Long-term trends in mortality from adverse effects of medical treatment in older populations in the United States from 1990 to 2019.

BACKGROUND: Adverse Effects of Medical Treatment (AEMT) refer to unintended harm caused by medical care and are a significant public health concern. OBJECTIVE: This study utilizes the Global Burden of Disease database to investigate AEMT mortality trends among older adults in the United States from 1990 to 2019, focusing on crude mortality rates and age-standardized mortality rate trends by age group and sex. METHODS: The study employs cause-of-death ensemble modeling and statistical analysis to examine crude and age-standardized mortality rates (ASRs) for AEMT in older age groups and identify trends in mortality due to AEMTs in those over 65 years of age in the United States. Trends in the ASR of AEMT were analyzed using the Joinpoint regression model. RESULTS: AEMT mortality rates increased among older adults from 2012 to 2019, with the highest increase observed in the 95 years or older age group. Significant differences were noted in AEMT mortality rates between older men and women, with older men having higher rates and showing an upward trend, while rates among older women decreased from 1990 to 2019. CONCLUSION: The study highlights an overall increase in ASR related to AEMT among older adults in the United States, with men shown to have a greater susceptibility to death from AEMT. Increased attention toward the detrimental impact of AEMT on our aging population, particularly for men, in conjunction with reinforcement of health policies and education, is warranted.

Ibuprofen dosing measurement accuracy using infants' versus children's ibuprofen: a randomized crossover comparison.

BACKGROUND: Ibuprofen liquid comes in two pediatric concentrations: 200 mg/5 mL for infants and 100 mg/5 mL for children. This study aimed to investigate the misdosing of ibuprofen liquid products by comparing administration accuracy with differing pediatric concentrations and dosages. METHODS: Subject selection included 116 volunteers. Participants were provided with the children's ibuprofen package including the dosing cup, the infants' ibuprofen package including the infant dosing dropper, and a 5 mL syringe. Each subject drew up a specified dose of infants' ibuprofen and children's ibuprofen and deposited each sample into a graduated cylinder. The dose (70 or 100 mg) and order of concentration usage (infants' first or children's first) were randomized. RESULTS: A total of 116 subjects, with a mean age of 32 ± 14 years, participated in the study. Mean absolute dosing errors for all trials, including those who made no errors, were significantly higher for infants' ibuprofen compared to children's ibuprofen: 39 vs. 27 mg (p = 0.036). A total of 31% of all ibuprofen dosage experiments (71 of 232 trials) had greater than 50% error of the assigned dose. CONCLUSION: Dosage errors using infants' ibuprofen were significantly higher than the children's ibuprofen. This suggests that removing the infant form from consumer availability may help reduce dosing errors when administering ibuprofen to pediatric patients. IMPACT: Pediatric misdosing is a significant problem with over-the-counter medications, such as ibuprofen. A previous study found that 51% of patients under the age of 10 were inaccurately dosed with antipyretic medication, including ibuprofen, with an increased incidence in infants. We found significantly more dosing errors with the infant concentration (200 mg/5 mL) as opposed to the children's concentration (100 mg/5 mL), 39 vs. 27 mg, respectively (p = 0.036). We believe that this research is beneficial to pediatric patient caregivers, clinicians, and policymakers to identify the problem of inaccurate ibuprofen dosing and to propose a way to mitigate this by having one concentration easily accessible.

Management of anti-M antibody during pregnancy: a case report.

BACKGROUND: Anti-M antibodies are relatively common and naturally occurring. When anti-M antibodies cross the placenta, they may cause hemolytic disease of the fetus and newborn (HDFN). Anti-M antibodies account for less than 15 cases of HDFN reported in the published English literature. HDFN can lead to foetal anaemia, hydrops fetalis, hypoxia, heart failure, and even death. OBJECTIVE: To review the general guidelines and propose a less intensive management approach of anti-M antibody during pregnancy through the context of a case report. METHODS: We report a 25-year-old healthy pregnant G3P1011 woman presenting for antepartum care. At the time of delivery for the patient's second pregnancy, she was found to have a positive anti-M blood screen, though she birthed a healthy-term infant. For her current pregnancy, the initial and repeat testings for anti-M were positive. RESULTS: Since multiple samples from this patient were of low levels extensive maternal and foetal monitoring were deemed unnecessary in reflection of further reading and research. The patient had a spontaneous vaginal delivery of her third pregnancy at 38 weeks without complications. CONCLUSION: Anti-RBC antibodies, including anti-M, are frequently identified in blood type and screening for pregnant patients. Guidelines call for intensive surveillance during pregnancy; however, knowledge of the specific antibody can help to provide more nuanced and less intensive care. As primary care physicians, being familiar with the guideline and the ability to counsel patients on anticipated care during pregnancy can help with family planning, compliance with testing, and patient anxiety and decrease intensive use of services that may not affect outcomes.

Development and Validation of a Prediction Model for Infant Fat Mass.

OBJECTIVES: To develop and validate a prediction model for fat mass in infants ≤12 kg using easily accessible measurements such as weight and length. STUDY DESIGN: We used data from a pooled cohort of 359 infants age 1-24 months and weighing 3-12 kg from 3 studies across Southern California and New York City. The training data set (75% of the cohort) included 269 infants and the testing data set (25% of the cohort) included 90 infants age 1-24 months. Quantitative magnetic resonance was used as the standard measure for fat mass. We used multivariable linear regression analysis, with backwards selection of predictor variables and fractional polynomials for nonlinear relationships to predict infant fat mass (from which lean mass can be estimated by subtracting resulting estimates from total mass) in the training data set. We used 5-fold cross-validation to examine overfitting and generalizability of the model's predictive performance. Finally, we tested the adjusted model on the testing data set. RESULTS: The final model included weight, length, sex, and age, and had high predictive ability for fat mass with good calibration of observed and predicted values in the training data set (optimism-adjusted R2: 92.1%). Performance on the test dataset showed promising generalizability (adjusted R2: 85.4%). The mean difference between observed and predicted values in the testing dataset was 0.015 kg (-0.043 to -0.072 kg; 0.7% of the mean). CONCLUSIONS: Our model accurately predicted infant fat mass and could be used to improve the accuracy of assessments of infant body composition for effective early identification, surveillance, prevention, and management of obesity and future chronic disease risk.

Herpesvirus trigger accelerates neuroinflammation in a nonhuman primate model of multiple sclerosis.

Pathogens, particularly human herpesviruses (HHVs), are implicated as triggers of disease onset/progression in multiple sclerosis (MS) and other neuroinflammatory disorders. However, the time between viral acquisition in childhood and disease onset in adulthood complicates the study of this association. Using nonhuman primates, we demonstrate that intranasal inoculations with HHV-6A and HHV-6B accelerate an MS-like neuroinflammatory disease, experimental autoimmune encephalomyelitis (EAE). Although animals inoculated intranasally with HHV-6 (virus/EAE marmosets) were asymptomatic, they exhibited significantly accelerated clinical EAE compared with control animals. Expansion of a proinflammatory CD8 subset correlated with post-EAE survival in virus/EAE marmosets, suggesting that a peripheral (viral?) antigen-driven expansion may have occurred post-EAE induction. HHV-6 viral antigen in virus/EAE marmosets was markedly elevated and concentrated in brain lesions, similar to previously reported localizations of HHV-6 in MS brain lesions. Collectively, we demonstrate that asymptomatic intranasal viral acquisition accelerates subsequent neuroinflammation in a nonhuman primate model of MS.

The spectrum of spinal cord lesions in a primate model of multiple sclerosis.

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) in the common marmoset is a nonhuman primate model of multiple sclerosis (MS) that shares numerous clinical, radiological, and pathological features with MS. Among the clinical features are motor and sensory deficits that are highly suggestive of spinal cord (SC) damage. OBJECTIVE: To characterize the extent and nature of SC damage in symptomatic marmosets with EAE using a combined magnetic resonance imaging (MRI) and histopathology approach. MATERIALS AND METHODS: SC tissues from five animals were scanned using 7 T MRI to collect high-resolution ex vivo images. Lesions were segmented and classified based on shape, size, and distribution along the SC. Tissues were processed for histopathological characterization (myelin and microglia/macrophages). Statistical analysis, using linear mixed-effects models, evaluated the association between MRI and histopathology. RESULTS: Marmosets with EAE displayed two types of SC lesions: focal and subpial lesions. Both lesion types were heterogeneous in size and configuration and corresponded to areas of marked demyelination with high density of inflammatory cells. Inside the lesions, the MRI signal was significantly correlated with myelin content (p < 0.001). CONCLUSIONS: Our findings underscore the relevance of this nonhuman primate EAE model for better understanding mechanisms of MS lesion formation in the SC.

Prevalence of salivary human herpesviruses in pediatric multiple sclerosis cases and controls.

BACKGROUND: Multiple sclerosis (MS) is a multifactorial disease of unknown origin. The current paradigm is that disease develops in genetically susceptible individuals, influenced by environmental factors. Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) have particularly strong associations with the disease. Both viruses are typically acquired during childhood, decades before MS presents. However, in patients with pediatric MS, the temporal window between viral acquisition and disease onset is shortened, which may provide insights into the association of herpesviruses with MS. OBJECTIVE: To compare the frequency of EBV and HHV-6 in the saliva of a cohort of pediatric MS patients and age-matched controls. METHODS: The study enrolled 32 pediatric MS patients and 42 controls and evaluated saliva for HHV-6 u57 and EBV lmp-1 amplification by droplet digital polymerase chain reaction (ddPCR). RESULTS: Pediatric MS patients did not differ from controls in the frequency or magnitude of salivary viral shedding. During the assessment of EBV positivity, distinct profiles emerged that correlated with target amplicon mutations. CONCLUSIONS: None of these mutations were evident in EBV-positive samples from pediatric MS patients, whereas they were present in pediatric controls, in addition to MS and control adults, suggesting differential host-immune control of EBV in this pediatric MS cohort.

Spatiotemporal distribution of fibrinogen in marmoset and human inflammatory demyelination.

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Although it has been extensively studied, the proximate trigger of the immune response remains uncertain. Experimental autoimmune encephalomyelitis in the common marmoset recapitulates many radiological and pathological features of focal multiple sclerosis lesions in the cerebral white matter, unlike traditional experimental autoimmune encephalomyelitis in rodents. This provides an opportunity to investigate how lesions form as well as the relative timing of factors involved in lesion pathogenesis, especially during early stages of the disease. We used MRI to track experimental autoimmune encephalomyelitis lesions in vivo to determine their age, stage of development, and location, and we assessed the corresponding histopathology post-mortem. We focused on the plasma protein fibrinogen-a marker for blood-brain barrier leakage that has also been linked to a pathogenic role in inflammatory demyelinating lesion development. We show that fibrinogen has a specific spatiotemporal deposition pattern, apparently deriving from the central vein in early experimental autoimmune encephalomyelitis lesions <6 weeks old, and preceding both demyelination and visible gadolinium enhancement on MRI. Thus, fibrinogen leakage is one of the earliest detectable events in lesion pathogenesis. In slightly older lesions, fibrinogen is found inside microglia/macrophages, suggesting rapid phagocytosis. Quantification demonstrates positive correlation of fibrinogen deposition with accumulation of inflammatory cells, including microglia/macrophages and T cells. The peak of fibrinogen deposition coincides with the onset of demyelination and axonal loss. In samples from chronic multiple sclerosis cases, fibrinogen was found at the edge of chronic active lesions, which have ongoing demyelination and inflammation, but not in inactive lesions, suggesting that fibrinogen may play a role in sustained inflammation even in the chronic setting. In summary, our data support the notion that fibrinogen is a key player in the early pathogenesis, as well as sustained inflammation, of inflammatory demyelinating lesions.

Viruses in chronic progressive neurologic disease.

Viruses have long been implicated as triggers of disease onset and progression in multiple sclerosis (MS) and similar neuroinflammatory disorders. Decades of epidemiological, molecular, and pathologic studies have most strongly linked the human herpesviruses Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) with MS. However, these viruses are ubiquitous in the general population and typically acquired decades before disease presentation, complicating the study of how they might contribute to disease. As experimental animal models may help elucidate mechanisms that have linked viruses with MS, we have been studying HHV-6 infections in a small nonhuman primate. We recently demonstrated that the subsequent induction of an MS-like experimental neuroinflammatory disease results in significantly accelerated disease in HHV-6 inoculated marmosets compared to controls. Ultimately, disease intervention in the form of clinical trials with an antiviral agent is the best way to concretely demonstrate a role for HHV-6 or any other virus in MS.

Novel marmoset (Callithrix jacchus) model of human Herpesvirus 6A and 6B infections: immunologic, virologic and radiologic characterization.

Human Herpesvirus 6 (HHV-6) is a ubiquitous virus with an estimated seroprevalence of 95% in the adult population. HHV-6 is associated with several neurologic disorders, including multiple sclerosis, an inflammatory demyelinating disease affecting the CNS. Animal models of HHV-6 infection would help clarify its role in human disease but have been slow to develop because rodents lack CD46, the receptor for cellular entry. Therefore, we investigated the effects of HHV-6 infections in a non-human primate, the common marmoset Callithrix jacchus. We inoculated a total of 12 marmosets with HHV-6A and HHV-6B intravenously and HHV-6A intranasally. Animals were monitored for 25 weeks post-inoculation clinically, immunologically and by MRI. Marmosets inoculated with HHV-6A intravenously exhibited neurologic symptoms and generated virus-specific antibody responses, while those inoculated intravenously with HHV-6B were asymptomatic and generated comparatively lower antibody responses. Viral DNA was detected at a low frequency in paraffin-embedded CNS tissue of a subset of marmosets inoculated with HHV-6A and HHV-6B intravenously. When different routes of HHV-6A inoculation were compared, intravenous inoculation resulted in virus-specific antibody responses and infrequent detection of viral DNA in the periphery, while intranasal inoculation resulted in negligible virus-specific antibody responses and frequent detection of viral DNA in the periphery. Moreover, marmosets inoculated with HHV-6A intravenously exhibited neurologic symptoms, while marmosets inoculated with HHV-6A intranasally were asymptomatic. We demonstrate that a marmoset model of HHV-6 infection can serve to further define the contribution of this ubiquitous virus to human neurologic disorders.

The formation of inflammatory demyelinated lesions in cerebral white matter.

OBJECTIVE: Vascular permeability and inflammatory demyelination are intimately linked in the brain, but what is their temporal relationship? We aimed to determine the radiological correlates of the earliest tissue changes accompanying demyelination in a primate model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) in the common marmoset. METHODS: By 7T magnetic resonance imaging (MRI), T1 maps, proton density, and T2-weighted images were acquired before and after EAE induction in 5 marmosets (every other week before lesions appeared, weekly thereafter). From scans before and after intravenous injection of contrast material, we measured the evolution of lesional blood-brain barrier (BBB) permeability, comparing in vivo MRI to postmortem tissue examination. RESULTS: On average, BBB permeability increased 3.5-fold (p < 0.0001) over the 4 weeks prior to lesion appearance. Permeability gradually decreased after lesion appearance, with attendant changes in the distribution of inflammatory cells (predominantly macrophages and microglia) and demyelination. On tissue analysis, we also identified small perivascular foci of microglia and T cells without blood-derived macrophages or demyelination. These foci had no visible MRI correlates, although permeability within the foci, but not outside, increased in the weeks before the animals died (p < 0.0001). INTERPRETATION: This study provides compelling evidence that in marmoset EAE, which forms lesions strongly resembling those of MS, early changes in vascular permeability are associated with perivascular inflammatory cuffing and parenchymal microglial activation but precede the arrival of blood-derived monocytes that accompany demyelination. Prospective detection of transient permeability changes could afford an opportunity for early intervention to forestall tissue damage in newly forming lesions.

Digital droplet PCR (ddPCR) for the precise quantification of human T-lymphotropic virus 1 proviral loads in peripheral blood and cerebrospinal fluid of HAM/TSP patients and identification of viral mutations.

An elevated human T cell lymphotropic virus 1 (HTLV)-1 proviral load (PVL) is the main risk factor for developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in HTLV-1 infected subjects, and a high cerebrospinal fluid (CSF) to peripheral blood mononuclear cell (PBMC) PVL ratio may be diagnostic of the condition. However, the standard method for quantification of HTLV-1 PVL-real-time PCR-has multiple limitations, including increased inter-assay variability in compartments with low cell numbers, such as CSF. Therefore, in this study, we evaluated a novel technique for HTVL-1 PVL quantification, digital droplet PCR (ddPCR). In ddPCR, PCR samples are partitioned into thousands of nanoliter-sized droplets, amplified on a thermocycler, and queried for fluorescent signal. Due to the high number of independent events (droplets), Poisson algorithms are used to determine absolute copy numbers independently of a standard curve, which enables highly precise quantitation. This assay has low intra-assay variability allowing for reliable PVL measurement in PBMC and CSF compartments of both asymptomatic carriers (AC) and HAM/TSP patients. It is also useful for HTLV-1-related clinical applications, such as longitudinal monitoring of PVL and identification of viral mutations within the region targeted by the primers and probe.

Perivenular brain lesions in a primate multiple sclerosis model at 7-tesla magnetic resonance imaging.

BACKGROUND Magnetic resonance imaging (MRI) can provide in vivo assessment of tissue damage, allowing evaluation of multiple sclerosis (MS) lesion evolution over time--a perspective not obtainable with postmortem histopathology. Relapsing-remitting experimental autoimmune encephalomyelitis (EAE) is an experimental model of MS that can be induced in the common marmoset, a small new world primate, and that causes perivenular white matter (WM) lesions similar to those observed in MS. METHODS Brain lesion development and evolution were studied in vivo and postmortem in four marmosets with EAE through serial T2- and T2*-weighted scans at 7-tesla. Supratentorial WM lesions were identified and characterized. RESULTS Of 97 lesions observed, 86 (88%) were clearly perivenular, and 62 (72%) developed around veins that were visible even prior to EAE induction. The perivenular configuration was confirmed by postmortem histopathology. Most affected veins, and their related perivascular Virchow-Robin spaces, passed into the subarachnoid space rather than the ventricles. CONCLUSION As in human MS, the intimate association between small veins and EAE lesions in the marmoset can be studied with serial in vivo MRI. This further strengthens the usefulness of this model for understanding the process of perivenular lesion development and accompanying tissue destruction in MS.

Impact Deceleration Differences on Natural Grass Versus Synthetic Turf High School Football Fields.

American football has the highest rate of concussions in United States high school sports. Within American football, impact against the playing surface is the second-most common mechanism of injury. The objective of this study was to determine if there is a difference in impact deceleration between natural grass and synthetic turf high school football fields. A Century Body Opponent Bag (BOB) manikin was equipped with a Riddell football helmet and 3 accelerometers were placed on the forehead, apex of the head, and right ear. The manikin was dropped from a stationary position onto its front, back, and left side onto natural grass (n = 10) and synthetic turf (n = 9) outdoor football fields owned and maintained by public and private institutions on O'ahu, Hawai'i. Data was collected on 1,710 total drops. All accelerometers in forward and backward falls, and 1 accelerometer in side falls showed significantly greater impact deceleration on synthetic turf compared to the natural grass surfaces (P < .05). The results of this study provide evidence-based rationale to inform youth sports policies, particularly those aimed at injury prevention through safer playing environments and equipment.

In vivo MRI is sensitive to remyelination in a nonhuman primate model of multiple sclerosis.

Remyelination is crucial to recover from inflammatory demyelination in multiple sclerosis (MS). Investigating remyelination in vivo using magnetic resonance imaging (MRI) is difficult in MS, where collecting serial short-interval scans is challenging. Using experimental autoimmune encephalomyelitis (EAE) in common marmosets, a model of MS that recapitulates focal cerebral inflammatory demyelinating lesions, we investigated whether MRI is sensitive to, and can characterize, remyelination. In six animals followed with multisequence 7 T MRI, 31 focal lesions, predicted to be demyelinated or remyelinated based on signal intensity on proton density-weighted images, were subsequently assessed with histopathology. Remyelination occurred in four of six marmosets and 45% of lesions. Radiological-pathological comparison showed that MRI had high statistical sensitivity (100%) and specificity (90%) for detecting remyelination. This study demonstrates the prevalence of spontaneous remyelination in marmoset EAE and the ability of in vivo MRI to detect it, with implications for preclinical testing of pro-remyelinating agents.

Human herpesvirus 6 and epilepsy.

We investigated the association between human herpesvirus 6 (HHV-6) and mesial temporal sclerosis (MTS) in 87 patients who had surgery for drug-resistant epilepsy. Fifty-four had MTS, 22 focal cortical dysplasia (FCD), four tumors, three vascular malformations, and three a history of encephalitis. We extracted DNA from fresh brain tissue immediately after surgery and performed viral detection with quantitative real-time polymerase chain reaction (PCR) or digital droplet PCR specific for HHV-6A and HHV-6B. Tissue was studied with standard clinical techniques, including hematoxylin and eosin, glial fibrillary acidic protein, and NeuN stains. Twenty-nine of 54 patients with MTS, six of 23 with focal cortical dysplasia (FCD), and one of three with a history of encephalitis were positive for HHV-6 (P < .02). Febrile seizure history was not associated with HHV-6 detection. Patients with MTS had significantly lower seizure onset age than those with other pathologies. Thirteen patients had positron emission tomography with [11C]PBR28, a marker for reactive astrocytes and activated microglia; there was a trend for HHV-6-positive patients to have higher binding in their seizure foci, suggesting inflammation. Our study supports a potential role for HHV-6 in the etiology of MTS.

HHV-6 and hippocampal volume in patients with mesial temporal sclerosis.

OBJECTIVE: To study the effects of human herpes virus 6 (HHV-6) on the hippocampal volume in patients with mesial temporal sclerosis (MTS). BACKGROUND: HHV-6 may play an etiologic role in MTS. Previous studies found a possible association with febrile status epilepticus. Several investigators have reported a higher prevalence of HHV-6 in MTS resections compared to other epilepsy etiologies. DESIGN/METHODS: We used FreeSurfer to segment cortical structures and obtain whole hippocampal and subfield volumes in 41 patients with intractable epilepsy. In addition, an investigator blinded to other data traced hippocampi manually on each slice. The main study outcome measure was the asymmetry index (AI) between hippocampal volumes ipsilateral and contralateral to seizure foci compared between HHV-6 positive and negative patients. Viral DNA was isolated from fresh brain tissue obtained at temporal lobectomy. For 25 patients, viral detection was performed using quantitative real-time PCR specific for HHV-6A and HHV-6B. For 16 patients, viral DNA detection was performed using digital droplet PCR specific for HHV-6A and HHV-6B. RESULTS: Twenty-two patients were positive (14 of 25 tested with real-time PCR, and 8 of 16 with digital droplet PCR), and 19 negatives for HHV-6. HHV-6 negative patients had significantly greater AI and lower total hippocampal volume ipsilateral to seizure foci than HHV-6 positive patients. Epilepsy duration and age of onset did not affect results. INTERPRETATION: Our data suggest multiple potential etiologies for MTS. HHV-6 may have a less severe effect on the hippocampus than other etiologies.

Atomic structure of the human herpesvirus 6B capsid and capsid-associated tegument complexes.

Human herpesvirus 6B (HHV-6B) belongs to the ß-herpesvirus subfamily of the Herpesviridae. To understand capsid assembly and capsid-tegument interactions, here we report atomic structures of HHV-6B capsid and capsid-associated tegument complex (CATC) obtained by cryoEM and sub-particle reconstruction. Compared to other ß-herpesviruses, HHV-6B exhibits high similarity in capsid structure but organizational differences in its CATC (pU11 tetramer). 180 "VΛ"-shaped CATCs are observed in HHV-6B, distinguishing from the 255 "Λ"-shaped dimeric CATCs observed in murine cytomegalovirus and the 310 "Δ"-shaped CATCs in human cytomegalovirus. This trend in CATC quantity correlates with the increasing genomes sizes of these ß-herpesviruses. Incompatible distances revealed by the atomic structures rationalize the lack of CATC's binding to triplexes Ta, Tc, and Tf in HHV-6B. Our results offer insights into HHV-6B capsid assembly and the roles of its tegument proteins, including not only the ß-herpesvirus-specific pU11 and pU14, but also those conserved across all subfamilies of Herpesviridae.