Economic Status and Mortality in Patients with Alzheimer's Disease in Japan: The Longevity Improvement and Fair Evidence Study

ObjectivesAs more countries are implementing measures to address Alzheimer’s disease (AD), it is essential to update the available knowledge on the relationship between economic status and mortality in patients with AD. This study examined the influence of economic status on mortality in Japanese individuals with AD using a medical claims dataset.DesignThis was a retrospective cohort study.Setting and ParticipantsMedical claims data from April 2014 to March 2019 were obtained from 13 local cities participating in the Longevity Improvement and Fair Evidence study. The inclusion criteria were patients aged 65 years and older who were newly diagnosed with AD during the study period.MethodsThe outcome was death during the follow-up period. We assessed economic status by household income (middle to high income and low income); data were obtained from the use of the Medical Expenditure Ceiling Application and Standard Copayment Reduction Card (fee reduction card) when receiving an AD diagnosis, as an indicator of low-income status. We performed multivariate Cox proportional hazards analyses to examine the relationship between economic status and mortality; the model was adjusted for age, sex, the Charlson comorbidity index, and antidementia drug use.ResultsWe identified 39,081 newly diagnosed patients with AD from the Longevity Improvement and Fair Evidence study database (mean age, 83.6 years; female, 67.1%). Of these, 3189 individuals were identified as having a low-income status. After adjusting for possible confounders, low-income status was associated with mortality (hazard ratio, 1.95; 95% confidence interval, 1.84–2.07).Conclusions and ImplicationsLow-income status was associated with substantially poorer prognoses in new AD cases, indicating a need for a thorough examination of medical and nursing care services utilized by low-income individuals with AD and to explore improvement strategies.     

Epidemiology of Connectional Silence in specialist serious illness conversations

ContextHuman connection can reduce suffering and facilitate meaningful decision-making amid the often terrifying experience of hospitalization for advanced cancer. Some conversational pauses indicate human connection, but we know little about their prevalence, distribution or association with outcomes.PurposeTo describe the epidemiology of Connectional Silence during serious illness conversations in advanced cancer.MethodsWe audio-recorded 226 inpatient palliative care consultations at two academic centers. We identified pauses lasting 2+ seconds and distinguished Connectional Silences from other pauses, sub-categorized as either Invitational (ICS) or Emotional (ECS). We identified treatment decisional status pre-consultation from medical records and post-consultation via clinicians. Patients self-reported quality-of-life before and one day after consultation.ResultsAmong all 6769 two-second silences, we observed 328 (4.8%) ECS and 240 (3.5%) ICS. ECS prevalence was associated with decisions favoring fewer disease-focused treatments (OR_adj: 2.12; 95% CI: 1.12, 4.06). Earlier conversational ECS was associated with improved quality-of-life (p = 0.01). ICS prevalence was associated with clinicians' prognosis expectations.ConclusionsConnectional Silences during specialist serious illness conversations are associated with decision-making and improved patient quality-of-life. Further work is necessary to evaluate potential causal relationships.Practice implicationsPauses offer important opportunities to advance the science of human connection in serious illness decision-making.     

Outcomes of Foot Infections Secondary to Puncture Injuries in Patients With and Without Diabetes

It is difficult to compare foot infections in patients with diabetes to those without diabetes because foot infections are uncommon in people without diabetes. The aim of this study is to compare clinical outcomes in people with and without diabetes admitted to the hospital for an infected puncture wound. We evaluated 114 consecutive patients from June 2011 to March 2019 with foot infection resulting from a puncture injury; 83 had diabetes and 31 did not have diabetes. We evaluated peripheral arterial disease (PAD), sensory neuropathy, the need for surgery and amputation, length of hospitalization, and presence of osteomyelitis. Patients with diabetes were 31 times more likely to have neuropathy (91.6% versus 25.8%, p < .001, confidence interval [CI] 10.2 to 95.3), 8 times more likely to have PAD (34.9% versus 6.5%, p = .002, CI 1.7 to 35), and 7 times more likely to have kidney disease (19.3% versus 3.2%, p < .05, CI 0.9 to 56.5). They also took longer before presenting to the hospital (mean 20.1 ± 36.3 versus 18.8 ± 34.8 days, p = .09, CI 13 to 26.5); however, this result was not statistically significant. Patients with diabetes were 9 times more likely to have osteomyelitis (37.3% versus 6.5%, p = .001, CI 1.9 to 38.8). In addition, they were more likely to require surgery (95% versus 77%, p < .001, CI 1.6 to 21.4), required more surgeries (2.7 ± 1.3 versus 1.3 ± 0.8, p < .00001, CI 2.1 to 2.5), were 14 times more likely to have amputations (48.2% versus 6.5%, p < .0001, CI 3.0 to 60.2), and had 2 times longer hospital stays (16.2 ± 10.6 versus 7.5 ± 9 days, p = .0001, CI 11.9 to 15.9. Infected puncture wounds in patients with diabetes often fair much worse with more detrimental outcomes than those in patients without diabetes.     

Lack of Antinociceptive Cross-Tolerance With Co-Administration of Morphine and Fentanyl Into the Periaqueductal Gray of Male Sprague-Dawley Rats

Tolerance to the antinociceptive effect of mu-opioid receptor agonists, such as morphine and fentanyl, greatly limits their effectiveness for long-term use to treat pain. Clinical studies have shown that combination therapy and opioid rotation can be used to enhance opioid-induced antinociception once tolerance has developed. The mechanism and brain regions involved in these processes are unknown. The purpose of this study was to evaluate the contribution of the ventrolateral periaqueductal gray (vlPAG) to antinociceptive tolerance and cross-tolerance between administration and co-administration of morphine and fentanyl. Tolerance was induced by pretreating rats with morphine or fentanyl or low-dose combination of morphine and fentanyl into the vlPAG followed by an assessment of the cross-tolerance to the other opioid. In addition, tolerance to the combined treatment was assessed. Cross-tolerance did not develop between repeated vlPAG microinjections of morphine and fentanyl. Likewise, there was no evidence of cross-tolerance from morphine or fentanyl to the co-administration of morphine and fentanyl. Co-administration did not cause cross-tolerance to fentanyl. Cross-tolerance was only evident to morphine or morphine and fentanyl combined in rats pretreated with co-administration of low doses of morphine and fentanyl. This finding is consistent with the functionally selective signaling that has been reported for antinociception and tolerance after morphine and fentanyl binding to the mu-opioid receptor. This research supports the notion that combination therapy and opioid rotation may be useful clinical practices to decrease opioid tolerance and other side effects.PerspectiveThis preclinical study shows that there is a decrease in cross-tolerance between morphine and fentanyl within the periaqueductal gray, which is a key brain region in opioid antinociception and tolerance.     

Genomic and phenotypic delineation of congenital microcephaly

PurposeCongenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM.MethodsClinical phenotyping, targeted or exome sequencing, and autozygome analysis.ResultsWe describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly —as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference—is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1.ConclusionOur study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.     

Geriatric Comanagement of Older Vascular Surgery Inpatients Reduces Hospital-Acquired Geriatric Syndromes

ObjectiveThis study evaluates the impact of a novel model of care called Geriatric Comanagement of Older Vascular surgery inpatients on clinical outcomes.Design, Setting, and ParticipantsA pre-post study of geriatric comanagement, comparing prospectively recruited preintervention (February–October 2019) and prospectively recruited postintervention (January–December 2020) cohorts. Consecutively admitted vascular surgery patients age ≥65 years at a tertiary academic hospital in Concord and with an expected length of stay (LOS) greater than 2 days were recruited.InterventionA comanagement model where a geriatrician was embedded within the vascular surgery team and delivered proactive comprehensive geriatric assessment based interventions.MethodsPrimary outcomes of incidence of hospital-acquired geriatric syndromes, delirium, and LOS were compared between groups using univariable and multivariable logistic regression analyses. Prespecified subgroup analysis was performed by frailty status.ResultsThere were 150 patients in the preintervention group and 152 patients in the postintervention group. The postintervention group were more frail [66 (43.4%) vs 45 (30.0%)], urgently admitted [72 (47.4%) vs 56 (37.3%)], and nonoperatively managed [52 (34.2%) vs 33 (22.0%)]. These differences were attributed to the coronavirus disease 2019 pandemic during the postintervention phase. The postintervention group had fewer hospital-acquired geriatric syndromes [74 (48.7%) vs 97 (64.7%); P = .005] and reduced incident delirium [5 (3.3%) vs 15 (10.0%); P = .02], in unadjusted and adjusted analyses. Cardiac [8 (5.3%) vs 30 (20.0%); P < .001] and infective complications [4 (2.6%) vs 12 (8.0%); P = .04] were also fewer. LOS was unchanged. Frail patients in the postintervention group experienced significantly fewer geriatric syndromes including delirium.Conclusions and ImplicationsThis is the first prospective study of inpatient geriatric comanagement for older vascular surgery patients. Reductions in hospital-acquired geriatric syndromes including delirium, and cardiac and infective complications were observed after implementing geriatric comanagement. These benefits were also demonstrated in the frail subgroup.     

Midazolam exposure in the paediatric intensive care unit predicts acute post-traumatic stress symptoms in children

BackgroundClinically significant post-traumatic stress symptoms (PTSS) have been reported in up to a quarter of paediatric intensive care unit (PICU) survivors. Ongoing PTSS negatively impacts children's psychological development and physical recovery. However, few data regarding associations between potentially modifiable PICU treatment factors, such as analgosedatives and invasive procedures, and children's PTSS have been reported.ObjectivesWe sought to investigate the medical treatment factors associated with children's PTSS after PICU discharge.MethodsA prospective longitudinal cohort study was conducted in two Australian tertiary referral PICUs. Children aged 2-16 y admitted to the PICU between June 2008 and January 2011 for >8 h and <28 d were eligible for participation. Biometric and clinical data were obtained from medical records. Parents reported their child's PTSS using the Trauma Symptom Checklist for Young Children at 1, 3, 6, and 12 months after discharge. Logistic regression was used to assess potential associations between medical treatment and PTSS.ResultsA total of 265 children and their parents participated in the study. In the 12-month period following PICU discharge, 24% of children exhibited clinically elevated PTSS. Median risk of death (Paediatric Index of Mortality 2 [PIM2]) score was significantly higher in the PTSS group (0.31 [IQR 0.14–1.09] v 0.67 [IQR 0.20–1.18]; p = 0.014). Intubation and PICU and hospital length of stay were also significantly associated with PTSS at 1 month, as were midazolam, propofol, and morphine. After controlling for gender, reason for admission, and PIM2 score, only midazolam was significantly and independently associated with PTSS and only at 1 month (adjusted odds ration (aOR) 3.63, 95% CI 1.18, 11.12, p = 0.024). No significant relationship was observed between the use of medications and PTSS after 1 month.ConclusionsElevated PTSS were evident in one quarter (24%) of children during the 12 months after PICU discharge. One month after discharge, elevated PTSS were most likely to occur in children who had received midazolam therapy.