Economic burden of recurrent Clostridioides difficile infection in adults admitted to Spanish hospitals. A multicentre retrospective observational study.

OBJECTIVE: Clostridioides difficile infection (CDI) is associated with increased hospital stays and mortality and a high likelihood of rehospitalization, leading to increased health resource use and costs. The objective was to estimate the economic burden of recurrent CDI (rCDI). METHODS: Observational, retrospective study carried out in six hospitals. Adults aged ≥18 years with ≥1 confirmed diagnosis (primary or secondary) of rCDI between January 2010 and May 2018 were included. rCDI-related resource use included days of hospital stay (emergency room, ward, isolation and ICU), tests and treatments. For patients with primary diagnosis of rCDI, the complete hospital stay was attributed to rCDI. When diagnosis of rCDI was secondary, hospital stay attributed to rCDI was estimated using 1:1 propensity score matching as the difference in hospital stay compared to controls. Controls were hospitalizations without CDI recorded in the Spanish National Hospital Discharge Database. The cost was calculated by multiplying the natural resource units by the unit cost. Costs (euros) were updated to 2019. RESULTS: We included 282 rCDI episodes (188 as primary diagnosis): 66.31% of patients were aged ≥65 years and 57.80% were female. The mean hospital stay (SD) was 17.18 (23.27) days: 86.17% of rCDI episodes were isolated for a mean (SD) of 10.30 (9.97) days. The total mean cost (95%-CI) per episode was €10,877 (9,499-12,777), of which the hospital stay accounted for 92.56. CONCLUSIONS: There is high cost and resource use associated with rCDI, highlighting the importance of preventing rCDI to the Spanish National Health System.

The juxta-oral organ of Chievitz (organum yuxtaorale) updated: Embryology, anatomy, function and pathology.

BACKGROUND: The Chievitz's organ or juxta-oral organ is a mysterious bilateral structure, phylogenetically preserved, which develops from the mouth epithelium as an invagination that loses connection to it in the prenatal period. It is located laterally to the walls of the oral cavity in an imprecise anatomical location and receives abundant innervation from the buccal nerve. Structurally it consists of non-keratinizing squamous-like neuroepithelial cells surrounded by two layers of connective tissue with nerve fibers and different morphotypes of sensory corpuscles. Its function is completely unknown although based on its rich innervation it is assumed that works as a mechanoreceptor. METHODS: We have performed immunohistochemistry for axonal and Schwann cells, and the putative mechanoproteins ASIC2, TRPV4 and Piezo2 in sections of fetal juxta-oral organ. RESULTS: Intraparenchymatous nerve fibers and sensory corpuscles were observed as well as immunoreactivity for Piezo2 in both nerve fibers and epithelial parenchymatous cells. CONCLUSIONS: We add indirect evidence that the juxtaoral organ is a mechanoreceptor because in addition to its dense innervation, the epithelial cells and sensory nerve fibers display immunoreactivity for the mechanogated ion channel Piezo2. Based on current knowledge, the functional and clinical importance of the juxta-oral organ should be further investigated.

Recommendations for the diagnosis and treatment of Clostridioides difficile infection: An official clinical practice guideline of the Spanish Society of Chemotherapy (SEQ), Spanish Society of Internal Medicine (SEMI) and the working group of Postoperative Infection of the Spanish Society of Anesthesia and Reanimation (SEDAR).

This document gathers the opinion of a multidisciplinary forum of experts on different aspects of the diagnosis and treatment of Clostridioides difficile infection (CDI) in Spain. It has been structured around a series of questions that the attendees considered relevant and in which a consensus opinion was reached. The main messages were as follows: CDI should be suspected in patients older than 2 years of age in the presence of diarrhea, paralytic ileus and unexplained leukocytosis, even in the absence of classical risk factors. With a few exceptions, a single stool sample is sufficient for diagnosis, which can be sent to the laboratory with or without transportation media for enteropathogenic bacteria. In the absence of diarrhoea, rectal swabs may be valid. The microbiology laboratory should include C. difficile among the pathogens routinely searched in patients with diarrhoea. Laboratory tests in different order and sequence schemes include GDH detection, presence of toxins, molecular tests and toxigenic culture. Immediate determination of sensitivity to drugs such as vancomycin, metronidazole or fidaxomycin is not required. The evolution of toxin persistence is not a suitable test for follow up. Laboratory diagnosis of CDI should be rapid and results reported and interpreted to clinicians immediately. In addition to the basic support of all diarrheic episodes, CDI treatment requires the suppression of antiperistaltic agents, proton pump inhibitors and antibiotics, where possible. Oral vancomycin and fidaxomycin are the antibacterials of choice in treatment, intravenous metronidazole being restricted for patients in whom the presence of the above drugs in the intestinal lumen cannot be assured. Fecal material transplantation is the treatment of choice for patients with multiple recurrences but uncertainties persist regarding its standardization and safety. Bezlotoxumab is a monoclonal antibody to C. difficile toxin B that should be administered to patients at high risk of recurrence. Surgery is becoming less and less necessary and prevention with vaccines is under research. Probiotics have so far not been shown to be therapeutically or preventively effective. The therapeutic strategy should be based, rather than on the number of episodes, on the severity of the episodes and on their potential to recur. Some data point to the efficacy of oral vancomycin prophylaxis in patients who reccur CDI when systemic antibiotics are required again.

Suppressive antibiotic therapy in prosthetic joint infections: a multicentre cohort study.

OBJECTIVES: The aim was to describe the effectiveness of suppressive antibiotic treatment (SAT) in routine clinical practice when used in situations in which removal of a prosthetic implant is considered essential for the eradication of an infection, and it cannot be performed. METHODS: This was a descriptive retrospective and multicentre cohort study of prosthetic joint infection (PJI) cases managed with SAT. SAT was considered to have failed if a fistula appeared or persisted, if debridement was necessary, if the prosthesis was removed due to persistence of the infection or if uncontrolled symptoms were present. RESULTS: In total, 302 patients were analysed. Two hundred and three of these patients (67.2%) received monotherapy. The most commonly used drugs were tetracyclines (39.7% of patients) (120/302) and cotrimoxazole (35.4% of patients) (107/302). SAT was considered successful in 58.6% (177/302) of the patients (median time administered, 36.5 months; IQR 20.75-59.25). Infection was controlled in 50% of patients at 5 years according to Kaplan-Meier analysis. Resistance development was documented in 15 of 65 (23.1%) of the microbiologically documented cases. SAT failure was associated with age <70 years (sub-hazard ratio (SHR) 1.61, 95% CI 1.1-2.33), aetiology other than Gram-positive cocci (SHR 1.56, 95% CI 1.09-2.27) and location of the prosthesis in the upper limb (SHR 2.4, 95% CI 1.5-3.84). SAT suspension was necessary due to adverse effects in 17 of 302 patients (5.6%). CONCLUSIONS: SAT offers acceptable results for patients with PJI when surgical treatment is not performed or when it fails to eradicate the infection.

Medication-related osteonecrosis of the jaw. Implant presence-triggered osteonecrosis: Case series and literature review.

PURPOSE: The aim of this study was to review the characteristics of 'implant presence-triggered osteonecrosis' (IPTO) in the literature and identify possible differences between IPTOs and 'implant surgery-triggered osteonecrosis' (ISTO). MATERIALS AND METHODS: Reviews using PubMed and the Cochrane Database of Systematic Reviews were performed from 2009-2018; the focus was on medication-related osteonecrosis of the jaw (MRONJ) and dental implants. In addition, the hospital records of all patients presented in our department with IPTO were retrospectively reviewed. In both studies, the following data were collected: the number of patients with ISTO or IPTO, age, gender, location, stage of MRONJ, number of implants involved in MRONJ, the elapsed time between the placement of the implants and the development of MRONJ, applied treatment and the presence of mandibular fractures and progress. RESULTS: The literature review provided 111 articles. Nine of the articles were selected for bibliographic review. The number of osteonecrosis cases was significantly higher in the IPTO group (74 cases) compared with the ISTO group (27 cases). The duration of the anti-resorptive treatment (oral and intravenous) was also longer in the IPTO group. In our centre, seven patients with IPTO were chosen; however, no patients with ISTO were selected. The significant differences between the patients in our series and the information collected in the literature for the IPTO group were the time of ingestion of alendronate, the elapsed time from the placement of the implants to the development of the MRONJ and the number of implants linked to the development of a complication. CONCLUSIONS: The use of antiresorptives causes osteonecrosis in patients with implants that are subjected to functional loading, and this occurs at a higher frequency than what is observed after implant placement surgery.

Safety and Efficacy of Prolonged Use of Dalbavancin in Bone and Joint Infections.

Dalbavancin is a lipoglycopeptide with potent activity against Gram-positive microorganisms, a long half-life, a favorable safety profile, and a high concentration in bone, which makes it an interesting alternative for treatment of osteoarticular infections. We performed a multicentric retrospective study of all patients with an osteoarticular infection (septic arthritis, spondylodiscitis, osteomyelitis, or orthopedic implant-related infection) treated with at least one dose of dalbavancin between 2016 and 2017 in 30 institutions in Spain. In order to evaluate the response, patients with or without an orthopedic implant were separated. A total of 64 patients were included. Staphylococcus epidermidis and Staphylococcus aureus were the most frequent microorganisms. The reasons for switching to dalbavancin were simplification (53.1%), adverse events (25%), or failure (21.9%). There were 7 adverse events, and no patient had to discontinue dalbavancin. In 45 cases, infection was related to an orthopedic implant. The implant material was retained in 23 cases, including that in 15 (65.2%) patients that were classified as cured and 8 (34.8%) that presented improvement. In 21 cases, the implants were removed, including those in 16 (76.2%) cases that were considered successes, 4 (19%) cases were considered improved, and 1 (4.8%) case that was considered a failure. Among the 19 cases without implants, 14 (73.7%) were considered cured, 3 (15.8%) were considered improved, and 2 (10.5%) were considered failures. The results show that dalbavancin is a well-tolerated antibiotic, even when >2 doses are administered, and is associated with a high cure rate. These are preliminary data with a short follow-up; therefore, it is necessary to gain more experience and, in the future, to establish the most appropriate dose and frequency.

[Recommendations from a panel of experts on the usefulness of fidaxomicin for the treatment of infections caused by Clostridium difficile]. / Recomendaciones de un panel de expertos sobre la utilidad de fidaxomicina para el tratamiento de las infecciones causadas por Clostridium difficile.

OBJECTIVE: Clostridium difficile infections have a high recurrence rate, which can complicate the prognosis of affected patients. It is therefore important to establish an early detection and an appropriate therapeutic strategy. The objective of this manuscript was to gather the opinion of an expert group about the predictive factors of poor progression, as well as when to use fidaxomicin in different groups of high-risk patients. METHODS: A scientific committee of three experts in infectious diseases reviewed the most recent literature on the management of C. difficile infections, and the use of fidaxomicin. They developed a questionnaire of 23 items for consensus by 15 specialists in this type of infection using a modified Delphi method. RESULTS: The consensus reached by the panelists was 91.3% in terms of agreement. The most important agreements were: recurrence is a risk criterion per se; fidaxomicin is effective and safe for the treatment of infections caused by C. difficile in critical patients, immunosuppressed patients, or patients with chronic renal failure; fidaxomicin is recommended from the first episode of infection to ensure maximum efficacy in patients with well-contrasted recurrence risk factors. CONCLUSIONS: The experts consulted showed a high degree of agreement on topics related to the selection of patients with poorer prognosis, as well as on the use of fidaxomicin in groups of high-risk patients, either in the first line or in situations of recurrence.

Active and passive surveillance for bat lyssaviruses in Italy revealed serological evidence for their circulation in three bat species.

The wide geographical distribution and genetic diversity of bat-associated lyssaviruses (LYSVs) across Europe suggest that similar viruses may also be harboured in Italian insectivorous bats. Indeed, bats were first included within the passive national surveillance programme for rabies in wildlife in the 1980s, while active surveillance has been performed since 2008. The active surveillance strategies implemented allowed us to detect neutralizing antibodies directed towards European bat 1 lyssavirus in six out of the nine maternity colonies object of the study across the whole country. Seropositive bats were Myotis myotis, M. blythii and Tadarida teniotis. On the contrary, the virus was neither detected through passive nor active surveillance, suggesting that fatal neurological infection is rare also in seropositive colonies. Although the number of tested samples has steadily increased in recent years, submission turned out to be rather sporadic and did not include carcasses from bat species that account for the majority of LYSVs cases in Europe, such as Eptesicus serotinus, M. daubentonii, M. dasycneme and M. nattereri. A closer collaboration with bat handlers is therefore mandatory to improve passive surveillance and decrypt the significance of serological data obtained up to now.

A comprehensive approach for the patient with Clostridium difficile infection.

During the last decade there have been many changes and advances in the research on Clostridium difficile infection (CDI). We have improved diagnostic and therapeutic tools and, at the same time, we have learned that the CDI implies, especially in the most vulnerable patients, an important morbidity. CDI has traditionally been undervalued and it is widely dispersed in hospitals. Surely, there is inertness in its management and there are also broad areas of improvement. If we add to this the high cost of the new drugs and the practical difficulties to implement the faecal microbiota transplant, we realize that we may not be taking full advantage of all the opportunities to improve patient's outcomes. The implementation of policies that favour the supervision of all CDI cases by an expert in infectious diseases will contribute to a better global management of this important disease.

The development of human digital Meissner's and Pacinian corpuscles.

Meissner's and Pacinian corpuscles are cutaneous mechanoreceptors responsible for different modalities of touch. The development of these sensory formations in humans is poorly known, especially regarding the acquisition of the typical immunohistochemical profile related to their full functional maturity. Here we used a panel of antibodies (to specifically label the main corpuscular components: axon, Schwann-related cells and endoneurial-perineurial-related cells) to investigate the development of digital Meissner's and Pacinian corpuscles in a representative sample covering from 11 weeks of estimated gestational age (wega) to adulthood. Development of Pacinian corpuscles starts at 13 wega, and it is completed at 4 months of life, although their basic structure and immunohistochemical characteristics are reached at 36 wega. During development, around the axon, a complex network of S100 positive Schwann-related processes is progressively compacted to form the inner core, while the surrounding mesenchyme is organized and forms the outer core and the capsule. Meissner's corpuscles start to develop at 22 wega and complete their typical morphology and immunohistochemical profile at 8 months of life. In developing Meissner's corpuscles, the axons establish complex relationships with the epidermis and are progressively covered by Schwann-like cells until they complete the mature arrangement late in postnatal life. The present results demonstrate an asynchronous development of the Meissner's and Pacini's corpuscles and show that there is not a total correlation between morphological and immunohistochemical maturation. The correlation of the present results with touch-induced cortical activity in developing humans is discussed.

Availability and use of healthcare resources in prisons according to the transference model: a comparative study in Spain.

OBJECTIVE: In most European countries, correctional healthcare provision is under strain or in the process of change regarding its management model and the implications that such modifications may entail for the improvement of inmates' health. This paper compares the functioning and the results of health management in a facility whose healthcare service is integrated within an autonomic health system and others which depend on the department of corrections. MATERIALS AND METHODS: Cross-sectional study where the study unit is the facility itself. From the data collected from the record of Monthly Health Statistics of Penitentiary Institutions we have constructed a series of indicators according to the recommendations of the National Health System. RESULTS: The physician to nurse ratio per inmate is higher in the transferred facility. Only the transferred establishment has telemedicine resources. Attendance to primary health services is higher that in all non-transferred establishments, while the mean attendance to specialized consultation in the transferred facility doubles that of the remaining centers. DISCUSSION: We have observed greater access to specialized care in the correctional facility managed by the community health system when compared to that of the facilities managed by Penitentiary Institutions. This statement is based on a series of effectivity indicators and results that have provided significantly improved outcome in the transferred facility.

Periostin, dentin matrix protein 1 and P2rx7 ion channel in human teeth and periodontal ligament.

The periostin is a matricellular protein present in the human periodontal ligament and human dental pulp-derived cells lines, that up-regulates the in vitro expression of some genes involved in the dentin mineralization, such as dentin matrix protein 1 and P2x7-ion channel receptor. Here we investigated the distribution of periostin in human teeth and periodontal ligaments, mapping in parallel the localization of dentin matrix protein 1 and P2x7-ion channel receptor to establish whether or not they are expressed in the same places as periostin. The periodontal ligament and the subodontoblastic layer of the dental pulp displayed strong periostin immunoreactivity, whereas dentin matrix protein 1 was detected in the periodontal ligament co-localized with periostin in the vicinity of the cement. The P2x7 ion channel receptor was regularly absent in both the periodontal ligament and dental tissues, but in some cases, it was observed in the odontoblasts. Present results demonstrate the occurrence of periostin in the healthy adult human tooth without co-localization with proteins involved in tooth mineralization, the expression of which it regulates. These results might serve as a baseline for future studies on pathological conditions.

Molecular basis of dental sensitivity: The odontoblasts are multisensory cells and express multifunctional ion channels.

Odontoblasts are the dental pulp cells responsible for the formation of dentin. In addition, accumulating data strongly suggest that they can also function as sensory cells that mediate the early steps of mechanical, thermic, and chemical dental sensitivity. This assumption is based on the expression of different families of ion channels involved in various modalities of sensitivity and the release of putative neurotransmitters in response to odontoblast stimulation which are able to act on pulp sensory nerve fibers. This review updates the current knowledge on the expression of transient-potential receptor ion channels and acid-sensing ion channels in odontoblasts, nerve fibers innervating them and trigeminal sensory neurons, as well as in pulp cells. Moreover, the innervation of the odontoblasts and the interrelationship been odontoblasts and nerve fibers mediated by neurotransmitters was also revisited. These data might provide the basis for novel therapeutic approaches for the treatment of dentin sensibility and/or dental pain.

Merkel cells and Meissner's corpuscles in human digital skin display Piezo2 immunoreactivity.

The transformation of mechanical energy into electrical signals is the first step in mechanotransduction in the peripheral sensory nervous system and relies on the presence of mechanically gated ion channels within specialized sensory organs called mechanoreceptors. Piezo2 is a vertebrate stretch-gated ion channel necessary for mechanosensitive channels in mammalian cells. Functionally, it is related to light touch, which has been detected in murine cutaneous Merkel cell-neurite complexes, Meissner-like corpuscles and lanceolate nerve endings. To the best of our knowledge, the occurrence of Piezo2 in human cutaneous mechanoreceptors has never been investigated. Here, we used simple and double immunohistochemistry to investigate the occurrence of Piezo2 in human digital glabrous skin. Piezo2 immunoreactivity was detected in approximately 80% of morphologically and immunohistochemically characterized (cytokeratin 20+ , chromogranin A+ and synaptophisin+ ) Merkel cells. Most of them were in close contact with Piezo2- nerve fibre profiles. Moreover, the axon, but not the lamellar cells, of Meissner's corpuscles was also Piezo2+ , but other mechanoreceptors, i.e. Pacinian or Ruffini's corpuscles, were devoid of immunoreactivity. Piezo2 was also observed in non-nervous tissue, especially the basal keratinocytes, endothelial cells and sweat glands. The present results demonstrate the occurrence of Piezo2 in cutaneous sensory nerve formations that functionally work as slowly adapting (Merkel cells) and rapidly adapting (Meissner's corpuscles) low-threshold mechanoreceptors and are related to fine and discriminative touch but not to vibration or hard touch. These data offer additional insight into the molecular basis of mechanosensing in humans.

Pacinian Corpuscles in Human Lymph Nodes.

The occurrence of Pacinian corpuscles associated to lymph nodes is an anatomical rarity and very scarce information exists in this regard. Here we examined immunohistochemically four Pacinian corpuscles found in the close vicinity of the hiliar blood vessels of lymph nodes (2 cervical, 1 axillary, and 1 inguinal) during routine surgical pathology. Pacinian corpuscles were normally arranged and displayed a pattern of protein distribution as follows: the axon was positive for neurofilament proteins and neuron specific enolase, the inner core cells showed intense S100 protein and vimentin immunostaining while they were negative for glial fibrillary acidic protein, type IV collagen and glucose transporter 1; vimentin, type IV collagen, and glucose transporter 1 were also observed also in the outer-core and the capsule. These results are in agreement with those reported for cutaneous Pacinian corpuscles, demonstrating that the immunohistochemical profile of these corpuscles is independent of its anatomical localization. The possible functional significance of Pacinian corpuscles in lymph nodes is discussed. Anat Rec, 300:2233-2238, 2017. © 2017 Wiley Periodicals, Inc.

Innervation of the Human Cavum Conchae and Auditory Canal: Anatomical Basis for Transcutaneous Auricular Nerve Stimulation.

The innocuous transcutaneous stimulation of nerves supplying the outer ear has been demonstrated to be as effective as the invasive direct stimulation of the vagus nerve for the treatment of some neurological and nonneurological disturbances. Thus, the precise knowledge of external ear innervation is of maximal interest for the design of transcutaneous auricular nerve stimulation devices. We analyzed eleven outer ears, and the innervation was assessed by Masson's trichrome staining, immunohistochemistry, or immunofluorescence (neurofilaments, S100 protein, and myelin-basic protein). In both the cavum conchae and the auditory canal, nerve profiles were identified between the cartilage and the skin and out of the cartilage. The density of nerves and of myelinated nerve fibers was higher out of the cartilage and in the auditory canal with respect to the cavum conchae. Moreover, the nerves were more numerous in the superior and posterior-inferior than in the anterior-inferior segments of the auditory canal. The present study established a precise nerve map of the human cavum conchae and the cartilaginous segment of the auditory canal demonstrating regional differences in the pattern of innervation of the human outer ear. These results may provide additional neuroanatomical basis for the accurate design of auricular transcutaneous nerve stimulation devices.

Endoneurial-CD34 positive cells define an intermediate layer in human digital Pacinian corpuscles.

The endoneurial and/or perineurial origin of the outer core; i.e. the concentric and continuous lamellae located outside the complex formed by the axon and the Schwann-related cells, in human Pacinian corpuscles is still debated. Here we used immunohistochemistry coupled with a battery of antibodies to investigate the expression of perineurial (Glucose transporter 1 and epithelial membrane antigen) or endoneurial (CD34 antigen) markers in human digital Pacinian corpuscles. CD34 immunoreactivity was restricted to one layer immediately outside the inner core, whereas the proper outer core displayed antigens typical of the perineurial cells. These results demonstrate an intermediate endoneurial layer that divides the Pacinian corpuscles into two distinct compartments: the avascular inner neural compartment (formed by the axon and the Schwann-related cells that form the inner core), and the outer non-neural compartment (formed by the outer core). The functional relevance of these findings, if any, remains to be clarified.

Acid-sensing ion channel immunoreactivities in the cephalic neuromasts of adult zebrafish.

The neuromasts are the morphofunctional unit of the lateral line system serving as mechanosensors for water flow and movement. The mechanisms underlying the detection of the mechanical stimuli in the vertebrate mechanosensory cells remain poorly understood at the molecular level, and no information is available on neuromasts. Mechanotransduction is the conversion of a mechanical stimulus into an electrical signal via activation of ion channels. The acid-sensing ion channels (ASICs) are presumably involved in mechanosensation, and therefore are expected to be expressed in the mechanoreceptors. Here we used immunohistochemistry to investigate the occurrence and distribution of ASICs in the cephalic neuromasts of the adult zebrafish. Specific immunoreactivity for ASIC1 and ASIC4 was detected in the hair cells while ASIC2 was restricted to the nerves supplying neuromasts. Moreover, supporting and mantle cells; i.e., the non-sensory cells of the neuromasts, also displayed ASIC4. For the first time, these results demonstrate the presence of the putative mechanoproteins ASIC1, ASIC2 and ASIC4 in neuromasts, suggesting a role for these ion channels in mechanosensation.

Immunohistochemical localization of periostin in human gingiva.

The periostin is a matricellular protein expressed in collagen-rich tissues including some dental and periodontal tissues where it is regulated by mechanical forces, growth factors and cytokines. Interestingly the expression of this protein has been found modified in different gingival pathologies although the expression of periostin in normal human gingiva was never investigated. Here we used Western blot and double immunofluorescence coupled to laser-confocal microscopy to investigated the occurrence and distribution of periostin in different segments of the human gingival in healthy subjects. By Western blot a protein band with an estimated molecular mass of 94 kDa was observed. Periostin was localized at the epithelial-connective tissue junction, or among the fibers of the periodontal ligament, and never co-localized with cytokeratin or vimentin thus suggesting it is an extracellular protein. These results demonstrate the occurrence of periostin in adult human gingiva; its localization suggests a role in the bidirectional interactions between the connective tissue and the epithelial cells, and therefore in the physiopathological conditions in which these interactions are altered.