Impact of molecular ciprofloxacin resistance testing in management of gonorrhoea in a large urban clinic.

OBJECTIVES: Antibiotic resistance in gonorrhoea is of significant public health concern with the emergence of resistance to last-line therapies such as ceftriaxone. Despite around half of Neisseria gonorrhoeae isolates tested in the UK being susceptible to ciprofloxacin, very little ciprofloxacin is used in clinical practice. Testing for the S91F mutation associated with ciprofloxacin resistance is now available in CE-marked assays and may reduce the requirement for ceftriaxone, but many patients are treated empirically, or as sexual contacts, which may limit any benefit. We describe the real-world impact of such testing on antimicrobial use and clinical outcomes in people found to have gonorrhoea in a large urban UK sexual health clinic. METHODS: Molecular ciprofloxacin resistance testing (ResistancePlus GC assay (SpeeDx)) was undertaken as an additional test after initial diagnosis (m2000 Realtime CT/NG assay (Abbott Molecular)) in those not already known to have had antimicrobial treatment. Data from a 6-month period (from March to September 2022) were analysed to determine treatment choice and treatment outcome. RESULTS: A total of 998 clinical samples tested positive for N. gonorrhoeae in 682 episodes of infection. Of the 560 (56%) samples eligible for resistance testing, 269 (48.0%) were reported as wild-type, 180 (32.1%) were predicted to be resistant, 63 (11.3%) had an indeterminate resistance profile, and in 48 (8.6%) samples, N. gonorrhoeae was not detected. Ciprofloxacin was prescribed in 172 (75%) of 228 episodes in which the wild-type strain was detected. Four (2%) of those treated with ciprofloxacin had a positive test-of-cure sample by NAAT, with no reinfection risk. All four had ciprofloxacin-susceptible infection by phenotypic antimicrobial susceptibility testing. CONCLUSIONS: In routine practice in a large UK clinic, molecular ciprofloxacin resistance testing led to a significant shift in antibiotic use, reducing use of ceftriaxone. Testing can be targeted to reduce unnecessary additional testing. Longer term impact on antimicrobial resistance requires ongoing surveillance.

True prevalence of long-COVID in a nationwide, population cohort study.

Long-COVID prevalence estimates vary widely and should take account of symptoms that would have occurred anyway. Here we determine the prevalence of symptoms attributable to SARS-CoV-2 infection, taking account of background rates and confounding, in a nationwide population cohort study of 198,096 Scottish adults. 98,666 (49.8%) had symptomatic laboratory-confirmed SARS-CoV-2 infections and 99,430 (50.2%) were age-, sex-, and socioeconomically-matched and never-infected. While 41,775 (64.5%) reported at least one symptom 6 months following SARS-CoV-2 infection, this was also true of 34,600 (50.8%) of those never-infected. The crude prevalence of one or more symptom attributable to SARS-CoV-2 infection was 13.8% (13.2%,14.3%), 12.8% (11.9%,13.6%), and 16.3% (14.4%,18.2%) at 6, 12, and 18 months respectively. Following adjustment for potential confounders, these figures were 6.6% (6.3%, 6.9%), 6.5% (6.0%, 6.9%) and 10.4% (9.1%, 11.6%) respectively. Long-COVID is characterised by a wide range of symptoms that, apart from altered taste and smell, are non-specific. Care should be taken in attributing symptoms to previous SARS-CoV-2 infection.

Natural history of long-COVID in a nationwide, population cohort study.

Previous studies on the natural history of long-COVID have been few and selective. Without comparison groups, disease progression cannot be differentiated from symptoms originating from other causes. The Long-COVID in Scotland Study (Long-CISS) is a Scotland-wide, general population cohort of adults who had laboratory-confirmed SARS-CoV-2 infection matched to PCR-negative adults. Serial, self-completed, online questionnaires collected information on pre-existing health conditions and current health six, 12 and 18 months after index test. Of those with previous symptomatic infection, 35% reported persistent incomplete/no recovery, 12% improvement and 12% deterioration. At six and 12 months, one or more symptom was reported by 71.5% and 70.7% respectively of those previously infected, compared with 53.5% and 56.5% of those never infected. Altered taste, smell and confusion improved over time compared to the never infected group and adjusted for confounders. Conversely, late onset dry and productive cough, and hearing problems were more likely following SARS-CoV-2 infection.

Outcomes among confirmed cases and a matched comparison group in the Long-COVID in Scotland study.

With increasing numbers infected by SARS-CoV-2, understanding long-COVID is essential to inform health and social care support. A Scottish population cohort of 33,281 laboratory-confirmed SARS-CoV-2 infections and 62,957 never-infected individuals were followed-up via 6, 12 and 18-month questionnaires and linkage to hospitalization and death records. Of the 31,486 symptomatic infections,1,856 (6%) had not recovered and 13,350 (42%) only partially. No recovery was associated with hospitalized infection, age, female sex, deprivation, respiratory disease, depression and multimorbidity. Previous symptomatic infection was associated with poorer quality of life, impairment across all daily activities and 24 persistent symptoms including breathlessness (OR 3.43, 95% CI 3.29-3.58), palpitations (OR 2.51, OR 2.36-2.66), chest pain (OR 2.09, 95% CI 1.96-2.23), and confusion (OR 2.92, 95% CI 2.78-3.07). Asymptomatic infection was not associated with adverse outcomes. Vaccination was associated with reduced risk of seven symptoms. Here we describe the nature of long-COVID and the factors associated with it.

Sexual transmission of infections across Europe: appraising the present, scoping the future.

Objectives: Our journal partnered with the Europe section of the International Union against STI (IUSTI) at a workshop held at the 18th European AIDS Conference in London on 30 October 2021. The workshop reviewed epidemiological trends and discussed STI care provision within HIV services across Europe. Methods and Results: We started by highlighting trends in bacterial STIs reported to the European Centre for Disease Prevention and Control from countries in the European Union/European Economic Area. This showed that notifications of bacterial STIs reached an all-time high in 2019, but are expected to be impacted by the COVID-19 pandemic in 2020-2021. We then reviewed the evolving relationship between STIs and HIV and pointed out how antiretroviral treatment and pre-exposure prophylaxis remain highly effective against HIV transmission despite the rising incidence of STIs. Within emerging concepts in STIs, we appraised the benefits and risks of asymptomatic screening for chlamydia, and also considered the potential perils of routinely testing for agents that lack a defined role in disease. Finally, we discussed standards of STI care for people living with HIV, informed by a brief survey of IUSTI Europe country representatives and members of the Euroguidelines in Central and Eastern Europe network. Conclusions: The survey indicated substantial variability and identified key improvement targets: fighting barriers to effective service provision and access, increasing diagnostic capability and taking leadership in driving up the quality of care. We must not forget the STI-related needs of the many people who will be living with HIV for decades into the future.

The subfornical organ regulates acidosis-evoked fear by engaging microglial acid-sensor TDAG8 and forebrain neurocircuits in male mice.

An important role of pH homeostasis has been suggested in the physiology of panic disorder, with acidosis as an interoceptive trigger leading to fear and panic. Identification of novel mechanisms that can translate acidosis into fear will promote a better understanding of panic physiology. The current study explores a role of the subfornical organ (SFO), a blood-brain barrier compromised brain area, in translating acidosis to fear-relevant behaviors. We performed SFO-targeted acidification in male, wild-type mice and mice lacking microglial acid-sensing G protein-coupled receptor-T-cell death-associated gene 8 (TDAG8). Localized SFO acidification evoked significant freezing and reduced exploration that was dependent on the presence of acid-sensor TDAG8. Acidosis promoted the activation of SFO microglia and neurons that were absent in TDAG8-deficient mice. The assessment of regional neuronal activation in wild-type and TDAG8-deficient mice following SFO acidification revealed significant acidosis and genotype-dependent alterations in the hypothalamus, amygdala, prefrontal cortex, and periaqueductal gray nuclei. Furthermore, mapping of interregional co-activation patterns revealed that SFO acidosis promoted positive hypothalamic-cortex associations and desynchronized SFO-cortex and amygdala-cortex associations, suggesting an interplay of homeostatic and fear regulatory areas. Importantly, these alterations were not evident in TDAG8-deficient mice. Overall, our data support a regulatory role of subfornical organ microglial acid sensing in acidosis-evoked fear, highlighting a centralized role of blood-brain barrier compromised nodes in interoceptive sensing and behavioral regulation. Identification of pathways by which humoral information can modulate fear behavior is relevant to panic disorder, where aberrant interoceptive signaling has been reported.

Subfornical organ interleukin 1 receptor: A novel regulator of spontaneous and conditioned fear associated behaviors in mice.

Impaired threat responding and fear regulation is a hallmark of psychiatric conditions such as post-traumatic stress disorder (PTSD) and Panic Disorder (PD). Most studies have focused on external psychogenic threats to study fear, however, accumulating evidence suggests a primary role of homeostatic perturbations and interoception in regulating emotional behaviors. Heightened reactivity to interoceptive threat carbon dioxide (CO2) inhalation associates with increased risk for developing PD and PTSD, however, contributory mechanisms and molecular targets are not well understood. Previous studies from our group suggested a potential role of interleukin 1 receptor (IL-1R1) signaling within BBB-devoid sensory circumventricular organ, the subfornical organ (SFO) in CO2-evoked fear. However, the necessity of SFO-IL-1R1 in regulating CO2-associated spontaneous fear as well as, long-term fear potentiation relevant to PD/PTSD has not been investigated. The current study tested male mice with SFO-targeted microinfusion of the IL-1R1 antagonist (IL-1RA) or vehicle in a recently developed CO2-startle-fear conditioning-extinction paradigm. Consistent with our hypothesis, SFO IL-1RA treatment elicited significant attenuation of freezing and increased rearing during CO2 inhalation suggesting SFO-IL1R1 regulation of spontaneous fear to CO2. Intriguingly, SFO IL-1RA treatment normalized CO2-associated potentiation of conditioned fear and impaired extinction a week later suggesting modulation of long-term fear by SFO-IL-1R1 signaling. Post behavior FosB mapping revealed recruitment of prefrontal cortex-amygdala-periaqueductal gray (PAG) areas in SFO-IL-1RA mediated effects. Additionally, we localized cellular IL-1R1 expression within the SFO to blood vessel endothelial cells and observed CO2-induced alterations in IL-1ß/IL-1R1 expression in peripheral mononuclear cells and SFO. Lastly, CO2-evoked microglial activation was attenuated in SFO-IL-1RA treated mice. These observations suggest a peripheral monocyte-endothelial-microglia interplay in SFO-IL-1R1 modulation of CO2-associated spontaneous fear and delayed fear memory. Collectively, our data highlight a novel, "bottom-up" neuroimmune mechanism that integrates interoceptive and exteroceptive threat processing of relevance to fear-related pathologies.

Five-year review of ocular Neisseria gonorrhoeae infections presenting to ophthalmology departments in Greater Glasgow & Clyde, Scotland.

INTRODUCTION: As gonococcal infections continue to increase, we wanted to review the number and clinical course of recent ocular gonococcal cases presenting to ophthalmology departments in NHS Greater Glasgow and Clyde. METHODS: A 5-year retrospective review of adult ocular gonococcal cases, where the diagnosis of Neisseria gonorrhoeae was made on microbiological culture, was undertaken. RESULTS: Fifteen cases were identified (80% male). Average age was 26 years (range 17-42; median 24). Most common presenting features included purulent discharge (14/15; 93%), haemorrhagic conjunctivitis (10/15; 67%) and pre-septal cellulitis (9/15; 60%). Corneal involvement was documented in 5 (33%), with marginal ulceration in 1 (7%) but none had corneal perforation. Most common systemic treatment was IV ceftriaxone, alone or in combination with another antibiotic (6/15; 40%), followed by IM ceftriaxone, alone or in combination with another antibiotic (5/15; 33%). Median time from presentation to treatment was 1 day (0-23). All patients were referred or recommended to attend sexual health services. Seven patients (47%) attended and received complete sexually transmitted infection (STI) testing and contact tracing: 3 patients had systemic treatment initiated or changed at this visit and 1 patient had concurrent syphilis identified. CONCLUSIONS: This series confirms purulent conjunctivitis and cellulitis as the main presenting features of ocular gonococcal infection requiring hospital review. Early identification with appropriate systemic antibiotic treatment avoided corneal melting in this cohort. As concurrent STIs were identified and/or treatments changed in 4/7 (57%) following sexual health review, we recommend a shared care approach between ophthalmology, microbiology and sexual health services to effectively address all management issues.

Fixed duration vs. prolonged duration treatment after first line therapy in patients with systemic light chain amyloidosis.

BACKGROUND: The main objective of treatment in systemic light chain amyloidosis (AL amyloidosis) is to achieve the best hematological response. Deeper responses are associated with better organ responses and survival. In this study, we analysed the efficacy of prolonged duration treatment after first line in patients with AL amyloidosis. METHODS: Retrospective analysis that included patients older than 18 years with AL amyloidosis. We excluded patients with more than 30% marrow plasmacytosis or concurrent multiple myeloma. Two cohorts identified accordingly if they received or not prolonged treatment after the first line. Survival analysis regarding progression free survival (PFS) and overall survival (OS) estimated with Kaplan-Meier and comparisons between groups with log-rank. RESULTS: Thirty-eight patients were included in the analysis with a median age of 55 years. Twenty-one patients received prolonged duration treatment and 17 did not. In the prolonged duration group, after a median duration of 12 months, the median PFS was 58.8 months. In the fixed duration treatment group, PFS was 30.6 months. The difference was significant with p = .0045 favouring prolonged duration treatment. Organ response was sustained for a longer period in the prolonged duration treatment group. For OS, the difference was not significant. CONCLUSIONS: Prolonged duration treatment in patients with systemic light chain amyloidosis correlated with better PFS and deeper organ responses. Prospective studies are needed to analyse this further.

A scaling relation for the molecular cloud lifetime in Milky Way-like galaxies.

We study the time evolution of molecular clouds across three Milky Way-like isolated disc galaxy simulations at a temporal resolution of 1 Myr and at a range of spatial resolutions spanning two orders of magnitude in spatial scale from ∼10 pc up to ∼1 kpc. The cloud evolution networks generated at the highest spatial resolution contain a cumulative total of ∼80 000 separate molecular clouds in different galactic-dynamical environments. We find that clouds undergo mergers at a rate proportional to the crossing time between their centroids, but that their physical properties are largely insensitive to these interactions. Below the gas-disc scale height, the cloud lifetime τlife obeys a scaling relation of the form τlife∝ℓ-0.3 with the cloud size ℓ, consistent with over-densities that collapse, form stars, and are dispersed by stellar feedback. Above the disc scale height, these self-gravitating regions are no longer resolved, so the scaling relation flattens to a constant value of ∼13 Myr, consistent with the turbulent crossing time of the gas disc, as observed in nearby disc galaxies.

Ten-year review of a shared care approach in the management of ocular chlamydia trachomatis infections.

INTRODUCTION: Since 2007, the ocular 4:1 multiplex PCR assay in NHS Greater Glasgow and Clyde includes Chlamydia trachomatis (ocular chlamydia (OC)) testing. OC can be identified following routine 'viral' ophthalmic testing, including in asymptomatic patients. A published audit from 2008 identified only 25% of our OC patients attended and completed sexual health management, particularly when ophthalmologists initiated treatment. We subsequently created a shared care network between ophthalmology, virology and sexual health (including a designated sexual health advisor) to address these clinical issues. METHODS: A 10-year retrospective service review audit from January 2010 to December 2019 was performed to evaluate this approach. RESULTS: A total of 86 patients were identified (49 males (57%), median age 23 years (range 16-77)). Ophthalmologists initiated treatment for 37 patients (43%) prior to onward sexual health referral. Of this group, 5 (13.5%) received sub-optimal treatments, and 15 (40.5%) subsequently failed to attend sexual health services for partner notification. Of the 49 (57%) patients who attended sexual health, 25 (51%) had genital chlamydia co-infection, and 98% received adequate systemic treatment. All were offered full sexual health screening and 46 (93.9%) completed partner notification. CONCLUSIONS: This shared care approach more than doubled the proportion of OC patients attending sexual health services over this 10-year period (previously 25%, now 57%). Ophthalmologists could defer treatment to sexual health for more effective OC management; however, challenges remain to address real-world issues of non-attendance, inadequate treatment and incomplete contact tracing. We recommend a multi-disciplinary approach to best manage OC cases identified following ophthalmic testing.

Oxidized Low-Density Lipoprotein Drives Dysfunction of the Liver Lymphatic System.

BACKGROUND AND AIMS: As the incidence of nonalcoholic steatohepatitis (NASH) continues to rise, understanding how normal liver functions are affected during disease is required before developing novel therapeutics which could reduce morbidity and mortality. However, very little is understood about how the transport of proteins and cells from the liver by the lymphatic vasculature is affected by inflammatory mediators or during disease. METHODS: To answer these questions, we utilized a well-validated mouse model of NASH and exposure to highly oxidized low density lipoprotein (oxLDL). In addition to single cell sequencing, multiplexed immunofluorescence and metabolomic analysis of liver lymphatic endothelial cells (LEC)s we evaluated lymphatic permeability and transport both in vitro and in vivo. RESULTS: Confirming similarities between human and mouse liver lymphatic vasculature in NASH, we found that the lymphatic vasculature expands as disease progresses and results in the downregulation of genes important to lymphatic identity and function. We also demonstrate, in mice with NASH, that fluorescein isothiocyanate (FITC) dextran does not accumulate in the liver draining lymph node upon intrahepatic injection, a defect that was rescued with therapeutic administration of the lymphatic growth factor, recombinant vascular endothelial growth factor C (rVEGFC). Similarly, exposure to oxLDL reduced the amount of FITC-dextran in the portal draining lymph node and through an LEC monolayer. We provide evidence that the mechanism by which oxLDL impacts lymphatic permeability is via a reduction in Prox1 expression which decreases lymphatic specific gene expression, impedes LEC metabolism and reorganizes the highly permeable lymphatic cell-cell junctions which are a defining feature of lymphatic capillaries. CONCLUSIONS: We identify oxLDL as a major contributor to decreased lymphatic permeability in the liver, a change which is consistent with decreased protein homeostasis and increased inflammation during chronic liver disease.

Stellar clustering shapes the architecture of planetary systems.

Planet formation is generally described in terms of a system containing the host star and a protoplanetary disk1-3, of which the internal properties (for example, mass and metallicity) determine the properties of the resulting planetary system4. However, (proto)planetary systems are predicted5,6 and observed7,8 to be affected by the spatially clustered stellar formation environment, through either dynamical star-star interactions or external photoevaporation by nearby massive stars9. It is challenging to quantify how the architecture of planetary sysems is affected by these environmental processes, because stellar groups spatially disperse within less than a billion years10, well below the ages of most known exoplanets. Here we identify old, co-moving stellar groups around exoplanet host stars in the astrometric data from the Gaia satellite11,12 and demonstrate that the architecture of planetary systems exhibits a strong dependence on local stellar clustering in position-velocity phase space. After controlling for host stellar age, mass, metallicity and distance from the star, we obtain highly significant differences (with p values of 10-5 to 10-2) in planetary system properties between phase space overdensities (composed of a greater number of co-moving stars than unstructured space) and the field. The median semi-major axis and orbital period of planets in phase space overdensities are 0.087 astronomical units and 9.6 days, respectively, compared to 0.81 astronomical units and 154 days, respectively, for planets around field stars. 'Hot Jupiters' (massive, short-period exoplanets) predominantly exist in stellar phase space overdensities, strongly suggesting that their extreme orbits originate from environmental perturbations rather than internal migration13,14 or planet-planet scattering15,16. Our findings reveal that stellar clustering is a key factor setting the architectures of planetary systems.

Reducing time to treatment of bacterial sexually transmitted infections in an HIV cohort.

Sexually transmitted infections (STIs) are known to increase the risk of transmission of HIV and care of sexual health needs should form part of routine HIV care. Delayed treatment of STIs can lead to complications and avoidable onward transmission. Management of acute STIs in UK specialist sexual health services usually involves a multidisciplinary approach to ensure patient recall, antimicrobial treatment and partner notification. While this works well in dedicated sexual health clinics, we found this was less optimal in our hospital-based HIV care unit. We describe a quality improvement project to improve interdisciplinary pathways by using electronic shared worklists that reduced time to treatment for chlamydia and gonorrhoea infections. Use of electronic shared worklists could be applied to other settings where rapid treatment is required or has transmission implications.

Immunomodulatory T cell death associated gene-8 (TDAG8) receptor in depression-associated behaviors.

Converging evidence supports neuroimmune factors in depression psychopathology. We previously reported reduced depression-like behavior in immunomodulatory G-protein-coupled receptor, T cell death-associated gene-8 (TDAG8) deficient mice. Here, we expand on those findings by investigating depression- and anxiety-associated behaviors, and cytokine profiles in TDAG8-deficient mice. TDAG8-deficiency reduced depression- and anxiety-associated behaviors in the forced swim test (FST), open-field test and elevated zero maze. Interestingly, cytokine expression, particularly IL-6, was attenuated within hippocampus and spleen in TDAG8-deficient mice following the FST. There were no differences in immune-cell frequencies. Collectively, these data suggest a contributory role of TDAG8 in neuroimmune regulation and depression-associated physiology.

PD-1 Blockade During Post-partum Involution Reactivates the Anti-tumor Response and Reduces Lymphatic Vessel Density.

Post-partum breast cancer patients, or breast cancer patients diagnosed within 10 years of last childbirth, are ~3-5 times more likely to develop metastasis in comparison to non-post-partum, or nulliparous, patients. Additionally, post-partum patients have increased tumor-associated lymphatic vessels and LN involvement, including when controlled for size of the primary tumor. In pre-clinical, immune-competent, mouse mammary tumor models of post-partum breast cancer (PPBC), tumor growth and lymphogenous tumor cell spread occur more rapidly in post-partum hosts. Here we report on PD-L1 expression by lymphatic endothelial cells and CD11b+ cells in the microenvironment of post-partum tumors, which is accompanied by an increase in PD-1 expression by T cells. Additionally, we observed increases in PD-L1 and PD-1 in whole mammary tissues during post-partum mammary gland involution; a known driver of post-partum tumor growth, invasion, and metastasis in pre-clinical models. Importantly, implantation of murine mammary tumor cells during post-partum mammary gland involution elicits a CD8+ T cell population that expresses both the co-inhibitory receptors PD-1 and Lag-3. However, upon anti-PD-1 treatment, during post-partum mammary gland involution, the involution-initiated promotional effects on tumor growth are reversed and the PD-1, Lag-3 double positive population disappears. Consequently, we observed an expansion of poly-functional CD8+ T cells that produced both IFNγ and TNFα. Finally, lymphatic vessel frequency decreased significantly following anti-PD-1 suggesting that anti-PD-1/PD-L1 targeted therapies may have efficacy in reducing tumor growth and dissemination in post-partum breast cancer patients.

Recruitment of central angiotensin II type 1 receptor associated neurocircuits in carbon dioxide associated fear.

Individuals with fear-associated conditions such as panic disorder (PD) and posttraumatic stress disorder (PTSD) display increased emotional responses to interoceptive triggers, such as CO2 inhalation, that signal a threat to physiological homeostasis. Currently, effector systems and mechanisms underlying homeostatic modulation of fear memory are not well understood. In this regard, the renin angiotensin system (RAS), particularly the angiotensin receptor type 1 (AT1R), a primary homeostatic regulatory target, has gained attention. RAS polymorphisms have been reported in PD and PTSD, and recent studies report AT1R-mediated modulation of fear extinction. However, contribution of AT1Rs in fear evoked by the interoceptive threat of CO2 has not been investigated. Using pharmacological, behavioral, and AT1R/ACE gene transcription analyses, we assessed central AT1R recruitment in CO2-associated fear. CO2 inhalation led to significant AT1R and ACE mRNA upregulation in homeostatic regulatory regions, subfornical organ (SFO) and paraventricular nucleus (PVN), in a temporal manner. Intracerebroventricular infusion of selective AT1R antagonist, losartan, significantly attenuated freezing during CO2 inhalation, and during re-exposure to CO2 context, suggestive of AT1R modulation of contextual fear. Regional Fos mapping in losartan-treated mice post-behavior revealed significantly attenuated labeling in areas regulating defensive behavior, contextual fear, and threat responding; such as, the bed nucleus of stria terminalis, dorsal periaqueductal gray, hypothalamic nuclei, hippocampus, and prefrontal areas such as the prelimbic, infralimbic, and anterior cingulate cortices. Sub-regions of the amygdala did not show CO2-associated AT1R regulation or altered Fos labeling. Collectively, our data suggests central AT1R recruitment in modulation of fear behaviors associated with CO2 inhalation via engagement of neurocircuits regulating homeostasis and defensive behaviors. Our data provides mechanistic insights into the interoceptive regulation of fear, relevant to fear related disorders such as PD and PTSD.