However, the association of HSV reactivation with cardiogenic shock (CS) is unclear. As CS is often accompanied by pulmonary congestion and reduced immune system activity, the aim of our study was to determine the incidence and outcome of HSV reactivation in these patients. (2) In this retrospective, single-center study, bronchial lavage (BL) was performed on 181 out of 837 CS patients with mechanical ventilation. (3) In 44 of those patients, HSV was detected with a median time interval of 11 days since intubation. The occurrence of HSV was associated with an increase in C-reactive protein and the fraction of inspired oxygen at the time of HSV detection. Arterial hypertension, bilirubin on ICU admission, the duration of mechanical ventilation and out-of-hospital cardiac arrest were associated with HSV reactivation. (4) HSV reactivation could be detected in 24.3% of patients with CS on whom BL was performed, and its occurrence should be considered in patients with prolonged mechanical ventilation. Due to the limited current evidence, the initiation of treatment for these patients remains an individual choice. Dedicated randomized studies are necessary to investigate the efficacy of antiviral therapy. To this day, cardiogenic shock is a cardinal driver of mortality in patients in intensive care units (ICU). It is defined by the European Society of Cardiology (ESC) as hypotension despite adequate filling status (with signs of hypoperfusion due to primary cardiac dysfunction) and affects around 10% of patients with acute myocardial infarction . Today, Patients with cardiogenic shock might be prone to HSV reactivation due to their frequently long-lasting mechanical ventilation. However, the impact of HSV occurrence in these patients is unknown so far. Hence, our retrospective study aimed to analyze the incidence, clinical outcome and patient characteristics associated with HSV reactivation in cardiogenic shock.After approval by the local ethics committee , patients with cardiogenic shock who were treated in the cardiac intensive care unit (ICU) of Ludwig-Maximilians-University (LMU) from 01/2010 until 08/2021 were included in the LMUshock registry, in compliance with the Declaration of Helsinki and German data protection laws. Cardiogenic shock was defined by the ESC guidelines  and the 2/FiO2 or an unexplained increase in inflammatory markers and catecholamines. BL samples were analyzed in the local virology department by performing a quantitative HSV1-PCR test.Initially, all patients were ventilated in controlled biphasic positive airway pressure mode  and respirator settings were adjusted according to arterial blood gas analyses. Where applicable, VA-ECMO and coaxial left ventricular assist device (Impella) implantation, weaning and explantation were performed as described previously ,5,13,14.T-test and Mann–Whitney U test were used to compare groups, respectively. One-way analysis of variance and the Kruskal–Wallis rank sum test was used, respectively, to compare three or more groups. Categorical variables were reported as absolute numbers and percentages, and the Chi-square or Fisher’s exact test was utilized for comparison. All tests were two-tailed and p-values < 0.05 were considered to be significant. To assess the correlation of clinical and laboratory parameters with HSV infection, univariate and multivariate binary logistic regression models were used. Covariates included age, male gender, hypertension, diabetes mellitus, body mass index, first measured lactate in ICU, first measured creatinine in ICU, first measured bilirubin in ICU, Horowitz (paO2/FiO2) index, cardiac arrest, out-of-hospital cardiac arrest, myocardial infarction, VA-ECMO treatment, coaxial left ventricular assist device (Impella) treatment, renal replacement therapy, tracheotomy, average systolic blood pressure and duration of mechanical ventilation. Parameters for multivariate analysis were stepwise selected by Akaike information criterion (AIC) with backward direction and 1000 bootstrap iterations using the step AIC function of the R package MASS (version 7.3–51.6).The statistical analysis was performed with R  following the STROBE  statement . Normall2. Cardiac arrest occurred in 72% of patients and out-of-hospital cardiac arrest occurred in 36% with a median cardio-pulmonary resuscitation duration of 20 min. The primary causes of cardiogenic shock were ST-elevation myocardial infarction (STEMI) in 34% of patients and non-ST-elevation myocardial infarction (NSTEMI) in 25% of patients , patients with no HSV detection in BL (n = 137) and patients without BL performed (n = 656)  .p < 0.01). Moreover, the duration of mechanical ventilation was longer in the HSV positive group with 454 h (IQR 326–604) vs. 255 h (IQR 161–458) (p < 0.01) in the HSV negative group. Significantly more patients with HSV detection were tracheotomized in comparison to HSV negative patients . Median SAPS2 score , median SOFA score , lactate on ICU admission , glomerular filtration rate  and platelet count  were not statistically different between both groups. However, bilirubin levels were significantly higher in the group with HSV detection . Renal replacement therapy tended to be required more frequently in the HSV positive group . Usage of VA-ECMO treatment , coaxial left ventricular assist device (Impella) treatment  and IABP  were comparable between both groups. All ICU parameters are summarized in There was no statistical difference concerning the baseline characteristics between patients with HSV detection in BL and patients without HSV detection . For patThe median time from intubation to first HSV detection was 11 days (IQR 9–13) A. The meAs most patients received antiviral therapy, the impact of HSV detection in BL was investigated by comparing the inflammatory and ventilation parameters.Concomitant pathogens detected seven days before until seven days after the first HSV occurrence were recorded to identify conflicting causes of inflammatory activity . In 15 op = 0.04, p = 0.02 vs. p = 0.30, p < 0.01, p = 0.25, CRP values were significantly higher in the second and third quartile of HSV detection time points for patients with HSV, in comparison to patients without HSV detected in BL (p = 0.034), bilirubin measured on ICU admission , the duration of mechanical ventilation  and out-of-hospital cardiac arrest  were all associated with HSV occurrence  In 181 patients with cardiogenic shock and mechanical ventilation undergoing bronchial lavage , HSV was detected in 44 (24.3%) with a median time from intubation to HSV verification of 11 days; (2) reactivation was associated with an increase in CRP and FiO2 at the time of detection; (3) arterial hypertension, bilirubin on ICU admission, the duration of mechanical ventilation and out-of-hospital cardiac arrest were all associated with an increase in HSV occurrence; (4) the ventilation time of patients with HSV detection was longer compared to patients without HSV; and (5) the 30-days mortality rate of patients with HSV was 22.7%.To the best of our knowledge, this is the first study analyzing HSV incidence in patients with cardiogenic shock. It is known that these patients display systemic inflammation, with a depletion of immune cells identified in the most severely affected patients throughout the course of the disease. This may facilitate the reactivation of HSV . InteresOur data indicate that the possibility of HSV reactivation should be considered in cardiogenic shock patients with long-term mechanical ventilation, considering the observed increase in CRP and FiO2 values from day nine onwards. Concerning the impact of antiviral therapy, a meta-analysis was able to show a possible benefit regarding 30-day all-cause mortality in HSV patients treated with antiviral therapy . HoweverDue to the low number of cases and other factors heavily influencing mortality, randomized controlled trials assessing the efficacy of antiviral treatment may be challenging to perform on patients with cardiogenic shock and HSV reactivation. First, prospective, multicenter registries should systemically screen patients with cardiogenic shock and long-term mechanical ventilation for HSV detection to quantify the incidence of HSV occurrence and its impact on different organ systems more precisely.Our results cannot be generalized due to the single-center design, but this study is the largest analysis carried out in cardiogenic shock patients so far. Additionally, HSV incidence was not tested in all patients with cardiogenic shock, as BL was only performed in a subset of patients at the physician’s discretion and more patients could have had undetected HSV reactivation. However, physicians were required to perform a BL in case of an unexplained increase in inflammation markers in our ICU. Furthermore, our study cannot estimate the efficacy of antiviral treatment, as most patients were treated with aciclovir.


Neurofibromatosis type 1 (NF-1) can manifest with various neurological symptoms. However, sensory ataxia has not been reported.A 44-year-old man with NF-1 presented with several weeks of unsteady gait. He was diagnosed with gastric neuroendocrine tumor with multiple hepatic metastases 6 years ago and received palliative chemotherapy. Neurological examination revealed ataxia veering to the right side with no motor weakness.Clinical manifestations and electrodiagnostic studies suggested the dysfunction of the thoracic dorsal column (DC). Initial magnetic resonance imaging showed a lateral thoracic meningocele (LTM) located in the right paravertebral area at the T3-T4 vertebral level, but the spinal cord was unremarkable. Gait disturbance worsened after 9 months, and follow-up magnetic resonance imaging showed high signal intensity involving the right DC at the level adjacent to the LTM and spinal cord atrophy distal to the DC lesion. Tests for well-characterized paraneoplastic antibodies were negative. Ultimately, the patient was assumed to have sensory neuronopathy due to compressive damage to the dorsal root ganglia within the intervertebral foramina by LTM.Empirical treatment with vitamin B12 supplementation and corticosteroids failed to improve his condition. The patient underwent decompressive laminectomy and excision of the meningocele with dura repair.The patient temporarily improved to walk with assistance postoperatively. However, he developed dyspnea and hypotension 5 weeks later. Carcinoid heart disease confined the patient to the bed. The patient died of pneumonia 3 months after the operation.This case with NF-1 shows asymmetric sensory ataxia of subacute progression. LTM may contribute to the development of sensory neuronopathy by damaging sensory neurons of the dorsal root ganglia. The comorbidities of the patient, including gastric neuroendocrine tumor and LTM, made it challenging to investigate the pathomechanism. It is associated with NF1 tumor suppressor gene mutations, and the affected individuals are prone to developing benign or malignant neoplasm. Meanwhile, NF-1 patients can present with various neurological manifestations, and some of them could be caused by the involvement of the spinal nerves or adjacent structures by paravertebral neurofibroma, kyphoscoliosis, or lateral thoracic meningocele (LTM).–6 However, to the best of our knowledge, sensory ataxia has not yet been reported in patients with NF-1. We recently experienced an NF-1 patient with LTM and gastric neuroendocrine tumor (NET) who presented with sensory ataxia of subacute progression. The patient was finally diagnosed with sensory neuronopathy (SNN), but the scarcity of previous reports and the patient’s comorbidities made it challenging to investigate the etiology.Neurofibromatosis type 1 (NF-1) is an autosomal dominant multi-systemic disorder characterized by cutaneous features such as multiple café-au-lait spots, freckles, and neurofibromas.A 44-year-old man with NF-1 presented with a several weeks’ history of unsteady gait. Since adolescence, he had multiple café-au-lait spots and neurofibromas, and NF-1 was confirmed by identifying a pathogenic heterozygous splicing mutation . The patient received 14 cycles of palliative combination chemotherapy with cisplatin and etoposide for about 4 years due to gastric NET with multiple hepatic metastases since he was 38. During chemotherapy, he complained of paresthesia in the fingertips and tiptoes on both sides, which was diagnosed as chemotherapy-induced peripheral neuropathy. His malignancy had been stable for over 2 years without further chemotherapy on regular checkups, but he continued receiving a monthly somatostatin analogue injection due to chronic diarrhea.Neurological examination revealed ataxia veering to the right side while walking with no motor weakness. Vibration sensation was significantly impaired in the right leg, but pain/temperature sensation was relatively spared in the 4 limbs. Leg somatosensory evoked potential (SEP) showed increased latencies of peripheral and central conduction time on the right side, while the result of arm SEP was normal. Nerve conduction study showed symmetric distal sensory axonopathies in the 4 limbs, but it showed no interval change compared with a previous study performed when he was diagnosed with chemotherapy-induced peripheral neuropathy. Dorsal column (DC) myelopathy was suspected, but magnetic resonance imaging (MRI) of the spine showed no signal abnormality in the spinal cord. Instead, a non-enhancing cystic mass was observed in the paraspinal area Fig. A–C. ChesNine months after symptom onset, the patient complained of paresthesia in the right leg, and his ataxic gait worsened. Thoracic MRI showed T2 high signal intensity involving the right DC without contrast enhancement, mainly at the T3-T4 vertebral levels (Fig.  However, sensory ataxia has never been reported in patients with NF-1, especially in association with LTM. In the current case, the patient showed asymmetric sensory ataxia of subacute onset, abnormal leg SEP, and signal change within the DC on MRI. Based on these findings, the patient was diagnosed with probable SNN according to the criteria proposed by Camdessanché et al.This report discusses an NF-1 patient with LTM who presented with gait disturbance. In the previous literature, a case of a patient with NF-1 who had progressive paraparesis due to a giant LTM compressing the spinal cord has been reported. Regarding the etiology, half of the cases of SNN are idiopathic, 20% are paraneoplastic, and the rest are linked to Sjögren’s syndrome, pyridoxine toxicity, platinum-based chemo-agent toxicity, and viral infection.–11 Our patient had factors related to SNN, such as cisplatin and malignancy, but it was not evident that they were the leading cause. There seemed to be little temporal correlation between cisplatin chemotherapy and SNN in that ataxia developed 2 years after the completion of chemotherapy, even considering the coasting phenomenon. Furthermore, SNN is not commonly associated with NETs, and only 1 case with anti-Hu antibody in a patient with gastric NET has been reported to date. In our case, sensory ataxia developed as much as 6 years after the cancer diagnosis, and was confined to the right leg without spreading to the upper limbs over time. CSF examination results were also unremarkable, while CSF inflammation is known to be common in paraneoplastic neurological syndromes. In addition, no well-characterized onconeural antibodies were detected.SNN is a rare neurological disorder characterized by the primary degeneration of sensory neurons of the DRG and subsequent impairment of its central and peripheral projections. In this context, we assumed that mechanical compression by the LTM might have damaged the cell bodies of sensory neurons of the DRG or their central processes, and the segmental spinal cord atrophy could be explained as centripetal Wallerian degeneration following damage to the DRG. Although the LTM is not very huge, DRG has been reported to be susceptible to compressive damage. Moreover, even though the neurotoxic effect of cisplatin on the DRG was not enough to cause overt symptoms after chemotherapy, prior cisplatin use might have made the sensory neurons of the DRG more vulnerable to additional injury due to direct compression or local ischemia by a space-occupying lesion, such as LTM. This study had several limitations. A biopsy of the DRG was not performed, and the long-term surgical outcome could not be assessed adequately because the patient died early after the operation.Intriguingly, the focal lesion in the DC on MRI was located ipsilaterally adjacent to the LTM, which may provide a clue for inferring the pathomechanism of SNN in our case. Although LTM is often asymptomatic, it can cause symptoms such as dyspnea, radicular pain, or motor weakness due to local compression of the lung, peripheral nerves, or spinal cord, depending on its size and location.In summary, this case showed that LTM might cause SNN due to local compression of the DRG in patients with NF-1. Comorbidities have made it difficult to determine the etiology of sensory ataxia. Further studies are needed on neurological complications in NF-1 patients.Conceptualization: Tai-Seung Nam.Data curation: You-Ri Kang, Seong-Min Hong, Jong-Hee Choi, Jae-Myung Kim.Formal analysis: You-Ri Kang, Kyung Wook Kang, Seung-Jin Lee.Investigation: You-Ri Kang, Tai-Seung Nam.Writing – original draft: You-Ri Kang, Tai-Seung Nam.


Hospitalizations involving opioid use disorder (OUD) have been increasing among Medicare beneficiaries of all ages. With rising OUD-related acute care use comes the need to understand where post-acute care is provided and the capacities for OUD treatment in those settings. Our objective was to describe hospitalized Medicare beneficiaries with OUD, their post-acute care locations, and all-cause mortality and readmissions stratified by post-acute care location.We conducted a retrospective cohort study of acute hospitalizations using 2016–2018 Medicare Provider Analysis and Review (MedPAR) files linked to Medicare enrollment data and the Residential History File (RHF) for 100% of Medicare fee-for-service beneficiaries. The RHF which provides a person-level chronological history of health service utilization and locations of care was used to identify hospital discharge locations. We used ICD-10 codes for opioid dependence or “abuse” to identify OUD diagnoses from the MedPAR file. We conducted logistic regression to identify factors associated with discharge to an institutional setting versus home adjusting for demographics, comorbidities, and hospital stay characteristics.Our analysis included 459,763 hospitalized patients with OUD. Of these, patients aged < 65 years and those dually enrolled in Medicaid comprised the majority (59.1%). OUD and opioid overdose were primary diagnoses in 14.3% and 6.2% of analyzed hospitalizations, respectively. We found that 70.3% of hospitalized patients with OUD were discharged home, 15.8% to a skilled nursing facility (SNF), 9.6% to a non-SNF institutional facility, 2.5% home with home health services, and 1.8% died in-hospital. Within 30 days of hospital discharge, rates of readmissions and mortality were 29.7% and 3.9%; respectively, with wide variation across post-acute locations. Factors associated with greater odds of discharge to institutional settings were older age, female sex, non-Hispanic White race and ethnicity, dual enrollment, longer hospital stay, more comorbidities, intensive care use, surgery, and primary diagnoses including opioid or other drug overdoses, fractures, and septicemia.More than one-quarter (25.8%) of hospitalized Medicare beneficiaries with OUD received post-acute care in a setting other than home. High rates and wide variation in all-cause readmissions and mortality within 30 days post-discharge emphasize the need for improved post-acute care for people with OUD.The online version contains supplementary material available at 10.1186/s13722-022-00338-x. There is growing evidence of rising rates of opioid use disorder (OUD) and opioid-related hospitalizations and emergency department (ED) among older adults and younger adults with long-term disabilities, many of whom are enrolled in Medicare –7. MedicSeveral other circumstances magnify the urgency to better understand and respond to rising OUD diagnoses and related acute care use in the Medicare population , 12. FirPost-acute care plays an important role in the healthcare system and involves rehabilitation, recuperation, symptom management, and continued medical treatment after an individual has undergone acute hospital care. Varied post-acute care options exist, including skilled nursing facilities (SNFs), inpatient rehabilitation facilities, long-term care hospitals, and home health agencies , 22. InsOur objective was to characterize Medicare beneficiaries with OUD-related acute hospitalizations, describe their post-acute care locations, and describe their post-hospitalization outcomes stratified by post-acute care location. We hypothesized that receipt of post-acute care in institutional settings is common among hospitalized patients with OUD and that older adults represent a higher proportion of beneficiaries who are discharged to locations other than home. Examining Medicare beneficiary characteristics and their settings of care after OUD-related hospitalizations can inform understanding of the post-acute care needs of this population. Developing this understanding can promote the integration of addiction treatment with both geriatric/primary care and post-acute medical care in order to holistically address the behavioral health and other medical needs of patients across the care continuum .We used the national Medicare Provider Analysis and Review (MedPAR) file for 2016–2018 linked to the Medicare Master Beneficiary Summary File (MBSF) and the Residential History File (RHF) . MedicalOur study population included adult (18 years of age and older) Medicare beneficiaries residing in the 50 states and Washington D.C. who had acute inpatient stays involving OUD. We excluded beneficiaries enrolled in Medicare Advantage as they may not generate complete claims. See Additional file Among patients who were discharged alive, the location of post-acute care was captured within one day of the hospital discharge date. The hospital discharge location was classified into four mutually exclusive categories namely community without home health services, community with home health services, SNFs—a nursing home or distinct part of a nursing home, and non-SNF institutional/inpatient setting . In addition to clinical considerations of the level of care across different post-acute care settings, our categorization was informed by the distribution of the data and consideration of SNFs as a distinct location that has been the focus of the emerging literature on referral and admission practices for hospitalized patients with OUD –30. As sTransfers to another acute care hospital were considered as a single hospitalization. Due to the data structure of the RHF, the subsequent location for individuals who chose to leave the hospital before the treating physician recommended discharge  was home without home health unless there were claims or assessments that indicated care in other locations or receipt of home health services. A variable for beneficiary discharge status in inpatient claims allowed estimation of patient-directed discharges; however, the accuracy of the measurement is unclear. It is possible that some beneficiaries were discharged directly to hospice; however, hospice claims are not location specific because hospice services can be provided in community or institutional settings. For this reason and because of the expected small numbers of referrals to hospice, we did not directly assess hospice as a hospital discharge location. We analyzed in-hospital death as an additional hospital discharge disposition.To understand the clinical profiles of hospitalized Medicare beneficiaries with OUD, we assessed their primary diagnosis for the hospitalization and calculated a Gagne comorbidity score to summarize disease burden and estimate mortality risk , 32. We We conducted a descriptive analysis where we calculated frequencies, proportions, and means and standard deviations to characterize who has OUD-related hospitalizations and their location of care following hospital discharge. We further used multivariable logistic regression models to identify factors associated with discharge to an institutional setting compared with home  adjusting for demographics, comorbidities, and hospital stay characteristics including length of stay, ICU use, receipt of surgical procedures, and primary diagnoses. Separate models were implemented for the overall sample and stratified by age under 65 vs. 65 and older. Regression analyses accounted for repeated measures at the beneficiary level. Data analysis was conducted using R version 4.0.1  and SAS version 9.4  software. The Brown University Institutional Review Board designated the study as exempt.Our study included 459,763 acute inpatient stays with a primary 14.3%) or secondary (85.7%) diagnosis of OUD among Medicare fee-for-service beneficiaries during 2016–18. There were 8291 deaths during hospitalization. Septicemia was common among in-hospital decedents with almost one-third (32.1%) identified with this primary diagnosis  and older adults (at least 65 years of age) accounted for 39.7% of OUD-related hospitalizations in Medicare (Table % and oldThe mean age among younger Medicare beneficiaries was 50.5 (standard deviation: 10.4) years compared with 73.5 (standard deviation: 7.1) years among older adults. Among older adults, 59.5% were discharged home and 26.1% to SNFs; whereas, among beneficiaries under 65 years of age, 77.4% were discharged home and 9.0% to SNFs. In-hospital mortality was 2.5% among older adults versus 1.4% among beneficiaries under 65 years. See Additional file We observed that beneficiaries with more comorbid conditions were more likely to die in-hospital or be discharged to SNFs Table . OverallOverall, the odds of being discharged to an institutional post-acute care location increased with older age, female sex, non-Hispanic White race and ethnicity, dual Medicare and Medicaid enrollment, longer duration of hospitalization, greater number of comorbidities, ICU use, and receipt surgical procedures during hospitalization Table . BeneficRising rates of OUD and opioid overdoses contribute to increasing opioid-related hospitalizations and may increase the demand for post-acute care. This national study of all acute hospitalizations involving OUD among fee-for-service Medicare beneficiaries during 2016–18 provides insights about who experienced these hospitalizations, where they went following hospital discharge, and how they fared with respect to 30-day readmissions and mortality. Several results stood out in our analysis. First, OUD-related hospitalizations among our sample were characterized by high proportions of beneficiaries of female sex, Non-Hispanic White race and ethnicity, age under 65 years, or dually-enrolled in Medicare and Medicaid. Second, among approximately one-quarter of OUD-related hospitalizations, the hospital discharge location was an institutional setting such as a SNF, long-term care hospital or inpatient rehabilitation facility. Third, OUD-related hospitalizations among Medicare beneficiaries were resource intensive with one-third requiring ICU use and more than one-quarter resulting in all-cause readmission within 30 days post-hospitalization. Additionally, we found that OUD was predominantly a secondary, rather than a primary diagnosis among these hospitalizations; this observation suggests that this population often has co-occurring non-OUD diagnoses warranting inpatient care and emphasizes the importance of post-acute care that addresses behavioral health and other medical issues.It is concerning that among hospitalized Medicare beneficiaries with OUD nearly 30% had a hospital readmission for any reason and almost 4% died within 30 days post-discharge. In contrast, an analysis of data from an academic medical center in Boston Massachusetts reported a prevalence of hospital readmissions among patients with OUD at 18.2% . FurtherThe U.S is undergoing rapid expansion of the older adult population, which is projected to double in size from 2016 to 2060 , 37. ThiNational practice guidelines recommend the use of medications to treat OUD; however, questions exist about the appropriateness and feasibility of providing OUD treatment in different locations for post-acute and long-term care. Moreover, only 15.9% of beneficiaries with OUD received medication for OUD (MOUD) through Medicare in 2020 , adding There are indications that SNFs are receiving more referrals for patients diagnosed with OUD and that many facilities deny admission due to the presence of substance use or MOUD despite this practice violating antidiscrimination laws , 30, 46.Efforts to reduce or eliminate regulatory, reimbursement, and logistical barriers that hamper MOUD initiation or continuation for Medicare beneficiaries in institutional settings for post-acute and long-term care are needed. Given Drug Enforcement Agency (DEA) regulations that prohibit the dispensing of methadone outside highly-regulated clinics, considerations of the practicality of transporting individuals to methadone clinics or delivering MOUD to SNFs and other institutional settings must be considered. Stocking buprenorphine or naltrexone medications to treat OUD in post-acute or long-term care pharmacies could be another avenue to reduce barriers to accessing OUD treatment during post-acute and long-term care. Medicare reimbursement for MOUD also needs to be flexible to cover OUD treatment during post-acute and long-term stays outside the community. Such modifications stand to benefit not only older adults who are more likely to be discharged to institutional post-acute care locations but also younger adults who research indicates are entering SNFs in greater numbers due in part to housing instability , 51. AddOur study had some limitations. First, outpatient medical and pharmacy claims data were unavailable; therefore, we lack information about the history of OUD diagnosis and receipt of MOUD. However, our study provides a complete national picture of all Medicare inpatient acute care with a diagnosis of OUD. Second, a limitation inherent to secondary analysis of administrative claims is potential underreporting or misclassification of OUD status owing to coding practices that may prioritize diagnoses with higher reimbursement , 53. PriOur findings demonstrated that more than one-quarter of OUD-related hospitalizations in Medicare resulted in discharge to institutional post-acute care settings. The high rates of 30-day all-cause readmissions and mortality further highlight the relevance and importance of improving post-acute care for hospitalized patients with OUD. Opportunities exist to not only raise awareness about the post-acute care needs of individuals with OUD but to also develop strategies that optimize the quality of care for people with OUD of all ages and in diverse locations. While federal legislation and major initiatives by the Centers for Medicare and Medicaid Services (CMS) promise to improve Medicare beneficiaries’ access to MOUD in community settings , the impAdditional file 1: Appendix S1. Sample selection flow diagram indicating hospital discharge location following OUD-related hospitalizations. Appendix S2. Percentages of select primary diagnoses identified during OUD-related hospitalizations in Medicare during 2016-2018. Appendix S3. Demographic, comorbidity and health care utilization characteristics of opioid use disorder-related hospitalizations among older adult (age ≥65 years) fee-for-service Medicare beneficiaries, 2016-18. Appendix S4. Demographic, comorbidity and health care utilization characteristics of opioid use disorder-related hospitalizations among younger (age <65 years) fee-for-service Medicare beneficiaries, 2016-18.


COVID-19, as a global health crisis, has triggered the fear emotion with unprecedented intensity. Besides the fear of getting infected, the outbreak of COVID-19 also created significant disruptions in people’s daily life and thus evoked intensive psychological responses indirect to COVID-19 infections. In this study, we construct a panel expressed fear database tracking the universe of social media posts (16 million) generated by 536 thousand individuals between January 1st, 2019 and August 31st, 2020 in China. We employ deep learning techniques to detect expressions of fear emotion within each post, and then apply topic model to extract the major topics of fear expressions in our sample during the COVID-19 pandemic. Our unique database includes a comprehensive list of topics, not being limited to post centering around COVID-19. Based on this database, we find that sleep disorders (“nightmare” and “insomnia”) take up the largest share of fear-labeled posts in the pre-pandemic period (January 2019-December 2019), and significantly increase during the COVID-19. We identify health and work-related concerns are the two major sources of non-COVID fear during the pandemic period. We also detect gender differences, with females having higher fear towards health topics and males towards monetary concerns. Our research shows how applying fear detection and topic modeling techniques on posts unrelated to COVID-19 can provide additional policy value in discerning broader societal concerns during this COVID-19 crisis. Fear is one of the six basic emotions , which iResearchers and policy-makers mainly rely on surveys to measure fear perception . Howeverst, 2019) and comprehensively covers all topics, rather than restricting our sample to posts talking explicitly about COVID-19. This data allows us to control for the historical pre-pandemic fear expression patterns of individuals within our sample, and avoid the confounding effects from sample composition change . Based on the compiled panel social media posts, we use the Bidirectional Encoder Representations from Transformers (BERT) model to detect fear expressions in all posts in the sample, and apply the BERTopic to extract topics in posts that expressed fear emotions.In this paper, we study how the expression of fear for different aspects of people’s daily life changed during the COVID-19 (the contents that people posted not directly mentioning virus-related words) using social media posts and NLP. We compile an individual-based panel social media dataset containing all original posts (16 million posts) from a cohort of 536 thousand individuals from one year before the pandemic  application programming interface (API). The data contains 16 million original posts from a cohort of 536 thousand active users between January 1st, 2019; 2) We exclude the posts generated by institutional accounts  from our sample; 3) We drop users with post numbers within the top 10% to reduce the influence from extreme posters; 4) We randomly select and scrutinize 50 thousand posts to identify advertisements with a fixed format . We then apply regular expressions to remove advertisements in these formats for all posts; 5) We apply a series of functions to remove URLs, emojis, special characters, hash symbols from the posts to reduce the impacts of irrelevant information.Besides the raw content, we collect the exact posting time, number of likes, and re-posts for each post. To ensure data quality, we follow several rules when collecting data and constructing the research database: 1) We only collect posts from those users who registered before January 1In addition, we retrieve all the publicly accessible personal information from the profile page of each individual in our sample, including the birth date, gender, number of fans, number of followers, and the registration location. Natural Language Processing (NLP) is a computational method that translates unstructured large-scale text data into structured measures . SentimeIn this study, we use BERT, a text classification model developed by Google , to clasFollowing Lyu et al. , we consIn total, after combining three sources of datasets as one and ensure the class balance, we have 3,719 for each of the six emotions. We assign 80% of the posts to the training dataset, and 20% to the validation and additional eight thousand posts in two general topics provided by SMP-2020 as the test set, we train a one-layer fully connected network to achieve emotion classification. Overall, the model achieves 74.43% accuracy on the validation dataset. On the testing datasets, the overall accuracy is 75.84% and 74.00% for non-COVID-19 topics and COVID-19 topics respectively. For fear emotion, the model gets 84% and 74% for two topics .To better understand how the fear in topics not directly related to COVID-19 developed, we construct a dictionary of COVID-19 related words . The posTo understand why people express fear in social media during a health crisis, we implement a topic modelling algorithm to discover the abstract topics within the posts in the dataset. Topic modelling is widely used by researchers to understand public opinion ,35. BERTTo visualize the most informative keywords for each topic, we take the following steps: (1) We apply BERTopic model on the vectorized sentences and get the class id for each of the sentence. (2) We join the sentences in the same topic class together and apply class-based TF-IDF algorithms to extract the TF-IDF value for each word. (3) We select the top 3 Chinese words with the highest TF-IDF score within each class and translate them into English using Google translate.rd (the date that epi-center Wuhan city was announced to lockdown). The share of fear posts steadily drops afterwards and remains stable around 2.64% (681 posts) of total posts after April 8th, 2020, slightly higher than the 2019 baseline. Besides the onset of COVID-19, there are several spikes in the fear posts within our sample period, which are mostly affected by weather and catastrophes   in total from the original 16 million Weibo posts. t-tests to compare the fear share by topics in different sub-periods after the peak COVID-19 pandemic with the same period in 2019. Specifically, we define the following two sub-periods in China as follows: (1) COVID-19 peak period started from January 20th, 2020 and ended on April 8th, 2020 ; (2) post-COVID-19 period started from April 9th and ended at August 31st for 2020.We use BERTopic to automatically split the data into meaningful clusters. In total, there are 60 fear topics unrelated to COVID-19 . In particular, we find that topics about sleep  have the largest share in fear posts during our sample period of two years. On average, 10% and 7% of fear posts are related to nightmares and insomnia, respectively. As shown in Health and work-related topics had the largest change during the COVID-19 peak sub-period  comparing to males . After the COVID-19 peak sub-period, both genders remain to have a significantly higher frequency of nightmare-related fear posts relative to their levels in 2019 . In addition, the insomnia topic shows a similar pattern that the female had a significant increase in posting during the COVID-19 period . The results from the two sleep-related topics suggest that females are more likely to have sleep disorders during the COVID-19 and such impact lasts for months.Regarding the fear related to “nightmare”, we find that both genders increase posting during the COVID-19 period, with females having a larger and more significant extent  comparing to females . Such a concern becomes more significant after the COVID-19 peak period . The work-related topic result indicates that, in opposite to health-related topics, males pay more attention to the economic side, indicating a different type of stress. The result could serve as a potential explanation of why men are having a higher suicide rate during the COVID-19 period [Finally, both males and females post more about monetary topics during the COVID-19 period, with males having a larger extent  symptoms of fear , (2) fear related to other health problems , (3) fear about socio-economic consequences (such as “money”).Our results have important implications. First, the significant increases in fear towards these topics indicate an increase in the mental distress and anxiety caused by the COVID-19. Our result shows that fear posts related to “nightmare”, the largest non-COVID-19 related fear source, take up a significantly higher proportion of fear posts even months after the peak pandemic. Deteriorated sleep quality brought by mental distress during the COVID-19 could contribute to latent risks for the population’s physical and psychological health, which should receive added attention. Second, our results suggest that COVID-19 and related policies induced health and financial concerns. Staying at home was accompanied by a reduction in physical activities and an increase in screen time, thus inducing more fear posts for weight and eye problems. The increased attention to “money” indicates that people were also faced with higher economic burdens during the pandemic. These results reveal the importance of paying attention to the broader social consequences of the COVID-19 on people’s daily life, instead of solely focusing on the COVID-19 related posts when analyzing the fear response. Finally, our findings indicate that both genders are affected by the COVID-19 in general with different focus. Besides showing the topic trends on specific topics, we reclassify 60 posts into six general aspects including “Health”, “Weather and Catastrophe” “Transportation” etc., and visualize the temporal trend Click here for additional data file.


The cognitive trajectories of cognitively normal (CN) individuals rapidly progressing to Alzheimer’s disease dementia (AD) have not been investigated.To explore the preclinical pattern of cognitive performance heralding the rapid progression from normal cognition to AD.The HELIAD cohort underwent comprehensive neuropsychological assessments  at baseline and after approximately 3-year intervals. The cognitive trajectories of those with normal cognition at baseline were explored according to the follow-up diagnosis using adjusted generalised estimating equations analyses.A total of 932 predominantly female (61%), older (72.9 ± 4.9), CN participants were followed for 3.09 (± 0.83) years. Among them, 761 individuals remained CN, 29 progressed to AD and 142 developed MCI . Those progressing to AD were already performing worse than the healthy reference in every single cognitive domain at baseline. Cognitive deficits ranged between ~ 0.5SD  and ~ 1.0SD . Throughout the 3-year follow-up, memory constantly exhibited the most prominent impairment compared to the remaining cognitive domains while executive function diminished in the most abrupt fashion (~ 0.19SD yearly) separating from the remaining three cognitive functions before the development of full-blown AD. Heterogeneous patterns of cognitive decline clearly differentiated those progressing to MCI from those rapidly converting to AD, as well.Poor performance in every cognitive domain may characterise cognitively normal individuals at high risk of fast progression to AD.Strict neuropsychological cut-offs fail to detect a considerable number of individuals at high risk of rapid progression to AD.The online version contains supplementary material available at 10.1007/s40520-022-02265-y. The identification of biomarkers which may assist in the preclinical detection of individuals under an increased risk of developing dementia could contribute to the early implementation of interventions that may delay or prevent cognitive impairment (or serve relevant research purposes). Previous studies have consistently indicated the value of several imaging and laboratory indices which can reveal undergoing neuropathological alterations in a prodromal stage , 2. HoweTo that end, several researchers have reported that memory complaints and cognitive changes may start even as early as 15 years before the clinical identification of Alzheimer’s Disease (AD) , 4. HoweAdvancing along the clinical continuum towards AD, usually involves the key intermediate stage of mild cognitive impairment (MCI) due to AD . The speIn view of the aforementioned literature gap, we decided to undertake the present study. Our objective was to compare the 3-year—preclinical cognitive trajectories of CN individuals rapidly progressing to AD in relation to the trajectories of those progressing to MCI or maintaining normal cognition . In this way, we aimed to delineate potential discrepancies in the preclinical patterns of cognitive performance that may serve as prognostic markers for the imminent development of AD in individuals with normal cognition. For this purpose, we capitalized on data from the older, population-based HELIAD (Hellenic Investigation of Aging and Diet) cohort.Our sample was derived from the HELIAD study, the rationale and key elements of which have been previously described in great detail , 13. In Older (≥ 65 years) participants were randomly selected from the registries of two Greek municipalities, Larissa  and Marousi (a suburban area in the metropolitan city of Athens). Collaborative assessments (2–2.5 h long) were conducted by certified neurologists, trained neuropsychologists, and dieticians during baseline and follow-up . A maximum of two assessments (baseline and 2nd visit) are readily available per individual, so far. Relevant information was collected from participants or participant carers , whenever deemed necessary. For the present analysis, eligible individuals were CN at baseline and had available follow-up assessments.Dementia and possible-probable AD were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders -IV-text revision criteria and the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer Disease and Related Disorders Association criteria correspondingly , 15. MilA comprehensive neuropsychological evaluation was performed by trained neuropsychologists: Global cognition and Orientation (MMSE) , Non-verRaw scores from each individual neuropsychological test were converted into z-scores using mean and standard deviation values, estimated from the cognitively normal group of individuals at baseline (no dementia or mild cognitive impairment). Subsequently, z-scores of individual tests were averaged to produce domain z-scores for memory, language, attention, executive and visuospatial ability, for each participant . These 2), physical activity  and daily energy intake  were treated as continuous variables [In an effort to isolate the differential effect of the underlying, preclinical, evolving neurocognitive processes characterising MCI and AD, multiple potential confounders were accounted for in our analyses: age at baseline, years of formal schooling, body-mass index  and Pearson’s chi-squared test . The longitudinal cognitive trajectories of the CN individuals were explored according to the cognitive diagnosis at follow-up using adjusted generalised estimating equations (GEE) analyses. GEE accounts for the potential correlation of repeated measurements in the same individual. We treated each participants’ baseline and follow-up evaluations as a cluster. Exchangeable (compound symmetry) covariance matrices were conventionally chosen as working correlation structures. Consecutive adjusted GEE models were explored using global and individual domain cognitive indices as the dependent scale variables. Apart from the main effects of the above-listed confounders (previous section), each GEE model featured the main effect of time (in years from baseline), the main effects of the follow-up diagnoses  and the follow-up diagnoses by time interactions (six interactions).Our aim was to delineate the preclinical pattern of cognitive performance preluding the imminent onset of AD in individuals with normal cognition. Baseline differences between the group that converted to AD after the 3-year follow-up and those progressing to MCI or maintaining normal cognition were examined using the independent samples α = 0.05 was set for revealing significant interactions.To retain the power of our study despite the inclusion of multiple confounders in our analyses , automatic multiple data imputation was conducted for the above-listed potential confounders. Neuropsychological assessments were exclusively used as auxiliary-predictive variables, whereas all confounders were both imputed and used as auxiliary-predictive variables . All statistical analyses were performed using the IBM SPSS Statistics Software Version 25 . The conventional significance threshold of The HELIAD cohort included 1107 participants who had undergone at least one follow-up neuropsychological assessment. Among them, 28 were diagnosed with dementia at baseline, 118 were diagnosed with MCI while 4 had inconclusive cognitive diagnoses and were excluded from the present investigation. From the remaining 957 participants, 5 were diagnosed with dementia other than AD at follow-up while another 20 had missing data leading to inconclusive cognitive diagnoses and were excluded from our analysis. A total of 932 CN, predominantly female (61%), older (72.9 ± 4.9) participants were finally included in the current report. After a mean follow-up of 3.09 (± 0.83) years, 761 subjects remained unimpaired, 29 progressed to AD, whereas 142 converted to MCI. Among them, 33 were diagnosed with aMCI-SD, 41 with aMCI-MD, 37 with naMCI-SD and 31 with naMCI-MD. The baseline characteristics of the CN baseline sample according to the follow-up diagnoses are presented in Table Tables CN participants that developed AD after the 3-year follow-up were already performing worse than the healthy reference in every single cognitive domain at baseline. Relative differences ranged between ~ 0.5 SD  and ~ 1.0 SD . During the 3-year follow-up, with the exception of visuospatial skills , the remaining cognitive functions declined in an accelerated fashion . From a qualitative point of view, episodic memory constantly exhibited the worst relative trajectory throughout the 3-year follow-up (the most prominent deficits compared to the other functions), whereas executive function diminished in the most abrupt manner separating from the remaining three cognitive domains before the development of full-blown AD , whereas attention deficits were constantly the most prominent in the naMCI-MD group throughout the 3-year follow-up period towards the onset of the disorder (as opposed to the prominent impairment of episodic memory in the AD group) Fig. . Of inteThe present study explored the 3-year—preclinical cognitive trajectories of CN individuals rapidly converting to AD in relation to the trajectories of those progressing to MCI or maintaining normal cognition . The preclinical pattern of cognitive performance differentiated quite well between those that converted to AD and the rest of the participants. Considerable, multidomain baseline deficits involving every domain of cognition and associated with predominant episodic memory impairment throughout the 3-year follow-up portended the imminent development of AD. Less prominent, multidomain baseline deficits with intact attention and predominant episodic memory impairment throughout the 3-year follow-up heralded the onset of aMCI-MD. Multidomain baseline deficits involving attention, with predominant attention impairment throughout the 3-year follow-up were a harbinger of naMCI-MD.Although the present article is the first to examine the preclinical cognitive trajectories portending the imminent onset of AD, previous researchers have also explored the factors related to rapid cognitive decline and incident dementia. Older age, genetic susceptibility, physical inactivity, lower frequency of leisure activities, worse functional status, poorer psychological welfare, neuropsychiatric symptoms, subjective memory concerns, worse nutritional status and poorer vascular health have all been associated with steeper cognitive decline in CN older adults –38. Of nOf note, the baseline pattern of cognitive performance of those rapidly converting to AD was determined quite similar to the predicted pattern of cognitive impairment at the onset of aMCI-MD (after the completion of the 3-year follow-up)  (Online Resource 1). This finding is of particular interest considering the high (~ 50%), 3-year conversion rate of aMCI-MD to AD . In specPrevious research has suggested that cognitive changes tend to precede the diagnosis of AD for many years, potentially reflecting the undergoing neurodegenerative alterations which are present even as long as 20–25 years before its onset , 4. EpisEpisodic memory deficits are also arguably the first to forebode the development of MCI due to AD, usually 4–8 years prior to the formal identification of the disorder , 48. LanUnlike the aMCI subgroup, the longitudinal cognitive trajectories towards the development of naMCI have not been investigated to date. The current report has revealed that attention is predominantly affected throughout the 3-year, preclinical course towards the development of naMCI-MD, which is probably consistent with the higher risk of DLB in individuals with naMCI-MD . Of noteThe present article compared the 3-year, preclinical cognitive trajectories of CN individuals rapidly converting to AD in relation to the trajectories of those progressing to MCI or maintaining normal cognition. The study sample was drawn from the population-based, prospective HELIAD cohort which consists of a randomly selected sample of older adults from two Greek communities, a provincial and a metropolitan municipality. Participants underwent comprehensive baseline and follow-up neuropsychological evaluation while clinical diagnoses (dementia and MCI) were established during expert-consensus meetings based on standard clinical criteria. All analyses were adjusted for multiple important confounders to isolate the differential effect of the underlying evolving neurodegenerative processes.However, our study had a number of important limitations, as well. First, although the diagnosis of dementia was clinically established by a consortium of senior experts, it was not supported by imaging and biological biomarkers . Second, our analyses may have been influenced by the loss of follow-up since a non-trivial proportion of our sample did not undergo follow-up investigations. Moreover, despite accounting for the latent impact of a great number of important parameters, our investigations may still be affected by residual confounding. Of note, although the majority of the main vascular determinants of cognitive decline and incident dementia were accounted for, we did not adjust our analyses for the presence of atrial fibrillation, a well-established predictor of cognitive impairment and dementia . FurtherSupplementary file1 (PDF 431 KB)Below is the link to the electronic supplementary material.


Published literature documents tremendous gender inequities in the social, economic and health effects of the COVID-19 pandemic, but less evidence has come from low- and middle-income countries (LMICs) and even less from LMIC-based authors. We examine whether a) COVID-19 burden and b) LMIC-based authorship were associated with academic publications related to COVID-19 and women's well-being in LMICs.n=1076 articles), using six electronic databases . Multilevel, mixed effects linear regressions assessed the relationships between each of our independent variables - a) COVID-19 burden  and b) author's country of primary affiliation, with publications related to COVID-19 and women's well-being, both overall and stratified by country income group.We reviewed academic articles on COVID-19 and women's well-being in LMICs published between February 2020 and May 2021 .Bill and Melinda Gates Foundation  We searched for articles indexed in PubMed (pubmed.gov), Web of Science (Clarivate), PsycINFO (ProQuest), EconLit (EBSCO), NBER (nper.org) and RePeC (repec.org)] for articles indexed by March 30, 2022 including “COVID-19” AND “gender” AND “bibliometric” AND (“LMIC” OR “low and middle income”). No papers were identified which looked at the relationship between COVID-19 burden and author affiliations with publications related to COVID-19 and women's well-being.Despite growing evidence that the COVID-19 pandemic has serious and detrimental gendered effects, there has been no comprehensive assessment to date of the ways in which publications related to COVID-19 and women's well-being vary across low and middle-income countries, what topics are being most commonly published on, and how COVID-19 burden and author affiliations relate to those publications. This bibliometric analysis fills these gaps by providing a statistical overview and assessment of publications related to COVID-19 and women's well-being including focus on low and middle-income countries over the first 16 months of the pandemic.While publications related to COVID-19 and women's well-being were generally reflective of COVID-19 burden in low and middle-income countries, these relationships were driven by upper-middle income countries, and were lacking in low-income and lower-middle income countries. Involvement of lead and/or senior authors affiliated with institutions in article focal countries was not associated with publications related to COVID-19 and women's well-being focused on economic impacts. There is a need for greater involvement of in-country authors on research examining a wider range of gendered COVID-19 impacts, as well as increased representation of diverse topics and publications related to COVID-19 and women's well-being focused on lower income countries.Alt-text: Unlabelled box,,,As of early March 2022, the COVID-19 pandemic has killed more 5.9 million people worldwide, and infected more than 437 million.,These impacts are exacerbated in low- and middle-income countries (LMIC), where higher levels of existing gender inequalities, power imbalances, and regressive gender norms compound pandemic challenges.,Authorship is another important marker of representation in research efforts. Multiple empirical studies and opinion pieces by experts have pointed to the low representation of researchers from LMICs in research concerned with these regions.,What has been learned about the gendered impacts of the COVID-19 pandemic is in large part derived from scientific publications.th May 2021. Our search criteria were developed by gender research experts, and included terms related to five broad thematic areas related to COVID-19 and women's well-being: a) Women and girls’ health, b) Gendered social impacts (including norms), c) Gendered economic impacts, d) Women's collectives, and e) Women's leadership (search terms in Appendix https://doi.org/10.6084/m9.figshare.12830513.v3).We conducted a recurring literature review of academic articles related to COVID-19 and women's well-being in LMIC. Six electronic bibliographic databases  were searched for peer-reviewed literature and working papers. The reviews were conducted every 1-2 weeks between June 2020 and May 2021, thus covering all relevant articles on COVID-19 and women's well-being indexed in the selected databases through 28Over 5800 articles were identified using our search criteria during the review period. Of these, 1123 studies were found to satisfy eligibility criteria . Data onFour country-level variables were also included in this analysis. Country level data on COVID-19 cases and deaths were extracted from the WHO database.From our literature review, we calculated the number of academic publications on COVID-19 and women's well-being focusing on each LMIC for each of the 16 months of observation. These publications were further categorized by topical area of focus: women and girls’ health (inclusive of but not limited to COVID-19 infection), gendered social outcomes, gendered economic impacts, women's leadership, and women's collectives. Topical focal areas were not exclusive, thus articles could be noted as having two or more focal areas. We also reviewed the country of institutional affiliation for the lead and senior authors of each paper, and identified whether that country was the focal country of the article in question . Authorship affiliations in the article focal country were categorized as neither lead nor senior author's primary institutional affiliation was in the focal country, lead only, senior only, or both lead and senior. Articles with a single author whose primary affiliation was in the focal country were categorized as both lead and senior authors being affiliated in the focal country.Study quality and risk of bias are important tools in understanding the quality and composition of research included in scientific reviews. While we considered an assessment of study quality and risk of bias based on existing guidance,We used three variables to measure COVID-19 burden in a country: number of COVID-19 cases per 100 population, number of COVID-19 deaths per 100 population, and COVID-19 case fatality ratio. The case fatality ratio was defined as the number of COVID-19 deaths per 100 COVID-19 cases in each country. These three variables were estimated for the overall review period, as well as monthly (June 2020 – May 2021).Information related to income groups for the LMICs was based on the World Bank classification for the financial year 2021-22, which categorizes LMICs as upper-middle income, lower-middle income, and low-income. Venezuela was unclassified in 2021-22 by the World Bank, hence its categorization for 2019 was used in this analysis.The GII is an aggregate measure of gender inequality calculated at the country level by the United Nations Development Program. The GII measures gender inequalities across three aspects of human development: reproductive health, measured by maternal mortality ratio and adolescent birth rates; empowerment, measured by proportion of parliamentary seats occupied by females and proportion of adult females and males aged 25 years and older with at least some secondary education; and economic status, expressed as labor market participation and measured by labor force participation rate of female and male populations aged 15 years and older. We used the GII for 2019 for each LMIC, with values ranging from 0  to 1 .Total development assistance captured the total amount of development assistance funds received by each LMIC in 2019, from private donors, official development assistance, and other official flows. This measure is designed to represent the volume of external funds aimed at promoting growth in economic, health and social systems, as a proxy for support to in-country research infrastructures.This bibliometric analysis summarizes data from the 1,076 articles eligible for review, providing cross-sectional, article-level descriptive frequencies of author primary institutional affiliations with the number of publications overall, and across assessed focal areas. Country-level descriptive analyses summarize focal topics, author affiliations, COVID-19 burden , GII, and total development assistance for the 137 LMICs included in this sample overall and stratified by income group.,,Multilevel, mixed effects linear regression models were used to assess the relationship between our independent variables - COVID-19 burden and authorship affiliations in a given country, and our outcome variable- the number of publications related to COVID-19 and women's well-being focusing on that same country. These models assessed these relationships by country using a longitudinal panel data structure to implement within-between modelsTo fully understand the effect of country income group on the relationship between COVID-19 burden and publications related to COVID-19 and women's well-being, an additional exploratory analysis ran country income group-stratified iterations of the within-between models for each three COVID-19 burden predictors, again modeled using a six-month lag between COVID-19 burden.A secondary analysis examined the relationship between our independent variables and the following outcomes- the number of women's well-being related publications focusing on that same country in three primary focal areas: women and girls’ health, gendered social outcomes, and gendered economic impacts. Models adjusted for all factors included in the main regression models.All regression models were also tested with no lag between COVID-19 burden and publication date, but model fits were worse than those with the six-month lag (data not shown). We also modeled three- and nine-month lags for comparative purposes, and results did not differ meaningfully from the six-month lag presented below (data not shown).All analyses were conducted in R, version 4.0.4.The funder had no role in manuscript writing, analysis, interpretation or submission. Authors were not precluded from accessing data in the study, and accept responsibility to submit for publication. All authors had access to the raw data, and all authors approved submission of the final manuscript for publication.n=7) or women's collectives (n=1); these two focal areas were thus excluded from regression-based analyses.The 1076 women's well-being related COVID-19 articles reviewed and included in this analysis focus on 136 different LMICs. Three-quarters of reviewed articles (78%) were written by both first and senior authors with primary affiliations in the country (or one of the countries) of focus of that article; one in eight articles (78%) were neither lead- nor senior-authored by an individual with a primary affiliation matching that article's focal country. The majority of reviewed articles (91%) focused on women and girls’ health, with fewer focusing on gendered social outcomes (12%) and gendered economic impacts (5%) . The mosIn-country authorship for both lead and senior authors was most common among articles focusing on women and girls’ health (79%), and least common among articles focusing on gendered economic impacts (46%) and women's leadership (29%). Nearly half of articles focusing on gendered economic impacts (49%) were authored by neither in-country affiliated lead nor senior authors. The single article focusing on women's collectives was authored by neither a lead nor senior author with in-country affiliation. In-country affiliation for lead and senior authors was much more common among papers focusing on a single focal country ; affiliation of neither lead nor senior author with the focal country was more evenly distributed .Reviewed articles represented 2,175 country-articles (some articles focused on more than one LMIC). Women's well-being related COVID-19 articles in this review include all LMICs with the exception of the Democratic People's Republic of Korea , though these trends also varied by country income group, with greater representation of upper-middle income countries than lower-income countries  (p<0·001).In multivariable linear mixed effect modelling, the number of COVID-19 cases per 100 population in a country was significantly and positively associated with the number of women's well-being related COVID-19 academic publications during our study period. For every one unit increase in the natural log number of COVID-19 cases per 100 people in a country in a given month, there was a 0·2 unit increase in the natural log of women's well-being related COVID-19 publications in that country six months later (p<0·001) . COVID-1All assessed author affiliation categories were significantly and positively associated with the number of publications related to COVID-19 and women's well-being in models adjusting for COVID-19 cases, deaths and case-fatality ratio . In all p<0·001 [Appendix p<0·001 [Appendix p<0·001 [Appendix Income-group stratified analyses indicate that the positive association between COVID-19 burden and women's well-being related publications six months later was significant only in upper-middle income countries . Authorp=0·02)(p<0·001) . In contp<0·001) . There wp<0·001) . Having p<0·001) , Table 6This bibliometric analysis of publications related to COVID-19 and women's well-being identified more than 1,000 peer-reviewed articles published between February 2020 and May 2021, exploring ways that gender and COVID-19 have intersected in LMICs. This work documents gendered impacts of the pandemic with regard to health as well as social and economic concerns in LMIC contexts, though the social and economic impacts have received less attention. Importantly, our analysis highlights that publication numbers on this topic were generally reflective of COVID-19 burden, but this was limited to upper-middle income nations, suggesting that lower-middle and low-income countries may be under-represented in our developing understanding of gender and the pandemic. Our findings correspond with data showing that pandemic-related publications were generally produced by authors in the most affected countries, though this early work was largely concentrated in upper-middle and high-income nations.There were important distinctions in the topical foci of publications related to COVID-19 and women's well-being based on the nature of COVID-19 case burdens. Increases in COVID-19 cases in LMICs were associated with decreases in publications focused on women and girls’ health, while increases in COVID-19 deaths were associated with increases in publications on gendered social outcomes, including social norms. Nonetheless, we found no association between case fatality ratios and publications. Case fatality ratios represent a broader range of structural inequities and vulnerabilities, including health system access and infrastructure, and are thus a meaningful lens through which to examine pandemic response.Upper-middle income countries are most represented in this body of literature, influenced in particular by China, which was a focal country in more than one in three articles published during this period. As the country where the first COVID-19 outbreak was identified,,,,,Research leadership from a more diverse array of scientists, particularly those from LMICs, is widely recognized as an area in need of expansion.,Having a body of researchers in-country able to produce published research on topics such as the gendered effects of COVID-19 is critical to ensure that governments, aid organizations, multilateral and donor organizations and scientists can learn more about the effects of this pandemic and design appropriately targeted and responsive policies, programs and future research endeavours. These levels of affiliation with in-country institutions are similar to those seen in prior research,,Development assistance was not associated with publications related to COVID-19 and women's well-being in any income group, or in any focal topic. This may in part be due to the fact that these figures represent total development assistance; only 4% of these monies are dedicated primarily to gender programming, and a smaller portion still is dedicated to gendered health responses.Study findings must be interpreted in light of known limitations. This is an ecological, bibliometric analysis of English-language publications, and is neither able to make causal assumptions nor able to draw conclusions about individual countries or health systems. It is possible that some literature related to women's well-being and COVID-19 was not identified using the study search terms, though we attempted to be as comprehensive as possible. Further, consideration of the impact of non-empirical pieces was outside of the scope of the analysis and may merit further review elsewhere. Our data on COVID-19 cases and deaths relies on numbers reported to the World Health Organization, and thus represents primarily lab-confirmed cases and deaths, not total cases and deaths.The COVID-19 pandemic has adversely impacted the lives of millions of people around the world, and research has been foundational in understanding the health, social and economic consequences of crisis. Many of these consequences manifest in gendered ways, and understanding these differential manifestations is critical to informing responsive recovery and support policies and programs. Our findings generally found higher levels of publications related to COVID-19 and women's well-being in countries with higher levels of population-adjusted cases and deaths, an encouraging finding that many scientists, funders and governments are prioritizing understanding the gender-related lessons of this pandemic. However, these relationships were significant only among upper-middle income countries, and varied by specific gender focal topic. We also found that in-country affiliated authorship is associated with more women's well-being and COVID-19 publications, but disproportionately limited to health. In fact, lower levels of representation of in-country affiliated authorship in leadership positions was associated with generation of papers focusing on social, economic, and political impacts of the pandemic. Gender-intentional lenses are an essential aspect of COVID-19 response plans in all countries, and should be prioritized by governments, funders, and researchers alike. Strong leadership by in-country scientists inclusive of social and behavioural scientists within health research, as well as flexible, responsive gender data systems are foundational. Application of these lenses and research led by local scholars should be bolstered in low resource settings, or we will continue to have inadequate understanding of gendered health impacts in these contexts.LM, ND and AR contributed to study design and conceptualization. LM, ND, WWC and AD contributed to data collection. LM and ND contributed to data analysis and figure and table creation. LM wrote the original manuscript, all authors contributed to manuscript review and editing.No individually identifiable information is included in the studies included in this review. All extracted data have been made publicly available at Mendeley Data (doi: 10.17632/5hfcxsbstk.1).All authors report funding support in the form of a grant from the Bill and Melinda Gates Foundation to their institution to conduct this research (PI: AR). All authors have nothing else to disclose.


In advanced Parkinson’s disease (PD), dyskinesias and non-motor symptoms such as sleep dysfunction can significantly impair quality of life, and high-quality management is an unmet need.To analyze changes in dyskinesia and non-motor symptoms (including sleep) among studies with levodopa-carbidopa intestinal gel (LCIG) in patients with advanced PD.A comprehensive literature review identified relevant studies examining LCIG efficacy. Outcomes of interest were dyskinesia , overall non-motor symptoms (NMSS), mentation/behavior/mood (UPDRS I), and sleep/daytime sleepiness . The pooled mean  change from baseline per outcome was estimated for each 3-month interval with sufficient data  up to 24 months using a random-effects model.Seventeen open-label studies evaluating 1243 patients with advanced PD were included. All outcomes of interest with sufficient data for meta-analysis showed statistically significant improvement within 6 months of starting LCIG. There were statistically significant improvements in dyskinesia duration as measured by UPDRS IV item 32 at 6 months  and 12 months . There were statistically and clinically significant improvements in non-motor symptoms as measured by NMSS scores at 3 months . Significant reduction of NMSS burden was maintained through 24 months . UPDRS I scores significantly improved at 3 months . Clinically significant improvements in PDSS-2 and ESS scores were observed at 6 and 12 months in individual studies.Patients with advanced PD receiving LCIG showed significant sustained improvements in the burden of dyskinesia and non-motor symptoms up to 24 months after initiation. Parkinson’s disease (PD) is a chronic and progressive disorder primarily associated with the degeneration of brain dopamine neurons and depletion of striatal dopamine . The golLevodopa-carbidopa intestinal gel (LCIG) is a stable gel suspension suitable for continuous delivery through percutaneous gastrojejunostomy via a portable pump . By contAlthough motor symptoms traditionally define PD, patients with PD can experience both motor and non-motor symptoms. The development of dyskinesia, a motor symptom, is common in patients with advanced PD . While mResults from a previously conducted meta-analysis showed improvement in “off” time, activities of daily living (ADLs), and quality of life for patients with advanced PD treated with LCIG persisting up to 24 months . LCIG haWe conducted a literature review to identify interventional, prospective observational, or retrospective studies published in the Embase and Medline databases through October 6, 2020. Studies of interest were single-arm or comparative evaluations of patients with advanced PD who were initiating LCIG treatment; studies had to report at least 1 outcome of interest and have a follow-up time of at least 3 months. Studies of patients with early PD, case reports, conference abstracts without a full-text publication, and trials or observational studies that did not examine the outcomes of interest were excluded. Following the literature search, 2 reviewers independently screened each title and abstract to identify relevant articles and reviewed the full-text articles for final study inclusion. Disagreements were resolved by discussion and consensus.Outcomes of interest for measuring dyskinesia were the Unified Dyskinesia Rating Scale (UDysRS) and item 32 (modified from percent improvement to hours per day) or items 32–34 (score) of the Unified Parkinson’s Disease Rating Scale (UPDRS) Part IV (UPDRS IV), depending on the study. Outcomes for measuring non-motor symptoms included the Non-Motor Symptoms Scale for Parkinson’s Disease (NMSS), Part I of the UPDRS (UPDRS I) for measuring mood/behavior, the Parkinson’s Disease Sleep Scale-2 (PDSS-2) for sleep, and the Epworth Sleepiness Scale Questionnaire (ESS) for daytime sleepiness.2 and Q statistics.Data for each outcome were grouped into 3-month intervals  up to 24 months. For each outcome of interest, the pooled mean change from baseline (CFB) with 95% CI was estimated for each time interval with sufficient data for meta-analysis . Data were pooled using random-effects methods to generate overall estimates for each outcome and time point  that was sustained through 24 months . Changes from baseline in UDysRS and UPDRS IV items 32–34 scores were not meta-analyzed, as there were no 3-month intervals in which 3 or more studies reported these outcomes. However, among the individual studies, improvements in UDysRS and UPDRS IV items 32–34 scores were observed at 3 months, 6 months, and 12 months.Non-motor symptoms as measured on the NMSS scale showed statistically and clinically significant improvement starting at 3 months  that was sustained through 24 months  .Mentation, behavior, and mood as measured by UPDRS I scores was significantly improved at 3 months . No statistically significant CFB in UPDRS I scores was observed at 12 months . There were insufficient data for meta-analysis for the 4 to 6 month, 16 to 18 month, and 22 to 24 month intervals, but among the individual studies, improvements were observed at 6 months and 24 months, with no improvement observed at 18 months.Sleep outcomes as measured by PDSS-2 and ESS scores were not meta-analyzed, as there were no 3-month intervals in which 3 or more studies reported these outcomes. However, among the individual studies, clinically significant improvements in PDSS-2 scores were observed at 3 months , 6 monthForest plots showing input data from individual studies along with the meta-analysis outcomes are presented in the Interactive Appendix.Our analysis including data from 17 clinical and observational studies provides one of the most comprehensive assessments to date of the impact of LCIG therapy on non-motor symptom and dyskinesia outcomes among patients with advanced PD. Results of the meta-analysis suggest that the effects of LCIG on non-motor symptoms and dyskinesia are evident as early as 1 to 3 months and 4 to 6 months following treatment initiation, respectively, and are sustained over a period of 24 months. The improvement in non-motor symptoms from baseline was statistically significant and greater than the reported minimum clinically important difference for NMSS scores (–13.91) across 24 months . Mood anAlthough multiple treatments address dyskinesia in advanced PD, there is an unmet need for therapies to address the substantial burden of non-motor symptoms . The resThe results of our meta-analysis suggest the use of LCIG for sleep and other key non-motor symptoms of PD. While pathophysiology for improvements in non-motor symptoms is not fully understood, several domains may be partly driven by dopamine control . These dIn observational studies, improvement in non-motor symptoms and dyskinesias was associated with improved quality of life in patients with advanced PD receiving LCIG treatment as well as their caregivers . In a crResults from this meta-analysis show statistically and clinically significant improvements in non-motor symptoms and a statistically significant reduction in dyskinesia duration, which contribute to LCIG’s overall impact in improving patients’ quality of life and ability to perform ADLs. Few studies assessed dyskinesia disability , leading to limited evidence and an inability to evaluate these outcomes in meta-analysis. PD is associated with substantial economic burden to patients, caregivers, payers, and society ; improveHowever, while LCIG has been shown to improve dyskinesia, it is worth noting that breakthrough dyskinesia has been described in the long term, although this occurs only in a minority of patients . Few patAlthough there were insufficient data to meta-analyze sleep outcomes in our analysis, clinically significant improvements with LCIG were observed in at least 1 study at 3, 6, 12, 18, and 24 months for PDSS-2 scores , and at To our knowledge, there has been only one other meta-analysis to date evaluating LCIG in patients with advanced PD that included any of the outcomes used in our analysis. Liu et al. found significant improvement for subthalamic nucleus deep-brain stimulation versus LCIG for dyskinesia/motor fluctuation, measured using overall UPDRS IV scores . These rOur meta-analysis presents a robust evaluation of the impact of LCIG on key PD-related outcomes over 24 months, overcoming the challenge of sample size in individual studies. However, as in all meta-analyses, our evaluation pools data from multiple studies with different study characteristics. We have closely examined the patient populations and outcome definitions to evaluate the impact these factors may have on LCIG treatment outcomes and to create a collection of studies with sufficient similarity to be suitable for meta-analytic combination. No studies were excluded during the similarity assessment.A tailored, multidisciplinary approach to treatment decisions is recommended in advanced PD , and theIn this large-scale meta-analysis involving 1243 unique patients with advanced PD treated with LCIG, we found significant improvement in dyskinesia duration from 6 through 24 months and in non-motor symptoms from 3 through 24 months after treatment initiation. Improvement in NMSS scores was both statistically significant and clinically meaningful. Improvement in UPDRS IV and NMSS was rapid, appearing within the first 6 months, and remained consistent for up to 24 months. LCIG provided improvement in dyskinesia and NMSS including sleep and mood scores. The data available on other sleep endpoints were insufficient for meta-analysis, and additional studies are needed to evaluate the impacts of LCIG on sleep parameters in patients with PD.Click here for additional data file.