Doxycycline sclerotherapy in patients with periorbital lymphatic malformation: A case series and literature review.

PURPOSE: To describe and report the outcomes of doxycycline sclerotherapy in patients with periorbital lymphatic malformations(LMs). BASIC PROCEDURES: A retrospective review of consecutive patients diagnosed with periorbital LMs and who received doxycycline sclerotherapy at Hong Kong Eye Hospital and Queen Elizabeth Hospital, Hong Kong between January 2016 and June 2022. Doxycycline was prepared with a concentration of 100 mg diluted in 10 mL water for injection. A 23-gauge needle aiming at the center of the macrocyst was used to aspirate fluid from the lesion; this was then followed by an intralesional injection of 0.5 to 2 ml of doxycycline depending on the size of the cavity. MAIN FINDINGS: A total of eight patients(six females) were included in this study. All of them received doxycycline sclerotherapy for periorbital LMs(five extraconal, three intraconal). The median age for receiving sclerotherapy was 29 years old. Seven patients had macrocystic LMs, and one had mixed macro- and microcystic LM. Two of the LMs had venous components radiologically. The average number of sclerotherapy treatment in one patient was 1.4 ± 0.7times. Seven of the eight patients had excellent response radiologically or clinically. One patient showed a satisfactory response after three cycles of sclerotherapy. No recurrence was experienced at median follow-up of 14 months. None of the patients experienced visual threatening or systemic complication. PRINCIPLE CONCLUSIONS: Our preliminary experience with doxycycline sclerotherapy has shown encouraging results for the treatment of macrocystic or mixed-type periorbital LMs, with a favourable safety profile. Further clinical trials with longer follow-ups are warranted on this topic.

A general practice intervention for people at risk of poor health outcomes: the Flinders QUEST cluster randomised controlled trial and economic evaluation.

OBJECTIVE: To determine whether a multicomponent general practice intervention cost-effectively improves health outcomes and reduces health service use for patients at high risk of poor health outcomes. DESIGN, SETTING: Clustered randomised controlled trial in general practices in metropolitan Adelaide. PARTICIPANTS: Three age-based groups of patients identified by their general practitioners as being at high risk of poor health outcomes: children and young people (under 18 years), adults (18-64 years) with two or more chronic diseases, and older people (65 years or more). INTERVENTION: Enrolment of patients with a preferred GP, longer general practice appointments, and general practice follow-up within seven days of emergency department and hospital care episodes. Intervention practices received payment of $1000 per enrolled participant. MAIN OUTCOME MEASURES: Primary outcome: change in self-rated health between baseline and 12-month follow-up for control (usual care) and intervention groups. SECONDARY OUTCOMES: numbers of emergency department presentations and hospital admissions, Medicare specialist claims and Pharmaceutical Benefits Scheme (PBS) items supplied, Health Literacy Questionnaire scores, and cost-effectiveness of the intervention (based on the number of quality-adjusted life-years [QALYs] gained over 12 months, derived from EQ-5D-5L utility scores for the two adult groups). RESULTS: Twenty practices with a total of 92 GPs were recruited, and 1044 eligible patients participated. The intervention did not improve self-rated health (coefficient, -0.29; 95% CI, -2.32 to 1.73), nor did it have significant effects on the numbers of emergency department presentations (incidence rate ratio [IRR], 0.90; 95% CI, 0.69-1.17), hospital admissions (IRR, 0.90; 95% CI, 0.66-1.22), Medicare specialist claims (IRR, 1.00; 95% CI, 0.91-1.09), or PBS items supplied (IRR, 0.99; 95% CI, 0.96-1.03), nor on Health Literacy Questionnaire scores. The intervention was effective in terms of QALYs gained (v usual care: difference, 0.032 QALYs; 95% CI, 0.001-0.063), but the incremental cost-effectiveness ratio was $69 585 (95% CI, $22 968-$116 201) per QALY gained, beyond the willingness-to-pay threshold. CONCLUSIONS: Our multicomponent intervention did not improve self-rated health, health service use, or health literacy. It achieved greater improvement in quality of life than usual care, but not cost-effectively. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12617001589370 (prospective).

Feasibility and Effects of Virtual Reality Motor-Cognitive Training in Community-Dwelling Older People With Cognitive Frailty: Pilot Randomized Controlled Trial.

BACKGROUND: Cognitive frailty refers to the coexistence of physical frailty and cognitive impairment, and is associated with many adverse health outcomes. Although cognitive frailty is prevalent in older people, motor-cognitive training is effective at enhancing cognitive and physical function. We proposed a virtual reality (VR) simultaneous motor-cognitive training program, which allowed older people to perform daily activities in a virtual space mimicking real environments. OBJECTIVE: We aimed to (1) explore the feasibility of offering VR simultaneous motor-cognitive training to older people with cognitive frailty and (2) compare its effects with an existing motor-cognitive training program in the community on the cognitive function and physical function of older people with cognitive frailty. METHODS: A two-arm (1:1), assessor-blinded, parallel design, randomized controlled trial was employed. The eligibility criteria for participants were: (1) aged ≥60 years, (2) community dwelling, and (3) with cognitive frailty. Those in the intervention group received cognitive training (ie, cognitive games) and motor training (ie, cycling on an ergometer) simultaneously on a VR platform, mimicking the daily living activities of older people. Those in the control group received cognitive training (ie, cognitive games) on tablet computers and motor training (ie, cycling on the ergometer) sequentially on a non-VR platform. Both groups received a 30-minute session twice a week for 8 weeks. Feasibility was measured by adherence, adverse outcomes, and successful learning. The outcomes were cognitive function, physical frailty level, and walking speed. RESULTS: Seventeen participants were recruited and randomized to either the control group (n=8) or intervention group (n=9). At baseline, the median age was 74.0 years (IQR 9.5) and the median Montreal Cognitive Assessment score was 20.0 (IQR 4.0). No significant between-group differences were found in baseline characteristics except in the number of chronic illnesses (P=.04). At postintervention, the intervention group (Z=-2.67, P=.01) showed a significantly larger improvement in cognitive function than the control group (Z=-1.19, P=.24). The reduction in physical frailty in the intervention group (Z=-1.73, P=.08) was similar to that in the control group (Z=-1.89, P=.06). Improvement in walking speed based on the Timed Up-and-Go test was moderate in the intervention group (Z=-0.16, P=.11) and greater in the control group (Z=-2.52, P=.01). The recruitment rate was acceptable (17/33, 52%). Both groups had a 100% attendance rate. The intervention group had a higher completion rate than the control group. Training was terminated for one participant (1/9, 11%) due to minimal VR sickness (Virtual Reality Sickness Questionnaire score=18.3/100). Two participants (2/8, 25%) in the control group withdrew due to moderate leg pain. No injuries were observed in either group. CONCLUSIONS: This study provides preliminary evidence that the VR simultaneous motor-cognitive training is effective at enhancing the cognitive function of older people with cognitive frailty. The effect size on frailty was close to reaching a level of significance and was similar to that observed in the control group. VR training is feasible and safe for older people with cognitive frailty. TRIAL REGISTRATION: ClinicalTrials.gov NCT04467216; https://clinicaltrials.gov/ct2/show/NCT04467216.

The experience of Australian general practice patients at high risk of poor health outcomes with telehealth during the COVID-19 pandemic: a qualitative study.

BACKGROUND: The emergence of the COVID-19 pandemic has raised concerns about the potential decrease in access and utilisation of general practice services and its impact on patient care. In March 2020, the Australian Government introduced telehealth services to ensure that people more vulnerable to COVID-19 do not delay routine care from their general practitioners. Evidence about patients' experience of telehealth and its impact on patient care is scarce. This study aimed to investigate the experience with telehealth by Australian general practice patients at high risk of poor health outcomes during the COVID-19 pandemic. METHODS: Semi-structured telephone interviews were conducted with 30 patients from nine general practices in metropolitan Adelaide (May-June 2020). Participants were identified by their regular doctor as being at high risk of poor health outcomes. Interviews sought participants' perspectives and experiences about telehealth services in the general practice setting during COVID-19, and the value of offering continued telehealth services post pandemic. Interviews were recorded and transcribed verbatim. Data were analysed using a coding structure developed based on deductive codes derived from the research questions and any additional concepts that emerged inductively from interviews. RESULTS: Participants expressed satisfaction with telehealth including convenient and timely access to general practice services. Yet, participants identified challenges including difficulties in expressing themselves and accessing physical exams. Prescription renewal, discussing test results and simple follow-ups were the most common reasons that telehealth was used. Telehealth was mainly via phone that better suited those with low digital literacy. Participants indicated that an existing doctor-patient relationship was important for telehealth services to be effective. Subjects believed that telehealth services should be continued but needed to be combined with opportunities for face-to-face consultations after the COVID-19 pandemic was over. CONCLUSIONS: The expansion of telehealth supported access to general practice including chronic disease management during the COVID-19 pandemic. In the future, telehealth in Australia is likely to have a stronger place in primary healthcare policy and practice and an increased acceptance amongst patients.

The Relationship Between Androgens and Days per Month of Period Pain, Pelvic Pain, Headache, and TLR4 Responsiveness of Peripheral Blood Mononuclear Cells in Young Women with Dysmenorrhoea.

PURPOSE: Women bear a disproportionate burden of persistent pain conditions when compared to men. To determine whether the hormonal environment affects the clinical experience of pain, as measured by the days per month of pelvic pain (DPelvicPM), period pain (DPeriodPM), headache (DHeadachePM) or the in vitro EC50 for Interleukin-1ß (IL-1ß) release following TLR4 stimulation with Lipopolysaccharide from Peripheral Blood Mononuclear Cells (PBMCs). Findings were stratified according to use or non-use of the oral contraceptive pill. PATIENTS AND METHODS: Fifty-six women aged 16-35 years, with minimal or severe dysmenorrhea, and use or non-use of the OC, were enrolled. Blood was collected on two occasions in a single menstrual cycle: Days 1-2 and Days 7-10. Hormonal analysis for testosterone, dihydrotestosterone, dehydroepiandrosterone, Androstenedione, 3α-Androstanediol, 3ß-androstanediol, estradiol, estrone, 17α-hydroxyprogesterone, progesterone, cortisol and sex-hormone binding globulin was undertaken using ultra-sensitive Liquid Chromatography Mass-Spectrometry (LC-MS). PBMCs were exposed to lipopolysaccharide (LPS) and the resulting Interleukin-1ß output was determined. RESULTS: Non-users of the OC showed a strongly inverse correlation between a reducing free androgen index (FAI) and increasing DPelvicPM (p=0.0032), DPeriodPM (p=0.013), DHeadachePM (p=0.041). Non-users of the OC showed a significant increase in DPelvicPM (p=0.049) on Days 7-10. Modestly significant associations were found between reduced androgens and potentiated LPS-induced IL-1ß (lower EC50). CONCLUSION: This is the first study to investigate the relationship between the hormonal environment and activation of the immune system in young women with dysmenorrhoea-related pain conditions. Low androgen levels were consistently associated with increased pain. Translational implications for the findings are discussed.

Toll-Like Receptor Responsiveness of Peripheral Blood Mononuclear Cells in Young Women with Dysmenorrhea.

PURPOSE: Dysmenorrhea is a common disorder that substantially disrupts the lives of young women. To determine whether there is evidence of activation of the innate immune system in dysmenorrhea and whether the degree of activation may be used as a biomarker for pain, we compared the responsiveness of peripheral blood mononuclear cells (PBMCs) to toll-like receptor (TLR) 2 or 4 stimulation. We also investigated whether this effect is modulated by the use of the oral contraceptive pill (OC). PATIENTS AND METHODS: Fifty-six women aged 16-35 years, with either severe or minimal dysmenorrhea, and use or non-use of the OC, were enrolled. PBMCs were collected on two occasions in a single menstrual cycle: the menstrual phase and the mid-follicular phase. PBMCs were exposed to lipopolysaccharide (LPS), a TLR4 agonist, and PAM3CSK4 (PAM), a TLR2 agonist, and the resulting interleukin-1beta (IL-1ß) output was determined. Statistical analysis compared the EC50 between groups as a measure of TLR responsiveness of PBMCs. RESULTS: The key finding following LPS stimulation was a pain effect of dysmenorrhea (p=0.042) that was independent of use or non-use of OC, and independent of day of testing. Women with dysmenorrhea showed a large 2.15-fold (95% CI -4.69, -0.09) increase in IL-1ß release when compared with pain-free participants across both days. CONCLUSION: This is the first study to demonstrate an ex vivo immune relationship in women with dysmenorrhea-related pelvic pain. It provides evidence for the potential of immune modulation as a novel pharmacological target for future drug development in the management of dysmenorrhea.

A double-blind, randomized, placebo-controlled pilot trial to determine the efficacy and safety of ibudilast, a potential glial attenuator, in chronic migraine.

BACKGROUND: Chronic migraine (CM) is problematic, and there are few effective treatments. Recently, it has been hypothesized that glial activation may be a contributor to migraine; therefore, this study investigated whether the potential glial inhibitor, ibudilast, could attenuate CM. METHODS: The study was of double-blind, randomized, placebo-controlled, two-period crossover design. Participants were randomized to receive either ibudilast (40 mg twice daily) or placebo treatment for 8 weeks. Subsequently, the participants underwent a 4-week washout period followed by a second 8-week treatment block with the alternative treatment. CM participants completed a headache diary 4 weeks before randomization throughout both treatment periods and 4 weeks after treatment. Questionnaires assessing quality of life and cutaneous allodynia were collected on eight occasions throughout the study. RESULTS: A total of 33 participants were randomized, and 14 participants completed the study. Ibudilast was generally well tolerated with mild, transient adverse events, principally nausea. Eight weeks of ibudilast treatment did not reduce the frequency of moderate to severe headache or of secondary outcome measures such as headache index, intake of symptomatic medications, quality of life or change in cutaneous allodynia. CONCLUSION: Using the current regimen, ibudilast does not improve migraine with CM participants.

Glial Attenuation With Ibudilast in the Treatment of Medication Overuse Headache: A Double-Blind, Randomized, Placebo-Controlled Pilot Trial of Efficacy and Safety.

BACKGROUND: Medication overuse headache (MOH) is a condition bordering between a chronic pain condition and a substance dependence disorder. Activation of immunocompetent glial cells in the central nervous system has been linked to both pathological pain and drug addiction/reward. Preclinically, ibudilast attenuates glial activation and is able to reduce neuropathic pain and markers of substance dependence. We therefore hypothesized ibudilast would reduce headache burden and opioid analgesic requirements in patients with opioid overuse headache. OBJECTIVE: To determine if treatment with ibudilast provides a greater reduction in headache index than placebo in MOH patients consuming opioids. METHODS: Participants with MOH who were using opioids were randomized via computer-generated code to ibudilast 40 mg or placebo twice daily for 8 weeks in a double-blind, parallel groups study. Before randomization participants completed a 4-week baseline headache diary. During treatment, headache diary data collection continued and participants attended 4 study visits during which quantitative sensory testing was performed. Blood samples for immune biomarker analyses were collected before and after treatment in a subgroup of participants. RESULTS: Thirty-four participants were randomized, 13 of 15 randomized to ibudilast and 17 of 19 randomized to placebo completed treatment. Ibudilast was generally well-tolerated with mild, transient nausea reported as the most common adverse event (66.7% vs 10.5% in placebo group). Results are shown as mean (SD). At the end of treatment no differences in the primary outcome average daily headache index (placebo 62 [44] vs ibudilast 77 [72] groups, difference -15, CI -65 to 35 h × numerical rating scale), or secondary outcomes headache frequency (placebo 23 [8.1] vs ibudilast 24.5 [6.2], difference -1.5, CI -7.7 to 4.8 days/month) and opioid intake (placebo 20.6 [43] vs ibudilast 19 [24.3], difference 1.6, CI -31.5 to 34.8 mg morphine equivalent) were observed between placebo and ibudilast groups. CONCLUSIONS: Using the current dosing regimen, ibudilast does not improve headache or reduce opioid use in patients with MOH without mandated opioid withdrawal. However, it would be of interest to determine in future trials if ibudilast is able to improve ease of withdrawal during a forced opioid down-titration when incorporated into an MOH detoxification program.

TLR 2 and 4 responsiveness from isolated peripheral blood mononuclear cells from rats and humans as potential chronic pain biomarkers.

BACKGROUND: Chronic pain patients have increased peripheral blood mononuclear cell Interkeukin-1ß production following TLR2 and TLR4 simulation. Here we have used a human-to-rat and rat-to-human approach to further investigate whether peripheral blood immune responses to TLR agonists might be suitable for development as possible systems biomarkers of chronic pain in humans. METHODS AND RESULTS: Study 1: using a graded model of chronic constriction injury in rats, behavioral allodynia was assessed followed by in vitro quantification of TLR2 and TLR4 agonist-induced stimulation of IL-1ß release by PBMCs and spinal cord tissues (n = 42; 6 rats per group). Statistical models were subsequently developed using the IL-1ß responses, which distinguished the pain/no pain states and predicted the degree of allodynia. Study 2: the rat-derived statistical models were tested to assess their predictive utility in determining the pain status of a published human cohort that consists of a heterogeneous clinical pain population (n = 19) and a pain-free population (n = 11). The predictive ability of one of the rat models was able to distinguish pain patients from controls with a ROC AUC of 0.94. The rat model was used to predict the presence of pain in a new chronic pain cohort and was able to accurately predict the presence of pain in 28 out of the 34 chronic pain participants. CONCLUSIONS: These clinical findings confirm our previous discoveries of the involvement of the peripheral immune system in chronic pain. Given that these findings are reflected in the prospective graded rat data, it suggests that the TLR response from peripheral blood and spinal cord were related to pain and these clinical findings do indeed act as system biomarkers for the chronic pain state. Hence, they provide additional impetus to the neuroimmune interaction to be a drug target for chronic pain.

Low-dose endotoxin potentiates capsaicin-induced pain in man: evidence for a pain neuroimmune connection.

Despite the wealth of evidence in animals that immune activation has a key role in the development and maintenance of chronic pain, evidence to support this in humans is scant. We have sought such evidence by examining the effect of a subtle immunological stimulus, low dose intravenous endotoxin, on the allodynia, hyperalgesia, flare and pain produced by intradermal capsaicin in healthy volunteers. Here we provide evidence of immune priming of this neuropathic-like pain response in humans. Specifically, in 12 healthy volunteers, activation of Toll-Like Receptor 4 by endotoxin (0.4ng/kg IV) caused significant 5.1-fold increase in the 90-min integral of areas of capsaicin-induced allodynia (95% CI 1.3-9.1), 2.2-fold increase in flare (95% CI 1.9-2.6) and 1.8-fold increase in hyperalgesia (95% CI 1.1-2.5) following 50µg intradermal capsaicin injected into the forearm 3.5h after endotoxin. These data demonstrate clinically a significant role for the neuroimmune pain connection in modifying pain, thus providing evidence that immune priming may produce pain enhancement in humans and hence offer a novel range of pharmacological targets for anti-allodynics and/or analgesics. Additionally, the simplicity of the model makes it suitable as a test-bed for novel immune-targeted pain therapeutics.

Increased responsiveness of peripheral blood mononuclear cells to in vitro TLR 2, 4 and 7 ligand stimulation in chronic pain patients.

Glial activation via Toll-like receptor (TLR) signaling has been shown in animals to play an important role in the initiation and establishment of chronic pain. However, our ability to assess this central immune reactivity in clinical pain populations is currently lacking. Peripheral blood mononuclear cells (PBMCs) are an accessible source of TLR expressing cells that may mirror similarities in TLR responsiveness of the central nervous system. The aim of this study was to characterize the IL-1ß response to various TLR agonists in isolated PBMCs from chronic pain sufferers (on and not on opioids) and pain-free controls. Venous blood was collected from 11 chronic pain sufferers on opioids (≥ 20 mg of morphine / day), 8 chronic pain sufferers not on opioids and 11 pain-free controls. PBMCs were isolated and stimulated in vitro with a TLR2 (Pam3CSK4), TLR4 (LPS) or TLR7 (imiquimod) agonist. IL-1ß released into the supernatant was measured with ELISA. Significantly increased IL-1ß expression was found in PBMCs from chronic pain sufferers (on and not on opioids) compared with pain-free controls for TLR2 (F((6, 277)) = 15, P<0.0001), TLR4 (F((8, 263)) = 3, P = 0.002) and TLR7 (F((2,201)) = 5, P = 0.005) agonists. These data demonstrate that PBMCs from chronic pain sufferers were more responsive to TLR agonists compared with controls, suggesting peripheral cells may have the potential to become a source of biomarkers for chronic pain.

Cloning and characterization of a PAC1 receptor hop-1 splice variant in goldfish (Carassius auratus).

In several vertebrates, it has been demonstrated that alternative splicing of PAC1 receptor (PAC1-R) transcripts can generate a number of functional receptor variants which utilize different signal transduction pathways to mediate their activities. As PACAP is a physiological growth hormone-releasing factor in fish, and PACAP and the PAC1-R are highly conserved in vertebrate evolution, it would be of interest to investigate the structure and cellular distribution, particularly in the pituitary, of PAC1-R splice variants in a fish model. Our laboratory has previously cloned a receptor cDNA corresponding to the goldfish PAC1-R-s (goldfish PAC1-R-short). In the present study, a goldfish PAC1-R-hop1 variant was characterized. Functional expression of goldfish PAC1-R-s and PAC1-R-hop1 in Chinese Hamster Ovary cells revealed that, upon stimulation by ovine PACAP38, these receptor variants exhibited similar EC50 values (8.7+/-1.5 and 8.8+/-1.9 nM, respectively) and maximal responses in activating intracellular cAMP production. The presence and expression levels of these transcripts were measured by quantitative real-time PCR in the brain, heart, pituitary and male gonad, and goldfish PAC1-R-s were found to be the predominant form. In situ hybridization of goldfish PAC1-R in the pituitary revealed its prevalent presence in the pars distalis. In summary, the present study provides information to confirm the role of PACAP in the pituitary and to elucidate the pleiotropic effects of PACAP in fish.

Score in the Palmore's Aging Quiz, knowledge of community resources and working preferences of undergraduate nursing students toward the elderly in Hong Kong.

Health care professionals are the gate-keepers for elderly health information. Unfavorable attitude to the elderly posts an obstacle to health information delivery. Therefore, it is vital to identify the knowledge and attitude of nursing students toward working with the elderly. The present study aimed to examine the knowledge and working preferences toward the elderly among undergraduate nursing students in Hong Kong. Two hundred and sixty-nine students completed a questionnaire that incorporated 70 questions in the Palmore's Aging Quiz and 10 questions reflecting the knowledge on local community resources for the elderly. The results revealed that nursing students generally have a neutral to positive working preferences toward the elderly. 83% of them gained a mean Palmore's score of 40.90 out of 70 (SD=5.02) and good knowledge of the community resources (mean score=8.49, SD=1.85). Those who disliked working with the elderly had a significantly lower mean Palmore's score (F=7.73, p=0.001). Though the level of study had a positive correlation with the knowledge of community resources, it did not increase with Palmore's score. Further research on the study results and more detail examination of geriatric education for nursing students to refine their attitude toward the elderly are recommended.

Possible central nervous system infection by SARS coronavirus.

On day 22 of illness, generalized tonic-clonic convulsion developed in a 32-year-old woman with severe acute respiratory syndrome (SARS). Cerebrospinal fluid tested positive for SARS coronavirus (SARS-CoV) by reverse transcriptase-polymerase chain reaction. SARS-CoV may have caused an infection in the central nervous system in this patient.