Nicotine exerts its psychopharmacological effects by activating the nicotinic acetylcholine receptor (nAChR), composed of alpha and/or beta subunits, giving rise to a diverse population of receptors with a distinct pharmacology. β4-containing (β4*) nAChRs are located almost exclusively in the habenulo-interpeduncular pathway. We examined the role of β4* nAChRs in the medial habenula (MHb) and the interpeduncular nucleus (IPN) in nicotine reinforcement using behavioral, electrophysiological, and molecular techniques in transgenic mice. Nicotine intravenous self-administration (IVSA) was lower in constitutive β4 knockout (KO) mice at all doses tested (7.5, 15, 30, and 60 μg/kg/infusion) compared with wild-type (WT) mice. In vivo microdialysis showed that β4KO mice have higher extracellular dopamine (DA) levels in the nucleus accumbens than in WT mice, and exhibit a differential sensitivity to nicotine-induced DA outflow. Furthermore, electrophysiological recordings in the ventral tegmental area (VTA) demonstrated that DA neurons of β4KO mice are more sensitive to lower doses of nicotine than that of WT mice. Re-expression of β4* nAChRs in IPN neurons fully restored nicotine IVSA, and attenuated the increased sensitivity of VTA DA neurons to nicotine. These findings suggest that β4* nAChRs in the IPN have a role in maintaining nicotine IVSA.

Introduction: Prior to implementation of Haemophilus influenzae type b (Hib)-conjugate vaccination programs in the 1990s, Hib was the commonest cause of bacterial meningitis in children aged <5 years. While the burden of all Hib disease has significantly decreased in the post-vaccination era, Hib still accounted for >29,000 deaths worldwide in children aged <5 years in 2015. Areas covered: We reviewed literature data on the most widely used Hib vaccines and vaccination strategies which led to the global prevention and control of Hib disease and aim to highlight important factors for continued disease control and elimination in the future. Expert commentary: More than 90% of countries worldwide have implemented Hib-conjugate vaccination in their national immunization programs. Vaccines containing Hib polyribosylribitol phosphate (PRP) conjugated with tetanus toxoid (Hib-TT) are the most commonly used. Neisseria meningitidis outer membrane protein complex of PRP (Hib-OMP) is also used. Although the kinetics of the immune response varies with Hib vaccine and schedule used, high control of Hib disease was observed in all settings/scenarios. Further improving global Hib vaccination coverage may result in disease elimination.

Nicotine addiction, through smoking, is the principal cause of preventable mortality worldwide. Human genome-wide association studies have linked polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster, coding for the a5, a3, and b4 nicotinic acetylcholine receptor (nAChR) subunits, to nicotine addiction. b4*nAChRs have been implicated in nicotine withdrawal, aversion, and reinforcement. Here we show that b4*nAChRs also are involved in non-nicotinemediated responses that may predispose to addiction-related behaviors. b4 knockout (KO) male mice show increased novelty-induced locomotor activity, lower baseline anxiety, and motivational deficits in operant conditioning for palatable food rewards and in reward-based Go/No-go tasks. To further explore reward deficits we used intracranial selfadministration (ICSA) by directly injecting nicotine into the ventral tegmental area (VTA) in mice. We found that, at low nicotine doses, b4KO self-administer less than wild-type (WT) mice. Conversely, at high nicotine doses, this was reversed and b4KO self-administered more than WT mice, whereas b4-overexpressing mice avoided nicotine injections. Viral expression of b4 subunits in medial habenula (MHb), interpeduncular nucleus (IPN), and VTA of b4KO mice revealed dose-and region-dependent differences: b4*nAChRs in the VTA potentiated nicotine-mediated rewarding effects at all doses, whereas b4*nAChRs in the MHb-IPN pathway, limited VTA-ICSA at high nicotine doses. Together, our findings indicate that the lack of functional b4*nAChRs result in deficits in reward sensitivity including increased ICSA at high doses of nicotine that is restored by re-expression of b4*nAChRs in the MHb-IPN. These data indicate that b4 is a critical modulator of reward-related behaviors.

Chronic obstructive pulmonary disease (COPD) may increase the risk and severity of pertussis infection. Health care resource utilization (HCRU) and direct medical costs (DMC) of treating pertussis among patients with COPD are unknown. Reported incidence of pertussis among individuals aged ! 50 years with COPD was assessed in Clinical Practice Research Datalink and Hospital Episode Statistics databases during 2009-2018 using a retrospective cohort design. HCRU and DMC from the National Health Service perspective were compared between patients with COPD and pertussis and propensity score-matched patients with COPD without pertussis. Seventy-eight new pertussis events were identified among 387 086 patients with COPD aged ! 50 years (incidence rate: 4.73; 95% confidence interval 3.74-5.91 per 100 000 person-years). HCRU and DMC were assessed among 67 patients with COPD and pertussis and 267 matched controls. During the month before the pertussis diagnosis, the rates of general practitioner (GP)/nurse visits (4289 vs. 1774 per 100 patient-years) and accident and emergency visits (182 vs. 18 per 100 patient-years) were higher in the pertussis cohort; GP/nurse visits (2935 vs. 1705 per 100 patient-years) were also higher during the following 2 months (all p < 0.001). During the month before the pertussis diagnosis, annualized per-patient total DMC were £2012 higher in the pertussis cohort (£3729 vs. £1717; p < 0.001); during the following 2 months, they were £2407 higher (£5498 vs. £3091; p < 0.001). In conclusion, a pertussis episode among individuals with COPD resulted in significant increases in HCRU and DMC around the pertussis event.

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Purpose:The impact of pertussis in individuals with asthma is not fully understood. We estimated the incidence, health care resource utilization (HCRU), and direct medical costs (DMC) of pertussis in patients with asthma. Patients and Methods: In this retrospective cohort study, the incidence rate of pertussis (identified using diagnostic codes) among individuals aged ≥50 years with an asthma diagnosis was assessed during 2009-2018 using Clinical Practice Research Datalink and Hospital Episode Statistics databases. HCRU and DMC were compared -between patients with diagnoses of asthma and pertussis (asthma+/pertussis+) and propensity score-matched patients with a diagnosis of asthma without pertussis (asthma+/pertussis-) -in the months around the pertussis diagnosis (-6 to +11). Results: Among 687,105 individuals, 346 had a reported pertussis event (incidence rate: 9.6/ 100,000 person-years of follow-up; 95% confidence interval: 8.6-10.7). HCRU and DMC were assessed among 314 asthma+/pertussis+ patients and 1256 matched asthma+/pertussiscontrols. Baseline HCRU was similar in both cohorts, but increases were observed in the asthma+/pertussis+ cohort from -6 to -1 month before to 2-5 months after diagnosis. Rates of accident and emergency visits, general practitioner (GP)/nurse visits, and GP prescriptions were 4.3-, 3.1-, and 1.3-fold, respectively, in the asthma+/pertussis+ vs asthma+/pertussiscohorts during the month before diagnosis; GP/nurse visit rates were 2.0-and 1.2-fold during 0-2 and 2-5 months after diagnosis, respectively (all p<0.001). DMC was 1.9-and 1.6-fold during the month before and 2 months from diagnosis, respectively, in the asthma+/pertussis + vs asthma+/pertussis-cohorts (both p<0.001). During months -1 to +11, DMC in the asthma+/pertussis+ cohort was £370 higher than in the asthma+/pertussis-controls. Conclusion: A pertussis diagnosis among adults aged ≥50 years with asthma resulted in significant increases in HCRU and DMC across several months around diagnosis, suggesting lengthy diagnosis times and highlighting the need for prevention strategies.

Pertussis is underdiagnosed and underreported in adults and patients with underlying conditions. Patients with chronic obstructive pulmonary disease (COPD) may be at increased risk of severe pertussis. Understanding the true prevalence of pertussis infections in such patients is important. We therefore evaluated the seroprevalence of anti-pertussis toxin (PT) antibodies in a cohort of 40-85-year-old patients diagnosed with moderate, severe or very severe COPD enrolled (between June 2011 and June 2012) in the prospective, observational "Acute Exacerbation and Respiratory InfectionS in COPD" (AERIS; NCT01360398) study, conducted in England. Serum anti-PT antibodies were measured in 104 patients using an enzyme-linked immunosorbent assay on samples collected 12 months (M12) and 24 months (M24) after enrollment. Overall, 14/104 (13.5%) patients had anti-PT concentrations 50 IU/mL at M12 or M24, indicative of exposure to Bordetella pertussis during the preceding 2-3 years. Of these, 6/104 (5.8%) had anti-PT 70 IU/mL, of whom 3/104 (2.9%) had anti-PT 120 IU/mL, indicative of exposure within 12 and 6 months, respectively. These results show a high circulation of B. pertussis in 40-85-year-old patients with moderate, severe or very severe COPD in England between 2012 and 2014, and call for enhanced immunization to prevent pertussis infections in such patients.

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