Mediation analysis for survival data using semiparametric probit models.

Causal mediation modeling has become a popular approach for studying the effect of an exposure on an outcome through mediators. Currently, the literature on mediation analyses with survival outcomes largely focused on settings with a single mediator and quantified the mediation effects on the hazard, log hazard and log survival time (Lange and Hansen 2011; VanderWeele 2011). In this article, we propose a multi-mediator model for survival data by employing a flexible semiparametric probit model. We characterize path-specific effects (PSEs) of the exposure on the outcome mediated through specific mediators. We derive closed form expressions for PSEs on a transformed survival time and the survival probabilities. Statistical inference on the PSEs is developed using a nonparametric maximum likelihood estimator under the semiparametric probit model and the functional Delta method. Results from simulation studies suggest that our proposed methods perform well in finite sample. We illustrate the utility of our method in a genomic study of glioblastoma multiforme survival.

Debating Diseases in Nineteenth-Century Colombia: Causes, Interests, and the Pasteurian Therapeutics.

This article explores the medical conceptualization of the causes of diseases in nineteenth-century Colombia. It traces the history of some of the pathologies that were of major concern among nineteenth-century doctors: periodic fevers (yellow fever and malaria), continuous fevers (typhoid fever), and leprosy (Greek elephantiasis). By comparing the transforming conceptualizations of these diseases, this article shows that their changing pattern, the idea of climatic determinism of diseases (neo-Hippocratism and medical geography), the weak standing of the medical community in Colombian society, as well as Pasteurian germ practices were all crucial in the uneven and varied reshaping of their understanding.

El estigma en la lepra: conceptos, causas y determinantes / No disponible

Antecedentes: La lepra es una enfermedad infecciosa crónica que ha estigmatizado a los afectados desde la antigüedad hasta nuestros días. Objetivo: Se llevó a cabo esta revisión para entender el concepto, la causa y los determinantes del estigma de la lepra. Métodos: Se realizaron búsquedas electrónicas empleando PubMed (Medline) y las bases de datos CINAHL y Psyclnfo. Se buscaron trabajos no incluidos en estas bases de datos mediante Google Académico. El principal criterio para la inclusión fue el de trabajos relacionados con el estigma o lepra escritos en Thai o inglés. Resultados: Después de las búsquedas se identificaron 84 trabajos, 3 fueron eliminados por duplicidad y publicación paralela y 20 se eliminaron al revisar el resumen. Después de revisar 61 trabajos, se excluyeron 7. Por tanto, se incluyeron 54 trabajos en esta revisión. Se halló que el concepto de estigma implica no solamente características consideradas poco deseables, sino también el contexto social del individuo o grupo afectado. Las causas y determinantes del estigma relacionados con la lepra son las manifestaciones visibles de la enfermedad, las creencias culturales o religiosas, el miedo a la transmisión, la asociación con personas consideradas inferiores o intervenciones públicas relacionadas con la sanidad. Conclusión: El estigma es un fenómeno complejo que tiene múltiples causas, muchas veces relacionadas con el contexto cultural en que se presenta. A pesar de esto, se encontraron muchas similitudes con el estigma relacionado con la lepra en distintos países y culturas, que facilitaron el desarrollo de las intervenciones y el estudio

Background: Leprosy is a chronic infectious disease that has stigmatised people affected since ancient times until now. This has resulted in difficulties in the lives of those affected. Purpose: this literature review was conducted to understand the concept, causes, and determinants of stigma in leprosy. Methods: electronic searches were undertaken using PubMed (Medline), CINAHL and Psyclinfo databases. The internet was searched through Google Scholar for papers not found in these databases. The main inclusion criteria were papers related to stigma or leprosy written in Thai or English. Results: After searching the databases, 84 papers were identified, 3 were removed because of duplication and parallel publication, and 20 were removed on abstract screening. After reading 61 full papers, 7 were excluded. Finally, 54 were included in this review. It was found that the concept of stigma involves not only characteristics considered undesirable, but also the social context of the individual or group. Reported causes and determinants of stigma related to leprosy are the external manifestations of the disease, cultural and religious beliefs, fear of transmission, association with people considered inferior and public health-related interventions. Conclusion: Stigma is a complex phenomenon that has multiple causes, often linked to the cultural context in which it occurs. Despite this, many similarities were found in leprosy-related stigma across countries and cultures, which would facilitate the development of interventions

Investigation of neuropathic pain in treated leprosy patients in Ethiopia: a cross-sectional study.

Pain can be a significant problem for treated leprosy patients. It can be nociceptive due to tissue inflammation occurring during episodes of immune mediated reactions, or neuropathic due to leprosy affecting the somatosensory system. There are sparse epidemiological data on the prevalence and impact of neuropathic pain in treated leprosy patients. Tools for assessing neuropathic pain have not been validated in leprosy. We have examined nature of pain in a cross-sectional study to determine the prevalence of neuropathic pain (NP) in 80 recently treated leprosy patients in Ethiopia. Pain and depression were evaluated using the General Health Questionnaire (GHQ-12) and the Brief Pain Inventory (BPI) questionnaire. The Douleur Neuropathique en 4 Questions (DN4) and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) were used as screening tools for NP. Pain of any type was experienced by 60% of the patients. Pure nociceptive pain was experienced by 43%, pure NP by 11%, and mixed pain by 6%. Of the 14 patients who had NP either alone or in combination with nociceptive pain, 12 had high GHQ-12 scores, indicating possible depression. The DN4 had sensitivity and specificity of 100% and 45%, whereas the LANSS had 85% and 42%, respectively. This is the first study to differentiate nociceptive from NP in leprosy patients. The prevalence of NP is high in recently treated Ethiopian leprosy patients. We have validated the use of DN4 in leprosy and it is easier to use than LANSS. Depression is a common co-morbidity in patients with NP. The high prevalence and morbidity of NP in treated leprosy patients warrant clinical trials to assess the efficacy of pain therapies for leprosy-associated NP.

Comparison of child morbidity in two contrasting medieval cemeteries from Denmark.

This study compares associations between demographic profiles, long bone lengths, bone mineral content, and frequencies of stress indicators in the preadult populations of two medieval skeletal assemblages from Denmark. One is from a leprosarium, and thus probably represents a disadvantaged group (Naestved). The other comes from a normal, and in comparison rather privileged, medieval community (AEbelholt). Previous studies of the adult population indicated differences between the two skeletal collections with regard to mortality, dental size, and metabolic and specific infectious disease. The two samples were analyzed against the view known as the "osteological paradox" (Wood et al. [1992] Curr. Anthropol. 33:343-370), according to which skeletons displaying pathological modification are likely to represent the healthier individuals of a population, whereas those without lesions would have died without acquiring modifications as a result of a depressed immune response. Results reveal that older age groups among the preadults from Naestved are shorter and have less bone mineral content than their peers from AEbelholt. On average, the Naestved children have a higher prevalence of stress indicators, and in some cases display skeletal signs of leprosy. This is likely a result of the combination of compromised health and social disadvantage, thus supporting a more traditional interpretation. The study provides insights into the health of children from two different biocultural settings of medieval Danish society and illustrates the importance of comparing samples of single age groups.

Infections due to non-tuberculous mycobacteria (NTM).

The membership list of genus mycobacterium is ever expanding and it has grown to 95 in year 2003. While leprosy and tuberculosis are specific diseases caused by mycobacteria, other members are usually saprophytes but can be opportunistic and at times deadly pathogens. These other mycobacteria are referred to as atypical mycobacteria, non-tuberculous mycobacteria (NTM) or mycobacteria other than tubercle bacilli (MOTT). These organisms can produce localized disease in the lungs, lymph glands, skin, wounds or bone. Occasionally they may produce disseminated disease. Of the more than 90 known species of NTM, about one third have been associated with disease in humans. The species causing human disease are : Mycobacterium avium, M. intracellulare, M. kansasii, M. paratuberculosis, M. scrofulaceum, M. simiae, M. habana, M. interjectum, M. xenopi, M. heckeshornense, M. szulgai, M. fortuitum, M. immunogenum, M. chelonae, M. marinum, M. genavense, M. haemophilum, M. celatum, M. conspicuum, M. malmoense, M. ulcerans, M. smegmatis, M. wolinskyi, M. goodii, M. thermoresistible, M. neoaurum, M. vaccae, M.palustre, M. elephantis, M. bohemicam and M. septicum. Isolation of these mycobacteria from representative specimens and their rapid identification is very important as the treatment strategy for tuberculosis and other mycobacterioses is different. Several biochemical, chemical (lipid) and molecular techniques have been developed for rapid identification of these species. Along with suggestive clinical features, poor response to antitubercular treatment and repeated isolation of the organisms from the clinical specimens these techniques can help in establishing correct diagnosis. Further, many drugs like rifampicin, rifabutin, ethambutol, clofazimine, amikacin, new generation quinolones and macrolides effective against mycobacterial infections are available that can be used in appropriate combinations and dosage to treat these infections.

Chronic ulcers and myasis as ports of entry for Clostridium tetani

Evaluating tetanus immune status is not yet the usual clinical practice regarding patients with chronic ulcers or myasis. However, of 858 tetanus patients at Hospital Couto Maia (Salvador, Bahia, Brazil) aged 1 year or above, 2 had pressure ulcers and 17 had chronic ulceration of the lower limbs where these skin lesions were the ports of entry for Clostridium tetani. In these 19 cases, the following predisposing factors were described: venous insufficiency (n=6), sickle cell anemia (n=2), Hansen s disease (n=1), malnutrition (n=1), diabetes mellitus (n=1), trauma (n=1) and unknown factors (n=7). In 6 other cases, in addition to the Hansen s disease patient, the port of entry for tetanus was the site of extraction of Tunga penetrans larvae. In these 25 cases, the majority of patients (68) were over 40 years old (17/25) and all of these patients stated that they had either not followed a tetanus toxoid vaccination regimen (19/25), or had partially completed such a regimen, or did not give precise information (6/25). Among the same series studied, over half (52) of the patients died (13/25). We conclude that tetanus prevention must be included in the treatment of chronic skin ulcer patients, vaccination coverage should be increased among older people, and strategies aimed at improving coverage for all age groups must be reviewed.

Chronic ulcers and myasis as ports of entry for Clostridium tetani.

Evaluating tetanus immune status is not yet the usual clinical practice regarding patients with chronic ulcers or myasis. However, of 858 tetanus patients at Hospital Couto Maia (Salvador, Bahia, Brazil) aged 1 year or above, 2 had pressure ulcers and 17 had chronic ulceration of the lower limbs where these skin lesions were the ports of entry for Clostridium tetani. In these 19 cases, the following predisposing factors were described: venous insufficiency (n=6), sickle cell anemia (n=2), Hansen s disease (n=1), malnutrition (n=1), diabetes mellitus (n=1), trauma (n=1) and unknown factors (n=7). In 6 other cases, in addition to the Hansen s disease patient, the port of entry for tetanus was the site of extraction of Tunga penetrans larvae. In these 25 cases, the majority of patients (68%) were over 40 years old (17/25) and all of these patients stated that they had either not followed a tetanus toxoid vaccination regimen (19/25), or had partially completed such a regimen, or did not give precise information (6/25). Among the same series studied, over half (52%) of the patients died (13/25). We conclude that tetanus prevention must be included in the treatment of chronic skin ulcer patients, vaccination coverage should be increased among older people, and strategies aimed at improving coverage for all age groups must be reviewed.

Predisposing factors for recurrent skin ulcers in leprosy.

This study was designed to determine the factors associated with recurrence of leprosy ulcers. Between April and August 1992, 55 consecutive leprosy patients admitted with skin ulcers were studied. Factors predisposing to recurrence, e.g. patient's age, disease duration, ulcer site, ulcer depth and physical deformity (taking into account neuromuscular and skeletal damage) were evaluated. Ulcer recurrence occurred in 40/55 (75%) patients. Recurrent ulceration was associated with location in the lower extremity (P = 0.02), where recurrences were more common in the midfoot and heel (P = 0.01). Recurrence was also associated with severity of physical deformity (P = 0.01), which increased the odds of recurrent ulceration by 4.2 times (95% confidence interval, 1.01-18.3). The severity of physical deformity itself was associated with the age of the patient (P = 0.04) and the disease duration (P = 0.02). In conclusion, there is a need to focus on identification of risk factors for recurrent leprosy ulceration. Targeted prevention strategies would be required if morbidity associated with recurrent skin ulceration is to be avoided.

[Mutilating acrodystrophic neuropathy of alcoholic origin in the French West Indies]. / Acropathie ulcéromutilante d'origine alcoolique aux Antilles.

Among principal causes of acrodystrophic neuropathy-ie, leprosy, diabetes, amyloid neuropathy, hereditary sensory neuropathies-alcoholism is controversial since first descriptions (Bureau et al, 1957) incriminating heavy drinking. This retrospective review of 38 cases occurring in West-Indian rhum abusers, tends however to confirm its etiologic role. Patients present with three non specific signs or symptoms of the lower extremities: anaesthetic foot, plantar ulcers, and chronic, indolent, mutilating arthropathies. Motor function is spared. Male gender, massive (> or = 150 g pure alcohol daily) and prolonged (> or = 12 years) rhum intake, hygiene deficiency, poverty and social distress, exposition to repeated foot microtrauma and a protracted, non fatal, but disabling course leading to amputation, are the main features of this syndrome. The pathophysiology is poorly documented, and many questions remain unanswered including a genetic predisposition or a particular neuro-toxicity of West Indian rhum. However, the clinical and epidemiologic data presented here favour the concept of an "alcoholic foot" or true alcoholic acrodystrophic neuropathy, quite different from the most common sensory-motor form.

Clinical features and diagnosis of relapses in leprosy.

1. The definition of relapse as "occurrence of new signs and symptoms of the disease during the period of surveillance or thereafter in a patient who successfully completes an adequate course of multidrug therapy" accommodates the current policy of releasing patients even when there are clinical and bacteriological signs of activity after fixed duration treatment. 2. The predisposing cause of relapse in the persistence of live M. leprae in various tissues in MB leprosy and in the nerve in PB leprosy. 3. The precipitating causes of relapse include (a) inadequate therapy due to miscategorization of MB cases as PB when there are solitary or few MB lesions since skin smear examinations for AFB are not routinely done in PB cases. (b) Previously sulphone treated LL cases inactive for more than two years are not included for MDT. Relapses commonly seen in NLEP units are in such cases. (c) Multiple skin and nerve lesions in PB leprosy. (d) Pregnancy and lactation. (e) Mental depression which downgrades immunity. (f) HIV infection. 4. There may be a change in type on relapsing, PB cases relapsing as MB and MB cases relapsing as PB. 5. Criteria for diagnosis of relapse are: increase in the extent of lesions, infiltration and erythema, fresh skin and nerve lesions, positive skin smears for AFB in previously negative cases; and in bacteriologically positive cases during surveillance, an increase in BI by two logs at any site over the previous BI in two successive examinations. 6. Relapses are but too often diagnosed as reversal reactions inspite of the absence of symptoms and signs of acute inflammation to the detriment of patients; a course of steroid therapy which is administered to these patients on the diagnosis of reversal reaction does not halt the progress of the disease especially in the nerve, resulting in disability.

An unusual cause of hand trauma in the emergency department.

Leprosy was once a severely mutilating and incapacitating disease with little hope for the afflicted. Today, patients with leprosy do not suffer from the obvious deformities seen in earlier days, so recognition of this disease has become more difficult. We report the case of a man with no previous disabilities who presented to the emergency department with acute unintentional hand trauma secondary to peripheral neuropathy caused by leprosy.