**4.2 T-type Ca2+ channels**

T-type Ca2+ channels are formed by pore-forming α1 subunits with similar topology as that of the LTCC α1c subunit, but with no known auxiliary subunits that modulate channel function [74]. TTCCs are activated at more hyperpolarized potentials and show similar conductance with Ca2+ or Ba2+ as charge carriers. Vascular smooth muscle cells express several TTCC α1 subunits, including CaV3.1 (α1G) and CaV3.2 (α1H) [9, 94–98]. Intriguingly, CaV3.1, which is found in murine vascular smooth muscle, seems to be replaced by CaV3.3 (α1I) in human cells [96], suggesting that expression of TTCC α1 subunits is species-dependent. TTCCs have been shown to contribute to vascular smooth muscle excitability in several vascular beds from different species [9, 98]. However, rigorous analysis revealed that different CaV3.X subunits may have very divergent physiological responses. For instance, whereas CaV3.1 (CaV3.3) mediates low-pressure-induced constriction, CaV3.2 contributes to the negative feedback regulation of vascular tone by stimulating the RyR/BKCa axis (**Figure 3**) [64, 95, 96]. TTCCs can also be regulated by signaling molecules. Indeed, the NO/PKG and AC/PKA axes both inhibit vascular TTCCs [99, 100], which may have key implications in vascular smooth muscle excitability. Whether these signaling molecules are organized and targeted by scaffold proteins such as AKAPs to areas near TTCCs to fine-tune their function is unclear and therefore the subject of future studies.


*3.2. Anxiety, Depression, and Traumatic Stress*

We focused on anxiety, depression, traumatic stress and COVID-19 related anxiety, following Shevlin et al. (2020). In order to be consistent with the original study, traumatic stress and COVID-19 related anxiety where treated independently, whereas a new variable was computed to describe participants with anxiety, depression, or both. Sample size, percentages and adjusted odds ratio are summarized in Tables 3–5.

*Note*. \* *p* < 0.05; \*\* *p* < 0.01; \*\*\* *p* < 0.001 (adjusted controlling the false discovery rate [32]).

**Table 4.** Multiple logistic regression results predicting COVID-19-related anxiety.

*Note***.** \* *p* < 0.05; \*\* *p* < 0.01; \*\*\* *p* < 0.001 (adjusted controlling the false discovery rate [32]).

**Table 5.** Multiple logistic regression results predicting traumatic stress.

*Note*. \* *p* < 0.05; \*\* *p* < 0.01; \*\*\* *p* < 0.001 (adjusted controlling the false discovery rate [32]).

The rate of anxiety (GAD-7) in the overall sample was 21.59% (95% CI: 15.93%–20.72%), with no differences between regions (χ2 (3) = 4.07, *p* = 0.25) and with more women above the anxiety cut-off (11.75%, men: 6.45%; χ2 (1) = 15.94, *p* < 0.001). Depression (PHQ-9), with a rate of 21.4% (95% CI: 18.95%–24.03%), showed no differences between regions (χ2 (3) = 0.29, *p* = 0.96) but was significantly higher among women (12.52%), compared to men (8.86%; χ2 (1) = 5.82, *p* = 0.016).

The rate of anxiety and/or depression was 26.11 (95% CI: 23.48%–28.91%). No significant differences between regions were detected (χ2 (3) = 1.78 *p* = 0.61), whereas the gender difference was confirmed (women: 15.90%, men: 10.21%; χ2 (1) = 13.37, *p* < 0.001).

Using the ITQ scale, 25.92% of the sample was above the traumatic stress cut-off score (95% CI: 23.34%–28.77%). No difference was found between regions (χ2 (3) = 4.30, *p* = 0.23), while the gender effect was again significant (women: 15.11%, men: 10.88%; χ2 (1) = 7.16, *p* = 0.007). Finally, COVID-19 related anxiety was 18.30% overall (95% CI: 16.02%–20.82%). Regions showed a similar rate (χ2 (3) = 2.66, *p* = 0.44) whereas a gender difference was found (women: 12.14%, men: 6.17%; χ2 (1) = 20–65, *p* < 0.001).

We considered anxiety and/or depression, traumatic stress, and COVID-19-related Anxiety as dependent variables in three separate multiple logistic regressions (respectively, Tables 3–5). Figure 2 shows the plot of the odds ratio for the model of traumatic stress.

**Figure 2.** Plot of the odds ratio for the regression model of traumatic stress.

The age effect, observed by Shevlin and colleagues, was confirmed for anxiety/depression (Adj OR = 0.96, CI = 0.95–0.97, *p* < 0.001), and traumatic stress (Adj OR = 0.97, CI = 0.96–0.98, *p* < 0.001), showing more moderate cases in younger participants. A gender difference was observed only in COVID-19 anxiety, with men less anxious than women about the new virus (Adj OR = 0.33, CI = −0.03–0.69, *p* < 0.001). No differences were observed between regions.

The presence of minors in the house had a detrimental effect on anxiety/depression (Adj OR = 1.55, CI = 1.20–1.90, *p* = 0.002) and traumatic stress (Adj OR = 1.52, CI = 1.17–1.87, *p* = 0.004), as did the presence of pre-existing health conditions in others (anxiety/depression; Adj OR = 1.53, CI = 1.14–1.91, p = 0.006) and themselves (traumatic stress; Adj OR = 1.59, CI = 1.15–2.02; *p* = 0.008).

Interestingly, an increase in perceived risk to contract COVID-19 in the following four weeks had an effect on depression/anxiety (LR χ2 (3) = 54.24, *p* < 0.001), traumatic stress (LR χ2 (3) = 66.14, *p* < 0.001), and COVID-19 anxiety (LR χ2 (3) = 84.74, *p* < 0.001), mostly in the third and fourth quartile.


**6. Conclusions**

of radiotherapy are mucositis, xerostomia, dysphagia, hoarseness, erythema and desquama‐ tion of the skin (dermatitis). Other late complications that frequently are observed in radio‐ therapy post-treatment are dental decay, trismus, hypogeusia, subcutaneous fibrosis, thyroid dysfunction, esophageal stenosis, hoarseness, damage to the middle or inner ear, and osteor‐ adionecrosis (infection in a hypovascularized tissue with consequent tissue destruction). These post-radiotherapy sequelae are dependent on radiation field, radiation dose, use of antixerostomic medication, and post-radiotherapy time. In xerostomic patients, irreversible damage can occur to the salivary glands, resulting in dramatic hyposalivation and increases in oral and systemic infections. Moreover, oral mucositis induced by radiation therapy frequently occurs, leading to painful oral ulcerations and local and systemic infection. In patients treated with high dose radiation, swallowing can be affected several years after treatment due to a series of complications such as fixation of the hyolaryngeal complex, reduced range of tongue motion, reduced glottic closure, and cricopharyngeal relaxation, resulting in the potential for aspiration. Irradiated patients have longer oral transit times,

increased pharyngeal residue, and reduced cricopharyngeal opening times [106].

**5. The role of the dentist in an interdisciplinary effort to manage**

Oropharyngeal dysphagia arises as a result of so many types of endogenous or exogenous injuries that affect, isolated or combined, the salivation, chewing, and swallowing mecha‐ nisms. Injuries in these mechanisms usually impair the physical and mental health and quality of life of individuals. Undoubtedly, successful management requires an interdisciplinary collaboration among health professionals, which need to promote an accurate diagnostic workup, promote effective therapeutic strategies, and formulate an adequate management strategy of dysphagic patients in cases where cure of that condition is not currently possible. The dentist is a health professional that clinically evaluates the oral health of patients at frequent intervals. However, in most curriculums of dental schools, very little is presented and discussed about chewing and swallowing disturbances regarding the diagnosis, management, and treatment of these conditions. Moreover, nor is it strongly discussed about salivary gland

and food aspiration [106-108].

30 Seminars in Dysphagia

**oropharyngeal dysphagia**

Concurrent chemoradiation was introduced to improve prognosis of UADTC patients by increase the tumor cell killing with chemotherapy, which also acts as a radiosensitizer. However, although inoperable tumors showed a better prognosis, the toxicity of the two modalities combined resulted in more significant side-effects. Various side-effects like nausea, vomiting, mucositis induced by chemotherapy, dysphagia, neutropenia, and generalized weakness might occur. The anti-metabolites such as methotrexate and 5-fluorouracil are the cytotoxic agents most commonly associated with oropharyngeal and esophageal dysphagia. Chemotherapeutic agents can impact the ability of UADTC patients to swallow. Severe dysfunction of the base of the tongue, larynx and pharyngeal muscles are observed after chemoradiation, leading to stasis of the bolus, vallecular residue, dysmotility of the epiglottis,

> The different parts of the oral cavity and oropharynx are made up of several cell types of tissues (nerves, fibrovascular tissues, cartilaginous tissues, lining and salivary gland epithelium, and

smooth and striated muscles) along withenamel and dentin tissues of the teeth and the supporting bones. The morphophysiology of the oral cavity and oropharynx components is responsible for preservation and maintenance of oral health which contributes to systemic health and a better quality of life to individuals. These components are parts of the body that are highly accessible, sensitive to the action of environmental factors and, at the same time, are able to reflect changes occurring internally in the body. Oropharyngeal dysphagia represents a neuromuscular disorder which characterizes individuals with a difficulty in swallowing. That disorder may result from an accumulation of many factors caused by both endogenous and exogenous etiologic agents which compromise, directly or indirectly, mechanisms of salivation, chewing, and swallowing. The dentist is the health professional that clinically evaluates the oral health conditions of individuals regularly. That health professional must be considered as an integral component of the multidisciplinary health team in order to perform proper educational and preventive approaches, management, and therapeutical actions that might restore oral health to their patients.


*3.1.5 PNS manifestations*

Peripheral nervous system (PNS) presentations influence about 10 to 15% of NPSLE patients, and multiple concepts are taken into account in the late 1990s ACR-NPSLE patient descriptions. The greater part of patients present with peripheral neuropathy [40], which comprises mono-neuropathy, poly-neuropathy, cranialneuropathy, hyperinflammatory demyelinating poly-radiculoneuropathy, and plexopathy. A report noted that 17% of SLE-associated peripheral neuropathies are small-fiber neuropathy [41]. Small-fiber neuropathies are able to cause severe burning pain by targeting non-myelinated C fibers and finely myelinated A fibers. The diagnosis is verified via obtaining a cutaneous sample that exhibits injury to the dorsal root ganglia along with distal axons. The rest of the PNS presentations comprise autonomic disorders and myasthenia gravis [25].

## **3.2 Molecular mechanisms**