological interventions, and other drugs. Morphine, fentanyl, and remifentanil are the opioids most often used in neonates. However, negative impact of opioids on the structure and function of the developing brain has been reported. OBJECTIVES: To evaluate the benefits and harms of opioids in term or preterm neonates exposed to procedural pain, compared to placebo or no drug, non-pharmacological intervention, other analgesics or sedatives, other opioids, or the same opioid administered by a different route. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was December 2021. SELECTION CRITERIA: We included randomized controlled trials conducted in preterm and term infants of a postmenstrual age (PMA) up to 46 weeks and 0 days exposed to procedural pain where opioids were compared to 1) placebo or no drug; 2) non-pharmacological intervention; 3) other analgesics or sedatives; 4) other opioids; or 5) the same opioid administered by a different route. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were pain assessed with validated methods and any harms. We used a fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, and their confidence intervals (CI). We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 13 independent studies (enrolling 823 newborn infants): seven studies compared opioids to no treatment or placebo (the main comparison in this review), two studies to oral sweet solution or non-pharmacological intervention, and five studies (of which two were part of the same study) to other analgesics and sedatives. All studies were performed in a hospital setting. Opioids compared to placebo or no drug Compared to placebo, opioids probably reduce pain score assessed with the Premature Infant Pain Profile (PIPP)/PIPP-Revised (PIPP-R) scale during the procedure (MD -2.58, 95% CI -3.12 to -2.03; 199 participants, 3 studies; moderate-certainty evidence); may reduce Neonatal Infant Pain Scale (NIPS) during the procedure (MD -1.97, 95% CI -2.46 to -1.48; 102 participants, 2 studies; low-certainty evidence); and may result in little to no difference in pain score assessed with the Douleur Aiguë du Nouveau-né (DAN) scale one to two hours after the procedure (MD -0.20, 95% CI -2.21 to 1.81; 42 participants, 1 study; low-certainty evidence). The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R scale up to 30 minutes after the procedure (MD 0.14, 95% CI -0.17 to 0.45; 123 participants, 2 studies; very low-certainty evidence) or one to two hours after the procedure (MD -0.83, 95% CI -2.42 to 0.75; 54 participants, 2 studies; very low-certainty evidence). No studies reported any harms. The evidence is very uncertain about the effect of opioids on episodes of bradycardia (RR 3.19, 95% CI 0.14 to 72.69; 172 participants, 3 studies; very low-certainty evidence). Opioids may result in an increase in episodes of apnea compared to placebo (RR 3.15, 95% CI 1.08 to 9.16; 199 participants, 3 studies; low-certainty evidence). The evidence is very uncertain about the effect of opioids on episodes of hypotension (RR not estimable, risk difference 0.00, 95% CI -0.06 to 0.06; 88 participants, 2 studies; very low-certainty evidence). No studies reported parent satisfaction with care provided in the neonatal intensive care unit (NICU). Opioids compared to non-pharmacological intervention The evidence is very uncertain about the effect of opioids on pain score assessed with the Crying Requires oxygen Increased vital signs Expression Sleep (CRIES) scale during the procedure when compared to facilitated tucking (MD -4.62, 95% CI -6.38 to -2.86; 100 participants, 1 study; very low-certainty evidence) or sensorial stimulation (MD 0.32, 95% CI -1.13 to 1.77; 100 participants, 1 study; very low-certainty evidence). The other main outcomes were not reported. Opioids compared to other analgesics or sedatives The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R during the procedure (MD -0.29, 95% CI -1.58 to 1.01; 124 participants, 2 studies; very low-certainty evidence); up to 30 minutes after the procedure (MD -1.10, 95% CI -2.82 to 0.62; 12 participants, 1 study; very low-certainty evidence); and one to two hours after the procedure (MD -0.17, 95% CI -2.22 to 1.88; 12 participants, 1 study; very low-certainty evidence). No studies reported any harms. The evidence is very uncertain about the effect of opioids on episodes of apnea during (RR 3.27, 95% CI 0.85 to 12.58; 124 participants, 2 studies; very low-certainty evidence) and after the procedure (RR 2.71, 95% CI 0.11 to 64.96; 124 participants, 2 studies; very low-certainty evidence) and on hypotension (RR 1.34, 95% CI 0.32 to 5.59; 204 participants, 3 studies; very low-certainty evidence). The other main outcomes were not reported. We identified no studies comparing different opioids (e.g. morphine versus fentanyl) or different routes for administration of the same opioid (e.g. morphine enterally versus morphine intravenously). AUTHORS' CONCLUSIONS: Compared to placebo, opioids probably reduce pain score assessed with PIPP/PIPP-R scale during the procedure; may reduce NIPS during the procedure; and may result in little to no difference in DAN one to two hours after the procedure. The evidence is very uncertain about the effect of opioids on pain assessed with other pain scores or at different time points. No studies reported if any harms occurred. The evidence is very uncertain about the effect of opioids on episodes of bradycardia or hypotension. Opioids may result in an increase in episodes of apnea. No studies reported parent satisfaction with care provided in the NICU. The evidence is very uncertain about the effect of opioids on any outcome when compared to non-pharmacological interventions or to other analgesics. We identified no studies comparing opioids to other opioids or comparing different routes of administration of the same opioid.

Systemic opioids versus other analgesics and sedatives for postoperative pain in neonates.

BACKGROUND: Neonates may undergo surgery because of malformations such as diaphragmatic hernia, gastroschisis, congenital heart disease, and hypertrophic pyloric stenosis, or complications of prematurity, such as necrotizing enterocolitis, spontaneous intestinal perforation, and retinopathy of prematurity that require surgical treatment. Options for treatment of postoperative pain include opioids, non-pharmacological interventions, and other drugs. Morphine, fentanyl, and remifentanil are the opioids most often used in neonates. However, negative impact of opioids on the structure and function of the developing brain has been reported. The assessment of the effects of opioids is of utmost importance, especially for neonates in substantial pain during the postoperative period. OBJECTIVES: To evaluate the benefits and harms of systemic opioid analgesics in neonates who underwent surgery on all-cause mortality, pain, and significant neurodevelopmental disability compared to no intervention, placebo, non-pharmacological interventions, different types of opioids, or other drugs. SEARCH METHODS: We searched Cochrane CENTRAL, MEDLINE via PubMed and CINAHL in May 2021. We searched the WHO ICTRP, clinicaltrials.gov, and ICTRP trial registries. We searched conference proceedings, and the reference lists of retrieved articles for RCTs and quasi-RCTs.  SELECTION CRITERIA: We included randomized controlled trials (RCTs) conducted in preterm and term infants of a postmenstrual age up to 46 weeks and 0 days with postoperative pain where systemic opioids were compared to 1) placebo or no intervention; 2) non-pharmacological interventions; 3) different types of opioids; or 4) other drugs.  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were pain assessed with validated methods, all-cause mortality during initial hospitalization, major neurodevelopmental disability, and cognitive and educational outcomes in children more than five years old. We used the fixed-effect model with risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference (MD) for continuous data. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included four RCTs enrolling 331 infants in four countries across different continents. Most studies considered patients undergoing large or medium surgical procedures (including major thoracic or abdominal surgery), who potentially required pain control through opioid administration after surgery. The randomized trials did not consider patients undergoing minor surgery (including inguinal hernia repair) and those individuals exposed to opioids before the beginning of the trial. Two RCTs compared opioids with placebo; one fentanyl with tramadol; and one morphine with paracetamol. No meta-analyses could be performed because the included RCTs reported no more than three outcomes within the prespecified comparisons. Certainty of the evidence was very low for all outcomes due to imprecision of the estimates (downgrade by two levels) and study limitations (downgrade by one level).  Comparison 1: opioids versus no treatment or placebo Two trials were included in this comparison, comparing either tramadol or tapentadol with placebo. No data were reported on the following critical outcomes: pain; major neurodevelopmental disability; or cognitive and educational outcomes in children more than five years old. The evidence is very uncertain about the effect of tramadol compared with placebo on all-cause mortality during initial hospitalization (RR 0.32, 95% Confidence Interval (CI) 0.01 to 7.70; RD -0.03, 95% CI -0.10 to 0.05, 71 participants, 1 study; I² = not applicable). No data were reported on: retinopathy of prematurity; or intraventricular hemorrhage.  Comparison 2: opioids versus non-pharmacological interventions No trials were included in this comparison. Comparison 3: head-to-head comparisons of different opioids One trial comparing fentanyl with tramadol was included in this comparison. No data were reported on the following critical outcomes: pain; major neurodevelopmental disability; or cognitive and educational outcomes in children more than five years old. The evidence is very uncertain about the effect of fentanyl compared with tramadol on all-cause mortality during initial hospitalization (RR 0.99, 95% CI 0.59 to 1.64; RD 0.00, 95% CI -0.13 to 0.13, 171 participants, 1 study; I² = not applicable). No data were reported on: retinopathy of prematurity; or intraventricular hemorrhage.  Comparison 4: opioids versus other analgesics and sedatives One trial comparing morphine with paracetamol was included in this comparison. The evidence is very uncertain about the effect of morphine compared with paracetamol on COMFORT pain scores (MD 0.10, 95% CI -0.85 to 1.05; 71 participants, 1 study; I² = not applicable).  No data were reported on the other critical outcomes, i.e. major neurodevelopmental disability; cognitive and educational outcomes in children more than five years old, all-cause mortality during initial hospitalization; retinopathy of prematurity; or intraventricular hemorrhage. AUTHORS' CONCLUSIONS: Limited evidence is available on opioid administration for postoperative pain in newborn infants compared to either placebo, other opioids, or paracetamol. We are uncertain whether tramadol reduces mortality compared to placebo; none of the studies reported pain scores, major neurodevelopmental disability, cognitive and educational outcomes in children older than five years old, retinopathy of prematurity, or intraventricular hemorrhage. We are uncertain whether fentanyl reduces mortality compared to tramadol; none of the studies reported pain scores, major neurodevelopmental disability, cognitive and educational outcomes in children older than five years old, retinopathy of prematurity, or intraventricular hemorrhage. We are uncertain whether morphine reduces pain compared to paracetamol; none of the studies reported major neurodevelopmental disability, cognitive and educational outcomes in children more than five years old, all-cause mortality during initial hospitalization, retinopathy of prematurity, or intraventricular hemorrhage. We identified no studies comparing opioids versus non-pharmacological interventions.

Systemic opioid regimens for postoperative pain in neonates.

BACKGROUND: Postoperative pain clinical management in neonates has always been a challenging medical issue. Worldwide, several systemic opioid regimens are available for pediatricians, neonatologists, and general practitioners to control pain in neonates undergoing surgical procedures. However, the most effective and safe regimen is still unknown in the current body of literature. OBJECTIVES: To determine the effects of different regimens of systemic opioid analgesics in neonates submitted to surgery on all-cause mortality, pain, and significant neurodevelopmental disability. Potentially assessed regimens might include: different doses of the same opioid, different routes of administration of the same opioid, continuous infusion versus bolus administration, or 'as needed' administration versus 'as scheduled' administration. SEARCH METHODS: Searches were conducted in June 2022 using the following databases: Cochrane Central Register of Controlled Trials [CENTRAL], PubMed, and CINAHL. Trial registration records were identified via CENTRAL and an independent search of the ISRCTN registry. SELECTION CRITERIA: We included randomized controlled trials (RCTs), quasi-randomized, cluster-randomized, and cross-over controlled trials evaluating systemic opioid regimens' effects on postoperative pain in neonates (pre-term or full-term). We considered suitable for inclusion: I) studies evaluating different doses of the same opioid; 2) studies evaluating different routes of administration of the same opioid; 3) studies evaluating the effectiveness of continuous infusion versus bolus infusion; and 4) studies establishing an assessment of an 'as needed' administration versus 'as scheduled' administration. DATA COLLECTION AND ANALYSIS: According to Cochrane methods, two investigators independently screened retrieved records, extracted data, and appraised the risk of bias. We stratified meta-analysis by the type of intervention: studies evaluating the use of opioids for postoperative pain in neonates through continuous infusion versus bolus infusion and studies assessing the 'as needed' administration versus 'as scheduled' administration. We used the fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD), standardized mean difference (SMD), median, and interquartile range (IQR) for continuous data. Finally, we used the GRADEpro approach for primary outcomes to evaluate the quality of the evidence across included studies. MAIN RESULTS: In this review, we included seven randomized controlled clinical trials (504 infants) from 1996 to 2020. We identified no studies comparing different doses of the same opioid, or different routes. The administration of continuous opioid infusion versus bolus administration of opioids was evaluated in six studies, while one study compared 'as needed' versus 'as scheduled' administration of morphine given by parents or nurses. Overall, the effectiveness of continuous infusion of opioids over bolus infusion as measured by the visual analog scale (MD 0.00, 95% confidence interval (CI) -0.23 to 0.23; 133 participants, 2 studies; I² = 0); or using the COMFORT scale (MD -0.07, 95% CI -0.89 to 0.75; 133 participants, 2 studies; I² = 0), remains unclear due to study designs' limitations, such as the unclear risk of attrition, reporting bias, and imprecision among reported results (very low certainty of the evidence).  None of the included studies reported data on other clinically important outcomes such as all-cause mortality rate during hospitalization, major neurodevelopmental disability, the incidence of severe retinopathy of prematurity or intraventricular hemorrhage, and cognitive- and educational-related outcomes.  AUTHORS' CONCLUSIONS: Limited evidence is available on continuous infusion compared to intermittent boluses of systemic opioids. We are uncertain whether continuous opioid infusion reduces pain compared with intermittent opioid boluses; none of the studies reported the other primary outcomes of this review, i.e. all-cause mortality during initial hospitalization, significant neurodevelopmental disability, or cognitive and educational outcomes among children older than five years old. Only one small study reported on morphine infusion with parent- or nurse-controlled analgesia.

Measuring Personal Damage in a Large-Scale Disaster: A Review of the Reports Published by the Japanese Fire and Disaster Management Agency on the Great East Japan Earthquake and Tsunami.

OBJECTIVE: The study's aim is to identify the challenges in estimating personal damages in the early stages of a disaster. METHODS: The study reviewed personal damage data in the reports on the Great East Japan earthquake and tsunami published by Japanese public agencies from 2011 to 2020, including 159 situation reports by the Fire and Disaster Management Agency and 17 disaster-related indirect death reports by the Reconstruction Agency. The study compared the reported number of deaths, missing persons, and injuries with the latest statistics to evaluate how soon the disaster's real damages were estimated. RESULTS: The reported number of deaths significantly increased in the first 1.5 years, whereas the number of missing persons spiked in the first 30 days. It required approximately 1 year until the numbers approximated the current reference rate. The total casualties included 3739 indirect deaths. CONCLUSION: The results indicated an overestimation of missing persons, a possible underestimation of injuries, and the excess deaths due to indirect causes that complicated the estimation. The limitations of the current data collection approaches are the delay in reporting from the field and incomplete and unreliable information. A novel system is proposed, which directly collects data from all affected individuals anonymously.

Prenatal interventions for fetal growth restriction in animal models: A systematic review.

Fetal growth restriction (FGR) in human pregnancy is associated with perinatal mortality, short- and long-term morbidities. No prenatal therapy is currently established despite decades of research. We aimed to review interventions in animal models for prenatal FGR treatment, and to seek the next steps for an effective clinical therapy. We registered our protocol and searched MEDLINE, Embase, and The Cochrane Library with no language restrictions, in accordance with the PRISMA guideline. We included all studies that reported the effects of any prenatal intervention in animal models of induced FGR. From 3257 screened studies, 202 describing 237 interventions were included for the final synthesis. Mice and rats were the most used animals (79%) followed by sheep (16%). Antioxidants (23%), followed by vasodilators (18%), nutrients (14%), and immunomodulators (12%) were the most tested therapy. Two-thirds of studies only reported delivery or immediate neonatal outcomes. Adverse effects were rarely reported (11%). Most studies (73%), independent of the intervention, showed a benefit in fetal survival or birthweight. The risk of bias was high, mostly due to the lack of randomization, allocation concealment, and blinding. Future research should aim to describe both short- and long-term outcomes across various organ systems in well-characterized models. Further efforts must be made to reduce selection, performance, and detection bias.

Correlates of neutralizing/SARS-CoV-2-S1-binding antibody response with adverse effects and immune kinetics in BNT162b2-vaccinated individuals.

While mRNA vaccines against SARS-CoV-2 are exceedingly effective in preventing symptomatic infection, their immune response features remain to be clarified. In the present prospective study, 225 healthy individuals in Japan, who received two BNT162b2 doses, were enrolled. Correlates of BNT162b2-elicited SARS-CoV-2-neutralizing activity (50% neutralization titer: NT50; assessed using infectious virions) with various determinants were examined and the potency of sera against variants of concerns was determined. Significant rise in NT50s was seen in sera on day 28 post-1st dose. A moderate inverse correlation was seen between NT50s and ages, but no correlation seen between NT50s and adverse effects. NT50s and SARS-CoV-2-S1-binding-IgG levels on day 28 post-1st dose and pain scores following the 2nd dose were greater in women than in men. The average half-life of NT50s was ~ 68 days, and 23.6% (49 out of 208 individuals) failed to show detectable neutralizing activity on day 150. While sera from elite-responders (NT50s > 1,500: the top 4% among the participants) potently to moderately blocked all variants of concerns examined, some sera with low NT50s failed to block the B.1.351-beta strain. Since BNT162b2-elicited immunity against SARS-CoV-2 is short, an additional vaccine or other protective measures are needed.

Correlates of Neutralizing/SARS-CoV-2-S1-binding Antibody Response with Adverse Effects and Immune Kinetics in BNT162b2-Vaccinated Individuals.

BACKGROUND: While mRNA vaccines against SARS-CoV-2 have been exceedingly effective in preventing symptomatic viral infection, the features of immune response remain to be clarified. METHODS: In the present prospective observational study, 225 healthy individuals in Kumamoto General Hospital, Japan, who received two BNT162b2 doses in February 2021, were enrolled. Correlates of BNT162b2-elicited SARS-CoV-2-neutralizing activity (50% neutralization titer: NT 50 ; assessed using infectious virions and live target cells) with SARS-CoV-2-S1-binding-IgG and -IgM levels, adverse effects (AEs), ages, and genders were examined. The average half-life of neutralizing activity and the average time length for the loss of detectable neutralizing activity were determined and the potency of serums against variants of concerns was also determined. FINDINGS: Significant rise in NT 50 s was seen in serums on day 28 post-1st dose. A moderate inverse correlation was seen between NT 50 s and ages, but no correlation was seen between NT 50 s and AEs. NT 50 s and IgG levels on day 28 post-1st dose and pain scores following the 2nd shot were greater in women than in men. The average half-life of neutralizing activity in the vaccinees was approximately 67.8 days and the average time length for their serums to lose the detectable neutralizing activity was 198.3 days. While serums from elite-responders (NT 50 s>1,500-fold: the top 4% among all participants' NT 50 s) potently to moderately blocked the infectivity of variants of concerns, some serums with moderate NT 50 s failed to block the infectivity of a beta strain. INTERPRETATION: BNT162b2-elicited immune response has no significant association with AEs. BNT162b2-efficacy is likely diminished to under detection limit by 6-7 months post-1st shot. High-level neutralizing antibody-containing serums potently to moderately block the infection of SARS-CoV-2 variants; however, a few moderate-level neutralizing antibody-containing serums failed to do so. If BNT162b2-elicited immunity memory is short, an additional vaccine or other protective measures would be needed. RESEARCH IN CONTEXT: Evidence before this study: While mRNA vaccines against SARS-CoV-2 have been exceedingly effective in preventing symptomatic viral infection, the salient features of immune response including the persistence of protection remain to be clarified. There is a report that anti-SARS-CoV-2 antibodies persist through 6 months after the second dose of mRNA-1273 vaccine (Doria-Rose et al. N Engl J Med . 2021;384:2259-2261); however, more definite immune kinetics following mRNA-vaccine-elicited protection have to be clarified. The mRNA-vaccine-elicited protection against SARS-CoV-2 variants are also to be determined. Added value of this study: In the present prospective study, 225 twice-BNT162b2-dose-receiving individuals in Japan were enrolled. No significant correlation was seen between 50% neutralizing titers (NT 50 s), determined by using infectious SARS-CoV-2 virions and live target cells, and adverse effects. Largely, NT 50 s and IgG levels were greater in women than in men. Following 28 days post-2 nd shot, significant reduction was seen in NT 50 s, IgG, and IgM levels. The average half-life of NT 50 s was ∼68 days and the average time-length for participants' serums to lose the detectable activity was ∼198 days. Although serums from elite-responders potently to moderately blocked the infectivity of variants of concerns, some serums with moderate NT 50 s failed to block the infectivity of a beta strain. Implications of all the available evidence: BNT162b2 efficacy is likely to be diminished to under detection limit by 6-7 months post-1 st shot on average. Individuals with moderate NT 50 s may fail to block beta variants. If BNT162b2-elicited immune memory is lost soon, additional vaccine(s) or other protective means would be needed.

Strategies for intra-amniotic administration of fetal therapy in a rabbit model of intrauterine growth restriction.

Intrauterine growth restriction affects up to 10% of all pregnancies, leading to fetal programming with detrimental consequences for lifelong health. However, no therapeutic strategies have so far been effective to ameliorate these consequences. Our previous study has demonstrated that a single dose of nutrients administered into the amniotic cavity, bypassing the often dysfunctional placenta via intra-amniotic administration, improved survival at birth but not birthweight in an intrauterine growth restriction rabbit model. The aim of this study was to further develop an effective strategy for intra-amniotic fetal therapy in an animal model. Intrauterine growth restriction was induced by selective ligation of uteroplacental vessels on one uterine horn of pregnant rabbits at gestational day 25, and fetuses were delivered by cesarean section on GD30. During the five days of intrauterine growth restriction development, three different methods of intra-amniotic administration were used: continuous intra-amniotic infusion by osmotic pump, multiple intra-amniotic injections, and single fetal intraperitoneal injection. Technical feasibility, capability to systematically reach the fetus, and survival and birthweight of the derived offspring were evaluated for each technique. Continuous intra-amniotic infusion by osmotic pump was not feasible owing to the high occurrence of catheter displacement and amnion rupture, while methods using two intra-amniotic injections and one fetal intraperitoneal injection were technically feasible but compromised fetal survival. Taking into account all the numerous factors affecting intra-amniotic fetal therapy in the intrauterine growth restriction rabbit model, we conclude that an optimal therapeutic strategy with low technical failure and positive fetal impact on both survival and birthweight still needs to be found.

Opioids and alpha-2-agonists for analgesia and sedation in newborn infants: protocol of a systematic review.

BACKGROUND: Hospitalized newborn infants may require analgesia and sedation either for the management of procedural pain, during or after surgery, and other painful conditions. The benefits and harms of opioids administered at different doses and routes of administration have been reported in numerous trials and systematic reviews. The use of alpha-2-agonists such as clonidine and dexmedetomidine in newborn infants is more recent, and they might be prescribed to reduce the total amount of opioids which are thought to have more side effects. Moreover, alpha-2-agonists might play an important role in the management of agitation and discomfort. METHODS: We will conduct a systematic review and meta-analysis on the use of opioids, alpha-2-agonists, or the combination of both drugs. We will include randomized controlled trials to assess benefits and harms and observational studies to assess adverse events and pharmacokinetics; preterm and term infants; studies on any opioids or alpha-2-agonists administered for any indication and by any route except spinal, intraosseous, or administration for nerve blocks and wound infusions. The use of opioids or alpha-2-agonists will be compared to no intervention; placebo with normal saline or other non-sedative, non-analgesic drug; control with oral sugar solution or non-pharmacological intervention; same drug of different dose or route; or a different drug (not limiting to opioids and alpha-2-agonists) or combinations of such drugs. The primary outcomes for this review will be all-cause mortality during initial hospitalization and hypotension requiring medical therapy. We will conduct a search in the following databases: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, Embase, and CINAHL. Two review authors will independently screen records for inclusion, undertake data abstraction using a data extraction form and assess the risk of bias of all included trials using the Cochrane "Risk of bias" tool. DISCUSSION: This systematic review will summarize and update our knowledge about neonatal analgesia and sedation including pharmacokinetics/pharmacodynamics, and provide a platform for developing evidence-based guidelines that we can immediately apply to our clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2020 CRD42020170852.

Bevacizumab suppresses the growth of established non-small-cell lung cancer brain metastases in a hematogenous brain metastasis model.

Brain metastases are common in patients with non-small-cell lung cancer (NSCLC). The efficacy of bevacizumab, an anti-vascular endothelial growth factor (VEGF) humanized antibody, has been demonstrated in patients with nonsquamous NSCLC. We established a transplantable NSCLC cell line (Nluc-H1915) that stably expresses NanoLuc® reporter and confirmed the correlation between total Nluc activity in tumor and tumor volume in vivo. SCID mice inoculated with these cells through the internal carotid artery formed reproducible brain metastases, in which human VEGF was detected. Next, after metastases were established in the model mice (15-17 days), they were intraperitoneally administered weekly doses of human immunoglobulin G (HuIgG) or bevacizumab. Nluc activity in the brain was significantly lower in bevacizumab-treated mice than in HuIgG-treated mice. Additionally, bevacizumab concentration in the brain was higher in mice with brain metastasis than in normal mice, and bevacizumab was primarily observed in brain metastasis lesions. The microvessel density in brain metastasis was lower in bevacizumab-treated mice than in HuIgG-treated mice. We believe bevacizumab's anti-proliferative effect on brain metastasis is due to anti-angiogenic activity achieved by its penetration into brain metastases; this suggests that a bevacizumab-containing regimen may be a promising treatment option for patients with NSCLC brain metastasis.

Migrant patients living with HIV/AIDS in Japan: Review of factors associated with high dropout rate in a leading medical institution in Japan.

The present study aimed to identify factors associated with retention in HIV/AIDS care among migrant patients who visited the outpatient clinic of the AIDS Clinical Center, National Center for Global Health and Medicine in Tokyo, Japan. We reviewed the records of 551 selected (78 non-Japanese and 473 Japanese) patients who started visiting our clinic between 2011 and 2014. A total of 390 patients (70.8%: 38 non-Japanese and 352 Japanese) continued their visits during the study: from the date of their first visit to the end of 2015. The difference in retention rate was not significant (Incidence Rate Ratio (IRR) = 0.89, p = 0.27), but the loss-to-follow-up cases were considerably high among non-Japanese patients (n = 13, Incidence rate (IR) = 24.6 per 100,000 person-days, IRR = 3.65, p<0.01 after adjusting for time since diagnosis). The results showed, nevertheless, that there was no apparent association between retention and factors peculiar to non-Japanese. Twelve out of thirteen lost-to-follow-up non-Japanese patients held legal status to reside in Japan and were eligible for public health services. Nine had limited fluency in Japanese language, and six used alternative verbal communication. Further studies are needed to identify the factors responsible for the high dropout rate and to improve the care of migrant patients living with HIV/AIDS.

Community spread of extended-spectrum ß-lactamase-producing bacteria detected in social insurance hospitals throughout Japan.

We surveyed the status of community-acquired infections involving four extended-spectrum ß-lactamase (ESBL)-producing bacteria (Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis) isolated from clinical specimens from 11 social insurance hospitals in Japan in 2012. These are member hospitals of the Japan Community Healthcare Organization, an independent administrative hospital organization. The isolation rates for E. coli, K. pneumoniae, K. oxytoca, and P. mirabilis were 14.0% (165/1176), 3.3% (16/480), 3.1% (4/130), and 15.9% (17/107), respectively. The CTX-M-9 group, the most frequently detected genotype, was found in 77.0% (127/165) of E. coli and 43.8% (7/16) of K. pneumoniae isolates. Among K. oxytoca isolates, 75% (3/4) were the CTX-M-1 group, and all 17 P. mirabilis strains were the CTX-M-2 group. ESBL-producing bacteria isolation rates in each hospital ranged from 5.8% to 21.5% (median 9.5%), and the proportion of community-acquired infections among ESBL-producing bacteria isolates ranged from 1.6% to 30.8% (median 11.4%) in each hospital. Overall, the rates of ESBL-producing bacterial infection in all community-acquired infections and in all hospital infections were 10.6% (115/1081) and 10.7% (87/812), respectively. The ESBL-producing bacteria are not limited to certain regions or hospitals but are spreading in communities throughout Japan.

Estimating Post-Emergency Fertility Among Disaster-Affected Adolescents: Findings From a Case-Control Study in Aceh Province, Indonesia.

OBJECTIVE: We aimed to retrospectively estimate adolescent fertility rates before and after a large-scale natural disaster. METHODS: A case-control study was conducted in Aceh Province, Indonesia, 2 years after the Indian Ocean tsunami in 2004. The age-specific fertility rates of 15-19-year-old-women (ASFR 15-19) was estimated each year from 2004 to 2006 by creating hypothetical age cohorts. The results were compared with data from the closest edition of the Indonesian Demographic Health Survey (IDHS). RESULTS: The pre-disaster ASFR 15-19 (4.4% in 2004) was not significantly different from the 2002-2003 IDHS data (P=0.49), whereas the post-disaster ASFR 15-19 (1.1% in 2005-2006) was significantly lower than the provincial estimation in the 2007 IDHS (P<0.01). ASFR 15-19 was reduced by 76% in the post-disaster period compared with the pre-disaster period (rate ratio: 0.24, P=0.02). CONCLUSIONS: The creation of hypothetical age cohorts enabled valid and useful estimation of the ASFR in disaster-affected areas where reliable vital statistics are not available. For pre-disaster fertility estimation, however, we suggest excluding data from the 40-week period preceding the disaster, because the data may be biased by excess mortality in childbearing mothers and newborn babies in the disaster.

A neonate with intestinal volvulus without malrotation exhibiting early jaundice with a suspected fetal onset.

Intestinal volvulus without malrotation is a rare disease that causes volvulus of the small intestine despite normal intestinal rotation and fixation. We encountered a neonate with this disease who developed early jaundice and was suspected to have a fetal onset. This patient was characterized by early jaundice complicating intestinal volvulus without malrotation and is considered to have exhibited reduced fetal movement and early jaundice as a result of volvulus, necrosis, and hemorrhage of the small intestine in the fetal period. If abdominal distention accompanied by early jaundice is noted in a neonate, intestinal volvulus without malrotation and associated intraabdominal hemorrhage should be suspected and promptly treated.

[One-year surveillance study of antimicrobial resistance in major bacteria except for MRSA isolated in eight medical facilities in Kumamoto prefecture].

To investigate the current status of drug-resistant bacteria (except MRSA) in Kumamoto prefecture, a study was conducted to determine the isolation numbers and ratios of extended-spectrum beta-lactamase (ESBL)-Escherichia coli, ESBL-Klebsiella species, ESBL-Proteus mirabilis, two-drug resistant Pseudomonas aeruginosa, (resistant to two drugs either carbapenems, quinolones and aminoglycosides) multi-drug-resistant Pseudomonas aeruginosa, multi-drug-resistant Acinetobacter baumannii, and vancomyacin-resistant Enterococcii in eight general hospitals from May in 2009 to April in 2010. ESBL-E. coli was mostly isolated, and two-drug resistant P. aeruginosa came second. The isolation ratio of overall drug-resistant bacteria did not increase, while the isolation ratio of two-drugs resistant P. aeruginosa declined, suggesting that infection control was successfully conducted in these hospitals. However, the isolation numbers of ESBL-Klebsiella spp. and two-drug resistant P. aeruginosa were variable in each hospital. Furthermore, drug-resistant bacteria were occasionally spread into another medical facilities by patients transferred from these hospitals, indicating that sharing information on drug-resistant bacteria between medical facilities is required.

Developing institutional capacity of health service system management at the district level in rural Cambodia.

The implementation of decentralization policies in the health sector of many developing countries has been a major issue in international health. The objectives were to focus on health sector reform, health financing system, and human resource development. However, less attention has been paid to the institutional capacity development of health systems. In this paper, institutional capacity refers to the abilities of organizations to make effective management in order to build local capacity and to achieve goals with local ownership. The aims of this paper were to explore the developmental process of districts institutional capacity by assistance of an NGO in Cambodia, and to identify the key factors influencing this development. We chose five operational districts (ODs) and two of them were contracted to NGO for management assistance. We conducted semi-structured in-depth interview to 17 managers and 16 key informant interviews. For analysis, we used qualitative analysis based on a grounded theory approach to clarify a conceptual framework for understanding management practices at district health institutions. There is a 4-stage capacity developmental process at the district-level institution. Supportive supervision and widening of decision-making authority were identified as key factors for sustainable institutional capacity development. They have complementary function each other. External agencies such as NGOs can use these key factors to develop local management capacities, and also this capacity development can be done internally within institutions such as OD health offices and by upper authorities such as the PHD.

Tolerance induction by the blockade of CD40/CD154 interaction in pemphigus vulgaris mouse model.

Pemphigus vulgaris (PV) is an autoimmune blistering disease caused by IgG autoantibodies against desmoglein 3 (Dsg3). We have recently developed an active disease mouse model for PV by adoptive transfer of splenocytes from Dsg3(-/-) mice. The purpose of this study was to determine the role of CD40/CD154 interaction in the pathogenic antibody production and development of the disease in PV model mice. When anti-CD154 monoclonal antibody (mAb) was administered to recipient mice prior to adoptive transfer, anti-CD154 mAb almost completely blocked the anti-Dsg3 IgG production and prevented blister formation. The blockade of CD40/CD154 interaction induced tolerance against Dsg3 as the suppression of antibody production was observed through day 70, and it was maintained even after challenge by immunization with recombinant mouse Dsg3 or by adoptive transfer of immunized Dsg3(-/-) splenocytes. Furthermore, the tolerance to Dsg3 was transferable because cotransfer of splenocytes from anti-CD154 mAb-treated mice and naïve Dsg3(-/-) splenocytes significantly suppressed anti-Dsg3 IgG production in recipient mice. In contrast, when anti-CD154 mAb was injected after the mice had developed the PV phenotype, no significant suppression of the production of anti-Dsg3 IgG was observed. These findings indicate that the CD40/CD154 interaction is essential for the induction of pathogenic anti-Dsg3 IgG antibodies and that antigen-specific immune-regulatory cells induced by anti-CD154 mAb would hold a therapeutic option for autoimmune diseases.

Nocardia shimofusensis sp. nov., isolated from soil, and Nocardia higoensis sp. nov., isolated from a patient with lung nocardiosis in Japan.

Three actinomycete strains isolated from soils and one strain isolated from a patient with lung nocardiosis in 1999 and 2001 in Japan have been provisionally assigned to the genus Nocardia on the basis of morphological criteria. These isolates were further investigated to determine their specific taxonomic status. Detailed chemotaxonomic characterization and 16S rRNA gene sequence analysis of these isolates confirmed that they belong to the genus Nocardia. The 16S rRNA gene sequences of the four strains were most similar to that of Nocardia farcinica. However, the sequence similarity values between these four strains and N. farcinica were <98.9 %. These four strains were susceptible to 5-fluorouracil, and they have the ability to decompose urea, which is a very characteristic trait. Furthermore, DNA-DNA relatedness data revealed that IFM 10311(T), IFM 10312 and IFM 10313 comprise a single novel species of Nocardia, that IFM 10084(T) represents another novel species of Nocardia and that these two novel species could be distinguished from N. farcinica. The names Nocardia shimofusensis sp. nov. and Nocardia higoensis sp. nov. are proposed, with IFM 10311(T) (=NBRC 100134(T)=JCM 12122(T)=DSM 44733(T)) and IFM 10084(T) (=NBRC 100133(T)=JCM 12121(T)=DSM 44732(T)) as the respective type strains.