No evidence for persistent natural plague reservoirs in historical and modern Europe.

Caused by Yersinia pestis, plague ravaged the world through three known pandemics: the First or the Justinianic (6th-8th century); the Second (beginning with the Black Death during c.1338-1353 and lasting until the 19th century); and the Third (which became global in 1894). It is debatable whether Y. pestis persisted in European wildlife reservoirs or was repeatedly introduced from outside Europe (as covered by European Union and the British Isles). Here, we analyze environmental data (soil characteristics and climate) from active Chinese plague reservoirs to assess whether such environmental conditions in Europe had ever supported "natural plague reservoirs". We have used new statistical methods which are validated through predicting the presence of modern plague reservoirs in the western United States. We find no support for persistent natural plague reservoirs in either historical or modern Europe. Two factors make Europe unfavorable for long-term plague reservoirs: 1) Soil texture and biochemistry and 2) low rodent diversity. By comparing rodent communities in Europe with those in China and the United States, we conclude that a lack of suitable host species might be the main reason for the absence of plague reservoirs in Europe today. These findings support the hypothesis that long-term plague reservoirs did not exist in Europe and therefore question the importance of wildlife rodent species as the primary plague hosts in Europe.

Integrative approach using Yersinia pestis genomes to revisit the historical landscape of plague during the Medieval Period.

Over the last few years, genomic studies on Yersinia pestis, the causative agent of all known plague epidemics, have considerably increased in numbers, spanning a period of about 5,000 y. Nonetheless, questions concerning historical reservoirs and routes of transmission remain open. Here, we present and describe five genomes from the second half of the 14th century and reconstruct the evolutionary history of Y. pestis by reanalyzing previously published genomes and by building a comprehensive phylogeny focused on strains attributed to the Second Plague Pandemic (14th to 18th century). Corroborated by historical and ecological evidence, the presented phylogeny, which includes our Y. pestis genomes, could support the hypothesis of an entry of plague into Western European ports through distinct waves of introduction during the Medieval Period, possibly by means of fur trade routes, as well as the recirculation of plague within the human population via trade routes and human movement.

The Dramaturgy of Epidemics.

My essay focuses on Charles Rosenberg's provocative and enduring ideal type of epidemic drama in three acts, which he assembled from a vast knowledge of disease history that stretched from the end of the seventeenth century to his then-present pandemic, HIV/AIDS of the 1980s. Reaching back to the Plague of Athens, my essay elaborates on Rosenberg's dramaturgy by questioning whether blame, division, and collective violence were so universal or even the dominant "acts" of epidemics not only before the nineteenth century but to the present. Instead, with certain pandemics such as yellow fever in the Deep South or the Great Influenza of 1918-20, unity, mass volunteerism, and self-abnegation played leading roles. Finally, not all epidemics ended "with a whimper" as attested by the long early modern history of plague. These often concluded literally with a bang: lavish planning of festivals of thanksgiving, choreographed with processions, innumerable banners, commissions of paintings, ex-voto churches, trumpets, tambourines, artillery fire, and fireworks.

Social and institutional Reactions to the Influenza Pandemic of 1918-20.

This essay challenges generalizations since the late enlightenment about the effects of epidemics and pandemics on collective mentalities: that from antiquity to the present, epidemics, regardless of the disease, have sparked distrust, social violence, and the blaming of others. By contrast, the pandemic that killed the greatest numbers in world history-the Influenza of 1918-20 - was a pandemic of compassion. No one has yet to uncover this pandemic sparking collective violence or blaming any minorities for spreading the disease anywhere in the globe. The essay then explores the variety of charitable reactions and abnegation that cut across social divisions in communities from theatres of war in Europe to nations thousands of miles from the direct military encounters. Most remarkable, however, was the overflowing volunteerism of women, especially in the US, Canada, and Australia. To explain this widespread charitable reaction, the essay investigates the milieu of the First World War, showing how that context in domestic war settings was not conducive to risking life to aid total strangers, especially when those strangers came from different foreign countries classes, races, or religious faiths. I end with a reflection on the unfolding socio-psychological reactions to Covid-19 from the perspective of 1918-20.

Subacute Horizontal Diplopia, Jaw Dystonia, and Laryngospasm.

Jaw dystonia and laryngospasm in the context of subacute brainstem dysfunction have been described in a small number of diseases, including antineuronal nuclear antibody type 2 (ANNA-2, also known as anti-Ri) paraneoplastic neurologic syndrome. Severe episodes of laryngospasms causing cyanosis are potentially fatal. Jaw dystonia can also cause eating difficulty, resulting in severe weight loss and malnutrition. In this report, we highlight the multidisciplinary management of this syndrome associated with ANNA-2/anti-Ri paraneoplastic neurologic syndrome and discuss its pathogenesis.

Comparative efficacy and discontinuation of dimethyl fumarate and fingolimod in clinical practice at 24-month follow-up.

BACKGROUND: Dimethyl fumarate and fingolimod are oral disease-modifying therapies approved to treat relapsing multiple sclerosis. Prior observational studies and our previous 12-month investigation showed comparable clinical efficacy. OBJECTIVE: The purpose of this study was to assess real-world efficacy and discontinuation of dimethyl fumarate and fingolimod over 24 months in patients with multiple sclerosis. METHODS: Patients treated with dimethyl fumarate (n = 395) or fingolimod (n = 264) completed 24-month follow-up in a large academic multiple sclerosis center. Discontinuation rates and measures of disease activity were compared after propensity score weighting. The primary outcome was on-treatment annualized relapse rate ratio. Other measures included rate of drug discontinuation and brain magnetic resonance imaging activity defined as new T2 and/or gadolinium-enhancing lesions. RESULTS: Propensity score weighting showed excellent covariate balance. At 24 months, dimethyl fumarate demonstrated comparable annualized relapse rate (rate ratio = 1.45, 95% confidence interval 0.53-3.99) and brain magnetic resonance imaging activity (odds ratio = 1.38, 95% confidence interval 0.83-2.32). Dimethyl fumarate patients discontinued therapy earlier compared to fingolimod (hazard ratio = 1.40, 95% confidence interval 1.11-1.77) and were more likely to discontinue therapy due to intolerability (odds ratio = 1.98, 95% confidence interval 1.18-3.23). CONCLUSION: Dimethyl fumarate and fingolimod had similar reductions in annualized relapse rate in clinical trials, and our real-world experience supports this observation. Dimethyl fumarate-treated patients had higher likelihood of early discontinuation, and this was mostly due to intolerability.

Historical Parallels, Ebola Virus Disease and Cholera: Understanding Community Distrust and Social Violence with Epidemics.

In the three West African countries most affected by the recent Ebola virus disease (EVD) outbreak, resistance to public health measures contributed to the startling speed and persistence of this epidemic in the region. But how do we explain this resistance, and how have people in these communities understood their actions? By comparing these recent events to historical precedents during Cholera outbreaks in Europe in the 19th century we show that these events have not been new to history or unique to Africa. Community resistance must be analysed in context and go beyond simple single-variable determinants. Knowledge and respect of the cultures and beliefs of the afflicted is essential for dealing with threatening disease outbreaks and their potential social violence.

Infectious complications and ventilation tubes in pediatric cochlear implant recipients.

OBJECTIVES/HYPOTHESIS: At many centers, ventilating tubes (VTs) are placed routinely in otitis-prone pediatric cochlear implant recipients. However, this practice is controversial, as many otologists believe VTs represent a possible route for contamination of the device. Toward better understanding of the safety of VTs, we reviewed our center's infectious complications and their relationship to the presence of tubes. STUDY DESIGN: Retrospective cohort study. METHODS: All patients undergoing cochlear implantation at our institution between 1990 and 2012 were reviewed for complications and their association with the presence of VTs. RESULTS: A total of 478 patients (557 ears) were reviewed, representing over 2,978 patient-years of follow-up. In 135 ears (24.2%), a VT was present at time of, or placed at some point after, implantation. The remainder either never had a VT or it had extruded prior to implantation. Overall, 63 complications occurred, of which 17 were infectious. The most common were cellulitis (four), device infection (five), and meningitis (four). Only one occurred while a tube was present, and was a device infection in an ear having a retained VT in place for almost 4 years. No difference was observed in overall rates of infectious complications between the group with VTs and those who never had VTs. CONCLUSIONS: This series, the largest to date, indicates that infectious complications after cochlear implantation are rarely associated with the presence of VTs, supporting the concept that, overall, VTs are safe in cochlear implant recipients. Close monitoring is essential, including prompt removal of tubes when they are no longer needed. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1671-1676, 2016.

Comparative efficacy and discontinuation of dimethyl fumarate and fingolimod in clinical practice at 12-month follow-up.

BACKGROUND: Dimethyl fumarate (DMF) and fingolimod (FTY) are approved oral disease modifying therapies (DMT) for relapsing multiple sclerosis (MS). Phase 3 trials established these agents as effective and generally well tolerated, though comparative efficacy and discontinuation remain unknown. OBJECTIVE: To assess real-world efficacy and discontinuation of DMF and FTY over 12 months in patients with MS. METHODS: We identified 458 DMF-treated and 317 FTY-treated patients in a large academic MS center. Measures of disease activity and discontinuation were compared using propensity score (PS) weighting. Covariates in the PS model included demographics and baseline clinical and MRI characteristics within 12 months of DMT initiation. The primary outcome measure was on-treatment annualized relapse rate (ARR) ratio, which was analyzed using a Poisson regression model. Other measures included time to first relapse, drug discontinuation, time to discontinuation, and new brain MRI lesions at 12 months. RESULTS: The on-treatment ARR for DMF was 0.16 (95% CI (0.12, 0.18)) and 0.13 (95% CI (0.08, 0.16)) for FTY. PS weighting, which demonstrated excellent covariate balance, showed no differences between groups on ARR (rate ratio=1.56, 95% CI (0.78, 3.14)), overall brain MRI activity defined as new T2 and/or gadolinium enhancing (GdE) lesions (OR=1.38, 95% CI (0.78, 2.42)), new T2 lesions (OR=1.33, 95% CI (0.71, 2.49)), and discontinuation (OR=1.30, 95% CI (0.84, 1.99)). DMF had higher odds of GdE lesions (OR=2.19, 95% CI (1.10, 4.35)), earlier time to discontinuation (HR=1.35, 95% CI (1.05, 1.74)), and earlier relapses (HR=1.64, 95% CI (1.10, 2.46)) compared to FTY. CONCLUSION: Assessment in our clinical practice cohort showed comparable clinical efficacy, overall brain MRI activity, and discontinuation between DMF and FTY at 12 months. DMF had increased GdE lesions and intolerability early after treatment initiation.

Risk stratification and mitigation multiple sclerosis.

The increasing availability of new agents to treat multiple sclerosis poses new challenges for clinicians who seek therapies that are both safe and effective for their patients. The introduction of additional effective therapies has been accompanied by the recognition of serious side effects. The clinician now must weigh both the benefits and risks of therapies to help patients decide which treatment best fits each patient׳s risk/benefit profile. An optimal selection of therapies relies on a complete understanding of the risks of therapies and the factors that may help evaluate and mitigate those risks. An individualized treatment approach that incorporates patient and disease factors is needed for each patient. In this review we present risk stratification and mitigation strategies of disease modifying agents for multiple sclerosis.

Unilateral cochlear nerve deficiency in children.

OBJECTIVE: Cochlear nerve deficiency (CND) is increasingly diagnosed in children with sensorineural hearing loss (SNHL). We sought to determine the prevalence of CND, its imaging characteristics, and correlations with audiologic phenotype in children with unilateral SNHL. DESIGN: Case series with chart review. SETTING: Tertiary pediatric hospital. SUBJECTS/METHODS: In 128 consecutive children with unilateral SNHL who underwent high-resolution magnetic resonance imaging, the diameters, area, and signal intensity of the cochlear nerve (CN) were measured and normalized to the ipsilateral facial nerve. Presence of CND was determined by comparison to normative data. Relationships among hearing loss severity, progression, and nerve size were investigated. RESULTS: Cochlear nerve deficiency was present in 26% of children with unilateral SNHL. Its prevalence was higher (48%) in severe to profound SNHL, especially when in infants (100%). Width of the bony cochlear nerve canal (BCNC) correlated strongly with relative CN diameter, density, and area (R = 0.5); furthermore, a narrow BCNC (<1.7 mm) strongly predicted CND. Severity of hearing loss modestly correlated with nerve size, although significant variability was observed. Progression never occurred unless there were other inner ear malformations, whereas in the non-CND group, it occurred in 22%. Ophthalmologic abnormalities were very common (67%) in CND children, particularly oculomotor disturbances. CONCLUSION: Cochlear nerve deficiency is a common cause of unilateral SNHL, particularly in congenital unilateral deafness. Width of the BCNC effectively predicts CND, a finding useful when only computed tomography imaging is available. In an ear with CND, hearing can be expected to remain stable over time. Diagnosis should prompt evaluation by an ophthalmologist.

Pandemics: waves of disease, waves of hate from the Plague of Athens to A.I.D.S.

This article briefly surveys the history of pandemics in the West, contesting long-held assumptions that epidemics sparked hatred and blame of the 'Other', and that it was worse when diseases were mysterious as to their causes and cures. The article finds that blame and hate were rarely connected with pandemics in history. In antiquity, epidemics more often brought societies together rather than dividing them as continued to happen with some diseases such as influenza in modernity. On the other hand, some diseases such as cholera were more regularly blamed than others and triggered violence even after their agents and mechanisms of transmission had become well known.