Rejected

Lipoedema is an incurable chronic disease causing limb deformity, painful skin and excessive ecchymosis. Compression garments are frequently recommended to manage symptoms, but the existing products are not designed specifically for lipoedema, and are for other medical conditions. A structured questionnaire was prepared in Online Surveys in October 2018 to investigate lipoedema symptoms and the use of compression garments to manage them. Some 279 people with lipoedema completed the survey; 70% wore compression garments in all four compression classes, of which class 2 was most common (58% of wearers). The top three reasons for wearing compression garments were to feel supported (73%), reduce lipoedema pain (67%) and improve mobility (54%). Most people with lipoedema who wore compression garments found compression helpful in managing their symptoms, but overall satisfaction was low. Problems with existing compression garments were so severe in some cases that the garments were not worn at all or used less often. The information collected in this survey might be useful for the design and development of compression garments specifically for lipoedema.

Postoperative gastrointestinal dysfunction (PGD) refers to one of the common postoperative complications. Acupuncture can facilitate the recovery of PGD, whereas no therapeutic schedule of acupuncture has been internationally recognized for treating PGD. In the present study, a scientific trial protocol has been proposed to verify the feasibility of acupuncture in treating gastrointestinal dysfunction after laparoscopic cholecystectomy under general anesthesia. We conduct this protocol to investigate whether acupuncture recovery gastrointestinal dysfunction by influencing the expression of gastrointestinal hormone.

Airway projecting sensory neurons arising from the jugular vagal ganglia terminate centrally in the brainstem paratrigeminal nucleus, synapsing upon neurons expressing the neurokinin 1 receptor. This study aimed to assess the involvement of paratrigeminal neurokinin 1 receptor neurons in the regulation of cough, breathing and airway defensive responses. Lesioning neurokinin 1 receptor expressing paratrigeminal neurons significantly reduced cough evoked by inhaled bradykinin but not inhaled ATP or tracheal mechanical stimulation. The reduction in bradykinin-evoked cough was not accompanied by changes in baseline or evoked respiratory variables (e.g. frequency, volume or timing), animal avoidance behaviours or the laryngeal apnoea reflex. These findings warrant further investigations into targeting the jugular ganglia and paratrigeminal nucleus as a therapy for treating cough in disease.

ConspectusToll-like receptors (TLRs) are the "gatekeepers" of the immune system in humans and other animals to protect the host from invading bacteria, viruses, and other microorganisms. Since TLR4 was discovered as the receptor for endotoxin in the late 1990s, significant progress has been made in exploiting an understanding of the function of TLRs. The TLR-signaling pathway is crucial for the induction and progression of various diseases. Dysregulation of TLR signaling contributes to numerous pathological conditions, including chronic inflammation, sepsis, cancers, asthma, neuropathic pain, drug addiction, and autoimmune diseases. Therefore, manipulation of TLR signaling is promising to halt their activity in inflammatory diseases, to enhance their signaling to fight cancers, to modulate their role in autoimmune diseases, and to suppress them to treat drug addiction. TLR agonists have demonstrated great potential as antimicrobial agents and vaccine adjuvants, whereas TLR antagonists are being developed as reagents and drugs to dampen immune responses. Because of their pivotal potential therapeutic applications, fruitful small-molecule compounds and peptide fragments have been discovered, and many of them have advanced to various stages of clinical trials (though only two have been approved by the Food and Drug Administration (FDA): MPLA as a TLR4 agonist and imiquimod as a TLR7 agonist).In this Account, we focus on the progress in developing TLR signaling pathway modulators (mainly focused on the Yin and Wang laboratories) over the past decade and highlight the accomplishments and currently existing challenges in the development of TLR modulators. First, we briefly describe the members of the human TLR family along with their natural modulators. Second, we illustrate our endeavors to discover TLR-targeted agents using comprehensive approaches. Specifically, a discussion of identification and characterization of new chemical entities, determination of modes of action, and further applications is presented. For instance, the TLR3 antagonist was first discovered through screening, and the inhibitory activity was confirmed in murine cells. Considering the glycosylation on TLR3, a new direction for TLR3 modulator design was pointed out to target asparagine glycosylation. We have particularly focused on the discovery of TLR4 antagonists and have assessed their great potential in the clinical treatment of drug addiction and alcohol use disorders. In addition, we discuss multiple other popular and robust techniques for modulator discovery. Not only small organic modulators but also stapled peptides and peptidomimetics will attract more and more attention in the future. Finally, current challenges, opportunities, and future perspectives for TLR-targeted agents are also discussed.

At Queens Medical Centre, Nottingham, alveolar bone grafts (ABG) for patients with cleft lip and palate (CLP) were performed by two surgeons following the same surgical protocol, but with different postoperative iliac crest donor site analgesia: surgeon A used a donor site bolus of levobupivacaine, whilst surgeon B used a donor site epidural catheter (EC) infusing levobupivacaine. A healthcare evaluation was conducted in two phases to establish the effectiveness of analgesia for CLP patients undergoing ABGs. Data were collected prospectively in 2016 and 2018. Cleft patients postoperative to ABG were included. Outcome measures were pain scores at 2, 4, 6, 12, and 24 hours, time to mobilization, and time to food intake. Mean pain scores at the first evaluation were <1 out of 10 for all time points, except 24 hours (score 2.0 for bolus, 1.8 for EC). There was no statistically significant difference between the groups for any of the outcomes measured. As EC conferred no advantage, surgeon B changed to bolus administration and a second evaluation was performed. The mean pain score for the second evaluation was 1.7 and higher pain scores were more common with lower doses of levobupivacaine. The data suggest that bolus injection can produce safe, effective pain control provided an adequate dose is given.

Hernia repair surgery using synthetic mesh is the standard of care in modern surgery. Complications from uro-gynaecological mesh have been reported in the New Zealand media and there is public concern regarding the use of any mesh for any reason. This study reports long-term outcomes in inguinal hernia surgery in a large cohort of elective operations using mesh.

Treat-to-target (T2T) is an algorithm to reach a predefined outcome. Here we define a T2T outcome for moderate-to-severe psoriasis vulgaris.

Buprenorphine is a µ-partial agonist and k-antagonist acting on central opioid receptors. Patented for analgesia in 1968, buprenorphine has been used as opioid substitutive therapy since the 1990s, as well as methadone. The aim was to document pediatric poisoning, to discover the severity and to evaluate the treatment with naloxone. All pediatric poisonings reported to the poison control center Marseille (France) – from January 1 , 2009 to December 31 , 2018 – were included. Analysis put value on gender, age, estimated quantity, symptoms and their delay, place of treatment, medical treatment, utilization of antidotes, severity of intoxications and patients' outcome. 54 infant poisonings with buprenorphine were recorded, doses varied between 1 and 36mg, children showed mainly neurological (somnolence, miosis…) and gastro enteric (vomiting) effects. Pulmonary effects were described for four children. According to the poisoning severity score, 8 intoxications were classified as "no symptoms or signs", 37 as minor poisonings, 3 as moderate, none as severe or fatal and 6 were unknown. Medical care was required for 46 children, four of them were treated with naloxone. Buprenorphine poisoning can cause neurological, gastro enteric and respiratory symptoms. Even licking a tablet leads to intoxication because of maximal tablet's absorption while placing it under the tongue. Hospital admission is necessary even at small doses. Naloxone was efficient in the four described cases. Parents have to be aware of the poisoning risk with buprenorphine. Recently commercialized instantly dissolving formulations could cause more severe intoxications.

Atopic dermatitis (AD) is an incurable, inflammatory skin disease characterized by skin barrier disruption and immune dysregulation. Although AD is considered a childhood disease, adult onset is possible, presenting with daily sleep disturbance and functional impairment associated with itch, neuropsychiatric issues (anxiety and depression), and reduced health-related quality of life. Although such aspects of adult AD disease burden have been measured through standardized assessments and based on population-level data, the understanding of the disease experienced at the patient level remains poor. This text-mining study assessed the impact of AD on the lives of adult patients as described from an experiential perspective.

Spontaneous intracranial hypotension (SIH) is a rare syndrome, typically manifests as orthostatic headache. Sometimes considered asbenignillness, neurological complications are well described, in particular subdural hematoma and cerebral venous sinus thrombosis. Brain infarction as complication of SIH is rarely reported. The main mechanism supported in the literature is the stretching of arteries due to the sagging of the brain. We report a case of SIH followed with brain infarction, with a distinct presentation from previous literature, suggesting a different mechanism. A 35 year-old had severe orthostatic headache, responsible for prolonged bed rest. One month later, he had acute left hemiparesis secondary to stroke and right posterior cerebral artery occlusion. Stroke MRI showed arguments for intracranial hypotension (thickened meninges). He was successfully treated with intravenous rtPA thrombolysis. Headache were resolved after an epidural blood patch. A patent foramen ovale was detected. Clinical features of this description were compared with previous literature. This case suggest a different mechanism for cerebral infarction after intracranial hypotension. In case of prolonged lying down due to intracranial hypotension, the presence of patent foramen ovale could be a risk factor for embolic stroke.