Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Chronic pain is highly prevalent and involves a complex interaction of sensory, emotional, and cognitive processes, significantly influenced by ambient temperature. Despite advances in pain management, many patients continue to experience inadequate pain relief. This review aims to consolidate and critically evaluate the current evidence on the impact of ambient temperature on chronic pain conditions such as fibromyalgia (FM), multiple sclerosis (MS), complex regional pain syndrome (CRPS), and osteoarthritis (OA). RECENT FINDINGS/RESULTS:Patients with FM often report pain exacerbations due to temperature changes, with studies showing lower thresholds for heat and cold-induced pain compared to healthy controls. In MS, the Uhthoff phenomenon, characterized by temperature-induced neurological deterioration, underscores the significance of ambient temperature in pain management. CRPS patients exhibit heightened pain sensitivity to temperature changes, with both warm and cold stimuli potentially aggravating symptoms. OA patients frequently report increased pain and rigidity associated with lower temperatures and higher humidity. Understanding the mechanisms through which temperature influences pain can enhance pain management strategies. This review highlights the need for further research to elucidate these mechanisms and develop targeted interventions, ultimately improving the quality of life for individuals with chronic pain conditions.

Background/UNASSIGNED:Intrathecal baclofen is considered an adjuvant therapy for patients with intractable spasms due to stiff-person syndrome. There is increasing evidence to support the use of intrathecal baclofen in the management of symptomatic stiffperson syndrome, with improvement in function. Case report/UNASSIGNED:A 38-year-old woman with stiff- person syndrome initially presented to inpatient rehabilitation for intractable muscle spasms. The symptoms made her non-ambulatory and limited her tolerance to wheelchair use for mobility. The patient underwent up-titration of oral baclofen and diazepam, with concurrent intravenous immunoglobulin cycles, leading to transient symptom relief. She agreed to explore intrathecal baclofen therapy. An initial trial of a single bolus of 50 μg intrathecal baclofen resulted in a significant decrease in spontaneous spasms, enabling modified independence in transfers and ambulation. The patient was subsequently implanted with a permanent intrathecal delivery system. To date, the intrathecal baclofen had been titrated to 186 μg per day with simple continuous delivery. The patient was weaned off oral baclofen. She attained complete functional independence with ambulation without the need for assistive devices, and has had no lasting post-procedural complications to date. Conclusion/UNASSIGNED:This case report adds to the increasing evidence of cases of refractory stiff-person syndrome managed successfully using intrathecal baclofen therapy.

BACKGROUND/IMPORTANCE/BACKGROUND:Chronic coccydynia is a challenging condition to manage. Conflicting evidence exists regarding the role of the ganglion impar in coccygeal nociception. When conservative treatments fail, minimally invasive interventions at the ganglion impar may be effective in providing relief. OBJECTIVES/OBJECTIVE:To evaluate the effectiveness and safety of ganglion impar blocks (GIBs) for the management of chronic coccydynia. EVIDENCE REVIEW/METHODS:A systematic review and meta-analysis was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Relevant studies were identified through a comprehensive literature search of PubMed, Embase Classic+ Embase, CINAHL and the Web of Science in February 2024. Data on patient characteristics, intervention details, pain outcomes (measured by Visual Analog Scale and Numerical Pain Rating Scale) and adverse events were extracted. Meta-analysis was performed using standardized mean differences (SMDs) on scale of 0 to 10. FINDINGS/RESULTS:Seventeen studies described 625 coccydynia patients treated with GIB. All studies reported some level of improvement of pain after GIB. The meta-analysis included 11 studies totaling 391 patients with a baseline pain score of 7.93 (7.81 to 8.04 95% CI). GIBs were effective in reducing coccygeal pain at short-term (up to 3 months), intermediate-term (3-6 months) and long-term (greater than 6 months) follow-up. SMDs were -2.73 (95% CI -3.45 to -2.01), -3.22 (95% CI -2.82 to -1.45), -1.86 (95% CI -2.58 to -1.15) at 3 months, 3-6 months and >6 months, respectively. No serious adverse events were noted. Grading of Recommendations Assessment, Development and Evaluation assessment indicated 'very low' certainty of evidence across all outcomes. CONCLUSIONS:Non-neurodestructive GIB may be a safe and potentially effective treatment option for patients with chronic, refractory coccydynia. PROSPERO REGISTRATION NUMBER/UNASSIGNED:CRD42024506056.

UNLABELLED:Cryptococcus neoformans is a human fungal pathogen and a major cause of fungal meningitis in immunocompromised individuals. Treatment options for cryptococcosis are limited. Of the two major antifungal drug classes, azoles are active against C. neoformans but exert a fungistatic effect, necessitating long treatment regimens and leaving open an avenue for emergence of azole resistance. Drugs of the echinocandin class, which target the glucan synthase and are fungicidal against a number of other fungal pathogens, such as Candida species, are ineffective against C. neoformans Despite the sensitivity of the target enzyme to the drug, the reasons for the innate resistance of C. neoformans to echinocandins remain unknown. To understand the mechanism of echinocandin resistance in C. neoformans, we screened gene disruption and gene deletion libraries for mutants sensitive to the echinocandin-class drug caspofungin and identified a mutation of CDC50, which encodes the β-subunit of membrane lipid flippase. We found that the Cdc50 protein localized to membranes and that its absence led to plasma membrane defects and enhanced caspofungin penetration into the cell, potentially explaining the increased caspofungin sensitivity. Loss of CDC50 also led to hypersensitivity to the azole-class drug fluconazole. Interestingly, in addition to functioning in drug resistance, CDC50 was also essential for fungal resistance to macrophage killing and for virulence in a murine model of cryptococcosis. Furthermore, the surface of cdc50Δ cells contained increased levels of phosphatidylserine, which has been proposed to act as a macrophage recognition signal. Together, these results reveal a previously unappreciated role of membrane lipid flippase in C. neoformans drug resistance and virulence. IMPORTANCE:Cryptococcus neoformans is a fungal pathogen that is the most common cause of fungal meningitis, causing over 620,000 deaths annually. The treatment options for cryptococcosis are very limited. The most commonly used drugs are either fungistatic (azoles) or highly toxic (amphotericin B). Echinocandins are the newest fungicidal drug class that works well in treating candidiasis and aspergillosis, yet they are ineffective in treating cryptococcosis. In this study, we showed that the regulatory subunit of the lipid translocase (flippase), a protein that regulates the asymmetrical orientation of membrane lipids, is required for C. neoformans resistance to caspofungin, as well as for virulence during infection. This discovery identifies lipid flippase as a potential C. neoformans drug target, which plays an important role in the innate resistance of C. neoformans to echinocandins and in fungal virulence.