Peroneal Nerve Decompression in Patients with Multiple Hereditary Exostoses: Indications, Complications, and Recurrence.

BACKGROUND: To our knowledge, there have been no studies examining peroneal nerve decompression and proximal fibular osteochondroma excision exclusively in patients with multiple hereditary exostoses (MHE). The purpose of this study was to evaluate the indications, complications, and recurrence associated with nerve decompression and proximal fibular osteochondroma excision in patients with MHE. METHODS: The records on patients with MHE undergoing peroneal nerve decompression from 2009 to 2023 were retrospectively reviewed. Indications, clinical status, surgical technique, recurrence, and complications were recorded and were analyzed using the Fisher exact test, logistic regression, and the Kaplan-Meier method. RESULTS: There were 126 limbs identified in patients with MHE who underwent peroneal nerve decompression. The most common indications were pain over the proximal fibula, tibialis anterior and/or extensor hallucis longus weakness, and dysesthesias and/or neuropathic pain. Seven cases experienced postoperative foot drop as a complication of the decompression and osteochondroma excision. Logistic regression found significant relationships between complications and excision of anterior osteochondromas (odds ratio [OR], 5.21; p = 0.0062), proximal fibular excision (OR, 14.73; p = 0.0051), and previous decompression (OR, 5.77; p = 0.0124). The recurrence rate was 13.8%, and all recurrences occurred in patients who were skeletally immature at the index procedure. The probability of skeletally immature patients not experiencing recurrence was 88% at 3 years postoperatively and 73% at 6 years postoperatively. CONCLUSIONS: Indications for peroneal nerve decompression included neurologic symptoms and pain. The odds of a complication increased with excision of anterior osteochondromas and previous decompression. Recurrence of symptoms following decompression and osteochondroma excision was found exclusively in skeletally immature patients. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Long COVID Citizen Scientists: Developing a Needs-Based Research Agenda by Persons Affected by Long COVID.

BACKGROUND: Long-term health consequences following acute SARS-CoV-2 infection, referred to as post-COVID-19 condition or Long COVID, are increasing, with population-based prevalence estimates for adults at around 20%. Persons affected by Long COVID report various health problems, yet evidence to guide clinical decision making remains scarce. OBJECTIVE: The present study aimed to identify Long COVID research priorities using a citizen science approach and solely considering the needs of those affected. METHODS: This citizen science study followed an iterative process of patient needs identification, evaluation and prioritisation. A Long COVID Citizen Science Board (21 persons with Long COVID, and seven with myalgic encephalomyelitis/chronic fatigue syndrome) and a Long COVID Working Group (25 persons with Long COVID, four patients with myalgic encephalomyelitis/chronic fatigue syndrome and one relative) were formed. The study included four activities: three remote meetings and one online survey. First, Board members identified the needs and research questions. Second, Working Group members and persons affected by Long COVID (241 respondents, 85.5% with Long COVID, 14.5% with myalgic encephalomyelitis/chronic fatigue syndrome and 7.1% relatives) evaluated the research questions on a 1-5 Likert scale using an online survey. Then the Board gave feedback on this evaluation. Finally, Board members set the priorities for research through voting and discussion. RESULTS: Sixty-eight research questions were generated by the Board and categorised into four research domains (medicine, healthcare services, socioeconomics and burden of disease) and 14 subcategories. Their average importance ratings were moderate to high and varied from 3.41 (standard deviation = 1.16) for sex-specific diagnostics to 4.86 (standard deviation = 0.41) for medical questions on treatment. Five topics were prioritised: "treatment, rehabilitation and chronic care management", "availability of interfaces for treatment continuity", "availability of healthcare structures", "awareness and knowledge among professionals" and "prevalence of Long COVID in children and adolescents". CONCLUSIONS: To our knowledge, this is the first study developing a citizen-driven, explicitly patient-centred research agenda with persons affected by Long COVID, setting it apart from existing multi-stakeholder efforts. The identified priorities could guide future research and funding allocation. Our methodology establishes a framework for citizen-driven research agendas, suitable for transfer to other diseases.

Research shows that about one in five adults may experience lasting symptoms months after their initial coronavirus infection. Persons with Long COVID have various health problems and doctors often do not know their patients' most urgent needs. The project directly involved people with Long COVID who were asked to express, discuss and rank how research could meet their needs. For that, a Board and a Working Group were formed to take part in three online board meetings and one online questionnaire. In the meetings, the Board formulated 68 research questions, which fall into four research areas: (1) medicine, (2) healthcare services, (3) socioeconomics and (4) burden of disease. The Working Group and other persons affected by Long COVID ranked the importance of these 68 research questions using an online questionnaire. Most questions were ranked as somehow or very important, confirming the relevance of the selected research questions for patients with Long COVID. Finally, the Board selected its top five research topics: "treatment, rehabilitation and chronic care management", "availability of interfaces for treatment continuity", "availability of healthcare structures", "awareness and knowledge among professionals" and "prevalence of Long COVID in children and adolescents". This result will help prioritise and finance future research that is valued and needed by people with Long COVID.

Commonalities and differences in legal euthanasia and physician-assisted suicide in three countries: a population-level comparison.

OBJECTIVES: To describe and compare euthanasia and physician-assisted suicide (EAS) practice in Flanders, Belgium (BE), the Netherlands (NL) and Switzerland (CH). METHODS: Mortality follow-back surveys among attending physicians of a random sample of death certificates. RESULTS: We studied 349 EAS deaths in BE (4.6% of all deaths), 851 in NL (4.6% of all deaths) and 65 in CH (1.4% of all deaths). People who died by EAS were mostly aged 65 or older (BE: 81%, NL: 77% and CH: 71%) and were mostly diagnosed with cancer (BE: 57% and NL: 66%). Home was the most common place of death in NL (79%), while in BE and CH, more variation was found regarding to place of death. The decision to perform EAS was more frequently discussed with a colleague physician in BE (93%) and NL (90%) than in CH (60%). CONCLUSIONS: EAS practice characteristics vary considerably in the studied countries with legal EAS. In addition to the legal context, cultural factors as well as the manner in which legislation is implemented play a role in how EAS legislation translates into practice.

Does the DOSPERT scale predict risk-taking behaviour during travel? A study using smartphones.

Background: Despite the continuing growth of international tourism, very little research has been done on the link between individual risk attitudes and health behaviours during travel. Our study uses a validated risk-taking questionnaire Domain-Specific Risk-Taking Scale (DOSPERT) and data from a smartphone application to study the association between pre-travel risk attitudes and the occurrence of behaviours during travel. Methods: A prospective cohort of travellers to Thailand used a smartphone application to answer a daily questionnaire about health behaviours and events. Prior to travel, participants completed the DOSPERT, a validated 30-item scale that assesses risk-taking and perception in five content domains: financial decisions, health/safety, recreational, ethical and social decisions. Multiple linear regression models were used to model the relationship between DOSPERT risk-taking subdomain score and health behaviour. Results: Of the 75 travellers that completed the study, 70 (93.3%) completed the DOSPERT pre-travel. Men, backpackers and young travellers reported a higher willingness to take recreational risks than women, luxury travellers and older travellers. Incidence of drug and alcohol risk behaviours during travel, itching from mosquitoes, smoking and failing to use a seatbelt in automobiles while at home were all significantly associated with an individual's score on the health and safety DOSPERT subdomain. Conclusions: In our study, individual scores on risk-taking in the health and safety subdomain of the DOSPERT questionnaire seem to be predictive of health behaviours both during travel and at home. By pairing new methods of data collection with questionnaires such as DOSPERT that identify key traveller characteristics to intervene on, travel medicine doctors will be able to provide more specialised health advice, ensuring that all travellers receive well-rounded advice about the full range of health challenges they will face during travel.

Continuous deep sedation until death in patients admitted to palliative care specialists and internists: a focus group study on conceptual understanding and administration in German-speaking Switzerland.

BACKGROUND: Continuous deep sedation until death is increasingly used to treat intolerable suffering of terminally ill patients. One of the highest incidences and strongest increases has been observed in Switzerland. Variation in prevalence estimates indicates a potential effect of differences in sedation practice between care settings and professionals. AIM: To explore physicians' and nurses' conceptual understanding of continuous deep sedation and unravel decision-making processes in everyday clinical practice. METHODS: Between June and October 2016, we conducted seven qualitative focus groups with 47 healthcare professionals (21 physicians and 26 nurses) involved in sedation decision and administration. RESULTS: Participants had on average 20 years (range 3-39) of clinical experience, 10 years (range 0-30) of self-reported palliative care experience, and a mean annual number of 5 patients (range 1-20) continuously deeply sedated until death. Continuous deep sedation until death covers a wide spectrum of practices: specialised palliative sedation induced through benzodiazepines to treat refractory symptoms as option of last resort, sedation as comfort therapy with benzodiazepines or opioids, and sedation taken into account as a side effect of gradually increased analgesia. CONCLUSION: We found substantial variation in terminology and definition, indication and medication used for continuous deep sedation until death. To provide optimal symptom management in terminally ill patients, early involvement of palliative care experts as well as financial and regulatory support should be provided to encourage multi-disciplinary collaboration and thus consensus for defining the distinct sedation practices.

Continuous Deep Sedation Until Death-a Swiss Death Certificate Study.

BACKGROUND: In the last decade, the number of patients continuously deeply sedated until death increased up to fourfold. The reasons for this increase remain unclear. OBJECTIVE: To identify socio-demographic and clinical characteristics of sedated patients, and concurrent possibly life-shortening medical end-of-life decisions. DESIGN: Cross-sectional death certificate study in German-speaking Switzerland in 2001 and 2013. PARTICIPANTS: Non-sudden and expected deaths (2001: N = 2281, 2013: N = 2256) based on a random sample of death certificates and followed by an anonymous survey on end-of-life practices among attending physicians. MAIN MEASURES: Physicians' reported proportion of patients continuously deeply sedated until death, socio-demographic and clinical characteristics, and possibly life-shortening medical end-of life decisions. KEY RESULTS: In 2013, physicians sedated four times more patients continuously until death (6.7% in 2001; 24.5.5% in 2013). Four out of five sedated patients died in hospitals, outside specialized palliative care units, or in nursing homes. Sedation was more likely among patients younger than 65 (odds ratio 2.24, 95% CI 1.6 to 3.2) and those dying in specialized palliative care (OR 2.2, 95% CI 1.3 to 3.8) or in hospitals (1.7, 95% CI 1.3 to 2.3). Forgoing life-prolonging treatment with the explicit intention to hasten or not to postpone death combined with intensified alleviation of symptoms was very strongly associated with continuous deep sedation (OR 6.8, 95% CI 4.7 to 9.8). CONCLUSIONS: In Swiss clinical practice, continuously deeply sedated patients predominantly died outside specialized palliative care. The increasing trend over time appears to be related to changes in medical end-of-life practice rather than to patient's clinical characteristics.

The impact of the inpatient practice of continuous deep sedation until death on healthcare professionals' emotional well-being: a systematic review.

BACKGROUND: The practice of continuous deep sedation is a challenging clinical intervention with demanding clinical and ethical decision-making. Though current research indicates that healthcare professionals' involvement in such decisions is associated with emotional stress, little is known about sedation-related emotional burden. This study aims to systematically review the evidence on the impact of the inpatient practice of continuous deep sedation until death on healthcare professionals' emotional well-being. METHODS: A systematic review of literature published between January 1990 and October 2016 was performed following a predefined protocol. MEDLINE, EMBASE, PubMed, Cochrane Library, CINAHL, Scopus, and PsycINFO were searched using search terms within "end-of-life care", "sedation", and "emotional well-being". Dissertations and reference lists were screened by hand. Two independent reviewers conducted study selection, data extraction and quality assessment. We abstracted measures of psychological outcomes, which were related to the practice of continuous deep sedation until death, including emotional well-being, stress and exhaustion. We used the GRADE approach to rate the quality of evidence. RESULTS: Three studies remained out of 528 publications identified. A total of 3'900 healthcare professionals (82% nurses, 18% physicians) from Japan (n = 3384) and the Netherlands (n = 16) were included. The prevalence of sedation-related burden in nurses varied from 11 to 26%, depending on outcome measure. Physicians showed medium levels of emotional exhaustion and low levels of depersonalization. Common clinical concerns contributing to professionals' burden were diagnosing refractory symptoms and sedation in the context of possibly life-shortening decisions. Non-clinical challenges included conflicting wishes between patients and families, disagreements within the care team, and insufficient professionals' skills and coping. Due to the limited results and heterogeneity in outcome measure, the GRADE ratings for the quality of evidence were low. CONCLUSIONS: Current evidence does not suggest that practicing continuous deep sedation is generally associated with lower emotional well-being of healthcare professionals. Higher emotional burden seems more likely when professionals struggled with clinical and ethical justifications for continuous deep sedation. This appeared to be in part a function of clinical experience. Further research is needed to strengthen this evidence, as it is likely that additional studies will change the current evidence base.

Infection of Aedes albopictus with chikungunya virus rectally administered by enema.

Chikungunya virus (CHIKV) is an alphavirus transmitted by Aedes albopictus and Aedes aegypti mosquitoes in tropical areas of Africa, Asia, and the islands of the Indian Ocean. In 2007 and 2009, CHIKV was transmitted outside these tropical areas and caused geographically localized infections in people in Italy and France. To temporally and spatially characterize CHIKV infection of Ae. albopictus midguts, a comparison of viral distribution in mosquitoes infected per os or by enema was conducted. Ae. albopictus infected with CHIKV LR 5' green fluorescent protein (GFP) at a titer 10(6.95) tissue culture infective dose(50) (TCID(50))/mL, were collected and analyzed for virus dissemination by visualizing GFP expression and titration up to 14 days post inoculation (dpi). Additionally, midguts were dissected from the mosquitoes and imaged by fluorescence microscopy for comparison of midgut infection patterns between orally- and enema-infected mosquitoes. When virus was delivered via enema, the anterior midgut appeared more readily infected by 3 dpi, with increased GFP presentation observed in this same location of the midgut at 7 and 14 dpi when compared to orally-infected mosquitoes. This work demonstrates that enema delivery of virus is a viable technique for use of mosquito infection. Enema injection of mosquitoes may be an alternative to intrathoracic inoculation because the enema delivery more closely models natural infection and neither compromises midgut integrity nor involves a wound that can induce immune responses. Furthermore, unlike intrathoracic delivery, the enema does not bypass midgut barriers to infect tissues artificially in the hemocoel of the mosquito.

Experimental transmission of Mayaro virus by Aedes aegypti.

Outbreaks of Mayaro fever have been associated with a sylvatic cycle of Mayaro virus (MAYV) transmission in South America. To evaluate the potential for a common urban mosquito to transmit MAYV, laboratory vector competence studies were performed with Aedes aegypti from Iquitos, Peru. Oral infection in Ae. aegypti ranged from 0% (0/31) to 84% (31/37), with blood meal virus titers between 3.4 log(10) and 7.3 log(10) plaque-forming units (PFU)/mL. Transmission of MAYV by 70% (21/30) of infected mosquitoes was shown by saliva collection and exposure to suckling mice. Amount of viral RNA in febrile humans, determined by real-time polymerase chain reaction, ranged from 2.7 to 5.3 log(10) PFU equivalents/mL. Oral susceptibility of Ae. aegypti to MAYV at titers encountered in viremic humans may limit opportunities to initiate an urban cycle; however, transmission of MAYV by Ae. aegypti shows the vector competence of this species and suggests potential for urban transmission.

In vivo imaging of chikungunya virus in mice and Aedes mosquitoes using a Renilla luciferase clone.

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that in humans causes an acute febrile illness characterized by fever, arthralgia, and rash. It is currently associated with large outbreaks in Asia, Africa, and islands of the Indian Ocean and has been introduced from these tropical regions into Europe, where local transmission has been recorded on two occasions. The underlying basis of the pathogenesis of CHIKV and related alphaviruses that produce similar symptoms remains unclear. By applying new techniques, for example, in vivo imaging in live animals and arthropods, we may improve our understanding of viral pathogenesis in vertebrates and viral replication in mosquitoes. This technical report describes the evaluation of a CHIKV?luciferase clone to visualize infection and dissemination in both Aedes aegypti and Aedes albopictus mosquitoes and mice. In mosquitoes, luciferase activity was seen at 3 and 7 days post-infection in both head and abdomens. In vivo imaging of CHIKV-luciferase was detected in mice for up to 5 days post-infection at the site of inoculation with limited dissemination to the skeletal muscle.

Host immune response to mosquito-transmitted chikungunya virus differs from that elicited by needle inoculated virus.

BACKGROUND: Mosquito-borne diseases are a worldwide public health threat. Mosquitoes transmit viruses or parasites during feeding, along with salivary proteins that modulate host responses to facilitate both blood feeding and pathogen transmission. Understanding these earliest events in mosquito transmission of arboviruses by mosquitoes is essential for development and assessment of rational vaccine and treatment strategies. In this report, we compared host immune responses to chikungunya virus (CHIKV) transmission by (1) mosquito bite, or (2) by needle inoculation. METHODS AND FINDINGS: Differential cytokine expression was measured using quantitative real-time RT-PCR, at sites of uninfected mosquito bites, CHIKV-infected mosquito bites, and needle-inoculated CHIKV. Both uninfected and CHIKV infected mosquitoes polarized host cytokine response to a TH2 profile. Compared to uninfected mosquito bites, expression of IL-4 induced by CHIKV-infected mosquitoes were 150 fold and 527.1 fold higher at 3 hours post feeding (hpf) and 6 hpf, respectively. A significant suppression of TH1 cytokines and TLR-3 was also observed. These significant differences may result from variation in the composition of uninfected and CHIKV-infected mosquito saliva. Needle injected CHIKV induced a robust interferon-gamma, no detectable IL-4, and a significant up-regulation of TLR-3. CONCLUSIONS: This report describes the first analysis of cutaneous cytokines in mice bitten by CHIKV-infected mosquitoes. Our data demonstrate contrasting immune activation in the response to CHIKV infection by mosquito bite or needle inoculation. The significant role of mosquito saliva in these earliest events of CHIKV transmission and infection are highlighted.

A nonhuman primate model of chikungunya disease.

Chikungunya disease is a severely debilitating, mosquito-borne, viral illness that has reached epidemic proportions in Africa, Asia, and the islands of the Indian Ocean. A mutation enhancing the ability of the chikungunya virus (CHIKV) to infect and be transmitted by Aedes albopictus has increased the geographical range at risk for infection due to the continuing global spread of this mosquito. Research into disease pathogenesis, vaccine development, and therapeutic design has been hindered by the lack of appropriate animal models of this disease. The meticulous study reported in this issue of the JCI by Labadie et al. is one of the first reports describing CHIKV infection of adult immunocompetent nonhuman primates. Using traditional and modern molecular and immunological approaches, the authors demonstrate that macaques infected with CHIKV are a good model of human CHIKV infection and also show that persistent arthralgia in humans may be caused by persistent CHIKV infection of macrophages.

An animal model for studying the pathogenesis of chikungunya virus infection.

Newborn and 14-day-old mice inoculated subcutaneously with chikungunya virus (CHIKV) developed lethargy, difficulty walking, dragging of hind limbs, and reduced weight gain within 7-10 days after infection (PI). During the initial 6-7 days PI, the animals had viremia; high levels (10(6)-10(8) PFU) of CHIKV were also present in leg muscle. The virus persisted in muscle for several days after viremia disappeared. The major histopathologic changes were in skeletal muscle, which were focal necrosis and inflammation, followed by fibrosis and dystrophic calcification. Some mice also showed dystrophic calcification in the joint cartilage, but there were few deaths, and most of the animals eventually recovered. CHIKV antigen was shown by immunohistochemistry in the muscle for several weeks after infection. Based on the clinical and pathologic similarities with CHIKV infection in humans, young ICR and CD-1 mice offer a useful and realistic model for further study of the pathogenesis and treatment of CHIKV infection.

Heat shock protein 27 protects against aminolevulinic acid-mediated photodynamic therapy-induced apoptosis and necrosis in human breast cancer cells.

This study utilized two breast cancer cell lines differing only in their expression of heat shock protein 27 (hsp27). The DB46 cell line was engineered to express high constitutive levels of hsp27, while the DC4 cell line expresses normal low levels of hsp27. The cells were incubated in 1 mM aminolevlinic acid (ALA) 4 hr prior to light exposures (635 nm) ranging from 1 to 20 J/cm2. Both cell lines displayed a dose response to photodynamic therapy (PDT) as assayed by clonogenic survival. LD50s of 2.68 and 1.27 J/cm2 were observed for DB46 and DC4 cells respectively. ALA-PDT-induced resistance to both apoptosis and necrosis in the DB46 cell line was found from TUNEL assays and fluorescence microscopy studies using propidium iodide and Hoechst staining.

Photodynamic therapy of newly implanted glioma cells in the rat brain.

BACKGROUND AND OBJECTIVE: A syngeneic rat brain tumor model is used to investigate the effects of aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) on small clusters of tumor cells sequestered in normal brain. STUDY DESIGN/MATERIALS AND METHODS: Biodistribution studies on tumor-bearing animals were undertaken in order to determine the occurrence of photosensitizer in tumor cells invading normal brain. ALA-PDT toxicity in normal brain and gross tumor were evaluated from histopathology. Effects of PDT on isolated glioma cells in normal brain were investigated by treating animals 48 hours after tumor cell implantation. RESULTS: Fluorescence microscopy of frozen tissue sections showed that photosensitizer content was limited and variable in tumor tissue invading normal brain. ALA-PDT with high light doses resulted in significant damage to both gross tumor and normal brain, however, the treatment failed to prolong survival of animals with newly implanted glioma cells. In contrast, animals inoculated with tumor cells pre-incubated in vitro with ALA showed a significant survival advantage in response to PDT. CONCLUSION: The results show that ALA-PDT could not prevent tumors from forming if treatment was performed shortly after tumor initiation. This was likely due to inadequate levels of ALA/PpIX in the glioma cells.