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Recent years have seen a paradigm shift in the management of patients with diabetes mellitus. Rather than good glycaemic control being the sole primary aim, the therapeutic focus has broadened to consider potential additional cardiovascular and renal benefits. Sodium-glucose co-transporter 2 inhibitors, such as empagliflozin, canagliflozin and dapagliflozin, have gained increasing prominence, with evidence suggesting significant improvement in outcomes in patients with established cardiovascular and renal disease. Here, we discuss the benefits and relative risks of these novel agents and highlight important clinical issues of relevance to general physicians.

The neuraminidase (NA) of influenza A and B viruses plays a distinct role in viral replication and has a highly conserved catalytic site. Numerous sialic (neuraminic) acid analogs that competitively bind to the NA active site and potently inhibit enzyme activity have been synthesized and tested. Four NA inhibitors are now licensed in various parts of the world (zanamivir, oseltamivir, peramivir, and laninamivir) to treat influenza A and B infections. NA changes, naturally occurring or acquired under selective pressure, have been shown to reduce drug binding, thereby affecting the effectiveness of NA inhibitors. Drug resistance and other drawbacks have prompted the search for the next-generation NA-targeting therapeutics. One of the promising approaches is the identification of monoclonal antibodies (mAbs) targeting the conserved NA epitopes. Anti-NA mAbs demonstrate Fab-based antiviral activity supplemented with Fc-mediated immune effector functions. Antiviral Fc-conjugates offer another cutting-edge strategy that is based on a multimodal mechanism of action. These novel antiviral agents are composed of a small-molecule NA inhibitor and an Fc-region that simultaneously engages the immune system. The significant advancements made in recent years further support the value of NA as an attractive target for the antiviral development.

The impact of antibiotics on growth, cocoon production was assessed in addition to isolation and characterization of bacteria associated with silkworm gut of infected larvae. Larval rearing was maintained at recommended conditions of temperature and humidity. Silkworm larvae showing abnormal symptoms were collected from the control group and dissected for gut collection. Bacteria were isolated from the gut content by spreading on agar plates and incubated at 37 °C for 48 hrs. Bacterial identification and phylogenetic analysis were carried out by 16S rRNA gene sequencing. The isolated bacteria were subjected to antimicrobial susceptibility test (disc diffusion methods) by using Penicillin (10 µg/mL), Tetracycline (30 µg/mL), Amoxicillin (25 µg/mL), Ampicillin (10 µg/mL), and Erythromycin (15 µg/mL). All isolated strains showed positive results for the catalase test. We isolated and identified bacterial strains (n = 06) from the gut of healthy and diseased silkworm larvae. Based on the 16S rRNA gene sequence, isolated bacteria showed close relation with Serratia, Bacillus, and Pseudomonas spp. Notably, 83.3% of strains were resistant to Penicillin, Tetracycline, Amoxicillin, Ampicillin, and Erythromycin but 16.6% showed antibiotic susceptibility to the above-mentioned commonly used antibiotics. Silkworm larvae fed on penicillin-treated leaves showed significant improvement in larval weight, larval length, and cocoon production. Significantly higher larval weight (6.88g), larval length (5.84cm), and cocoon weight (1.33g) were recorded for larvae fed on leaves treated with penicillin as compared to other antibiotics. Isolated bacterial strains showed close relation with Serratia spp., Bacillus spp. and Pseudomonas spp.

• Infants born with ambiguous genitalia or nonpalpable testes need to be evaluated for congenital adrenal hyperplasia as it can be life threatening. • Adrenal steroid levels vary with gestational age. • Adrenal insufficiency should be treated with hydrocortisone to avoid adrenal crisis. High doses of hydrocortisone contain mineralocorticoid activity.

Myasthenia gravis (MG) is an autoimmune condition affecting the neuromuscular junction characterised by weakness and fatiguability, carrying a high morbidity if treatment is delayed. A clear association with thymoma has led to management with thymectomy as a common practice, but MG presenting post-thymectomy has rarely been reported. We present a case of an 82- year-old woman developing fatigue, ptosis and dysarthria 3 months after thymectomy. After a clinical diagnosis of MG was made, she responded well to prompt treatment with prednisolone and pyridostigmine. Her anti-acetylcholine receptor antibody (anti-AChR) subsequently came back positive. Our systematic review reveals that post-thymectomy MG can be categorised as early-onset or late-onset form with differing aetiology, and demonstrated correlation between preoperative anti-AChR titres and post-thymectomy MG. The postulated mechanisms for post-thymectomy MG centre around long-lasting peripheral autoantibodies. Clinicians should actively look for MG symptoms in thymoma patients and measure anti-AChR preoperatively to aid prognostication.

Chemotherapy can result in toxic side effects in the brain. Intake of marine-based omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), alter brain fatty acids, potentially improving brain function. However, it is unclear if alpha-linolenic acid (ALA), the plant-based n-3, affects brain PUFAs during chemotherapy. The objective of this study was to examine the effects of dietary ALA, EPA and DHA, with high or low sucrose, on brain PUFAs in a mouse model of chemotherapy. Secondarily, the use of liver PUFAs as surrogate measures of brain PUFAs was examined. Lipid peroxidation (4-HNE) and neurotrophic markers (BDNF) were assessed. Female C57Bl/6 mice (n = 90) were randomized to 1 of 5 diets (high EPA + DHA/high or low sucrose, high ALA/high or low sucrose, or control with no EPA + DHA/low ALA/low sucrose) and injected with doxorubicin-based chemotherapy or saline. Brain EPA and DHA were greater (p < 0.0001) with high EPA + DHA diets, regardless of sucrose; there were no significant differences in brain PUFAs between high ALA diets and control. Chemotherapy-treated mice had higher brain and liver DHA (p < 0.05) and lower brain and liver linoleic acid (p < 0.0001). Brain n-3 and n-6 PUFAs were strongly correlated with liver n-3 (r = 0.8214, p < 0.0001) and n-6 PUFAs (r = 0.7568, p < 0.0001). BDNF was correlated with brain total PUFAs (r = 0.36; p < 0.05). In conclusion, dietary ALA in proportions approximately two times greater than consumed by humans did not appreciably increase brain n-3 PUFAs compared to low ALA intake. Liver PUFAs may be a useful surrogate marker of brain PUFAs in this mouse model.

Objective To compare outcomes after surgery between patients who were not prescribed opioids and patients who were prescribed opioids. Summary of background data Postoperative opioid prescriptions carry significant risks. Understanding outcomes among patients who receive no opioids after surgery may inform efforts to reduce these risks. Methods We performed a retrospective study of adult patients who underwent surgery between January 1, 2019 and October 31, 2019. The primary outcome was the composite incidence of an emergency department visit, readmission, or reoperation within 30 days of surgery. Secondary outcomes were postoperative pain, satisfaction, quality of life, and regret collected via postoperative survey. A multilevel, mixed-effects logistic regression was performed to evaluate differences between groups. Results In a cohort of 22,345 patients, mean age (standard deviation) was 52.1 (16.5) years and 13,269 (59.4%) patients were female. About 3175 (14.2%) patients were not prescribed opioids, of whom 422 (13.3%) met the composite adverse event endpoint compared to 2255 (11.8%) of patients not prescribed opioids (P = 0.015). Patients not prescribed opioids had a similar probability of adverse events {11.7% [95% confidence interval (CI) 10.2%-13.2%] vs 11.9% (95% CI 10.6%-13.3%]}. Among 12,872 survey respondents, patients who were not prescribed an opioid had a similar rate of high satisfaction [81.7% (95% CI 77.3%-86.1%) vs 81.7% (95% CI 77.7%-85.7%)] and no regret [(93.0% (95% CI 90.8%-95.2%) vs 92.6% (95% CI 90.4%-94.7%)]. Conclusions Patients who were not prescribed opioids after surgery had similar clinical and patient-reported outcomes as patients who were prescribed opioids. This suggests that minimizing opioids as part of routine postoperative care is unlikely to adversely affect patients.

Background: The optimal vasopressor management for septic patients with left ventricular (LV) dysfunction has not been well established, and current evidence is conflicting regarding the optimal vasopressor discontinuation order. Objective: The objective was to evaluate the impact of LV dysfunction on the hemodynamic management of septic shock by assessing the incidence of clinically significant hypotension after vasopressor discontinuation. Methods: In this single-center, retrospective cohort study, adult patients were included if they met the Sepsis-3 definition of septic shock, had LV dysfunction (defined as an ejection fraction ≤40%), and received norepinephrine and vasopressin as the last vasopressors discontinued. The primary outcome was the incidence of clinically significant hypotension following discontinuation of vasopressin or norepinephrine. Clinically significant hypotension was defined as a MAP less than 60 mmHg and the need for either: 1) the reinstitution of the previously discontinued agent at any dosage, 2) the receipt of at least 500 mL of a crystalloid at a rate of at least 500 mL/hour, 3) or the receipt of at least 25 grams of albumin 5% at a rate of at least 25 gram/hour. Secondary outcomes included intensive care unit (ICU) and hospital lengths of stay, and ICU and hospital mortality. Results: A total of 78 patients met inclusion criteria, with 37 patients having vasopressin discontinued first and 41 having norepinephrine discontinued first. Clinically significant hypotension occurred in 28 patients (76%) following the discontinuation of vasopressin, compared to 28 patients (81%) following the discontinuation of norepinephrine (p = 0.61). ICU length of stay was 9 days in the vasopressin discontinued first cohort, compared to 15 days in the norepinephrine discontinued first cohort (p = 0.01). There was no statistically significant difference in mortality observed. Conclusion: The discontinuation order of norepinephrine and vasopressin did not impact the incidence of clinically significant hypotension in patients with septic shock and LV dysfunction, but may influence ICU length of stay, although other factors may have impacted this finding.

Background: Beta blockers, mainly propranalol, are usually administered to control heart rate in patients with thyrotoxicosis, especially when congestive heart failure presents. However, when thyrotoxicosis is not controlled, heart rate may be difficult to control even with maximal doses of propranolol. This presentation alerts physicians to the possibility of using ivabradine, a selective inhibitor of the sinoatrial pacemaker, for the control of heart rate. Case presentation: We present a 37-year-old woman with thyrotoxicosis and congestive heart failure whose heart rate was not controlled with a maximal dose of beta blockers during a thyroid storm. The addition of ivabradine, a selective inhibitor of the sinoatrial pacemaker, controlled her heart rate within 48 hours. Conclusion: Ivabradine should be considered in patients with thyrotoxicosis, including those with heart failure, in whom beta blockers are insufficient to control heart rate

Background Patients with obsessive-compulsive disorder (OCD) display disrupted performance and abnormal lateral orbitofrontal cortex (LOFC) activity during reversal learning tasks, yet it is unknown whether compulsions and reversal learning deficits share a common neural substrate. To answer this question, we measured neural activity with in vivo calcium imaging in LOFC during compulsive grooming and reversal learning before and after fluoxetine treatment. Methods Sapap3-knockout (KO) mice were used as a model for OCD-relevant behaviors. Sapap3-KOs and control littermates were injected with virus encoding GCaMP6f and implanted with gradient-index lenses to visualize LOFC activity using miniature microscopes. Grooming, reversal learning, and neural activity were measured pre- and post-fluoxetine treatment (18mg/kg, 4 weeks). Results Baseline compulsive grooming and reversal learning impairments in KOs improved after fluoxetine treatment. Additionally, KOs display distinct patterns of abnormal LOFC activity during grooming and reversal learning, both of which normalize after fluoxetine. Finally, reversal learning-associated neurons are distributed randomly amongst grooming-associated neurons (i.e. overlap is what would be expected by chance). Conclusions In OCD, the LOFC is disrupted during both compulsive behaviors and reversal learning, yet whether these behaviors share common neural underpinnings is unknown. We find that the LOFC plays distinct roles in compulsive grooming and impaired reversal learning and their improvement with fluoxetine. These findings suggest that LOFC plays separate roles in pathophysiology and treatment of different perseverative behaviors in OCD.

Background Neutrophilic dermatosis of the dorsal hands is an uncommon localised variant of Sweet syndrome first described in 1995. It is characterised by tender erythematous plaques, pustules and bullae on the dorsa of the hands. Literature Review A total of 123 cases of NDDH are included in this review. The mean patient age was 62.1 years and there was a slight female preponderance. 78.0% of cases had reported bilateral involvement and other sites were affected in almost a third of cases. Underlying disease was found in around 40% of patients, with the most common associations being haematological disorders (gammopathies, myelodysplasias or malignancies), recent infection, solid organ tumours and inflammatory bowel disease. Systemic and/or topical corticosteroids were employed in the treatment of 88.1% of cases while dapsone, colchicine and tetracyclines were the commonest steroid-sparing agents used. Improvement was often rapid and complete resolution the norm. Conclusions Whilst being uncommon, NDDH is frequently misdiagnosed and thus, its exact prevalence is probably underestimated. This may have significant implications including treatment delays or incorrect management. Moreover, recognition of NDDH is important since a correct diagnosis should trigger a search for underlying diseases and proper treatment with corticosteroids and/or steroid-sparing agents which is almost invariably curative.

BACKGROUND: Central histamine (HA) signaling modulates diverse cortical and subcortical circuits throughout the brain, including the nucleus accumbens (NAc). The NAc, a key striatal subregion directing reward-related behavior, expresses diverse HA receptor subtypes that elicit cellular and synaptic plasticity. However, the neuromodulatory capacity of HA within interneuron microcircuits in the NAc remains unknown. METHODS: We combined electrophysiology, pharmacology, voltammetry, and optogenetics in male transgenic reporter mice to determine how HA influences microcircuit motifs controlled by parvalbumin-expressing fast-spiking interneurons (PV-INs) and tonically active cholinergic interneurons (CINs) in the NAc shell. RESULTS: HA enhanced CIN output through an H(2) receptor (H(2)R)-dependent effector pathway requiring Ca(2+)-activated small-conductance K(1) channels, with a small but discernible contribution from H(1)Rs and synaptic H(3)Rs. While PV-IN excitability was unaffected by HA, presynaptic H(3)Rs decreased feedforward drive onto PV-INs via AC-cAMP-PKA (adenylyl cyclase-cyclic adenosine monophosphate-protein kinase A) signaling. H(3)R-dependent plasticity was differentially expressed at mediodorsal thalamus and prefrontal cortex synapses onto PV-INs, with mediodorsal thalamus synapses undergoing HA-induced long-term depression. These effects triggered downstream shifts in PV-IN- and CIN-controlled microcircuits, including near-complete collapse of mediodorsal thalamus-evoked feedforward inhibition and increased mesoaccumbens dopamine release. CONCLUSIONS: HA targets H-|R, H(2)R, and H(3)Rs in the NAc shell to engage synapse- and cell type-specific mechanisms that bidirectionally regulate PV-IN and CIN microcircuit activity. These findings extend the current conceptual framework of HA signaling and offer critical insight into the modulatory potential of HA in the brain.

A modified in vitro-in vivo correlation (IVIVC) of the oral solid dosage forms has been proposed as a linear correlation between in vitro and in vivo dissolution. Nevertheless, the analysis of in vivo dissolution is limited by the lack of available methods. In this proof-of-concept study, a novel pharmacokinetic (PK) model containing the in vivo dissolution process and its quantification was presented to directly estimate the in vivo dissolution rate constant (kd). The new model was validated with a hypothetical oral solution (kd → +∞). The accuracy of the new method was clarified by comparing with the relatively true value of kd from the literature. Isosorbide mononitrate (ISMN) was used as a model drug to explore the practicability of the novel method. The dissolution capacities of ISMN reference and test tablets were discriminated by an improved in vitro dissolution method. Following the human PK studies, the kd values and corresponding in vivo dissolution profiles of two formulations were obtained using the novel method. Finally, a modified level A IVIVC between in vitro and in vivo dissolution of ISMN tablets was established, which is expected to guide the optimization of the tablet formulation containing ISMN.

A 68-year-old woman was admitted to the hospital for elective total knee arthroplasty in both knees without preceding heparin exposure. She developed adrenal haemorrhage and thrombocytopaenia on postoperative day 12, followed by right leg arterial occlusion and multiple venous intra-abdominal sites thrombosis. After given unfractionated heparin to treat arterial occlusion, platelet count was gradually declined. Spontaneous heparin-induced thrombocytopaenia was diagnosed by heparin-induced platelet activation test with light transmission aggregometry. The patient was successfully treated with fondaparinux and intravenous immunoglobulin. Apixaban was given after recovery of platelet count. Resolution of both thrombus along aorta and adrenal haemorrhage were shown by CT of whole abdomen after 2 months of treatment. Our case demonstrates that this serious complication is important but seldom recognised early.

Takotsubo cardiomyopathy is characterised by left ventricular apical ballooning, in the absence of coronary artery disease, and classically occurs at times of intense stress. Due to the striking preponderance of Takotsubo cardiomyopathy occurring in postmenopausal women, it has been postulated that female sex hormones may also be implicated in its pathogenesis. This case report describes the first case of Takotsubo cardiomyopathy associated with the initiation of dydrogesterone (a synthetic retroprogesterone) in a premenopausal woman.

A 50-year-old woman was referred to rheumatology for new onset polyarthralgia and headache. She had a history of metastatic lung adenocarcinoma and was started on treatment with the programmed death 1 receptor (PD-1) antagonist pembrolizumab 2 months prior. Examination revealed left temporal artery tenderness and hand synovitis. Investigations revealed enlarged temporal artery on ultrasound imaging. On steroid treatment, she had resolution of symptoms, but due to significant steroid side effects required methotrexate and her PD-1 antagonist therapy was continued in consultation with her oncologist. Her malignant disease has remained stable, and she has improved functional status.

This is a case of a young woman who developed neurological and psychiatric symptoms 3 days after resection of an immature teratoma. She was diagnosed with anti-NMDA receptor encephalitis via positive serum antibody titres, which was later confirmed with cerebrospinal fluid antibody titres. Given her cancer diagnosis, she underwent treatment with bleomycin, etoposide and cisplatin chemotherapy in addition to 5 days of high-dose steroids (1 g of intravenous methylprednisolone) for the encephalitis. This treatment regimen led to significant clinical improvement 3 weeks after completion of one cycle of chemotherapy.

A 53-year-old woman presented with a 25-year history of acne excoriée and prurigo excoriée. Her symptoms began in 1988 coinciding with her husband’s death from a brain tumour when she was 27. The pruritus affected her quality of life and disturbed her sleep. She had scarring on her face and body resulting from persistent scratching. The pruritus proved refractory to treatment despite a multi-modal treatment approach including multiple topicals, phototherapy and systemic agents such as isotretinoin, antibiotics, anxiolytic agents and neuromodulators. She was extremely frustrated that various treatments had been ineffective at controlling the itch-scratch cycle. She was commenced on low dose naltrexone (LDN), 3 mg nocte, and she became itch free within a few weeks. She reports that the LDN has had a beneficial impact on her quality of life.

A 73-year-old man presented to the emergency department with lethargy and influenza-like symptoms. Incidentally, prominent blue sclera and blue-grey skin discolouration to the periorbital skin, pinnae, neck, upper and lower limbs, hands, feet, fingernails and toenails were noted. His general practitioner (GP) had previously ceased amiodarone, believing it to be the causative agent. A literature search confirms the side effects were likely due to minocycline, which the patient had been taking for 10 years. Long-term minocycline use is associated with scleral and skin hyperpigmentation, with no apparent adverse effect on ocular structure or function. The pigmentation may reverse with cessation of minocycline, or it may be permanent. Amiodarone may also cause skin hyperpigmentation, but scleral pigmentation is not a known association. This case report explores the side effect profiles of these two drugs, and highlights the potential for confusion regarding causative agents when used concurrently.

Current literature suggests an increased risk of venous thromboembolism (VTE) in people living with HIV (PLWH) with poorly controlled viraemia and immunodeficiency. VTE treatment guidelines do not specifically address anticoagulation management in PLWH. We report a case of a 33-year-old woman diagnosed with an unprovoked pulmonary embolism (PE) and deemed protein S deficient. Three years later, she was diagnosed with AIDS. Antiretroviral therapy (ART) was promptly initiated with viral suppression and immune reconstitution within 12 months. Eight years after her initial PE, the patient self-discontinued warfarin. Multiple repeat protein S values were normal. ART without anticoagulation has continued for 3 years with no thrombotic events. This case describes a patient with VTE presumably secondary to undiagnosed HIV with possible consequent acquired protein S deficiency. Additional research is needed to understand the characteristics of PLWH with VTE who may warrant long-term anticoagulation as opposed to shorter courses.

Multiple myeloma (MM) patients live longer due to more effective treatment, and we now see previously uncommon manifestations of MM, like extramedullary disease. We present a case of a 74-year-old man known with MM that relapsed with extramedullary manifestations at different locations. One of them as a gastric plasmacytoma (GP). He was successfully treated with chemoradiotherapy (Daratumumab, Bortezomib and Dexamethasone), which resulted in clinical response for 8 months, confirmed by biopsy and histopathology. Perforation of the GP occurred, and he underwent partial gastrectomy (Billroth II gastrojejunostomy). The patient’s disease progressed again 5 months after surgery, and he did not want any additional treatment. He accepted palliative care and died 10 months after the operation. A lack of knowledge about the characteristics and treatment of extramedullary MM exists, and prospective studies to investigate incidence, prognosis and treatment for extramedullary MM are needed for improving the poor prognosis of this manifestation.

Inhaled antibiotics are commonly used to treat persistent airway infection with Pseudomonas aeruginosa that contributes to lung damage in people with cystic fibrosis. Current guidelines recommend inhaled tobramycin for individuals with cystic fibrosis and persistent Pseudomonas aeruginosa infection who are aged six years or older. The aim is to reduce bacterial load in the lungs so as to reduce inflammation and deterioration of lung function. This is an update of a previously published review.To evaluate the effects of long-term inhaled antibiotic therapy in people with cystic fibrosis on clinical outcomes (lung function, frequency of exacerbations and nutrition), quality of life and adverse events (including drug-sensitivity reactions and survival).We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials registries. Date of last search: 28 June 2022.We selected trials where people with cystic fibrosis received inhaled anti-pseudomonal antibiotic treatment for at least three months, treatment allocation was randomised or quasi-randomised, and there was a control group (either placebo, no placebo or another inhaled antibiotic).Two authors independently selected trials, judged the risk of bias, extracted data from these trials and judged the certainty of the evidence using the GRADE system.The searches identified 410 citations to 125 trials; 18 trials (3042 participants aged between five and 45 years) met the inclusion criteria. Limited data were available for meta-analyses due to the variability of trial design and reporting of results. A total of 11 trials (1130 participants) compared an inhaled antibiotic to placebo or usual treatment for a duration between three and 33 months. Five trials (1255 participants) compared different antibiotics, two trials (585 participants) compared different regimens of tobramycin and one trial (90 participants) compared intermittent tobramycin with continuous tobramycin alternating with aztreonam. One trial (18 participants) compared an antibiotic to placebo and also to a different antibiotic and so fell into both groups. The most commonly studied antibiotic was tobramycin which was studied in 12 trials. Inhaled antibiotics compared to placebo We found that inhaled antibiotics may improve lung function measured in a variety of ways (4 trials, 814 participants). Compared to placebo, inhaled antibiotics may also reduce the frequency of exacerbations (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.47 to 0.93; 3 trials, 946 participants; low-certainty evidence). Inhaled antibiotics may lead to fewer days off school or work (quality of life measure) (mean difference (MD) -5.30 days, 95% CI -8.59 to -2.01; 1 trial, 245 participants; low-certainty evidence). There were insufficient data for us to be able to report an effect on nutritional outcomes and there was no effect on survival. There was no effect on antibiotic resistance seen in the two trials that were included in meta-analyses. We are uncertain of the effect of the intervention on adverse events (very low-certainty evidence), but tinnitus and voice alteration were the only events occurring more often in the inhaled antibiotics group. The overall certainty of evidence was deemed to be low for most outcomes due to risk of bias within the trials and imprecision due to low event rates. Different antibiotics or regimens compared Of the eight trials comparing different inhaled antibiotics or different antibiotic regimens, there was only one trial for each unique comparison. We found no differences between groups for any outcomes except for the following. Aztreonam lysine for inhalation probably improved forced expiratory volume at one second (FEVsub1/sub) % predicted compared to tobramycin (MD -3.40%, 95% CI -6.63 to -0.17; 1 trial, 273 participants; moderate-certainty evidence). However, the method of defining the endpoint was different to the remaining trials and the participants were exposed to tobramycin for a long period making interpretation of the results problematic. We found no differences in any measure of lung function in the remaining comparisons. Trials measured pulmonary exacerbations in different ways and showed no differences between groups except for aztreonam lysine probably leading to fewer people needing treatment with additional antibiotics than with tobramycin (RR 0.66, 95% CI 0.51 to 0.86; 1 trial, 273 participants; moderate-certainty evidence); and there were fewer hospitalisations due to respiratory exacerbations with levofloxacin compared to tobramycin (RR 0.62, 95% CI 0.40 to 0.98; 1 trial, 282 participants; high-certainty evidence). Important treatment-related adverse events were not very common across comparisons, but were reported less often in the tobramycin group compared to both aztreonam lysine and colistimethate. We found the certainty of evidence for these comparisons to be directly related to the risk of bias within the individual trials and varied from low to high.Long-term treatment with inhaled anti-pseudomonal antibiotics probably improves lung function and reduces exacerbation rates, but pooled estimates of the level of benefit were very limited. The best evidence available is for inhaled tobramycin. More evidence from trials measuring similar outcomes in the same way is needed to determine a better measure of benefit. Longer-term trials are needed to look at the effect of inhaled antibiotics on quality of life, survival and nutritional outcomes.

A 67-year-old man was referred to the renal team following an episode of acute kidney injury on a background of chronic kidney disease. He had a 9-year history of steroid-sensitive arthritis, epigastric pain and isolated submandibular gland enlargement. He was noted to have a raised eosinophil count, total serum protein and total immunoglobulin G4 (IgG4) level as well as a serum hypocomplementaemia. A renal biopsy showed a tubulointerstitial nephritis with lymphoplasmacytic infiltrates, fibrosis and IgG4-positive plasma cells on immunohistochemistry. A diagnosis of IgG4-related disease was made based on clinical presentation and pathology. Renal function improved with glucocorticoids and the patient was successfully transitioned to azathioprine as a steroid-sparing agent.

Recurrent painful ophthalmoplegic neuropathy (RPON), previously called ophthalmoplegic migraine, is a rare condition characterised by recurrent episodes of headache and ophthalmoplegia. We report a case of 11-year-old girl with recurrent painful ophthalmoplegia due to isolated right oculomotor nerve involvement. MR brain imaging showed enhancing lesion of cisternal segment of right oculomotor nerve. A possibility of Tolosa Hunt syndrome was considered and she was treated with glucocorticoids, followed by azathioprine due to recurrence. In the fourth episode, she developed migraine headache followed by right third nerve palsy, after which the diagnosis was revised to RPON. She was started on flunarizine along with short-term glucocorticoids. At 1-year follow-up, she remained asymptomatic. RPON should be considered in patients with recurrent third nerve palsy to avoid inadvertent long-term exposure to immunosuppressive agents.

We present a 65-year-old female smoker who presented with acute bilateral blurred vision. Investigations led to an endobronchial ultrasound-guided fine-needle aspiration resulting in an early diagnosis of limited stage small cell lung cancer. Positive recoverin antibodies supported the diagnosis of cancer-associated retinopathy (CAR). CAR was the first manifestation of systemic malignancy in our patient and early diagnosis enabled curative intent systemic treatment with chemotherapy and radiotherapy. Ocular-specific treatment is required in CAR, although no standardised treatment exists. Current treatment options include steroids and immunosuppressive agents. Our patient was administered bilateral intravitreal dexamethasone implants, resulting in significant visual field and electroretinogram improvement at 8 weeks post-intervention. To our knowledge, this represents the first reported successful use of intravitreal dexamethasone implants as first-line therapy, in conjunction with chemoradiotherapy. Intravitreal dexamethasone implants therefore may provide an effective and safe treatment for CAR by reducing intraocular inflammation without systemic effects.

A middle-aged woman was diagnosed with postural orthostatic tachycardia syndrome based on her clinical symptoms, elevated norepinephrine levels and positive tilt-table test. The patient was refractory to conventional treatment and improved only after she was treated with methylated B vitamins for her heterozygous catechol-O-methyltransferase Val158Met polymorphism.

Liver involvement in Graves’ disease can be seen as a part of autoimmune process or rarely, due to the direct effects of thyrotoxicosis on liver. Hyperthyroidism can also have gastrointestinal manifestations like frequent bowel movements, diarrhoea, even malabsorption with steatorrhoea. We report a 36-year-old man with hyperthyroidism, presenting with cholestatic jaundice and persistent small bowel diarrhoea. He was diagnosed to have Graves’ disease and after ruling out more common causes, the cause of cholestatic jaundice was supposed to be Graves’ disease. Considering this possibility, the patient was started on treatment with carbimazole. As patient’s thyroid function tests started improving, he showed significant clinical and biochemical improvement from liver point of view as well.

We present here the second documented case of severe immune checkpoint inhibitor-induced myocarditis successfully treated with abatacept. The patient was started on pembrolizumab for stage IIIA malignant melanoma, and after the first dose was admitted for worsening shortness of breath and weakness. Her symptoms were refractory to high-dose steroids and she decompensated rapidly necessitating cardiopulmonary resuscitation and subsequent intubation and mechanical ventilation. Intravenous immunoglobulin and plasmapheresis did not invoke significant improvement, so abatacept was then initiated. She began to show improvement and was eventually discharged to a skilled nursing facility. This case highlights a severe adverse reaction to an immunomodulator class steadily growing in its application. Providers of all specialties should be aware of the side effects and treatment options. Our case demonstrates that continued investigation into the utilisation of CTLA-4 agonists in the treatment of severe adverse reactions like myocarditis caused by pembrolizumab is required.

Gambierdiscus spp. are epi-benthic dinoflagellates that have been associated with ciguatera poisoning. These microalgae can have complex secondary metabolite profiles including ciguatoxins, maitotoxins, and gambierones, with varying compositions and toxicities across species and strains. Given this chemical diversity there is a need to develop selective and sensitive methods for secondary metabolite profiling. In this study, we used a cultured Caribbean strain of Gambierdiscus silvae to develop sample preparation and analysis strategies for characterizing vic-diol containing secondary metabolites. A pooled cellular extract was first screened by liquid chromatography–high–resolution mass spectrometry (LC–HRMS) for ciguatoxin-related compounds, which resulted in the confirmation of gambierone (1) and tentative identification of 29-methylgambierone (3). Treatment of the extract with periodate confirmed that the gambierones each contained one reactive vic-diol, which was exploited for the development of a selective extraction procedure using m-aminophenylboronic acid gel and the non-aqueous binding solvent chloroform. Using this non-traditional boronate affinity procedure, LC-HRMS also revealed the presence of additional sulfated polycyclic ethers in the gambierone-containing vic-diol fraction, while pigments and other contaminants were removed. The developed tools could be applied to screen collections of Gambierdiscus and other benthic algae to provide additional chemical characterization of gambierone-related compounds. The selective extraction procedure may also prove useful as a step in the isolation of these sulfated polyethers for structural, toxicological and biotransformation studies.

Background: Social and demographic factors may influence patient treatment by physicians. This study analyzes the influence of patient sociodemographics on prescription practices among hand surgeons. Methods: We performed a retrospective analysis of all hand surgeries (N = 5278) at a single academic medical center from January 2016 to September 2018. The average morphine milligram equivalent (MME) prescribed following each surgery was calculated and then classified by age, race, sex, type of insurance, and history of substance use or chronic pain. Multivariate linear regression was used to compare MME among groups. Results: Overall, patients with a history of substance abuse were prescribed 31.2 MME more than those without ( P < .0001), and patients with a history of chronic pain were prescribed 36.7 MME more than those without ( P < .0001). After adjusting for these variables and the type of procedure performed, women were prescribed 11.2 MME less than men ( P = .0048), and Hispanics were prescribed 16.6 MME more than whites ( P = .0091) overall. Both Hispanic and black patients were also prescribed more than whites following carpal tunnel release (+19.0 and + 20.0 MME, respectively; P < .001). Patients with private insurance were prescribed 24.5 MME more than those with Medicare ( P < .0001), but 25.0 MME less than those with Medicaid ( P < .0001). There were no differences across age groups. Conclusions: Numerous sociodemographic factors influenced postoperative opioid prescription among hand surgeons at our institution. These findings highlight the importance of establishing more uniform, evidence-based guidelines for postoperative pain management, which may help minimize subjectivity and prevent the overtreatment or undertreatment of pain in certain patient populations.

Background: The Rhode Island State Legislature passed the Uniform Controlled Substances Act in 2016 to limit opioid prescriptions. We aimed to objectively evaluate its effect on opioid prescribing for hand surgery patients and also identify risk factors for prolonged opioid use. Methods: A 6-month period (January-June 2016) prior to passage of the law was compared with a period following its implementation (July-December 2017). Thumb carpometacarpal arthroplasty and distal radius fracture fixation were classified as “major surgery” and carpal tunnel and trigger finger release as “minor surgery.” Prescription Drug Monitoring Database was used to review controlled substances filled during the study periods. Results: A total of 1380 patients met our inclusion criteria, with 644 prelaw and 736 postlaw patients. Patients undergoing “major surgery” saw a significant decrease in the number of pills issued in the first postoperative prescription (41.1 vs 21.0) and a corresponding decrease in morphine milligram equivalents (MMEs) (318.6 vs 159.2 MMEs) after implementation. A 30% decrease in MMEs was also seen in those undergoing “major surgery” in the first 30 days postoperatively (544.7 vs 381.7 MMEs). Risk factors for prolonged opioid use included male sex and preoperative opioid use. Conclusions: In Rhode Island, opioid-limiting legislation resulted in a significant decrease in the number of pills and MMEs of the initial prescription and a 30% decrease in total MMEs in the 30-day postoperative period after “major hand surgery.” Additional research is needed to explore the association between legislation and clinical outcomes.

Background Orthopedic procedures concerning the upper extremity commonly use a brachial plexus nerve block to achieve postoperative analgesia. The addition of dexamethasone to peripheral nerve blocks has been shown to significantly prolong its effect. We hypothesize that 1 mg doses of dexamethasone will prolong brachial plexus nerve block with similar efficacy to 4 mg and better than ropivacaine alone. Methods Seventy-nine patients who received a brachial plexus nerve block prior to undergoing upper extremity surgery were randomized to 1 of 4 treatment groups: group 1 received only 30 mL of 0.5% ropivacaine without dexamethasone (control); groups 2, 3, and 4 received 4, 2, and 1 mg of dexamethasone, respectively, added to 30 mL of 0.5% ropivacaine. Results Comparison of block duration, specifically “first signs of the block wearing off” to the 0-mg group, referencing the 1-, 2-, and 4-mg groups ( P = .02, .04, and .01, respectively) that received steroid adjuvant therapy demonstrated a significant increase in time until the block began to wear off. All study groups receiving steroids also demonstrated a significant increase in duration of the block prior to its effects being completely gone when compared with the control group ( P < .01 for all groups). Conclusions Our findings demonstrate that adjuvant dexamethasone can prolong brachial plexus nerve blocks effectively at low doses compared with high doses, in addition to prolonging analgesia compared with local anesthetic alone.

Tamoxifen exposure is a recognised risk for primary endometrial cancer. This case serves as a reminder to meticulously check the past medical history and inform patients of the risk-benefit of treatment as part of a shared-decision making process.

Ruxolitinib (RUX) is a kinase inhibitor used in the treatment of various medical conditions and its mechanism of action involves suppression of the immune system. While beneficial in treatment of polycythemia vera, myelofibrosis and other indications, it can also increase a patient’s susceptibility to various infections, including bacterial, viral and fungal. We present a case of a patient being treated with RUX who presented with a disseminated fungal infection. This case emphasises the need for vigilance of endemic fungal infections in individuals who are on RUX therapy.

A 25-year-old woman with a history of immune thrombocytopaenia (ITP) in childhood was referred to haematology clinic for review with a platelet count of 50 μ/L at 9 weeks gestation, gravida 2, para 0. She developed progressive severe thrombocytopaenia as the pregnancy progressed, with associated bleeding complications. The thrombocytopaenia was refractory to standard therapies. This led to a need for a planned delivery, which was performed via caesarean section under general anaesthetic with platelet transfusion support, Intravenous Immune Globulin (IVIG), high-dose corticosteroid and the thrombopoietin (TPO) mimetic romiplostim. Both the mother and the neonate survived; however, the neonate required treatment for severe prolonged neonatal thrombocytopaenia. The patient subsequently re-presented 15 months later with recurrent ITP complicating another pregnancy, refractory to rituximab but responsive to romiplostim. She had a successful elective caesarean section under epidural anaesthesia, but the neonate once again suffered severe thrombocytopaenia, which was responsive to IVIG.

Chronic inducible urticaria (CIndU) is a subset of chronic urticaria that has an identifiable trigger. We present a case of postural urticaria induced by change in position in a 14-year-old girl. The patient’s CIndU was not adequately managed with both antihistamine and omalizumab treatment, indicating a recalcitrant form of CIndU.

A 36-year-old man with schizophrenia, on two times per day clozapine, presented with a 2-year history of diffuse intermittent body pain.Per chart review—and on presentation—his physical examination had been consistently unremarkable, without point-tenderness elicited at any major muscle groups or focal neurological deficits. Workup for myopathy, neuropathy and supratherapeutic clozapine levels had similarly been unrevealing.Given that prior interventions had been unsuccessful in alleviating these symptoms, we queried whether clozapine might have been contributory. As a result, we adopted a previously described strategy of scheduling the bulk of patients’ medication during non-waking hours.At 1-month follow-up, the patient reported about a 50% improvement in his symptoms. At 6-month follow-up, this improvement in symptoms had been sustained.Our findings add to the limited anecdotal reports of this side effect whose true prevalence remains unknown. Timely recognition has the potential to promote adherence to therapy among patients in the maintenance phase.

Granulomatosis with polyangiitis (GPA) is a rare disorder characterised by inflammation of small-sized and medium-sized blood vessels that result in damage to various organ systems, but it most commonly affects the respiratory tract and kidneys. It is one of the few entities that can present with ocular inflammation as well as renal impairment at the same time. We describe a case of a 38-year-old man with conjunctivitis, episcleritis, anterior uveitis as a first manifestation of GPA. His presentation with red eye and anterior uveitis prompted further workup, which revealed acute renal failure (creatinine 442 mmol/L), elevated inflammatory markers (erythrocyte sedimentation rate of 85 mmol/hour and C reactive protein of 72 mg/L), and a c-antineutrophil cytoplasmic antibody titre >8. An urgent renal biopsy was performed demonstrating necrotising crescentic glomerulonephritis, which led to the final diagnosis of GPA. Treatment induction with intravenous methylprednisolone and plasmapheresis followed by an oral prednisone taper and intravenous rituximab infusions leading to resolution of all symptoms and normalisation of kidney function. This report highlights conditions that can present with both ocular inflammation and renal dysfunction with a focus on GPA and its ocular manifestations.

Inherited thrombophilic disorders are well‐established predisposing factors for venous thromboembolism, but their role in arterial ischaemic stroke is uncertain. The exact mechanism of arterial thrombosis in thrombophilias remains elusive. Herein, we report a case of a 30-year-old woman who was admitted to our facility with sudden-onset right-sided ptosis and ophthalmoplegia. Detailed clinical features, neuroimaging and laboratory evaluation clinched the diagnosis of ischaemic stroke in midbrain due to microvascular obstruction associated with isolated protein S deficiency. She was treated with oral anticoagulant (warfarin) and physiotherapy; without any improvement of her symptoms at 2 months of follow-up. A high index of clinical suspicion is needed in any case of young ischaemic stroke in absence of common cardiac and vascular risk factors, to recognise the presence of inherited thrombophilia.

Dabigatran, a novel oral anticoagulant, is a direct thrombin inhibitor and is being increasingly used owing to the advantage of dosing without the need for laboratory monitoring. While extensive skin necrosis is known to be associated with oral anticoagulants such as warfarin and factor Xa inhibitors, dabigatran toxicity typically manifests with bleeding, especially in the elderly. We describe a 70-year-old woman who was prescribed dabigatran for the treatment of unprovoked deep venous thrombosis. She developed bleeding diathesis along with extensive skin necrosis and acute kidney injury shortly after commencing the drug. Haemodialysis was given in view of dabigatran toxicity and complications of kidney dysfunction which resolved promptly over a week. However, the patient succumbed to severe sepsis from secondary skin infections. It is crucial to closely monitor for signs of dabigatran toxicity, especially in the elderly patients.

Induction of remission in biologic-experienced individuals with moderate to severe Crohn’s disease (CD) can be a challenge. We hereby present a case of CD with secondary non-response to infliximab. Adding methotrexate and switching to ustekinumab plus methotrexate did not stop the inflammatory process. Therefore, combination therapy with two classes of biologics consisting of ustekinumab and adalimumab plus methotrexate was initiated. He achieved clinical remission in 4 weeks and remained on triple therapy for 6 months which was subsequently tailored to adalimumab/methotrexate combination therapy due to insurance restriction on ustekinumab. He remained in remission for the duration of follow-up, 14 months after initiation of triple therapy and 8 months after switching to methotrexate/adalimumab biologic monotherapy. Triple therapy with anti-TNF, IL-12/23 inhibitor and methotrexate could potentially be an option for induction of remission in biologic-experienced individuals with good initial clinical response to anti-TNF agents.

Primary phlebitis of the central nervous system (PPCNS) is a rare condition that might be a subset of primary angiitis of the CNS. In this case report, the patient was a 39-year-old man with a 2-week history of anterograde amnesia and abnormal behaviours. Black-blood MRI (BB-MRI) showed contrast enhancement of the left basilar vein and cerebral superficial veins. Angiography showed unremarkable change in arteries. After a thorough differential diagnosis, we diagnosed PPCNS and then administered methylprednisolone pulse and cyclophosphamide pulse. The neuropsychological symptoms and MRI findings gradually improved, and after 2 months, the dose of prednisolone was gradually reduced to 20 mg. No recurrence was observed. This case shows that BB-MRI may be useful for diagnosing PPCNS.

Introduction: Phytocannabinoids have emerged as a potential alternative treatment option for individuals experiencing persistent pain. However, evidence-based research regarding their clinical utility in both males and females remains incomplete. In addition, it is unknown whether combining readily available cannabinoids with opioids has a synergistic or subadditive effect on pain modulation. To begin to fill this knowledge gap, we investigated the antinociceptive effects of the phytocannabinoid, CBD, either alone or in combination with opioids in male and female C57BL/6J mice. Results: Using the formalin test, our results show that CBD (10 mg/kg, i.p.) treatment evoked antinociception in phase I, but not in phase II, of the formalin test in male mice. However, in female mice, CBD showed no significant antinociceptive effect. In addition, a direct sex comparison showed that CBD evoked a significant increase in nociceptive behaviors in female versus male mice during phase I of the formalin test. Furthermore, we show that CBD (10 mg/kg, i.p.) in combination with low-dose morphine (1 mg/kg, i.p.) was ineffective at eliciting a synergistic antinociceptive response in both male and female mice. Lastly, consistent with previous literature, we showed that females treated with a relatively higher dose of morphine (10 mg/kg, i.p.) displayed a significant increase in the variability of nociceptive behaviors compared to morphine-treated male mice. Conclusion: Overall, our results suggest that CBD treatment may have beneficial antinociceptive effects during the acute phase of persistent pain, but these effects are more beneficial to males than females. We provide further pre-clinical support that treatments geared toward reducing nociceptive behaviors differentially affect males and females.

Wunderlich syndrome is a rare condition characterised by acute spontaneous non-traumatic renal haemorrhage into the subcapsular and perirenal spaces. Our case of anti-GAD65-associated autoimmune encephalitis (AE), aged 30 years, developed this complication following use of enoxaparin and was managed by selective glue embolisation of subsegmental branches of right renal cortical arteries. Our case had opsoclonus as one of the clinical manifestations, which has till now been described in only two patients of this AE. This patient received all forms of induction therapies (steroids, plasmapheresis, intravenous immunoglobulin and rituximab) following which she had good improvement in her clinical condition. The good response to immunotherapy is also a point of discussion as this has been rarely associated with anti-GAD65 AE.

No medications are approved for cannabis use disorder (CUD), though a small clinical trial demonstrated that the voltage-dependent calcium channel (VDCC) ligand gabapentin reduced cannabis use in treatment seekers. VDCCs are modulated by cannabinoid (CB) ligands, and there are shared effects between CB agonists and VDCC ligands. This overlapping neuropharmacology and the initial clinical results supported the evaluation of pregabalin, a "next-generation" VDCC ligand, as a CUD medication. Two separate placebo-controlled, double-blind, counterbalanced, within-subjects human laboratory studies tested placebo and 300 (N = 2 females, 11 males; Experiment [EXP] 1) or 450 (N = 3 females, 11 males; EXP 2) mg/day pregabalin in cannabis users who were not seeking treatment or trying to reduce/quit their cannabis use. The protocol consisted of two outpatient maintenance phases (11 days in EXP 1 and 15 days in EXP 2) that concluded with four experimental sessions within each phase. During experimental sessions, maintenance continued, and participants completed two 2-day blocks of sampling and self-administration sessions to determine the reinforcing effects of smoked cannabis (0% and 5.9% delta⁹-tetrahydrocannabinol [THC]), as well as subjective, attentional bias, performance, and physiological responses. In addition, naturalistic cannabis use, side effects, sleep quality, craving, and other self-reported substance use were measured during pregabalin maintenance. Cannabis was self-administered and produced prototypical effects, but pregabalin generally did not impact the effects of cannabis or alter naturalistic use. These human laboratory results in cannabis users not trying to reduce/quit their use do not support the efficacy of pregabalin as a stand-alone pharmacotherapy for CUD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background and Purpose Cochlear vascular micro-thrombosis has been hypothesized as one of the pathogenic mechanisms for sudden sensorineural hearing loss (SSNHL) refractory to regular management. This study aimed to evaluate the feasibility and safety of intra-arterial pulsed-injection urokinase (IAPU) as a salvage therapy for SSNHL after the failure of conventional therapy. Methods We retrospectively reviewed our patient database to identify refractory SSNHL patients between November 2017 and July 2020. Study outcomes before and after the IAPU therapy were compared between IAPU and conventional therapy groups. Results Sixty-seven moderate-profound SSNHL patients (29 in IAUP group, 38 in control group) were included in this study. Compared to the control group, patients in the IAPU group showed more significant improvement in pure tone average (PTA) (34.2 ± 23.5 vs. 10.7 ± 13.1, p < 0.001) and degree of hearing recovery (total: 20.7% vs. 5.3%, partial: 24.1% vs. 10.5%, mild: 27.6% vs. 13.2% and non: 27.6% vs. 71.1%) 2 weeks after admission. In the IAPU group, a significant improvement of PTA (86.6 ± 11.5 vs. 54.6 ± 20.1 dB, p < 0.005) was observed on the first day after IAPU treatment. Conclusion In carefully selected SSNHL cases with a highly suspected vascular origin, IAPU is a safe and effective therapy when conventional treatments have failed. Despite the encouraging findings of our work, large studies are needed to better investigate the strengths and limitations of this salvage therapy.

Substance use in young adulthood and polysubstance users (PSU), in particular, pose unique risks for adverse consequences. Prior research on young adult PSU has identified multiple classes of users, but most work has focused on college students. We examined PSU patterns by age and college attendance during young adulthood in two nationally representative samples. Using National Epidemiological Survey on Alcohol and Related Conditions (NESARC) Wave 1 and NESARC-III data sets, multigroup latent class analysis (MG-LCA) was employed to examine PSU patterns based on age (18-24 vs. 25-34) and determine whether solutions were similar (i.e., statistically invariant) by college attendance/graduation. Classes were estimated by binary past-year use of sedatives, tranquilizers, opioids/painkillers, heroin, amphetamines/stimulants, cocaine, hallucinogens, club drugs, and inhalants, and past-year frequency of alcohol, cigarette, and cannabis use. PSU patterns are largely replicated across waves. Model fit supported 3-class solutions in each MG-LCA: Low frequency-limited-range PSU (alcohol, cigarettes, and cannabis only), medium-to-high frequency limited-range PSU (alcohol, cigarettes, and cannabis only), and extended-range PSU (ER PSU; all substances). Apart from one model, MG-LCA solutions were not invariant by college attendance/graduation, suggesting important differences between these groups. Except for alcohol, cannabis, and cigarette use frequency, results showed that probabilities of illicit and prescription drug use declined in the older age group. Findings also supported examining college and noncollege youth separately when studying PSU. ER PSU may be uniquely vulnerable to coingesting substances, particularly for nongraduates, warranting future research to classify patterns of simultaneous PSU and identify predictors and consequences of high-risk combinations (e.g., alcohol and opioids). (PsycInfo Database Record (c) 2021 APA, all rights reserved).